Pharmacotherapy

A Pathophysiologic Approach
Seventh Edition
 NOTICE
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Pharmacotherapy
A Pathophysiologic Approach
Seventh Edition

Joseph T. DiPiro, PharmD, FCCP

Executive Dean and Professor, South Carolina
College of Pharmacy, University of South Carolina, Columbia, South Carolina
and Medical University of South Carolina, Charleston, South Carolina

Robert L. Talbert, PharmD, FCCP, BCPS, CLS

SmithKline Professor, College of Pharmacy, University of Texas at Austin,
Professor, Department of Medicine, University of Texas Health
Science Center at San Antonio, San Antonio, Texas

Gary C. Yee, PharmD, FCCP, BCOP

Professor, Department of Pharmacy Practice,
College of Pharmacy, University of Nebraska Medical Center,
Omaha, Nebraska

Gary R. Matzke, PharmD, FCP, FCCP

Professor of Pharmacy and Pharmaceutics and Associate
Dean for Clinical Research and Public Policy, School of Pharmacy,
Professor of Internal Medicine, Nephrology Division, School of Medicine,
Virginia Commonwealth University, Richmond, Virginia

Barbara G. Wells, PharmD, FASHP, FCCP, BCPP

Dean and Professor, Executive Director of the Research Institute
of Pharmaceutical Sciences, School of Pharmacy,
The University of Mississippi, Oxford, Mississippi

L. Michael Posey, BSPharm

Editorial Director, Periodicals Department, American Pharmacists Association,
Washington, D.C.

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DOI: 10.1036/007147899X
 DEDICATION

To our patients, who have challenged and inspired us

and given meaning to all our endeavors.

To practitioners, who continue to improve patient health outcomes

and thereby serve as role models for their colleagues and students
while clinging tenaciously to the highest standards of practice.

To our mentors, whose vision provided educational and training

programs that encouraged our professional growth and challenged us
to be innovators in our patient care, research, and education.

To our faculty colleagues for their efforts and support for our mission
to provide a comprehensive and challenging educational
foundation for the pharmacists of the future.

And finally to our families for the time that they have sacrificed
so that this seventh edition would become a reality.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 IN MEMORIAM

Mario M. Zeolla (1974–2007) earned his Bachelor of Science and Doctor of Pharmacy
degrees from the Albany College of Pharmacy, completed a Community Pharmacy Residency
at the University of Maryland School of Pharmacy, and was a Board Certified Pharmacotherapy
Specialist. In his brief but productive career as a pharmacy practitioner and educator at
the Albany College of Pharmacy, Dr. Zeolla quickly rose to the rank of Associate Professor
in the Department of Pharmacy Practice. In addition, he was the Patient Care Pharmacist
at Eckerd (and later Brooks) Pharmacy in Loudonville, New York, where he developed
innovative community-based clinical pharmacy services. He was an author in previous
editions of Pharmacotherapy: A Pathophysiologic Approach and published several
scholarly papers related to community pharmacy practice and dietary
supplements/herbal therapies. Dr. Zeolla was considered one of the brightest
stars on the Albany College of Pharmacy faculty and a passionate advocate for
pharmacy. He was a popular teacher, trusted advisor, and beloved peer.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 For more information about this title, click here vii

CONTENTS

Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii 11. Emergency Preparedness: Identification and

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxvii Management of Biological Exposures . . . . . . . . 91
Colleen M. Terriff, Jason E. Brouillard,
Foreword to the First Edition. . . . . . . . . . . . . . . . . . . . . . . xxix Lisa T. Costanigro, and Jessica S. Gruber
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxxi 12. Emergency Preparedness: Identification
and Management of Chemical and
Radiological Exposures . . . . . . . . . . . . . . . . . . . . 93
SECTION 1 Greene Shepherd and Richard B. Schwartz

Foundation Issues
Section Editor: L. Michael Posey SECTION 2
1. Pharmacoeconomics: Principles, Methods, Cardiovascular Disorders
and Applications .......................... 1
Section Editor: Robert L. Talbert
Lisa A. Sanchez
13. Cardiovascular Testing . . . . . . . . . . . . . . . . . . . . . . . 95
2. Health Outcomes and Quality of Life ......... 3
Robert Chilton and Robert L. Talbert
Stephen Joel Coons
14. Cardiopulmonary Arrest . . . . . . . . . . . . . . . . . . . . . 123
3. Evidence-Based Medicine ................... 5
Jeffrey F. Barletta and Jeffrey L. Wilt
Elaine Chiquette and L. Michael Posey
15. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
4. Documentation of Pharmacy Services ........ 7 Joseph J. Saseen and Eric J. MacLaughlin
George E. MacKinnon, III and Neil J. MacKinnon
16. Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
5. Clinical Pharmacokinetics Robert B. Parker, Jo E. Rodgers, and Larisa H. Cavallari
and Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . 9
Larry A. Bauer 17. Ischemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . 217
Robert L. Talbert
6. Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Larisa H. Cavallari and Y. W. Francis Lam 18. Acute Coronary Syndromes . . . . . . . . . . . . . . . . . . 249
Sarah A. Spinler and Simon de Denus
7. Pediatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Milap C. Nahata and Carol Taketomo 19. The Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Cynthia A. Sanoski, Marieke Dekker Schoen,
8. Geriatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 and Jerry L. Bauman
Catherine I. Starner, Shelly L. Gray, David R. P. Guay,
Emily R. Hajjar, Steven M. Handler, 20. Diastolic Heart Failure
and Joseph T. Hanlon and the Cardiomyopathies . . . . . . . . . . . . . . . . . . . 315
Jean M. Nappi and Robert L. Page, II
9. Pharmacoepidemiology . . . . . . . . . . . . . . . . . . . 67
Andy Stergachis, Thomas K. Hazlet, 21. Venous Thromboembolism . . . . . . . . . . . . . . . . . . 331
and Denise Boudreau Stuart T. Haines, Daniel M. Witt, and Edith A. Nutescu

10. Clinical Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . 69 22. Stroke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373

Peter A. Chyka Susan C. Fagan and David C. Hess

The complete chapter, learning objectives, and other resources can be found at www.pharmacotherapyonline.com.
 viii

23. Hyperlipidemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 38. Diarrhea, Constipation, and Irritable

Bowel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
CONTENTS

Robert L. Talbert
William J. Spruill and William E. Wade
24. Peripheral Arterial Disease . . . . . . . . . . . . . . . . . . . 409
Barbara J. Hoeben and Robert L. Talbert 39. Portal Hypertension and Cirrhosis . . . . . . . . . . . . 633
Julie M. Sease, Edward G. Timm,
25. Use of Vasopressors and Inotropes and James J. Stragand
in the Pharmacotherapy of Shock . . . . . . . . . . . . . 417
Robert MacLaren, Maria I. Rudis, and Joseph F. Dasta 40. Drug-Induced Liver Disease. . . . . . . . . . . . . . . . . . 651
William R. Kirchain and Rondall E. Allen
26. Hypovolemic Shock . . . . . . . . . . . . . . . . . . . . . . . . . 441
Brian L. Erstad 41. Pancreatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Rosemary R. Berardi and Patricia A. Montgomery

42. Viral Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675

SECTION 3 Paulina Deming, Renee-Claude Mercier,
Respiratory Disorders and Manjunath P. Pai

Section Editor: Robert L. Talbert 43. Drug Therapy Individualization in Patients

with Hepatic Disease or Genetic Alterations
27. Introduction to Pulmonary Function Testing. . . . 455 in Drug Metabolizing Activity . . . . . . . . . . . . . . . . 693
Jay I. Peters and Stephanie M. Levine
Y. W. Francis Lam
28. Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
H. William Kelly and Christine A. Sorkness

29. Chronic Obstructive Pulmonary Disease. . . . . . . . 495 SECTION 5

Dennis M. Williams and Sharya V. Bourdet Renal Disorders
30. Pulmonary Hypertension . . . . . . . . . . . . . . . . . 519 Section Editor: Gary R. Matzke
Robert L. Talbert, Rebecca Boudreaux, and Rebecca L. Owens 44. Quantification of Renal Function . . . . . . . . . . . . . 705
31. Drug-Induced Pulmonary Diseases . . . . . . . . . . . . 521 Thomas C. Dowling

Hengameh H. Raissy, Michelle Harkins, 45. Acute Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . 723

and Patricia L. Marshik William Dager and Anne P. Spencer
32. Cystic Fibrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 46. Chronic Kidney Disease:
Gary Milavetz Progression-Modifying Therapies . . . . . . . . . . . . . 745
Melanie S. Joy, Abhijit Kshirsagar, and Nora Franceschini

SECTION 4 47. Chronic Kidney Disease:

Management of Complications . . . . . . . . . . . . . . . 765
Gastrointestinal Disorders Joanna Q. Hudson
Section Editor: Joseph T. DiPiro
48. Hemodialysis and Peritoneal Dialysis . . . . . . . 793
33. Evaluation of the Gastrointestinal Tract . . . . . . . . 547 Edward F. Foote and Harold J. Manley
Keith M. Olsen, Marie A. Chisholm, and Mark W. Jackson
49. Drug-Induced Kidney Disease . . . . . . . . . . . . . . . . 795
34. Gastroesophageal Reflux Disease . . . . . . . . . . . . . . 555 Thomas D. Nolin and Jonathan Himmelfarb
Dianne B. Williams and Robert R. Schade
50. Glomerulonephritis. . . . . . . . . . . . . . . . . . . . . . . . . 811
35. Peptic Ulcer Disease . . . . . . . . . . . . . . . . . . . . . . . . . 569 Alan H. Lau
Rosemary R. Berardi and Lynda S. Welage
51. Drug Therapy Individualization for
36. Inflammatory Bowel Disease. . . . . . . . . . . . . . . . . . 589 Patients with Renal Insufficiency. . . . . . . . . . . . . . 833
Brian A. Hemstreet and Joseph T. DiPiro Gary R. Matzke and Reginald F. Frye

37. Nausea and Vomiting . . . . . . . . . . . . . . . . . . . . . . . 607 52. Disorders of Sodium and Water Homeostasis . . . 845
Cecily V. DiPiro James D. Coyle and Melanie S. Joy

The complete chapter, learning objectives, and other resources can be found at www.pharmacotherapyonline.com.
 ix

53. Disorders of Calcium and 66. Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 1041

Phosphorus Homeostasis . . . . . . . . . . . . . . . . . . . . 861

CONTENTS
Steven C. Stoner
Amy Barton Pai, Mark Rohrscheib,
and Melanie S. Joy 67. Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . 1051
Patricia W. Slattum, Russell H. Swerdlow,
54. Disorders of Potassium and and Angela Massey Hill
Magnesium Homeostasis . . . . . . . . . . . . . . . . . . . . 877
Donald F. Brophy and Todd W. B. Gehr
68. Substance-Related Disorders: Overview and
Depressants, Stimulants, and Hallucinogens. . . . 1067
55. Acid–Base Disorders . . . . . . . . . . . . . . . . . . . . . . . . 889 Paul L. Doering and Lisa A. Boothby
John W. Devlin, Gary R. Matzke, and Paul M. Palevsky
69. Substance-Related Disorders: Alcohol,
Nicotine, and Caffeine . . . . . . . . . . . . . . . . . . . . . . 1083
Paul L. Doering, W. Klugh Kennedy, and Lisa A. Boothby
SECTION 6 70. Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
Neurologic Disorders M. Lynn Crismon, Tami R. Argo, and Peter F. Buckley
Section Editor: Barbara G. Wells 71. Depressive Disorders . . . . . . . . . . . . . . . . . . . . . . . 1123
56. Evaluation of Neurologic Illness . . . . . . . . . . . . . . 909 Christian J. Teter, Judith C. Kando, Barbara G. Wells,
and Peggy E. Hayes
Susan C. Fagan and Fenwick T. Nichols

57. Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 913 72. Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . 1141

Shannon J. Drayton and Benjamin L. Weinstein
Jacquelyn L. Bainbridge and John R. Corboy

58. Epilepsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927 73. Anxiety Disorders I: Generalized Anxiety,

Panic, and Social Anxiety Disorders. . . . . . . . . . . 1161
Susan J. Rogers and Jose E. Cavazos
Cynthia K. Kirkwood and Sarah T. Melton
59. Status Epilepticus. . . . . . . . . . . . . . . . . . . . . . . . . . . 953
74. Anxiety Disorders II: Posttraumatic Stress Disorder
Stephanie J. Phelps, Collin A. Hovinga, and Obsessive-Compulsive Disorder . . . . . . . . . . 1179
and James W. Wheless
Cynthia K. Kirkwood, Eugene H. Makela,
60. Acute Management of the Brain Injury Patient . . .965 and Barbara G. Wells
Bradley A. Boucher and Shelly D. Timmons 75. Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191
61. Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . 977 John M. Dopp and Bradley G. Phillips
Jack J. Chen, Merlin V. Nelson, and David M. Swope 76. Developmental Disabilities . . . . . . . . . . . . . . . 1203
62. Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . 989 Nancy Brahm, Jerry McKee, and Robert C. Brown
Terry J. Baumann and Jennifer Strickland

63. Headache Disorders . . . . . . . . . . . . . . . . . . . . . . . 1005

SECTION 8
Deborah S. Minor and Marion R. Wofford
Endocrinologic Disorders
Section Editor: Robert L. Talbert

SECTION 7 77. Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . 1205

Curtis L. Triplitt, Charles A. Reasner, II, and William L. Isley
Psychiatric Disorders
Section Editor: Barbara G. Wells
78. Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 1243
Steven I. Sherman and Robert L. Talbert
64. Evaluation of Psychiatric Illness . . . . . . . . . . . . . 1021
Patricia A. Marken, Mark E. Schneiderhan,
79. Adrenal Gland Disorders. . . . . . . . . . . . . . . . . . . . 1265
and Stuart Munro John G. Gums and Shawn Anderson

65. Childhood Disorders. . . . . . . . . . . . . . . . . . . . . . . 1029 80. Pituitary Gland Disorders . . . . . . . . . . . . . . . . . . . 1281

Julie Ann Dopheide, Jane Tran Tesoro, and Michael Malkin Amy Heck Sheehan, Jack A. Yanovski, and Karim Anton Calis

The complete chapter, learning objectives, and other resources can be found at www.pharmacotherapyonline.com.
 x

SECTION 9 SECTION 12
CONTENTS

Gynecologic Disorders Rheumatologic Disorders

Section Editor: Barbara G. Wells Section Editor: L. Michael Posey
81. Pregnancy and Lactation: 93. Osteoporosis and Other Metabolic
Therapeutic Considerations . . . . . . . . . . . . . . . . . 1297 Bone Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483
Denise L. Walbrandt Pigarelli, Connie K. Kraus, Mary Beth O’Connell and Sheryl F. Vondracek
and Beth E. Potter
94. Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . 1505
82. Contraception. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313
Arthur A. Schuna
Lori M. Dickerson, Sarah P. Shrader, and Vanessa A. Diaz
95. Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1519
83. Menstruation-Related Disorders . . . . . . . . . . . . . 1329
Lucinda M. Buys and Mary Elizabeth Elliott
Elena M. Umland, Lara C. Weinstein, and Edward Buchanan
96. Gout and Hyperuricemia . . . . . . . . . . . . . . . . . . . 1539
84. Endometriosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345
Michael E. Ernst, Elizabeth C. Clark, and David W. Hawkins
Deborah A. Sturpe

85. Hormone Therapy in Women . . . . . . . . . . . . . . . 1351

Sophia N. Kalantaridou, Susan R. Davis, and SECTION 13
Karim Anton Calis
Ophthalmic and Otolaryngologic Disorders
Section Editor: L. Michael Posey
SECTION 10 97. Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551
Richard G. Fiscella, Timothy S. Lesar, and Deepak P. Edward
Urologic Disorders
Section Editor: L. Michael Posey 98. Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565
J. Russell May and Philip H. Smith
86. Erectile Dysfunction. . . . . . . . . . . . . . . . . . . . . . . . 1369
Mary Lee

87. Management of Benign SECTION 14

Prostatic Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . 1387
Dermatologic Disorders
Mary Lee
Section Editor: L. Michael Posey
88. Urinary Incontinence. . . . . . . . . . . . . . . . . . . . . . . 1399
99. Dermatologic Drug Reactions and
Eric S. Rovner, Jean Wyman, Thomas Lackner,
and David Guay
Self-Treatable Skin Disorders. . . . . . . . . . . . . . . . 1577
Nina H. Cheigh

100. Acne Vulgaris. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1591

SECTION 11 Dennis P. West, Amy Loyd, Kimberly A. Bauer, Lee E. West,
Laura Scuderi, and Giuseppe Micali
Immunologic Disorders
101. Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1603
Section Editor: Gary C. Yee
Dennis P. West, Amy Loyd, Lee E. West, Kimberly A. Bauer,
89. Function and Evaluation of the Maria Letizia Musumeci, and Giuseppe Micali
Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417
102. Atopic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . 1619
Philip D. Hall and Nicole A. Weimert
Nina H. Cheigh
90. Systemic Lupus Erythematosus and Other
Collagen-Vascular Diseases . . . . . . . . . . . . . . . . . . 1431
Jeffrey C. Delafuente and Kimberly A. Cappuzzo SECTION 15
91. Allergic and Pseudoallergic Drug Reactions . . . . 1447 Hematologic Disorders
Joseph T. DiPiro Section Editor: Gary C. Yee
92. Solid-Organ Transplantation . . . . . . . . . . . . . . . . 1459 103. Hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1627
Kristine S. Schonder and Heather J. Johnson William P. Petros and Michael Craig
 xi

104. Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1639 122. Bone and Joint Infections . . . . . . . . . . . . . . . . . . . 1933

CONTENTS
Beata A. Ineck, Barbara J. Mason, and William L. Lyons Edward P. Armstrong and Allan D. Friedman

105. Coagulation Disorders . . . . . . . . . . . . . . . . . . . . . 1665 123. Sepsis and Septic Shock . . . . . . . . . . . . . . . . . . . . . 1943
Betsy Bickert Poon and Char Witmer S. Lena Kang-Birken and Joseph T. DiPiro

106. Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . 1685 124. Superficial Fungal Infections. . . . . . . . . . . . . . . . . 1957
C. Y. Jennifer Chan and Reginald H. Moore Thomas E. R. Brown and Thomas W. F. Chin

107. Drug-Induced Hematologic Disorders . . . . . . . . 1701 125. Invasive Fungal Infections. . . . . . . . . . . . . . . . . . . 1973
Dale H. Whitby and Thomas E. Johns Peggy L. Carver

126. Infections in Immunocompromised Patients . . . 2003

Douglas N. Fish
SECTION 16
127. Antimicrobial Prophylaxis in Surgery . . . . . . . . . 2027
Infectious Diseases
Salmaan Kanji and John W. Devlin
Section Editor: Joseph T. DiPiro
128. Vaccines, Toxoids, and
108. Laboratory Tests to Direct Other Immunobiologics . . . . . . . . . . . . . . . . . . . . 2041
Antimicrobial Pharmacotherapy . . . . . . . . . . . . . 1715
Mary S. Hayney
Michael J. Rybak and Jeffrey R. Aeschlimann
129. Human Immunodeficiency Virus Infection . . . . 2065
109. Antimicrobial Regimen Selection . . . . . . . . . . . . 1731
Peter L. Anderson, Thomas N. Kakuda,
David S. Burgess and Courtney V. Fletcher
110. Central Nervous System Infections . . . . . . . . . . . 1743
Isaac F. Mitropoulos, Elizabeth D. Hermsen,
Jeremy A. Schafer, and John C. Rotschafer SECTION 17
111. Lower Respiratory Tract Infections . . . . . . . . . . . 1761 Oncologic Disorders
Mark L. Glover and Michael D. Reed Section Editor: Gary C. Yee
112. Upper Respiratory Tract Infections. . . . . . . . . . . 1779 130. Cancer Treatment and Chemotherapy . . . . . . . . 2085
Yasmin Khaliq, Sarah Forgie, and George Zhanel Patrick J. Medina and Chris Fausel

113. Influenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1791 131. Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2121

Elizabeth D. Hermsen and Mark E. Rupp Laura Boehnke Michaud, Janet L. Espirito,
and Francisco J. Esteva
114. Skin and Soft-Tissue Infections . . . . . . . . . . . . . . 1801
Douglas N. Fish, Susan L. Pendland, and Larry H. Danziger 132. Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2157
Jeannine S. McCune and Deborah A. Frieze
115. Infective Endocarditis . . . . . . . . . . . . . . . . . . . . . . 1821
Michael A. Crouch and Angie Veverka 133. Colorectal Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . 2175
Patrick J. Medina, Weijing Sun, and Lisa E. Davis
116. Tuberculosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1839
Charles A. Peloquin 134. Prostate Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2207
Jill M. Kolesar
117. Gastrointestinal Infections and . . . . . . . . . . . . . . 1857
Enterotoxigenic Poisonings 135. Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2219
Steven Martin and Rose Jung Val R. Adams and Gary C. Yee

118. Intraabdominal Infections . . . . . . . . . . . . . . . . . . 1875 136. Ovarian Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2245

Joseph T. DiPiro and Thomas R. Howdieshell Judith A. Smith and Judith K. Wolf

119. Parasitic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . 1887 137. Acute Leukemias. . . . . . . . . . . . . . . . . . . . . . . . . . . 2259

J. V. Anandan Helen L. Leather and Betsy Bickert Poon

120. Urinary Tract Infections and Prostatitis . . . . . . . 1899 138. Chronic Leukemias . . . . . . . . . . . . . . . . . . . . . . . . 2281
Elizabeth A. Coyle and Randall A. Prince Amy M. Pick, Marcel Devetten, and Timothy R. McGuire

121. Sexually Transmitted Diseases . . . . . . . . . . . . . . . 1915 139. Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . 2295

Leroy C. Knodel Timothy R. McGuire
 xii

140. Myelodysplastic Syndromes . . . . . . . . . . . . . . 2309 144. Prevalence and Significance of Malnutrition . . . 2367
CONTENTS

Julianna A. Burzynski and Trevor McKibbin Gordon Sacks and Catherine M. Crill

141. Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2311 145. Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . 2379

Rowena N. Schwartz and Lindsay J. Corporon Todd W. Mattox and Pamela D. Reiter

142. Hematopoietic Stem Cell Transplantation . . . . . 2331 146. Enteral Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . . 2399
Janelle B. Perkins and Gary C. Yee Vanessa J. Kumpf and Katherine Hammond Chessman

147. Nutritional Considerations in Major

Organ Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2417
SECTION 18
Brian M. Hodges and Mark DeLegge
Nutrition Disorders
148. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2437
Section Editor: Gary R. Matzke John V. St. Peter and Charles J. Billington
143. Assessment of Nutrition Status and
Nutrition Requirements . . . . . . . . . . . . . . . . . . . . 2349 Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2455
Katherine Hammond Chessman and Vanessa J. Kumpf Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2581

The complete chapter, learning objectives, and other resources can be found at www.pharmacotherapyonline.com.
 xiii

CONTRIBUTORS

Val R. Adams, PharmD, FCCP, BCOP Jeffrey F. Barletta, PharmD, FCCM

Associate Professor, University of Kentucky, College of Pharmacy, Clinical Specialist-Critical Care, Department of Pharmacy,
Lexington, Kentucky Spectrum Health, Adjunct Assistant Professor, College of
Chapter 135 Pharmacy, Ferris State University, Grand Rapids, Michigan
Chapter 14
Jeffrey R. Aeschlimann, PharmD
University of Connecticut, School of Pharmacy, Storrs, Connecticut Kimberly A. Bauer, MD
Chapter 108 Clinical Research Fellow, Department of Dermatology, Feinberg
School of Medicine, Northwestern University, Chicago, Illinois
Rondall E. Allen, PharmD Chapters 100 and 101
Clinical Assistant Professor and Assistant Dean for Program
Assessment, Xavier University of Louisiana College of Pharmacy, Larry A. Bauer, PharmD, FCP, FCCP
New Orleans, Louisana Professor, Departments of Pharmacy and Laboratory Medicine,
Chapter 40 University of Washington, Seattle, Washington
Chapter 5
J. V. Anandan, PharmD
Jerry L. Bauman, PharmD, FACC, FCCP
Adjunct Associate Professor, Eugene Applebaum College of
Pharmacy and Health Sciences, Wayne State University; Pharmacy Professor and Dean, College of Pharmacy; Professor, Department of
Specialist, Center for Drug Use Analysis and Information, Medicine, College of Medicine, University of Illinois, Chicago,
Department of Pharmacy Services, Henry Ford Hospital, Detroit, Illinois
Michigan Chapter 19
Chapter 119 Terry J. Baumann, PharmD, BCPS
Peter L. Anderson, PharmD Clinical Manager, Munson Medical Center, Traverse City,
Michigan; Adjunct Assistant Professor of Pharmacy, Ferris State
Assistant Professor, School of Pharmacy, University of Colorado,
University, College of Pharmacy, Big Rapids, Michigan
Denver, Colorado
Chapter 62
Chapter 129
Rosemary R. Berardi, PharmD, FCCP, FASHP, FAPhA
Shawn Anderson, PharmD
Professor of Pharmacy, College of Pharmacy, University of
Postdoctoral Fellow, Colleges of Pharmacy and Medicine, Michigan; Clinical Pharmacist, Gastrointestinal/Liver Diseases,
Departments of Pharmacy Practice and Family Medicine, Department of Pharmacy, University of Michigan Health System,
University of Florida, Gainesville, Florida Ann Arbor, Michigan
Chapter 79 Chapters 35 and 41
Tami R. Argo, PharmD, MS, BCPP Charles J. Billington, MD
Clinical Assistant Professor, Department of Pharmacy Practice, Professor, Department of Medicine, University of Minnesota,
College of Pharmacy, University of Texas at Austin, Austin, Texas Minneapolis VA Medical Center, Minneapolis, Minnesota
Chapter 70 Chapter 148
Edward P. Armstrong, PharmD Lisa A. Boothby, PharmD, BCPS
Professor, Department of Pharmacy Practice and Science, College of Coordinator, Drug Information Services, Columbus Regional
Pharmacy, University of Arizona, Tucson, Arizona Healthcare System; Affiliate Clinical Associate Professor, Auburn
Chapter 122 University Harrison School of Pharmacy, Columbus, Georgia
Chapters 68 and 69
Jacquelyn L. Bainbridge, PharmD
Associate Professor, Department of Clinical Pharmacy and Bradley A. Boucher, PharmD, FCCP, FCCM
Department of Neurology, University of Colorado at Denver and Professor, Department of Clinical Pharmacy, College of Pharmacy,
The Health Sciences Center, Denver, Colorado University of Tennessee, Memphis, Tennessee
Chapter 57 Chapter 60

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 xiv
Sharya V. Bourdet, PharmD, BCPS Julianna A. Burzynski, PharmD, BCPS, BCOP
CONTRIBUTORS

Critical Care Pharmacist, Veterans Affairs Medical Center, San Pharmacy Specialist-Hematology/Oncology, Mayo Clinic,
Francisco, Health Sciences Assistant Clinical Professor, School of Rochester, Minnesota
Pharmacy, University of California, San Francisco, San Francisco, Chapter 140
California
Chapter 29 Lucinda M. Buys, PharmD
Associate Professor , Clinical and Administrative Pharmacy
Denise Boudreau, RPh, PhD Division, University of Iowa, College of Pharmacy and the
Scientific Investigator, Group Health Center for Health Studies, Siouxland Medical Education Foundation, Sioux City, Iowa
Seattle, Washington Chapter 95
Chapter 9
Karim Anton Calis, PharmD, MPH, FASHP, FCCP
Rebecca Boudreaux, PharmD
Director, Drug Information Service and Clinical Specialist,
Clinical Instructor, College of Pharmacy, University of Texas at Endocrinology and Women’s Health, Mark O. Hatfield Clinical
Austin; Department of Medicine, University of Texas Health Research Center, National Institutes of Health, Bethesda, Maryland;
Science Center at San Antonio, San Antonio, Texas Professor of Pharmacy, School of Pharmacy, Virginia Commonwealth
Chapter 30 University, Richmond, Virginia; Clinical Professor, Department of
Nancy Brahm, PharmD, MS, BCPP Pharmacy Practice and Science, School of Pharmacy, University of
Maryland, Baltimore, Maryland; Clinical Professor, Department of
Clinical Associate Professor, Department of Pharmacy, Clinical and Pharmacy Practice, School of Pharmacy, Shenandoah University,
Administrative Sciences, University of Oklahoma College of Winchester, Virginia
Pharmacy, Tulsa, Oklahoma
Chapters 80 and 85
Chapter 76
Donald F. Brophy, PharmD, MSc, FCCP, BCPS Kimberly A. Cappuzzo, PharmD, MS, CGP
Associate Professor of Pharmacy and Internal Medicine, Virginia Assistant Professor of Pharmacy, School of Pharmacy, Virginia
Commonwealth University Medical College of Virginia Campus, Commonwealth University; Clinical Pharmacist/Geriatric
School of Pharmacy, Richmond, Virginia Pharmacotherapy Specialist, Virginia Commonwealth University
Medical Center, Richmond, Virginia
Chapter 54
Chapter 90
Jason E. Brouillard, PharmD
Adjunct Clinical Instructor, Department of Pharmacotherapy, Peggy L. Carver, PharmD, FCCP
College of Pharmacy, Washington State University; Critical Care Associate Professor of Pharmacy, College of Pharmacy, and Clinical
Pharmacist, Department of Pharmacy, Sacred Heart Medical Pharmacist, University of Michigan Health System, Ann Arbor,
Center, Spokane, Washington Michigan
Chapter 11 Chapter 125
Robert C. Brown, MD Larisa H. Cavallari, PharmD, BCPS
Adjunct Clinical Associate Professor, University of Oklahoma Assistant Professor, Department of Pharmacy Practice, University
College of Pharmacy, Department of Pharmacy, Clinical and of Illinois College of Pharmacy, Chicago, Illinois
Administrative Sciences, Oklahoma City, Oklahoma Chapters 6 and 16
Chapter 76
Jose E. Cavazos, MD, PhD
Thomas E. R. Brown, PharmD
Director of Research and Education, South Texas Comprehensive
Associate Professor, Leslie Dan Faculty of Pharmacy, University of Epilepsy Center, University of Texas Health Science Center, San
Toronto, and Clinical Coordinator, Women’s Health Sunnybrook Antonio, Texas
Health Sciences Centre, Toronto, Ontario
Chapter 58
Chapter 124
C. Y. Jennifer Chan, PharmD
Edward M. Buchanan, MD
Clinical Assistant Professor of Pharmacy, University of Texas in
Department of Family Medicine, Thomas Jefferson University,
Austin, College of Pharmacy, Clinical Associate Professor of
Philadelphia, Pennsylvania
Pediatrics, University of Texas Health Science Center in San
Chapter 83 Antonio; Clinical Manager, Pediatric Pharmacy Services, Methodist
Peter F. Buckley, MD Children’s Hospital, San Antonio, Texas
Professor and Chairman, Department of Psychiatry, Associate Dean Chapter 106
of Leadership Development, Medical College of Georgia, Augusta,
Georgia
Nina H. Cheigh, PharmD
Chapter 70 Clinical Associate Professor, University of Illinois College of
Pharmacy, Rye, New York
David S. Burgess, PharmD, FCCP Chapters 99 and 102
Clinical Professor of Pharmacy and Medicine, Center for
Advancement of Research and Education in Infectious Diseases, Jack J. Chen, PharmD, BCPS, CGP
University of Texas at Austin College of Pharmacy and Loma Linda University, School of Medicine, Department of
Pharmacotherapy Education and Research Center, University of Neurology and School of Pharmacy, Department of
Texas Health Science Center, San Antonio, Texas Pharmacotherapy, Outcomes and Research, Loma Linda, California
Chapter 109 Chapter 61
 xv
Katherine Hammond Chessman, PharmD, FCCP, Elizabeth A. Coyle, PharmD, BCPS

CONTRIBUTORS
BCPS, BCNSP Clinical Associate Professor, University of Houston College of
Associate Professor, Department of Pharmacy and Clinical Sciences, Pharmacy, Houston, Texas
South Carolina College of Pharmacy, MUSC Campus; Clinical Chapter 120
Pharmacy Specialist, Pediatrics/Pediatric Surgery, Department of
Pharmacy Services, Medical University of South Carolina James D. Coyle, PharmD
Children’s Hospital, Charleston, South Carolina Assistant Professor of Clinical Pharmacy, College of Pharmacy,
Chapters 143 and 146 Ohio State University, Columbus, Ohio
Robert Chilton, DO, FACC, FAHA Chapter 52
Professor, Department of Medicine, University of Texas Health
Michael Craig, MD
Science Center, San Antonio, Texas
Assistant Professor, Department of Medicine, Section of
Chapter 13
Hematology/Oncology, West Virginia University, Morgantown,
Thomas W. F. Chin, PharmD, BSc, FCSHP West Virginia
Clinical Pharmacy Specialist/Leader-Antimicrobials and Infectious Chapter 103
Diseases, St. Michael’s Hospital; Assistant Professor, Leslie Dan Faculty
of Pharmacy, University of Toronto, Toronto, Ontario, Canada Catherine M. Crill, PharmD, BCPS, BCNSP
Chapter 124 Associate Professor, Department of Clinical Pharmacy; Assistant
Professor, Department of Pediatrics, University of Tennessee Health
Elaine Chiquette, PharmD, BCPS Science Center, Memphis, Tennessee
Senior Medical Science Division, Medical Affairs, Amylin Chapter 144
Pharmaceuticals, Inc., San Antonio, Texas
Chapter 3 M. Lynn Crismon, PharmD, FCCP, BCPP
Dean, James T. Doluisio Chair and Behrens Professor, College of
Marie A. Chisholm-Burns, PharmD, MPH, FCCP,
Pharmacy, University of Texas at Austin, Austin, Texas
FASHP
Chapter 70
Professor and Head, Department of Pharmacy Practice and Science,
University of Arizona College of Pharmacy, Tuscon, Arizona
Michael A. Crouch, PharmD, BCPS
Chapter 33
Associate Professor of Pharmacy and Medicine, Virginia
Peter A. Chyka, PharmD, FAACT, DABAT Commonwealth University, Medical College of Virginia Campus,
Professor, Department of Clinical Pharmacy and Associate Dean, Richmond, Virginia
Knoxville Campus, College of Pharmacy, University of Tennessee, Chapter 115
Knoxville, Tennessee
William E. Dager, PharmD, FCSHP
Chapter 10
Pharmacist Specialist, UC Davis Medical Center, Clinical Professor
Elizabeth C. Clark, MD, MPH of Medicine, UC Davis School of Medicine, Sacramento, California;
University of Medicine and Denistry of New Jersey, Robert Wood Clinical Professor of Pharmacy, UC San Francisco School of
Johnson Medical School, Department of Family Medicine, Pharmacy, San Francisco, California
Somerset, New Jersey Chapter 45
Chapter 96
Joseph F. Dasta, MSc, FCCM, FCCP
Stephen Joel Coons, PhD Professor Emeritus, Ohio State University, College of Pharmacy,
Professor, Department of Pharmacy Practice and Service, College of Columbus, Ohio; Adjunct Professor, University of Texas, Austin,
Pharmacy, University of Arizona, Tuscon, Arizona Texas
Chapter 2 Chapter 25
John R. Corboy, MD Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
Professor, Department of Neurology, University of Colorado
Associate Professor and Vice Chair of Research, Philadelphia
School of Medicine; Denver Veteran’s Affairs Medical Center,
College of Pharmacy, University of the Sciences in Philadelphia,
Denver, Colorado
Philadelphia, Pennsylvania
Chapter 57
Chapter 133
Lindsay J. Corporon, PharmD, BCDP
Susan R. Davis, MD, PhD, FRAPC
Assistant Professor of Pharmacy and Therapeutics, University of
Pittsburgh, School of Pharmacy; Clinical Specialist in Oncology, Chair of Women’s Health, Department of Medicine, Monash
Magee Women’s Hospital, Pittsburgh, Pennsylvania University, Clayton, Victoria, Australia
Chapter 141 Chapter 85

Lisa T. Costanigro, Pharm D Larry H. Danziger, PharmD

Infectious Diseases Pharmacy Resident; Deaconess Medical Center, Professor of Pharmacy, Department of Pharmacy Practice, Interim
Washington State University College of Pharmacy, Spokane, Vice Chancellor for Research, University of Illinois, Chicago,
Washington Illinois
Chapter 11 Chapter 114
 xvi
Simon de Denus, MSc, BPharm Julie Ann Dopheide, PharmD, BCPP
CONTRIBUTORS

Assistant Professor, Faculty of Pharmacy, University of Montreal, Associate Professor of Clinical Pharmacy, Psychiatry and the
Montreal Heart Institute, Montreal, Quebec, Canada Behavioral Sciences, University of Southern California Schools of
Chapter 18 Pharmacy and Medicine, Los Angeles, California
Chapter 65
Jeffrey C. Delafuente, MS, FCCP, FASCP
Associate Dean for Professional Education; Professor of Pharmacy John M. Dopp, PharmD
and Director of Geriatric Programs, School of Pharmacy, Virginia Assistant Professor, Pharmacy Practice Division, School of
Commonwealth University, Richmond, Virginia Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin
Chapter 90 Chapter 75

Mark DeLegge, MD Thomas C. Dowling, PharmD, PhD

Professor and Director, Digestive Disease Center, School of Associate Professor, Director, Renal Clinical Pharmacology Lab,
Medicine, Medical University of South Carolina, Charleston, South School of Pharmacy, University of Maryland, Baltimore, Maryland
Carolina Chapter 44
Chapter 147
Shannon J. Drayton, PharmD
Paulina Deming, PharmD Assistant Professor, Department of Pharmacy and Clinical Sciences,
South Carolina College of Pharmacy, Medical University of South
Assistant Professor, College of Pharmacy and Department of
Carolina Campus, Charleston, South Carolina
Internal Medicine, University of New Mexico, Albuquerque, New
Mexico Chapter 72
Chapter 42 Deepak P. Edward, MD, FACS
Chair and Program Director; Professor/NEOUCOM, Department
Marcel Devetten, MD
of Ephthalmology, Summa Health System, Akron, Ohio
Associate Professor of Medicine and Director of Hematopoietic Cell
Chapter 97
Transplant Program, University of Nebraska Medical Center,
Omaha, Nebraska Mary Elizabeth Elliott, PharmD, PhD
Chapter 138 Associate Professor and Vice-Chair, Pharmacy Practice Division,
School of Pharmacy, University of Wisconsin-Madison, Madison,
John W. Devlin, PharmD, FCCP, FCCM, BCPS Wisconson, Clinical Pharmacist, Osteoporosis Clinic, VA Medical
Associate Professor, Department of Pharmacy Practice, School of Center, Madison, Wisconsin
Pharmacy, Northeastern University; Adjunct Associate Professor, Chapter 95
School of Medicine, Tufts University, Boston, Massachusetts
Chapters 55 and 127 Michael E. Ernst, PharmD, BCPS
Associate Professor (Clinical), Division of Clinical and Administrative
Vanessa A. Diaz, MD, MS Pharmacy, College of Pharmacy; Department of Family Medicine,
Assistant Professor, Department of Family Medicine, Medical Carver College of Medicine, University of Iowa, Iowa City, Iowa
University of South Carolina, Charleston, South Carolina Chapter 96
Chapter 82
Brian L. Erstad, PharmD
Lori M. Dickerson, PharmD, FCCP, BCPS Professor, Department of Pharmacy Practice and Science, College of
Associate Professor and Associate Residency Program Director, Pharmacy, University of Arizona, Tucson, Arizona
Department of Family Medicine, Medical University of South Chapter 26
Carolina, Charleston, South Carolina
Chapter 82 Janet L. Espirito, PharmD, BCOP
Clinical Pharmacy Specialist-Breast Oncology, Division of Pharmacy,
Cecily V. DiPiro, PharmD University of Texas M.D. Anderson Cancer Center, Houston, Texas
Consultant Pharmacist, Mt. Pleasant, South Carolina Chapter 131
Chapter 37
Francisco J. Esteva, MD, PhD
Joseph T. DiPiro, PharmD, FCCP Associate Professor of Medicine, Departments of Breast Medical
Executive Dean and Professor, South Carolina College of Pharmacy, Oncology and Molecular and Cellular Oncology, University of
Medical University of South Carolina, Charleston, South Carolina; Texas, M.D. Anderson Cancer Center, Houston, Texas
University of South Carolina, Columbia, South Carolina Chapter 131
Chapters 36, 91, 118, and 123
Susan C. Fagan, PharmD, BCPS
Paul L. Doering, MS Professor, Clinical and Administrative Pharmacy, College of
Distinguished Service Professor of Pharmacy Practice, College of Pharmacy, University of Georgia and Adjunct Professor of
Pharmacy, University of Florida, Gainesville, Florida Neurology, Medical College of Georgia, Augusta, Georgia
Chapters 68 and 69 Chapters 22 and 56
 xvii
Chris Fausel, PharmD, BCPS, BCOP Mark L. Glover, PharmD, BS Pharm

CONTRIBUTORS
Clinical Pharmacist, Hematology/Oncology/BMT, Indiana Associate Professor and Director, West Palm Beach Program,
University Cancer Center, Indianapolis, Indiana Department of Pharmacy Practice, College of Pharmacy, Nova
Chapter 130 Southeastern University, Palm Beach Gardens, Florida
Chapter 111
Richard G. Fiscella, BS Pharm, MPH
Shelly L. Gray, PharmD, MS
Clinical Professor, Department of Pharmacy Practice, Adjunct
Assistant Professor, Department of Ophthalmology, University of Professor, School of Pharmacy, University of Washington, Seattle,
Illinois, Chicago, Illinois Washington
Chapter 97 Chapter 8
Jessica S. Gruber, PhD, MPH
Douglas N. Fish, PharmD
Washington State University, College of Pharmacy, Deaconess
Professor, Department of Clinical Pharmacy, School of Pharmacy;
Medical Center, Spokane, Washington
Clinical Associate Professor, Division of Respiratory and Critical
Care Medicine, School of Medicine, University of Colorado, Chapter 11
Denver, Colorado David R. P. Guay, Pharm D
Chapters 114 and 126 Professor, Department of Experimental and Clinical Pharmacology,
College of Pharmacy, University of Minnesota; Department of
Courtney V. Fletcher, PharmD Geriatrics, Health Partners, Inc., Minneapolis, Minnesota
Dean and Professor, College of Pharmacy, University of Nebraska Chapters 8 and 88
Medical Center, Omaha, Nebraska
Chapter 129 John G. Gums, PharmD
Professor of Pharmacy and Medicine, Departments of Pharmacy
Edward F. Foote, PharmD, FCCP, BCPS Practice and Family Medicine, Director of Clinical Research in
Professor and Chair, Pharmacy Practice Department, Nesbitt Family Medicine, University of Florida, Gainesville, Florida
College of Pharmacy and Nursing, Wilkes-Barre University, Wilkes- Chapter 79
Barre, Pennsylvania
Stuart T. Haines, PharmD, BCPS
Chapter 48
Professor and Vice Chair, University of Maryland School of
Sarah Forgie, MD, FRCP(C) Pharmacy; Clinical Specialist, University of Maryland Medical
Assistant Professor, Pediatrics, Division of Infectious Diseases, System, Baltimore, Maryland
University of Alberta; Associate Director, Infection Control, Stollery Chapter 21
Children’s Hospital, Edmonton, Alberta, Canada
Emily R. Hajjar, PharmD
Chapter 112
Assistant Professor, Jefferson School of Pharmacy, Thomas
Jefferson University, Philadelphia, Pennsylvania
Nora Franceschini, MD, MPH
Chapter 8
Department of Epidemiology, School of Public Health, University
of North Carolina at Chapel Hill, Chapel Hill, North Carolina Philip D. Hall, PharmD, FCCP, BCPS, BCOP
Chapter 46 Associate Dean and Associate Professor, South Carolina College of
Pharmacy, Medical University of South Carolina Campus, Hollings
Allan D. Friedman, MD, MPH Cancer Center, Charleston, South Carolina
Professor and Chair, Division of General Pediatrics, Virginia Chapter 89
Commonwealth University, Richmond, Virginia
Chapter 122 Steven M. Handler, MP, MS, CMD
Assistant Professor, Department of Medicine, Division of Geriatic
Deborah A. Frieze, PharmD, BCOP Medicine and Department of Biomedical Informatics, University of
Clinical Pharmacist, Hematology/Oncology; Clinical Instructor, Pittsburgh, Pittsburgh, Pennsylvania
Seattle Cancer Care Alliance; University of Washington Medical Chapter 8
Center, Seattle, Washington
Joseph T. Hanlon, PharmD, MS, BCPS
Chapter 132
Professor, Division of Geriatrics and Gerontology, Department of
Medicine, School of Medicine; Department of Pharmacy and
Reginald F. Frye, PharmD, PhD
Therapeutics, School of Pharmacy, University of Pittsburgh;
Associate Professor, Departments of Pharmacy Practice and Research Health Scientist, Center for Health Equity Research and
Pharmaceutics, College of Pharmacy, University of Florida, Promotion, Geriatric Research Education (CHERP) and Clinical
Gainesville, Florida Center (GRECC), Pittsburgh, Pennsylvania
Chapter 51 Chapter 8
Todd W. B. Gehr, MD Michelle Harkins, MD
Professor and Chairman, Division of Nephrology, Department of Associate Professor, Department of Internal Medicine, Pulmonary
Internal Medicine, Virginia Commonwealth University, Richmond, and Critical Care, University of New Mexico Health Sciences
Virginia Center, Albuquerque, New Mexico
Chapter 54 Chapter 31
 xviii
David W. Hawkins, PharmD Thomas R. Howdieshell, MD, FACS, FCCP
CONTRIBUTORS

Professor and Dean, California Northstate College of Pharmacy, Professor of Surgery, Section of Trauma/Surgical Critical Care,
Sacramento, California Department of Surgery, University of New Mexico Health Sciences
Chapter 96 Center, Albuquerque, New Mexico
Chapter 118
Peggy E. Hayes, PharmD
President, Hayes CNS Services, LLC, San Diego, California Joanna Q. Hudson, PharmD, BCPS, FASN
Chapter 71 Associate Professor, Departments of Clinical Pharmacy and
Medicine (Nephrology), Schools of Pharmacy and Medicine,
Mary S. Hayney, PharmD, FCCP, BCPS University of Tennessee; Clinical Pharmacist, Methodist University
Associate Professor of Pharmacy (CHS) University of Wisconsin- Hospital, Memphis, Tennessee
Madison, School of Pharmacy, Madison, Wisconsin Chapter 47
Chapter 128
Beata A. Ineck, PharmD, BCPS, CDE
Thomas K. Hazlet, PharmD, DrPH Inpatient Clinical Staff Pharmacist, St. Luke’s Meridian Medical
Pharmaceutical Outcomes Research and Policy Program University Center, Meridian, Idaho
of Washington School of Pharmacy, Seattle, Washington Chapter 104
Chapter 9 William L. Isley, MD
Brian A. Hemstreet, PharmD, BCPS Consultant, Mayo Clinic; Associate Professor of Medicine, Mayo
Assistant Professor, University of Colorado at Denver and Health Clinic College of Medicine, Rochester, Minnesota (Deceased)
Sciences Center School of Pharmacy, Department of Clinical Chapter 77
Pharmacy, Denver, Colorado
Mark W. Jackson, MD
Chapter 36
Gastroenterologist, Fort Sanders Regional Medical Center and
Elizabeth D. Hermsen, PharmD, MBA, BCPS Baptist Hospital of East Tennessee, Knoxville, Tennesseee
Antimicrobial Specialist and Research Associate, Nebraska Medical Chapter 33
Center; Adjunct Assistant Professor, University of Nebraska Thomas E. Johns, PharmD, BCPS
Medical Center, College of Pharmacy and Medicine, Omaha,
Assistant Director, Clinical Pharmacy Services, Shands at the
Nebraska
University of Florida, Gainesville, Florida
Chapters 110 and 113
Chapter 107
David C. Hess, MD Heather J. Johnson, PharmD, BCPS, FASN
Professor and Chair, Department of Neurology, Medical College of
Assistant Professor, School of Pharmacy, University of Pittsburgh;
Georgia, Augusta, Georgia
Clinical Pharmacist, University of Pittsburgh Medical Center,
Chapter 22 Pittsburgh, Pennsylvania
Angela Massey Hill, PharmD, BCPP Chapter 92
Professor, Division Director of Pharmacy Practice, Florida A&M Melanie S. Joy, PharmD
University College of Pharmacy, Tallahassee, Florida Associate Professor, Division of Nephrology and Hypertension, UNC
Chapter 67 Kidney Center, School of Medicine, Division of Pharmacotherapy
and Experimental Therapeutics, School of Pharmacy, University of
Jonathan Himmelfarb, MD
North Carolina at Chapel Hill, Chapel Hill, North Carolina
Director, Division of Nephrology and Transplantation; Associate
Chapters 46 and 52
Chair for Research, Department of Medicine; Director of Clinical
and Translational Research, Maine Medical Center, Portland, Rose Jung, PharmD, BCPS
Maine Prestige Associate Professor, Department of Pharmacy Practice,
Chapter 49 University of Toledo, College of Pharmacy, Toledo, Ohio
Brian M. Hodges, PharmD, BCPS, BCNSP Chapter 117
Assistant Professor, Department of Clinical Pharmacy, School of Thomas N. Kakuda, PharmD
Pharmacy, West Virginia University, Morgantown, West Virginia Director, Human Pharmacokinetics, Tibotec, Inc., Yardley,
Chapter 147 Pennsylvania
Chapter 129
Barbara J. Hoeben, PharmD, MSPharm, BCPS
Clinical Pharmacy Flight Commander, 59 MDW, Wilford Hall Sophia N. Kalantaridou, MD, PhD
Medical Center, Lackland Airforce Base; Clinical Assistant Associate Professor of Obstetrics and Gynecology, Division of
Professor, Department of General Medicine, University of Texas Reproductive Endocrinology, University of Ioannina Medical
Health Science Center, San Antonio, Texas School, Ioannina, Greece
Chapter 24 Chapter 85
Collin A. Hovinga, PharmD Judith C. Kando, PharmD, BCPP
Assistant Professor, Pharmacy and Pediatrics, University of Senior Scientific Affairs Liaison, Ortho-McNeil Janssen Scientific
Tennessee Health Science Center, Memphis, Tennessee Affairs, LLC, Tewksbury, Massachusetts
Chapter 59 Chapter 71
 xix
S. Lena Kang-Birken, PharmD, FCCP Thomas Lackner, PharmD

CONTRIBUTORS
Associate Professor, Department of Pharmacy Practice, Thomas J. Professor, Department of Experimental and Clinical Pharmacy,
Long School of Pharmacy and Health Sciences, University of the College of Pharmacy, University of Minnesota, Minneapolis,
Pacific, Stockton, California Minnesota
Chapter 123 Chapter 88

Salmaan Kanji, PharmD, MSc Y. W. Francis Lam, PharmD, FCCP

Clinical Pharmacy Specialist, Ottawa Health Research Institute, Associate Professor of Pharmacology and Medicine, Clinical
Ottawa, Ontario, Canada Associate Professor of Pharmacy, Departments of Pharmacology
Chapter 127 and Medicine, University of Texas Health Science Center, San
Antonio, Texas
H. William Kelly, PharmD Chapters 6 and 43
Professor Emeritus, Department of Pediatrics, School of Medicine,
University of New Mexico Health Sciences Center, Albuquerque, Alan H. Lau, PharmD
New Mexico Professor, Department of Pharmacy Practice, College of Pharmacy,
Chapter 28 University of Illinois, Chicago, Illinois
Chapter 50
W. Klugh Kennedy, PharmD, BCPP
Helen L. Leather, BPharm
Clinical Associate Professor , University of Georgia College of
Pharmacy; Associate Professor, Mercer University School of Clinical Pharmacy Specialist BMT/Leukemia, Shands at the
Medicine, Savannah, Georgia University of Florida, Department of Pharmacy, Gainesville, Florida
Chapter 69 Chapter 137

Yasmin Khaliq, PharmD Mary Lee, PharmD, BCPS, FCCP

Ottawa Hospital, Ottawa, Ontario, Canada Professor of Pharmacy Practice, Chicago College of Pharmacy;
Vice President and Chief Academic Officer, Pharmacy and Health
Chapter 112
Science Education, Midwestern University, Downers Grove,
William R. Kirchain, PharmD Illinois
Wilbur and Mildred Robichaux Endowed Professor of Pharmacy, Chapters 86 and 87
Xavier University, College of Pharmacy, New Orleans, Louisana Timonthy S. Lesar, PharmD
Chapter 40 Director of Pharmacy, Patient Care Service Director, Department of
Cynthia K. Kirkwood, PharmD, BCPP Pharmacy, Albany Medical Center, Albany, New York
Associate Professor of Pharmacy, Vice Chair for Education, Chapter 97
Department of Pharmacy, School of Pharmacy, Virginia Stephanie M. Levine, MD
Commonwealth University, Richmond, Virginia
Professor of Medicine, Division of Pulmonary and Critical Care
Chapters 73 and 74 Medicine, University of Texas Health Science Center, San Antonio,
Texas
Leroy C. Knodel, PharmD
Chapter 27
Associate Professor, Department of Surgery, University of Texas
Health Science Center, San Antonio, Texas; Clinical Associate Amy Loyd, DO, CPT, MC
Professor, College of Pharmacy, University of Texas, Austin, Texas Resident, Army Medical Corps, Brooke Army Medical Center, San
Chapter 121 Antonio, Texas
Jill M. Kolesar, PharmD, FCCP, BCPS Chapters 100 and 101
Associate Professor, School of Pharmacy, University of Wisconsin, William L. Lyons, MD
Madison, Wisconsin Assistant Professor, Section of Geriatrics and Gerontology,
Chapter 134 University of Nebraska Medical Center, Omaha, Nebraska
Chapter 104
Connie R. Kraus, PharmD, BCPS
Clinical Professor, School of Pharmacy, University of Wisconsin- George E. MacKinnon, III, PhD, RPh, FASHP
Madison, Madison, Wisconsin Vice President of Academic Affairs, American Association of
Chapter 81 Colleges of Pharmacy, Alexandria, Virginia
Chapter 4
Abhijit Kshirsagar, MD, MPH
Assistant Professor of Medicine, Division of Nephrology and Neil J. MacKinnon, PhD, RPh, FCSHP
Hypertension, UNC Kidney Center, School of Medicine, University Associate Director for Research and Associate Professor, Dalhousie
of North Carolina at Chapel Hill, Chapel Hill, North Carolina University College of Pharmacy, Halifax, Nova Scotia, Canada
Chapter 46 Chapter 4
Vanessa J. Kumpf, PharmD, BCNSP Robert MacLaren, PharmD, BSc
Clinical Specialist, Nutrition Support, Vanderbilt University Associate Professor, Department of Clinical Pharmacy, University
Medical Center, Nashville, Tennessee of Colorado, Denver, School of Pharmacy, Aurora, Colorado
Chapters 143 and 146 Chapter 25
 xx
Eric J. MacLaughlin, PharmD, BS Pharm Timothy R. McGuire, PharmD, FCCP, BCOP
CONTRIBUTORS

Associate Professor, Texas Tech University Health Sciences Center, Associate Professor, College of Pharmacy, University of Nebraska
School of Pharmacy, Amarillo, Texas Medical Center, Omaha, Nebraska
Chapter 15 Chapters 138 and 139
Eugene H. Makela, PharmD, BCPP Jerry R. McKee, PharmD, MS, BCPP
Associate Professor, Schools of Pharmacy and Medicine, West Clinical Assistant Professor, Department of Pharmacotherapy,
Virginia University, Morgantown, West Virginia University of North Carolina School of Pharmacy, Chapel Hill,
Chapter 74 North Carolina; Pharmacy Director-Broughton Hospital,
Morganton, North Carolina
Michael Malkin, MD
Chapter 76
Director, Juvenile Court Mental Health Services, Los Angeles
County Department of Mental Health; Assistant Professor, UCLA Trevor McKibbin, PharmD, BCPS, MSc
Department of Psychiatry, Los Angeles, California Assistant Professor, Department of Clinical Pharmacy, College of
Chapter 65 Pharmacy, University of Tennessee Health Science Center,
Memphis, Tennessee
Harold J. Manley, PharmD, FASN, FCCP, BCPS
Chapter 140
Director of Clinical Pharmacy, Village Health Disease Management,
Glenmont, New York Patrick J. Medina, PharmD, BCOP
Chapter 48 Associate Professor, University of Oklahoma College of Pharmacy,
Oklahoma City, Oklahoma
Patricia A. Marken, PharmD, FCCP, BCPP
Chapters 130 and 133
Professor and Chair of Pharmacy Practice, School of Pharmacy;
Professor of Psychiatry, School of Medicine, University of Missouri, Sarah T. Melton, PharmD, BCPP, CGP
Kansas City, Missouri Adjunct Associate Professor of Pharmacy Practice, University of
Chapter 64 Appalachia College of Pharmacy; Clinical Pharmacist, Lebanon,
Patricia L. Marshik, PharmD Virginia
Associate Professor, University of New Mexico Health Sciences Chapter 73
Center, College of Pharmacy, Albuquerque, New Mexico Giuseppe Micali, MD
Chapter 31 Professor and Chairman, Dermatology Clinic, University of
Steven Martin, PharmD, BCPS, FCCP, FCCM Catania, Catania, Italy
Professor and Chairman, Department of Pharmacy Practice, Chapters 100 and 101
University of Toledo, College of Pharmacy, Toledo, Ohio Laura Boehnke Michaud, PharmD, BCOP, FASHP
Chapter 117 Manager, Clinical Pharmacy and Clinical Pharmacy Specialist–
Barbara J. Mason, PharmD, FASHP Breast Oncology, University of Texas M. D. Anderson Cancer
Professor and Vice Chair, Idaho State University College of Center, Houston, Texas
Pharmacy; Ambulatory Core Clinical Pharmacist, Boise VA Medical Chapter 131
Center, Boise, Idaho
Gary Milavetz, PharmD, RPh, BS, FCCP
Chapter 104
Associate Professor of Pharmacy, Division of Clinical and
Todd W. Mattox, PharmD, BCNSP Administrative Pharmacy, College of Pharmacy, University of Iowa,
Coordinator, Nutrition Support Team, H. Lee Moffitt Cancer Iowa City, Iowa
Center and Research Institute, Tampa, Florida Chapter 32
Chapter 145 Deborah S. Minor, PharmD
Gary R. Matzke, PharmD, FCP, FCCP Associate Professor, Department of Medicine, School of Medicine,
Professor of Pharmacy and Pharmaceutics and Associate Dean for University of Mississippi Medical Center, Jackson, Mississippi
Clinical Research and Public Policy, School of Pharmacy, Professor Chapter 63
of Internal Medicine, Nephrology Division, School of Medicine,
Virginia Commonwealth University, Richmond, Virginia Isaac F. Mitropoulos, PharmD
Chapters 51 and 55 Research Fellow, Experimental and Clinical Pharmacology, College
of Pharmacy, University of Minnesota, Minneapolis, Minnesota
J. Russell May, PharmD, FASHP Chapter 110
Clinical Professor, Department of Clinical and Administrative
Pharmacy, University of Georgia College of Pharmacy; Clinical Patricia A. Montgomery, PharmD
Pharmacy Specialist, Medical College of Georgia, Augusta, Georgia Clinical Pharmacy Specialist, Mercy General Hospital, Sacramento,
Chapter 98 California
Chapter 41
Jeannine S. McCune, PharmD, BCPS, BCOP
Associate Professor, University of Washington, School of Pharmacy; Reginald H. Moore, MD
Affiliate Investigator, Fred Hutchinson Cancer Research Center, Clinical Associate Professor, Department of Pediatrics, University
Seattle, Washington of Texas Health Science Center, San Antonio, Texas
Chapter 132 Chapter 106
 xxi
Stuart Munro, MD Amy Barton Pai, PharmD, BCPS, FASN

CONTRIBUTORS
Chair, Department of Psychiatry, School of Medicine, University of Associate Professor of Pharmacy, College of Pharmacy; School of
Missouri-Kansas City, Kansas City, Missouri Medicine, University of New Mexico, Albuquerque, New Mexico
Chapter 64 Chapter 53
Maria Letizia Musumeci, MD, PhD Paul M. Palevsky, MD
Assistant, Dermatology Clinic, University of Catania, Catania, Italy Chief Renal Section, VA Pittsburgh Healthcare System; Professor of
Chapter 101 Medicine, Renal-Electrolyte Division, School of Medicine,
University of Pittsburgh, Pittsburgh, Pennsylvania
Milap C. Nahata, PharmD, MS, FCCP
Chapter 55
Professor of Pharmacy, Pediatrics and Internal Medicine; Division
Chair, Pharmacy Practice and Administration, Ohio State
Robert B. Parker, PharmD, FCCP
University, College of Pharmacy, Associate Director, Department of
Pharmacy, Ohio State University Medical Center, Columbus, Ohio Professor, University of Tennessee College of Pharmacy, Memphis,
Tennessee
Chapter 7
Chapter 16
Jean M. Nappi, PharmD, FCCP, BCPS
Professor of Pharmacy and Clinical Sciences, South Carolina Charles A. Peloquin, PharmD
College of Pharmacy-MUSC Campus; Professor of Medicine, Director, Infectious Disease Pharmacokinetics Laboratory, National
Medical University of South Carolina, Charleston, South Carolina Jewish Medical and Research Center, Denver, Colorado
Chapter 20 Chapter 116
Merlin V. Nelson, MD, PharmD Susan L. Pendland, PharmD, MS
Neurologist, Affiliated Community Medical Centers, Willmar, Adjunct Associate Professor, Department of Pharmacy Practice,
Minnesota College of Pharmacy, University of Illinois at Chicago, Chicago,
Chapter 61 Illinois; Clinical Staff Pharmacist, Saint Joseph Berea Hospital,
Berea, Kentucky
Fenwick T. Nichols, III, MD
Chapter 114
Professor, Department of Neurology, Medical College of Georgia,
Augusta, Georgia Janelle B. Perkins, Pharm D
Chapter 56 Assistant Professor, Department of Interdisciplinary Oncology,
Thomas D. Nolin, PharmD, PhD Blood and Marrow Transplant Program, Moffitt Cancer Center,
Tampa, Florida
Clinical Pharmacologist, Department of Pharmacy Services,
Division of Nephrology and Transplantation, Department of Chapter 142
Medicine, Maine Medical Center, Portland, Maine
Jay I. Peters, MD
Chapter 49
Professor of Medicine, Pulmonary/Critical Care Division,
Edith A. Nutescu, PharmD, FCCP University of Texas Health Science Center, San Antonio, Texas
Clinical Associate Professor, Director, Antithrombosis Center, Chapter 27
University of Chicago College of Pharmacy and Medical Center,
Chicago, Illinois William P. Petros, PharmD, FCCP
Chapter 21 Mylan Chair of Pharmacology, Professor of Pharmacy and
Medicine, West Virginia University Health Sciences Center;
Mary Beth O’Connell, PharmD, BCPS Associate Director of Anti-Cancer Drug Development, Mary Babb
Department of Pharmacy Practice, Wayne State University, Detroit, Randolph Cancer Center, Morgantown, West Virginia
Michigan Chapter 103
Chapter 93
Stephanie J. Phelps, PharmD, BCPS
Keith M. Olsen, PharmD, FCCP, FCCM
Professor, Department of Clinical Pharmacy, University of
Professor and Chair, Department of Pharmacy Practice, College of Tennessee, Memphis, Tennessee
Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska
Chapter 59
Chapter 33
Rebecca L. Owens, PharmD Bradley G. Phillips, PharmD, BCPS, FCCP
Clinical Instructor, College of Pharmacy, University of Texas, Milliken-Reeve Professor and Head, Department of Clinical and
Austin, Texas; Department of Medicine, University of Texas Health Administrative Pharmacy, College of Pharmacy, University of
Science Center at San Antonio, San Antonio, Texas Georgia, Athens, Georgia
Chapter 30 Chapter 75

Robert L. Page, II, PharmD, CGP, BCPS Amy M. Pick, PharmD, BCOP
Associate Professor of Clinical Pharmacy and Physical Medicine; Assistant Professor of Pharmacy Practice, Creighton University
Clinical Specialist, Division of Cardiology, UHCSC, Schools of School of Pharmacy and Health Professions; Clinical Pharmacist,
Pharmacy and Medicine, Denver, Colorado Nebraska Methodist Hospital, Omaha, Nebraska
Chapter 20 Chapter 138
 xxii
Denise L. Walbrandt Pigarelli, PharmD, BC-ADM Mark Rohrscheib, MD
CONTRIBUTORS

Clinical Associate Professor, University of Wisconsin-Madison, Assistant Professor, Department of Internal Medicine, Division of
School of Pharmacy, Madison, Wisconsin Nephrology, University of New Mexico Health Sciences Center,
Chapter 81 Albuquerque, New Mexico
Chapter 53
Betsy Bickert Poon, PharmD
John C. Rotschafer, PharmD, FCCP
Oncology/Stem Cell Transplant Clinical Pharmacist, Children’s
Hospital of Philadelphia, Philadelphia, Pennsylvania Professor, Department of Experimental and Clinical Pharmacy,
College of Pharmacy, University of Minnesota, Minneapolis,
Chapters 105 and 137
Minnesota
L. Michael Posey, BSPharm Chapter 110
Editorial Director, Periodicals Department, American Pharmacists
Eric S. Rovner, MD
Association, Washington, D.C.
Associate Professor of Urology, Department of Urology, Medical
Chapter 3
University of South Carolina, Charleston, South Carolina
Beth E. Potter, MD Chapter 88
Associate Professor, Department of Family Medicine, School of Maria I. Rudis, PharmD, FCCM
Medicine and Public Health, University of Wisconsin-Madison,
Assistant Professor of Clinical Pharmacy, School of Pharmacy;
Madison, Wisconsin
Assistant Professor of Clinical Emergency Medicine, Keck School of
Chapter 81 Medicine, University of Southern California, Los Angeles,
California
Randall A. Prince, PharmD
Chapter 25
Professor, University of Houston, College of Pharmacy, Houston,
Texas Mark E. Rupp, MD
Chapter 120 Professor, Department of Internal Medicine, University of Nebraska
Medical Center; Medical Director, Department of Healthcare
Hengameh H. Raissy, PharmD Epidemiology, Nebraska Medical Center, Omaha, Nebraska
University of New Mexico, School of Medicine, Albuquerque, New Chapter 113
Mexico
Chapter 31 Michael J. Rybak, PharmD, MPH
Professor of Pharmacy and Medicine, Associate Dean for Research,
Charles A. Reasner, II, MD Director, Anti-Infective Research Laboratory, Eugene Applebaum
Professor, Department of Endocrinology, Metabolism, and College of Pharmacy and Health Sciences, Wayne State University,
Diabetes, University of Texas Health Science Center: Medical Detroit, Michigan
Director, Texas Diabetes Institute, San Antonio, Texas Chapter 108
Chapter 77 Gordon Sacks, PharmD
Michael D. Reed, PharmD, FCCP, FCP Clinical Professor and Chair, Pharmacy Practice Division, School of
Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin
Director, Division of Clinical Pharmacology and Toxicology,
Department of Pediatrics, Children’s Hospital Medical Center, Chapter 144
Akron, Ohio Lisa Sanchez, PharmD
Chapter 111 PE Applications, Highlands Ranch, Colorado
Chapter 1
Pamela D. Reiter, PharmD
Clinical Pharmacy Specialist, Pediatric ICU and Trauma, The Cynthia A. Sanoski, PharmD, BS
Children’s Hospital of Denver; Clinical Associate Professor, Associate Professor of Clinical Pharmacy, Department of Pharmacy
University of Colorado of Denver Health Sciences Center, School of Practice and Pharmacy Administration, Philadelphia College of
Pharmacy, Denver, Colorado Pharmacy, University of the Sciences, Philadelphia, Pennsylvania
Chapter 145 Chapter 19
Jo E. Rodgers, PharmD, BCPS (AQ Cardiology) Joseph J. Saseen, PharmD, FCCP, BCPS
Clinical Assistant Professor, Department of Pharmacotherapy and Associate Professor, University of Colorado-Denver, Department of
Experimental Therapeutics, School of Pharmacy, University of Clinical Pharmacy, School of Pharmacy; Department of Family
North Carolina at Chapel Hill, Chapel Hill, North Carolina Medicine, School of Medicine, Aurora, Colorado
Chapter 16 Chapter 15

Susan J. Rogers, PharmD, BCPS Robert R. Schade, MD, FACP, AGAF, FACG, FASGE
Assistant Clinical Professor, University of Texas at Austin; Clinical Professor of Medicine, Chief, Division of Gastroenterology/
Pharmacy Specialist Neurology, South Texas Healthcare System, Hepatology, Medical College of Georgia, Division of
Audie L. Murphy Memorial Veterans Hospital, San Antonio, Texas Gastroenterology/Hepatology, Augusta, Georgia
Chapter 58 Chapter 34
 xxiii
Jeremy A. Schafer, PharmD Sarah P. Shrader, PharmD, BCPS

CONTRIBUTORS
Manager of Formulary Development, Prime Therapeutics, Eagan, Assistant Professor, Department of Pharmacy and Clinical Sciences,
Minnesota South Carolina College of Pharmacy-MUSC Campus, Charleston,
Chapter 110 South Carolina
Chapter 82
Mark E. Schneiderhan, PharmD, BCPP
Clinical Assistant Professor, Department of Pharmacy Practice, Patricia W. Slattum, PharmD, PhD
Clinical Pharmacist, Department of Psychiatry, University of Associate Professor, Geriatric Pharmacotherapy Program,
Illinois, College of Pharmacy, Chicago, Illinois Department of Pharmacy, School of Pharmacy, Virginia
Chapter 64 Commonwealth University, Richmond, Virginia
Chapter 67
Marieke Dekker Schoen, PharmD, BCPS
Clinical Associate Professor, Department of Pharmacy and Judith A. Smith, PharmD, FCCP, BCOP
Department of Medicine, University of Illinois, Chicago, Illinois Assistant Professor, Department of Gynecologic Oncology,
Chapter 19 University of Texas MD Anderson Cancer Center, Houston, Texas
Kristine S. Schonder, PharmD Chapter 136
Assistant Professor, Pharmacy and Therapeutics Department,
Philip H. Smith, MD
School of Pharmacy, University of Pittsburgh; Clinical Pharmacist,
Thomas E. Starzl Transplantation Institute, University of Pittsburgh Section of Allergy and Immunology, Rheumatology, Department of
Medical Center, Pittsburgh, Pennsylvania Internal Medicine, Medical College of Georgia, Augusta, Georgia
Chapter 92 Chapter 98

Arthur A. Schuna, MS Christine A. Sorkness, PharmD

Clinical Coordinator, William S. Middleton VA Medical Center, Professor, Department of Pharmacy Practice, School of Pharmacy;
Clinical Professor, University of Wisconsin-Madison, School of Professor, Department of Medicine, Division of Allergy, Pulmonary
Pharmacy, Madison, Wisconsin and Critical Care Medicine, School of Medicine and Public Health,
Chapter 94 University of Wisconsin-Madison, Madison, Wisconsin
Chapter 28
Richard B. Schwartz, MD
Associate Professor, Department of Emergency Medicine, Medical Anne P. Spencer, PharmD
College of Georgia, Augusta, Georgia
Associate Professor, Department of Clinical Pharmacy and
Chapter 12 Outcome Sciences, South Carolina College of Pharmacy, Medical
Rowena N. Schwartz, PharmD, BCOP University of South Carolina, Charleston, South Carolina
Director of Weinberg and Oncology Pharmacy, Johns Hopkins Chapter 45
Hospital, Baltimore, Maryland
Sarah A. Spinler, PharmD, BCPS (AQ Cardiology)
Chapter 141
Professor, College of Pharmacy, University of the Sciences,
Laura Scuderi, MD Philadelphia, Pennsylvania
Assistant, Dermatology Clinic, University of Catania, Catania, Italy Chapter 18
Chapter 100
William J. Spruill, PharmD, FCCP, FASHP
Julie M. Sease, PharmD, BCPS Professor, University of Georgia, College of Pharmacy, Athens,
Clinical Assistant Professor, Department of Clinical Pharmacy and Georgia
Outcome Sciences, South Carolina, College of Pharmacy, University Chapter 38
of South Carolina, Columbia, South Carolina
Chapter 39 John V. St. Peter, BCPS
Adjunct Associate Professor of Pharmacy, College of Pharmacy,
Amy Heck Sheehan, PharmD
University of Minnesota, Minneapolis, Minnesota; Clinical and
Associate Professor of Pharmacy Practice, Purdue University School Outcomes Manager, Takeda Pharmaceuticals North America,
of Pharmacy and Pharmaceutical Sciences, Indianapolis, Indiana Deerfield, Illinois
Chapter 80 Chapter 48
Greene Shepherd, PharmD
Catherine I. Starner, PharmD, BCPS, CGP
Clinical Associate Professor, College of Pharmacy, University of
Georgia, Augusta, Georgia Senior Clinical Pharmacist, Prime Theapeutics; Clinical Assistant
Professor, University of Minnesota, College of Pharmacy, Eagan,
Chapter 12
Minnesota
Steven I. Sherman, MD Chapter 8
Chair and Professor, Department of Endocrine Neoplasia and
Hormonal Disorders, University of Texas M.D. Anderson Cancer Andy Stergachis, PhD, RPh
Center; Adjunct Associate Professor, Baylor College of Medicine, Professor of Epidemiology and Global Health, Adjunct Professor of
Houston, Texas Pharmacy, University of Washington, Seattle, Washington
Chapter 78 Chapter 9
 xxiv
Steven C. Stoner, PharmD, BCPP Edward G. Timm, PharmD, MS
CONTRIBUTORS

UMKC School of Pharmacy, Division of Pharmacy Practice, Senior Clinical Pharmacy Specialist, Critical Care and Adjunct
Clinical Associate Professor, Kansas City, Missouri Assistant Professor, Albany Medical Center Hospital and Albany
Chapter 66 College of Pharmacy, Albany, New York
Chapter 39
James J. Stragand, MD, PhD, FACG, FACP
Attendant Gastroenterologist, St. Charles Medical Center, Bend, Shelly D. Timmons, MD, PhD, FACS
Oregon Semmes-Murphey Clinic, Assistant Professor and Chief of
Chapter 39 Neurotrauma Division, University of Tennesee Health Science
Center, Memphis, Tennessee
Jennifer Strickland, PharmD, BCPS Chapter 60
Pain and Palliative Care Specialists, Lakeland Regional Medical
Center, Lakeland, Florida Curtis L. Triplitt, PharmD, CDE
Chapter 62 Texas Diabetes Institute; Assistant Professor, Department of
Medicine, Division of Diabetes, University of Texas Health Science
Deborah A. Sturpe, PharmD, BCPS
Center, San Antonio, Texas
Assistant Professor, Department of Pharmacy Practice and Science,
Chapter 77
University of Maryland, School of Pharmacy, Baltimore, Maryland
Chapter 84 Elena M. Umland, PharmD
Weijing Sun, MD Associate Dean for Academic Affairs, Jefferson School of Pharmacy,
Thomas Jefferson University, Philadelphia, Pennsylvania
Associate Professor of Medicine, University of Pennsylvania,
Abramson Cancer Center, Philadelphia, Pennsylvania Chapter 83
Chapter 133
Angie Veverka, PharmD
Russell H. Swerdlow, MD Assistant Professor of Pharmacy, Wingate University School of
Professor of Neurology, Molecular and Integrative Physiology, Pharmacy, Wingate, North Carolina
University of Kansas School of Medicine, Kansas City, Kansas Chapter 115
Chapter 67
Sheryl F. Vondracek, PharmD, FCCP, BCPS
David M. Swope, MD Associate Professor, Department of Clinical Pharmacy, University
Associate Professor of Neurology, Loma Linda University, Loma of Colorado-Denver; School of Pharmacy, Aurora, Colorado
Linda, California Chapter 93
Chapter 61
William E. Wade, PharmD, FASHP, FCCP
Carol Taketomo, PharmD
Professor, College of Pharmacy, University of Georgia, Athens,
Pharmacy Manager, Children’s Hospital of Los Angeles, Adjunct Georgia
Assistant Professor of Pharmacy Practice, University of Southern
Chapter 38
California School of Pharmacy, Los Angeles, California
Chapter 7 Nicole A. Weimert, PharmD, BCPS
Robert L. Talbert, PharmD, FCCP, BCPS, CLS Clinical Specialist, Solid Organ Transplantation, Department of
SmithKline Professor, College of Pharmacy, University of Texas at Pharmacy Services; Assistant Clinical Professor, South Carolina
Austin; Professor, Department of Medicine, University of Texas College of Pharmacy, Medical University of South Carolina
Health Science Center at San Antonio, San Antonio, Texas Campus, Charleston, South Carolina
Chapters 13, 17, 23, 24, 30, and 78 Chapter 89

Colleen M. Terriff, PharmD Benjamin L. Weinstein, MD

Assistant Professor, Pharmacy Department, College of Pharmacy, Assistant Professor, Department of Psychiatry, Medical University
Washington State University; Clinical Pharmacist, Deaconess of South Carolina, Charleston, South Carolina
Medical Center, Spokane, Washington Chapter 72
Chapter 11
Jane Tran Tesoro, PharmD, BCPP Lara C. Weinstein, MD
Clinical Pharmacist, Juvenile Court Mental Health Services, Los Assistant Professor, Department of Family and Community
Angeles, California Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
Chapter 65 Chapter 83

Christian J. Teter, PharmD, BCPP Lynda S. Welage, PharmD, FCCP

Assistant Professor, School of Pharmacy, Northwestern University, Professor of Pharmacy, College of Pharmacy and Associate Dean for
Boston, Massachusetts; Clinical Research Pharmacist, Alcohol and Academic Affairs, University of Michigan; Clinical Pharmacist,
Drug Abuse Treatment Program, McLean Hospital, Belmont, Critical Care, Department of Pharmacy, University of Michigan
Massachusetts Health-System, Ann Arbor, Michigan
Chapter 71 Chapter 35
 xxv
Barbara G. Wells, PharmD, FASHP, FCCP, BCPP Char Witmer, MD

CONTRIBUTORS
Dean and Professor, Executive Director of the Research Institute of Assistant Professor, Department of Pediatrics, Division of
Pharmaceutical Sciences, School of Pharmacy, University of Hematology, Philadelphia, Pennsylvania
Mississippi, Oxford, Mississippi Chapter 105
Chapters 71 and 74
Daniel M. Witt, PharmD, FCCP, BCPS, CACP
Lee E. West, BS
Manager, Clinical Pharmacy Services, Kaiser Permanente Colorado,
Clinical Pharmacist, Northwestern Memorial Hospital, Chicago, Aurora, Colorado
Illinois
Chapter 21
Chapters 100 and 101
Dennis P. West, PhD, FCCP, CIP Marion R. Wofford, MD, MPH
Vincent W. Foglia Family Research Professor of Dermatology; Associate Professor, Department of Medicine, School of Medicine,
Director, Dermatology Program, Chair for Administrative Review, University of Mississippi Medical Center, Jackson, Mississippi
IRB, Office for the Protection of Research Subjects, Feinberg School Chapter 63
of Medicine, Chicago, Illinois
Chapters 100 and 101 Judith K. Wolf, MD
Associate Professor, Department of Gynecologic Oncology,
James W. Wheless, MD
University of Texas MD Anderson Cancer Center, Houston, Texas
Professor and Chief of Pediatric Neurology, LeBonheur Chair in
Chapter 136
Pediatric Neurology, University of Tennessee Health Science
Center; Director, Neuroscience Institute and LeBonheur
Jean Wyman, PhD, RN
Comprehensive Epilepsy Program, LeBonheur Children’s Medical
Center, Memphis, Tennessee Professor and Cora, Meldi Siehl Chair in Nursing Research; Clinical
Director, Minnesota Continence Associates, University of
Chapter 59
Minnesota School of Nursing, Minneapolis, Minnesota
Dale H. Whitby, PharmD, BCPS Chapter 88
Pediatric Editor, Clinical Pharmacology, Gold Standard, Inc.,
Tampa, Florida Jack A. Yanovski, MD, PhD
Chapter 107 Head, Unit on Growth and Obesity, Program on Developmental
Endocrinology and Genetics, National Institute of Child Health and
Dennis M. Williams, PharmD, BCPS Human Development, National Institutes of Health, Bethesda,
Associate Professor, Division of Pharmacotherapy and Maryland
Experiemental Therapeutics, School of Pharmacy, University of Chapter 80
North Carolina, Chapel Hill, North Carolina
Chapter 29 Gary C. Yee, PharmD, FCCP, BCOP
Dianne B. Williams, PharmD, BCPS Professor, Department of Pharmacy Practice, College of Pharmacy,
Drug Information and Formulary Coordinator, MCG Health, Inc.; University of Nebraska Medical Center, Omaha, Nebraska
Associate Clinical Professor, University of Georgia College of Chapters 135 and 142
Pharmacy, Augusta, Georgia
Chapter 34 George Zhanel, PharmD, PhD
Professor, Department of Medical Microbiology; Faculty of
Jeffrey L. Wilt, MD, FACP, FCCP Medicine, University of Manitoba; Coordinator, Antimicrobial
Program Director, Critical Care Fellowship, Michigan State Resistance Program, Departments of Clinical Microbiology and
University, Kalamazoo Center for Medical Studies; Associate Medicine, Health Sciences Center of Clinical Microbiology and
Professor, College of Human Medicine, Michigan State University, Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada
Kalamazoo, Michigan Chapter 112
Chapter 14
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 xxvii

FOREWORD

It’s a safe assumption that you didn’t purchase this seventh edition areas of pharmacy practice by the Board of Pharmaceutical Special-
of Pharmacotherapy: A Pathophysiologic Approach for its foreword. ties. Psychiatric Pharmacy and Oncology Pharmacy followed in 1992
It’s probable that most of you will never read these musings. The and 1996, respectively. By 2007, more than 5200 pharmacy specialists
value of this text lies in its succeeding pages, in the collective had become board certified in one or more of these clinical special-
knowledge and wisdom conveyed by its authors, and in its ability to ties. Research in a variety of care settings has demonstrated the
help you provide better care for your patients. beneficial impact of pharmacists’ services on the clinical, humanistic,
It’s also a safe assumption that many—perhaps most—readers and economic outcomes of medication use.3,4 Research conducted
had not yet begun their careers in pharmacy when the first edition by pharmacists contributes important new knowledge to rational
of Pharmacotherapy: A Pathophysiologic Approach was published in pharmacotherapy. We’ve made real progress. But is it good enough?
1988. This seventh edition will mark the text’s 20th anniversary. Our focus has shifted from predominantly emphasizing the control
Noting this milestone, it’s appropriate to reflect on a few “then and of drug distribution to assuring that our patients receive the optimal
now” comparisons. benefits and outcomes from their use of medicines. Or has it?
Knowing the time required to conceive and create a new publica- In 1985, spending for prescription drugs in the United States was
tion of the scope and depth of Pharmacotherapy: A Pathophysiologic just over $22 billion. By 2005, that figure had increased to just over
Approach, I imagine that work began on its first edition sometime $200 billion (i.e., almost ten-fold in 20 years!), and is predicted to
around 1985. In February of that year, about 150 pharmacy practi- rise to almost $500 billion in 2016.5 A hefty sum indeed, but not the
tioners and educators gathered in Hilton Head, South Carolina for complete picture. Consider that in addition to these costs for the
an Invitational Conference on Directions for Clinical Pharmacy medications themselves, an additional $177 billion is estimated to
Practice. Organized by the American Society of Hospital (now be spent annually because of treatment failure or drug-related
Health-System) Pharmacists (ASHP), the conference objectives morbidity and mortality among ambulatory patients alone.6 Add to
included an evaluation of the status of clinical pharmacy practice and this the human and financial costs associated with medication
education, and identification of practical ways for advancing clinical errors, drug-related problems among nursing home residents, and
practice.1 Today, most readers of Pharmacotherapy: A Pathophysio- adverse drug events among hospitalized patients, and the real cost is
logic Approach would probably concisely describe their professional truly staggering.7,8 It is not hyperbole to say that we are in the midst
mission as “ensuring optimal medication therapy outcomes for of a public health crisis.
patients,” or something to that effect. But in 1985, pharmacy’s In 2004, the Joint Commission of Pharmacy Practitioners (JCPP)
perception of its professional mission could probably best be and the eleven national pharmacy organizations that comprise its
described by the concept of “drug use control” as articulated by Don membership endorsed a future vision of pharmacy practice:
Brodie: assuring “optimal safety in the distribution and use of
Pharmacists will be the health care professionals responsible for
medications.”2 Our emphasis had been focused more on the distri-
providing patient care that ensures optimal medication therapy
bution of medicines and was only just beginning to emphasize how
outcomes.
those medicines were used. The Hilton Head Conference, as it came
to be known, helped to catalyze a change in how organized pharmacy The JCPP vision statement goes on to describe pharmacy practice
and individual pharmacists viewed their professional mission—their and how pharmacy will benefit patients and society in 2015.9 It is
societal purpose. As noted by Max Ray, who was key in organizing my hope that all readers of Pharmacotherapy: A Pathophysiologic
the conference as a member of the ASHP staff at the time, the Approach would adopt this statement not just as a lofty vision for
conference represented “. . . a commitment to the establishment of the future of our profession but as their own professional mission—
pharmacy as a true clinical profession.” Subsequently, a more spe- the reason we exist today!
cific definition of clinical pharmacy would emerge, the practice But consider, by “optimal” do we mean “as good as can be expected
philosophy embodied by pharmaceutical care, and today, the set of under the circumstances” the way many dictionaries would define the
pharmacist services referred to as medication therapy management. word? Or do we mean “best possible”? If we’re satisfied with the
In 1985, 361 pharmacists graduated from ASHP accredited resi- former definition, then let’s declare victory and break out the cham-
dency programs. By 2006, that number had increased to nearly 1500 pagne. However, I hope you agree that we could do better for our
per year. In 1985, 33 schools of pharmacy awarded the Doctor of patients. This public health crisis demands rapid and significant
Pharmacy (PharmD) degree to 812 graduates (most as post-bacca- transformation of our medication use system and more effective
laureate degrees). Responding to evolving trends and future needs deployment of resources within that system. One such resource is the
within the profession, the Accreditation Council for Pharmacy Edu- nation’s pharmacists. As significant as our accomplishments of the
cation (ACPE) began to implement new accreditation standards and past 20 years may appear to be, we cannot rely on a similar, largely
guidelines in 2000. The PharmD degree is now pharmacy’s entry- evolutionary process as we address this crisis of medication use over
level degree. Accordingly, the number of PharmD graduates has the next decade or two. On the whole, today’s generation of pharma-
increased more than ten-fold (9040 in 2006). In 1988, Pharmacother- cists is better educated and trained as clinicians than any other in our
apy and Nutritional Support were formally recognized as specialty history. But as important as that foundation is, it will not suffice alone.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
xxviii
Our pharmacy practices—from the corner drug store in rural We should not expect private and government health plans to
America to the most specialized tertiary care center—must adopt a cover pharmacists’ medication therapy management and other
FOREWORD

philosophy of practice that emphasizes the pharmacist’s patient care patient care services if their customers (i.e., our patients) aren’t
responsibilities. The use of support personnel and technology must demanding that they do so. In turn, we should not expect our
be optimized so pharmacists can devote the majority of their effort customers (e.g., patients, other health professionals) to demand
to these patient care responsibilities. Management must adopt something they have not personally experienced and come to
different benchmarks for assessing pharmacist productivity. No value. It is our responsibility to create that demand through every
longer should the key measurement be the number of prescriptions encounter with a patient, caregiver, family member, or other health
filled. Our metrics must focus instead on patient outcomes that are professional.
affected by pharmacists’ medication therapy management and other It must begin with us. With our professional knowledge, skills, and
patient care responsibilities (e.g., wellness, disease prevention). attitudes. With a commitment to care for, and about, patients. With
Of course, this practice model must be economically viable. a commitment to drive change in a system that needs a lot of change.
Currently, payment for pharmacy services is largely based on Our patients need and deserve nothing less than our true best.
payment for the drug product and the act of dispensing it. Con- Robert M. Elenbaas, PharmD, FCCP
certed efforts are underway to change the payment policies of both
Kansas City, Missouri
private and government payers and develop the infrastructure
needed to enable a different paradigm. However, we cannot wait Executive Director, American College
until all of the payment ducks have been put in a row to broadly of Clinical Pharmacy (1986–2003)
implement the philosophy and model of practice alluded to above. Director, ACCP Research Institute (2004–2006)

References 5. Kaiser Family Foundation. Prescription drug trends. May 2007. Avail-
able from kff.org/rxdrugs/upload/3057_06.pdf. Accessed October 23,
1. Directions for clinical practice in pharmacy. Proceedings of an invita- 2007.
tional conference conducted by the ASHP Research and Education 6. Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: Updating
Foundation and the American Society of Hospital Pharmacists. Febru- the cost-of-illness model. J Am Pharm Assoc 2001;41:192–199.
ary 10–13, 1985. Am J Health Syst Pharm 1985;42:1287–1292. 7. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug
2. Brodie DC. Drug use control: Keystone to pharmaceutical service. reactions in hospitalized patients. A meta-analysis of prospective
Drug Intell Clin Pharm 1967;1:63–65 studies. JAMA 1998;279:1200–1205.
3. Schumock GT, Butler MG, Meek PD, et al. Evidence of the economic 8. Gurwitz JH. Improving the quality of medication use in elderly
benefit of clinical pharmacy services: 1996–2000. Pharmacotherapy patients. A not-so-simple prescription. Arch Intern Med 2002;162:
2003;23:113–132. 1670–1672.
4 Schumock GT, Meek PD, Ploetz PA, Vermeulen LC. Economic evalu- 9. JCPP future vision of pharmacy practice. Available from aacp.org/
ations of clinical pharmacy services—1988–1995. Pharmacotherapy Docs/MainNavigation/Resources/6725_JCPPFutureVisionofPharmacy
1996;16:1188–1208. PracticeFINAL.pdf. Accessed October 23, 2007.
 xxix

FOREWORD TO THE FIRST EDITION

Evidence of the maturity of a profession is not unlike that character- profession that we have matured sufficiently to be competent and
izing the maturity of an individual; a child’s utterances and behavior willing to take unprecedented responsibilities in the collaborative,
typically reveal an unrealized potential for attainment, eventually, of pharmacotherapeutic management of patient-specific problems. It
those attributes characteristic of an appropriately confident, inde- commits pharmacy to an intention that will not be uniformly or
pendently competent, socially responsible, sensitive, and productive rapidly accepted within the established healthcare community.
member of society. Nonetheless, this formal action places us on the road to an avowed
Within a period of perhaps 15 or 20 years, we have witnessed a goal, and acceptance will be gained as the pharmacotherapists
profound maturation within the profession of pharmacy. The proliferate and establish their importance in the provision of opti-
utterances of the profession, as projected in its literature, have mal, cost-effective drug therapy.
evolved from mostly self-centered and self-serving issues of trade Suspecting that other professions in other times must have faced
protection to a composite of expressed professional interests that similar quests for recognition of their unique knowledge and skills I
prominently include responsible explorations of scientific/techno- once searched the literature for an example that might parallel
logical questions and ethical issues that promote the best interests of pharmacy’s modern-day aspirations. Writing in the Philadelphia
the clientele served by the profession. With the publication of Medical Journal, May 27, 1899, D. H. Galloway, MD, reflected on
Pharmacotherapy: A Pathophysiologic Approach, pharmacy’s utter- the need for specialty training and practice in a field of medicine
ances bespeak a matured practitioner who is able to call upon lacking such expertise at that time. In an article entitled “The
unique knowledge and skills so as to function as an appropriately Anesthetizer as a Specialty,” Galloway commented:
confident, independently competent pharmacotherapeutics expert.
The anesthetizer will have to make his own place in medicine:
In 1987, the Board of Pharmaceutical Specialties (BPS), in deny-
the profession will not make a place for him, and not until he
ing the petition filed by the American College of Clinical Pharmacy
has demonstrated the value of his services will it concede him
(ACCP) to recognize “clinical pharmacy” as a specialty, conceded
the position which the importance of his duties entitles him to
nonetheless that the petitioning party had documented in its peti-
occupy. He will be obliged to define his own rights, duties and
tion a specialist who does in fact exist within the practice of
privileges, and he must not expect that his own estimate of the
pharmacy and whose expertise clearly can be extricated from the
importance of his position will be conceded without opposition.
performance characteristics of those in general practice. A refiled
There are many surgeons who are unwilling to share either the
petition from ACCP requests recognition of “pharmacotherapy” as
credit or the emoluments of their work with anyone, and their
a Specialty Area of Pharmacy Practice. While the BPS had issued no
opposition will be overcome only when they are shown that the
decision when this book went to press, it is difficult to comprehend
importance of their work will not be lessened, but enhanced, by
the basis for a rejection of the second petition.
the increased safety and dispatch with which operations may
Within this book one will find the scientific foundation for the
be done. . . .
essential knowledge required of one who may aspire to specialty
practice as a pharmacotherapist. As is the case with any such It has been my experience that, given the opportunity for one-on-
publication, its usefulness to the practitioner or the future practi- one, collaborative practice with physicians and other health profes-
tioner is limited to providing such a foundation. To be socially and sionals, pharmacy practitioners who have been educated and
professionally responsible in practice, the pharmacotherapist’s trained to perform at the level of pharmacotherapeutics specialists
foundation must be continually supplemented and complemented almost invariably have convinced the former that “the importance
by the flow of information appearing in the primary literature. Of of their work will not be lessened, but enhanced, by the increased
course this is not unique to the general or specialty practice of safety and dispatch with which” individualized problems of drug
pharmacy; it is essential to the fulfillment of obligations to clients in therapy could be managed in collaboration with clinical pharmacy
any occupation operating under the code of professional ethics. practitioners.
Because of the growing complexity of pharmacotherapeutic agents, It is fortuitous—the coinciding of the release of Pharmacotherapy:
their dosing regimens, and techniques for delivery, pharmacy is A Pathophysiologic Approach with ACCP’s petitioning of BPS for
obligated to produce, recognize, and remunerate specialty practi- recognition of the pharmacotherapy specialist. The utterances of a
tioners who can fulfill the profession’s responsibilities to society for maturing profession as revealed in the contents of this book, and the
service expertise where the competence required in a particular case intraprofessional recognition and acceptance of a higher level of
exceeds that of the general practitioner. It simply is a component of responsibility in the safe, effective, and economical use of drugs and
our covenant with society and is as important as any other facet of drug products, bode well for the future of the profession and for the
that relationship existing between a profession and those it serves. improvement of patient care with drugs.
The recognition by BPS of pharmacotherapy as an area of specialty Charles A. Walton, PhD
practice in pharmacy will serve as an important statement by the San Antonio, Texas

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 xxxi

PREFACE

Pharmacists and other healthcare professionals who evaluate, and focuses on public health and management of the individual. We
design, and recommend pharmacotherapy for the management of have incorporated the influence of the emerging pharmacogenetic
their patients face many new and exciting challenges as the twenty- knowledge on drug metabolism into an integrated authoritative
first century matures. With this seventh edition of Pharmacother- chapter entitled: Drug Therapy Individualization for Patients with
apy: A Pathophysiologic Approach, we recognize just how compli- Hepatic Disease or Altered Drug-Metabolizing Status. In the respi-
cated our tasks as editors have become. Balancing the need for ratory section of this edition, Primary Pulmonary Hypertension
accurate, thorough, and unbiased information about the treatment replaces Adult Respiratory Distress Syndrome. Other new chapters
of diseases against the publishing realities of deadlines, page counts, include Developmental Disabilities and two oncology chapters,
and book length, we strive to adhere to our founding precepts: Multiple Myeloma and Myelodysplastic Syndromes.
• Advance the quality of patient care through evidence-based To make room for these new chapters and stay with a single
medication therapy management based on sound pharmaco- volume of Pharmacotherapy, 11 chapters of this edition are being
therapeutic principles. published in our Pharmacotherapy Online Learning Center, accessi-
• Enhance the health of our communities by incorporating ble at www.pharmacotherapyonline.com or http://highered.mcgraw-
contemporary health promotion and disease-prevention strat- hill.com/sites/0071416137/information_center_view0/. The chapters
egies in our practice environments. chosen for Web publication include those of specialized application
• Motivate young practitioners to enhance the breadth, depth, that may be predominantly used by practitioners rather than serving
and quality of care they provide to their patients. as core elements of the pharmacotherapy sequences at colleges of
• Challenge pharmacists and other primary-care providers to pharmacy. In addition, seven introductory chapters provide students
learn new concepts and refine their understanding of the and practitioners with an overview of topics typically covered in other
pathophysiology tenets that undergird the development of courses. Two of the new chapters in this edition are online chapters
individualized therapeutic regimens. that focus on the healthcare community’s need for accurate, defini-
• Present the pharmacy and health care communities with inno- tive, and concise information regarding emergency preparedness:
vative patient assessment, triage, and pharmacotherapy man- Identification and Management of Biological Exposures, and Identi-
agement skills. fication and Clinical Management of Chemical and Radiological
While our emphasis in past editions has been to incorporate Exposures. These 11 online chapters are accessible to anyone via the
diseases that were previously untreatable with pharmacologic Online Learning Center; users need not have purchased the print text
agents, this seventh edition is focused on application of evidence- to read this material. Thus, the online chapters are actually more
based pharmacotherapy. Most of the disease-oriented chapters have available than are the chapters published in print for this edition.
incorporated evidence-based treatment guidelines that include, While preparing for this edition, we sought the advice of users
when available, rating indicators for the key therapeutic approaches. and colleagues to guide modifications. During editing, we reviewed
Also, as in recent editions: each passage of text—and the references cited—for continued
• Key concepts are listed at the beginning of each chapter and are relevance and accuracy. We made deletions, asked authors to
identified in the text with numbered icons so that the reader summarize concepts more succinctly or use tables to present details
can easily jump to the material of interest. more concisely, included new medications as they entered the U.S.
• The most common signs and symptoms of diseases are pre- market or emerged in other countries, and updated references. This
sented in highlighted Clinical Presentation boxes in disease- process continued as the book entered production, and even during
specific chapters. the review of final proofs, we continued to make changes to ensure
• Clinical controversies in treatment or patient management are that this book is as current and complete as is possible.
highlighted to assure that the reader is aware of these issues and As the world increasingly relies on electronic means of commu-
discuss how practitioners are responding to them. nication, we are committed to keeping Pharmacotherapy and its
• Each chapter has about 100 of the most important and current companion works, Pharmacotherapy Casebook: A Patient-Focused
references relevant to each disease, with most published since Approach and Pharmacotherapy Handbook integral components of
2000. clinicians’ toolboxes. Two other new works have been created in
• For easy reference, abbreviations and acronyms and their parallel with the preparation of this edition, Pharmacotherapy Prin-
meanings are presented at the end of each chapter. ciples and Practice and Pharmacotherapy: A Primary Care Approach.
• A glossary of the medical terms used throughout the text is These texts are intended to meet the needs of additional audiences,
presented at the end of the book. including nurse practitioner and physician assistant programs and
• Finally, the diagnostic flow diagrams, treatment algorithms, practicing primary care physicians, nurse practitioners, and physi-
dosing guideline recommendations, and monitoring approaches cian assistants. The Online Learning Center continues to provide
that were present in the sixth edition have been refined. unique features designed to benefit students, practitioners, and
This edition includes eight new chapters. The new Influenza faculty around the world. The site includes learning objectives and
chapter addresses changing presentation of this group of infections self-assessment questions for each chapter, and the full text of this

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
xxxii
book is now available on the publisher’s Access Pharmacy site thank Michael Weitz, Kim Davis, and James Shanahan and their
(www.accesspharmacy.com). colleagues at McGraw-Hill for their consistent support of the
PREFACE

In closing, we acknowledge the many hours that Pharmacother- Pharmacotherapy family of resources, insights into trends in pub-
apy’s 200 authors contributed to this labor of love. Without their lishing and higher education, and the critical attention to detail so
devotion to the cause of improved pharmacotherapy and dedication necessary in pharmacotherapy.
in maintaining the accuracy, clarity, and relevance of their chapters, The Editors
this text would unquestionably not be possible. In addition, we March 2008
 1

SECTION 1
FOUNDATION ISSUES

1
C HAP T E R

Pharmacoeconomics: Principles,
Methods, and Applications

LISA A. SANCHEZ

of interventions, costs and consequences, discounting, study

KEY CONCEPTS results, sensitivity analysis, study conclusions, and sponsorship.

 Pharmacoeconomics identifies, measures, and compares the Use of economic models and conducting pharmacoeconomic
costs and consequences of drug therapy to healthcare systems analyses on a local level both can be useful and relevant sources
and society. of pharmacoeconomic data when rigorous methods are
employed, as outlined in this chapter.
 The perspective of a pharmacoeconomic evaluation is para-
mount because the study results will be highly dependent on
the perspective selected.
Today’s cost-sensitive healthcare environment has created a com-
 Healthcare costs can be categorized as direct medical, direct petitive and challenging workplace for clinicians. Competition for
nonmedical, indirect nonmedical, intangible, opportunity, and diminishing resources has necessitated that the appraisal of health-
incremental costs. care goods and services extends beyond evaluations of safety and
efficacy and considers the economic impact of these goods and
 Economic, humanistic, and clinical outcomes should be con- services on the cost of healthcare. A challenge for healthcare
sidered and valued using pharmacoeconomic methods, to in- professionals is to provide quality patient care while assuring an
form local decision making whenever possible. efficient use of resources.
 To compare various healthcare choices, economic valuation Defining the value of medicine is a common thread that unites
methods are used, including cost-minimization, cost-benefit, today’s healthcare practitioners. With serious concerns about rising
cost-effectiveness, and cost-utility analyses. These methods all medication costs and consistent pressure to decrease pharmacy
provide the means to compare competing treatment options expenditures and budgets, clinicians/prescribers, pharmacists, and
and are similar in the way they measure costs (dollar units). other healthcare professionals must answer the question, “What is
They differ, however, in their measurement of outcomes and the value of the pharmaceutical goods and services I provide?”
expression of results. Pharmacoeconomics, or the discipline of placing a value on drug
therapy,1 has evolved to answer this question.
 In today’s healthcare settings, pharmacoeconomic methods Challenged to provide high-quality patient care in the least expen-
can be applied for effective formulary management, individual sive way, clinicians have developed strategies aimed at containing
patient treatment, medication policy determination, and re- costs. However, most of these strategies focus solely on determining
source allocation. the least expensive alternative rather than the alternative that repre-
 When evaluating published pharmacoeconomic studies, the sents the best value for the money. The “cheapest” alternative—with
following factors should be considered: study objective, study respect to drug acquisition cost—is not always the best value for
perspective, pharmacoeconomic method, study design, choice patients, departments, institutions, and healthcare systems.
Quality patient care must not be compromised while attempting
to contain costs. The products and services delivered by today’s
health professionals should demonstrate pharmacoeconomic value,
that is, a balance of economic, humanistic, and clinical outcomes.
The complete chapter, Pharmacoeconomics can provide the systematic means for this
learning objectives, and other quantification. This chapter discusses the principles and methods of
pharmacoeconomics and how they can be applied to clinical phar-
resources can be found at
macy practice and thereby how they can assist in the valuation of
www.pharmacotherapyonline.com.
pharmacotherapy and other modalities of treatment in clinical
practice.

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C HAP T E R

2 Health Outcomes and Quality of Life

STEPHEN JOEL COONS

HEALTH OUTCOMES
KEY CONCEPTS
 The evaluation of healthcare is increasingly focused on the as- Although the implicit objective of medical care is to improve health
sessment of the outcomes of medical interventions. outcomes, until relatively recently, little attention was paid to the
explicit measurement of them. An outcome is one of the three
 An essential patient-reported outcome is self-assessed func- components of the conceptual framework articulated by Donabedian
tion and well-being, or health-related quality of life (HRQOL). for assessing and ensuring the quality of healthcare: structure, process,
 In certain chronic conditions, HRQOL may be the most impor- and outcome.5 For far too long, the approach to evaluating healthcare
tant health outcome to consider in assessing treatment. had emphasized the structure and processes involved in medical care
delivery rather than the outcomes. However, healthcare regulators,
 Information about the impact of pharmacotherapy on HRQOL payers, providers, manufacturers, and patients are placing increasing
can provide additional data for making decisions regarding emphasis on the outcomes that medical care products and services
medication use. produce.6 As stated by Ellwood, outcomes research is “designed to
 HRQOL instruments can be categorized as generic/general or help patients, payers, and providers make rational medical care
targeted/specific. choices based on better insight into the effect of these choices on the
patient’s life.”7
 In HRQOL research, the quality of the data collection tool is the
major determinant of the overall quality of the results. TYPES OF OUTCOMES
The types of outcomes that result from medical care interventions can
Although it has not involved the comprehensive reform that may be be described in a number of ways. One classic list, called the five D’s—
necessary,1 the medical care marketplace in the United States death, disease, disability, discomfort, and dissatisfaction—captures a
continues to experience change in both the financing and delivery limited range of outcomes for use in assessing the quality of medical
of care.2 This change is evidenced by a variety of developments, care.7 The five D’s do not reflect any positive health outcomes and, as
including an increase in investor-owned organizations, heightened a result, have little value in contemporary outcomes research.
competition, numerous mergers and acquisitions, increasingly A more comprehensive conceptual framework, the ECHO model,
sophisticated clinical and administrative information systems, and places outcomes into three categories: economic, clinical, and
new financing and organizational structures. In this dynamic and humanistic outcomes.8 As described by Kozma et al.,8 economic
increasingly competitive environment, there is a concern that outcomes are the direct, indirect, and intangible costs compared with
healthcare quality is being compromised in the push to contain the consequences of a medical intervention. Clinical outcomes are the
costs.  As a consequence, there has been a growing movement to medical events that occur as a result of the condition and/or its
focus the evaluation of healthcare on the assessment of the end treatment.  Humanistic outcomes, which now are more commonly
results, or outcomes, associated with medical care delivery systems as called patient-reported outcomes,9 are the consequences of the disease
well as specific medical interventions. The primary objective of this and/or its treatment as perceived and reported by the patient.
effort is to maximize the net health benefit derived from the use of Patient-reported outcomes (PROs) refer to a number of important
finite healthcare resources.3 However, there is a serious lack of outcomes, including self-assessed health status, symptom experi-
critical information as to what value is received for the tremendous ence, treatment satisfaction, and functioning and perceived well-
amount of resources expended on medical care.4 This lack of critical being. PROs are increasingly being used to complement safety data,
information as to the outcomes produced is an obstacle to optimal survival rates, and traditional indicators of clinical efficacy in thera-
healthcare decision making at all levels. peutic intervention trials.10

The complete chapter,

learning objectives, and other
resources can be found at
www.pharmacotherapyonline.com.

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 5

C HAP T E R

3 Evidence-Based Medicine

ELAINE CHIQUETTE AND L. MICHAEL POSEY

decision making. These strategies can help physicians, pharmacists,

KEY CONCEPTS and other healthcare professionals to distinguish reliably beneficial
pharmacotherapies from those that are ineffective or harmful. Also,
 The best current evidence integrated into clinical expertise en- EBM approaches can be applied to keep up-to-date and to make an
sures optimal care for patients. overwhelming task seem more manageable.
 The four steps in the process of applying evidence-based med- This chapter describes the principles of EBM, offers guidance for
icine (EBM) in practice are (a) formulate a clear question from finding EBM sources on the World Wide Web, provides a model for
a patient’s problem, (b) identify relevant information, (c) criti- applying EBM in patient care, and explains how EBM strategies can
cally appraise available evidence, and (d) implement the find- help a practitioner stay current.
ings in clinical practice.
 The decision as to whether to implement the results of a spe- WHAT IS EVIDENCE-BASED MEDICINE?
cific study, conclusions of a review article, or another piece of
evidence in clinical practice depends on the quality (i.e., inter- EBM is an approach to medical practice that uses the results of
nal validity) of the evidence, its clinical importance, whether patient care research and other available objective evidence as a
benefits outweigh risks and costs, and its relevance in the clin- component of clinical decision making. Similarly, evidence-based
ical setting and patient’s circumstances. pharmacotherapy, defined by Etminan et al.,1 is an approach to
decision making whereby clinicians appraise the scientific evidence
 EBM strategies can be applied to help in keeping current. and its strength in support of their therapeutic decisions.
 EBM is realistic. Although few would argue against the necessity for basing clinical
decisions on the best possible evidence available, considerable contro-
versy actually surrounds the practice of EBM. Critics note that not all
questions relevant to the care of a patient are of a scientific nature and
In the information age, clinicians are presented with a daunting that EBM favors a “cookbook” approach. In fact, EBM integrates
number of diseases and possible treatments to consider as they care knowledge from research with other factors affecting clinical decision
for patients each day. As knowledge increases and as the technology making. EBM does not replace clinical judgment. Rather, it informs
for accessing information becomes widely available, healthcare clinical judgment with the current best evidence. The expertise and
professionals are expected to stay current in their fields of expertise experience of the clinician who understands the disease are crucial in
and to remain competent throughout their careers. In addition, the determining whether the external evidence applies to the patient and
number of information sources for the typical practitioner has whether it should be integrated in the therapeutic plan. Also, nonmed-
ballooned, and clinicians must sort out information from many ical factors affect decision making, such as the patient’s preferences
sources: college courses and continuing education (including semi- and readiness and the healthcare delivery system’s characteristics.
nars and journals), pharmaceutical representatives, and colleagues, Other critics state that EBM considers randomized controlled trials
as well as guidelines from committees of healthcare facilities, gov- (RCTs) as the only evidence to be used in clinical decision making.
ernmental agencies, and expert committees and organizations. Actually, EBM seeks the best existing evidence, from basic science to
 How does the healthcare professional find valid information clinical research, with which to inform clinical decision. For example,
from such a cacophony? Increasingly, clinicians are turning to the a decision about the accuracy of a diagnostic test is best informed by
principles of evidence-based medicine (EBM) to identify the best evidence from a cross-sectional study, not a RCT. A cohort study, not
course of action for each patient. EBM strategies help healthcare a RCT, best answers a question about prognosis. However, in select-
professionals to ferret out these gold nuggets, enabling them to ing a treatment, the RCT is the best study design to provide the most
integrate the best current evidence into their pharmacotherapeutic accurate estimate of treatment efficacy and safety.

The complete chapter,

learning objectives, and other
resources can be found at
www.pharmacotherapyonline.com.

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C HAP T E R

4 Documentation of
Pharmacy Services

GEORGE E. MACKINNON III AND NEIL J. MACKINNON

actions, the importance of documenting pharmacists’ professional

KEY CONCEPTS activities related to patient care will become paramount in the years
to come. Processes to document the clinical activities and therapeu-
 Documentation of pharmacists’ interventions, their actions, tic interventions of pharmacists have been described extensively in
and the impact on patient outcomes is central to the process the pharmacy literature, yet universal adoption of documentation
of pharmaceutical care. throughout pharmacy practice remains inconsistent, incomplete,
 Unless pharmacists in all practice settings document their ac- and misunderstood.
tivities and communicate with other health professionals, they  Documentation is central to the provision of patient-centered
may not be considered an essential and integral part of the care/pharmaceutical care.1 Pharmaceutical care is provided through
healthcare team. a “system” in which feedback loops are established for monitoring
purposes. This has advantages compared with the traditional medi-
 Manual systems of documentation for pharmacists have been cation-use process because the system enhances communication
described in detail, but increasingly electronic systems are among members of the healthcare team and the patient. Pharma-
used to facilitate integration with other clinicians, payer records, ceutical care requires responsibility by the provider to identify drug/
and healthcare systems. medication-related problems (DRPs), provide a therapeutic moni-
 Integrated electronic information systems can facilitate provi- toring plan, and ensure that patients receive the most appropriate
sion of seamless care as patients move among ambulatory, medicines and ultimately achieve their desired level of health-
acute, and long-term care settings. related quality of life (HRQOL).
To provide pharmaceutical care, the pharmacist, patient, and
 Medication reconciliation, a process of ensuring documenta- other providers enter a covenantal relationship that is considered to
tion of the patient’s correct medication profile, has become a be mutually beneficial to all parties. The patient grants the pharma-
central part of patient safety activities in recent years. cist the opportunity to provide care, and the pharmacist, in turn,
 Systems of pharmacy documentation are becoming increas- must accept this and the responsibility it entails. Documentation
ingly important models in the United States as the Medicare enables the pharmaceutical care model of pharmacy practice to be
Part D Prescription Drug Plan and accompanying Medication maximized and communicated to vested parties. Communication
Therapy Management Services are implemented and revised. among sites of patient care must be accurate and timely to facilitate
pharmaceutical care. As discussed by Hepler and Stand,1 documen-
 Electronic medical records and prescribing systems have sev- tation supports care that is coordinated, efficient, and cooperative.
eral advantages over manual systems that will facilitate access Conversely, failure to document activities and patient outcomes
by community pharmacists and their participation as fully par- can directly affect patients’ quality of care. There are several reasons
ticipating and acknowledged members of the healthcare team. for failure to document in the medication-use system, and they are
related to the process of documentation, the specific data collected
on a consistent basis, how documentation is shared (e.g., other
As the opportunities to become more patient-focused increase and pharmacists, healthcare providers, patients, insurers), and methods
market pressures exert increased accountability for pharmacists’ by which the data are shared.

The contributions of Denise Sprague to the content of this chapter are

acknowledged.

The complete chapter,

learning objectives, and other
resources can be found at
www.pharmacotherapyonline.com.

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C HAP T E R

5 Clinical Pharmacokinetics
and Pharmacodynamics

LARRY A. BAUER

Factors to be taken into consideration when deciding on the
KEY CONCEPTS best drug dose for a patient include age, gender, weight, ethnic
background, other concurrent disease states, and other drug
 Clinical pharmacokinetics is the discipline that describes the therapy.
absorption, distribution, metabolism, and elimination of drugs
in patients requiring drug therapy.  Cytochrome P450 is a generic name for the group of enzymes
that are responsible for most drug metabolism oxidation reac-
 Clearance is the most important pharmacokinetic parameter tions. Several P450 isozymes have been identified, including
because it determines the steady-state concentration for a giv- CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
en dosage rate. Physiologically, clearance is determined by
blood flow to the organ that metabolizes or eliminates the drug  The importance of transport proteins in drug bioavailability and
and the efficiency of the organ in extracting the drug from the elimination is now better understood. The principal transport
bloodstream. protein involved in the movement of drugs across biologic mem-
branes is P-glycoprotein. P-glycoprotein is present in many or-
 The volume of distribution is a proportionality constant that re- gans, including the gastrointestinal tract, liver, and kidney.
lates the amount of drug in the body to the serum concentra-
tion. The volume of distribution is used to calculate the loading When deciding on initial doses for drugs that are renally elimi-
dose of a drug that will immediately achieve a desired steady- nated, the patient’s renal function should be assessed. A com-
state concentration. The value of the volume of distribution is mon, useful way to do this is to measure the patient’s serum
determined by the physiologic volume of blood and tissues creatinine concentration and convert this value into an estimat-
and how the drug binds in blood and tissues. ed creatinine clearance (CLcr est). For drugs that are eliminated
primarily by the kidney (≥60% of the administered dose),
 Half-life is the time required for serum concentrations to de- some agents will need minor dosage adjustments for CLcr est
crease by one-half after absorption and distribution are com- between 30 and 60 mL/min, moderate dosage adjustments
plete. Half-life is important because it determines the time for CLcr est between 15 and 30 mL/min, and major dosage ad-
required to reach steady state and the dosage interval. Half-life justments for CLcr est less than 15 mL/min. Supplemental dos-
is a dependent kinetic variable because its value depends on es of some medications also may be needed for patients
the values of clearance and volume of distribution. receiving hemodialysis if the drug is removed by the artificial
 The fraction of drug absorbed into the systemic circulation after kidney or for patients receiving hemoperfusion if the drug is re-
extravascular administration is defined as its bioavailability. moved by the hemofilter.

 Most drugs follow linear pharmacokinetics, whereby steady-  When deciding on initial doses for drugs that are hepatically
state serum drug concentrations change proportionally with eliminated, the patient’s liver function should be assessed. The
long-term daily dosing. Child-Pugh score can be used as an indicator of a patient’s abil-
ity to metabolize drugs that are eliminated by the liver. In the
 Some drugs do not follow the rules of linear pharmacokinetics. absence of specific pharmacokinetic dosing guidelines for a
Instead of steady-state drug concentration changing propor- medication, a Child-Pugh score equal to 8 or 9 is grounds for
tionally with dose, serum concentration changes more or less a moderate decrease (~25%) in initial daily drug dose for
than expected. These drugs follow nonlinear pharmacokinetics. agents that are metabolized primarily hepatically (≥60%), and
Pharmacokinetic models are useful to describe data sets, to a score of 10 or greater indicates that a significant decrease in
predict serum concentrations after several doses or different initial daily dose (~50%) is required for drugs that are metab-
routes of administration, and to calculate pharmacokinetic con- olized mostly hepatically.
stants such as clearance, volume of distribution, and half-life.  For drugs that exhibit linear pharmacokinetics, steady-state
The simplest case uses a single compartment to represent the drug concentration (Css) changes proportionally with dose (D).
entire body. To adjust a patient’s drug therapy, a reasonable starting dose is
administered for an estimated three to five half-lives. A serum
concentration is obtained, assuming that it will reflect Css. Inde-
Learning objectives, review questions, pendent of the route of administration, the new dose (Dnew)
and other resources can be found at needed to attain the desired Css (Css,new) is calculated: Dnew =
www.pharmacotherapyonline.com. Dold(Css,new/Css,old), where Dold and Css,old are the old dose and
old Css, respectively.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 10
 If it is necessary to determine the pharmacokinetic constants TABLE 5-2 Pharmacokinetic Abbreviations
for a patient to individualize the patient’s dose, a small pharma-
SECTION 1

Abbreviation Definition
cokinetic evaluation is conducted in the individual. Additionally,
Bayesian computer programs that aid in the individualization of CL Clearance
therapy are available for many different drugs. k0 Intravenous infusion rate
CSS Steady-state concentration
 Pharmacodynamics is the study of the relationship between D Dose
the concentration of a drug and the response obtained in a pa- τ Dosage interval
tient. If pharmacologic effect is plotted versus concentration for F Fraction of drug absorbed into the systemic circulation
most drugs, a hyperbola results with an asymptote equal to Q Blood flow
maximum attainable effect. E Extraction ratio
Foundation Issues

fb Fraction of drug in the blood that is unbound

CLint Intrinsic clearance
Css, u Steady-state concentration of unbound drug
Pharmacokinetic concepts have been used successfully by pharma- VD Volume of distribution
cists to individualize patient drug therapy for about a quarter of a LD Loading dose
century. Pharmacokinetic consultant services and individual clini- MD Maintenance dose
cians routinely provide patient-specific drug-dosing recommenda- t1/2 Half-life
tions that increase the efficacy and decrease the toxicity of many k Elimination rate constant
medications. Laboratories routinely measure patient serum or ka Absorption rate constant
plasma samples for many drugs, including antibiotics (e.g., ami- α Distribution rate constant
noglycosides and vancomycin), theophylline, antiepileptics (e.g., β Terminal rate constant
phenytoin, carbamazepine, valproic acid, phenobarbital, and etho- t′ Postinfusion time
suximide), methotrexate, lithium, antiarrhythmics (e.g., lidocaine, T Duration of infusion
AUC Area under serum- or blood-concentration-versus-time curve
procainamide, quinidine, and digoxin), and immunosuppressants
Vmax Maximum rate of drug metabolism
(e.g., cyclosporine and tacrolimus). Combined with a knowledge of Km Serum concentration at which the rate of metabolism equals Vmax /2
the disease states and conditions that influence the disposition of a Cmax Maximum serum or blood concentration
particular drug, kinetic concepts can be used to modify doses to Cmin Minimum serum or blood concentration
produce serum drug concentrations that result in desirable pharma- DR Dosage rate
cologic effects without unwanted side effects. This narrow range of P-gp P-glycoprotein
concentrations within which the pharmacologic response is pro-
duced and adverse effects prevented in most patients is defined as
the therapeutic range of the drug. Table 5–1 lists the therapeutic Throughout this chapter, abbreviations for various pharmacoki-
ranges for commonly used medications. netic parameters are used frequently. Table 5–2 lists commonly
Although most individuals experience favorable effects with used abbreviations.
serum drug concentrations in the therapeutic range, the effects of a
given serum concentration can vary widely among individuals.
Clinicians should never assume that a serum concentration within CLINICAL PHARMACOKINETIC CONCEPTS
the therapeutic range will be safe and effective for every patient. The
response to the drug, such as number of seizures a patient experi-  Clinical pharmacokinetics is the discipline that describes the
ences while taking an antiepileptic agent, always should be assessed absorption, distribution, metabolism, and elimination of drugs in
when serum concentrations are measured. patients requiring drug therapy. When a drug is administered
extravascularly to patients, it must be absorbed across biologic
membranes to reach the systemic circulation. If the drug is given
Selected Therapeutic Ranges orally, the drug molecules must pass through the gastrointestinal
TABLE 5-1
tract wall into capillaries. For transdermal patches, the drug must
Drug Therapeutic Range penetrate the skin to enter the vascular system. In general, the
Digoxin 0.5–2 ng/mL pharmacologic effect of the drug is delayed when it is given
Lidocaine 1.5–5 mcg/mL extravascularly because time is required for the drug to be absorbed
Procainamide/N-acetylprocainamide 10–30 mcg/mL (total) into the vascular system.
Quinidine 2–5 mcg/mL The vascular system generally provides the “transportation” for
Amikacina 20–30 mcg/mL (peak) the drug molecule to its site of activity. After the drug reaches the
<5 mcg/mL (trough) systemic circulation, it can leave the vasculature and penetrate the
Gentamicin, tobramycin, netilmicina 5–10 mcg/mL (peak) various tissues or remain in the blood. If the drug remains in the
<2 mcg/mL (trough)
blood, it may bind to endogenous proteins such as albumin or α1-
Vancomycin 20–40 mcg/mL (peak)
5–10 mcg/mL (trough)
acid glycoprotein. This binding usually is reversible, and an equilib-
Chloramphenicol 10–20 mcg/mL rium is created between protein-bound drug and unbound drug.
Lithium 0.6–1.4 mEq/L Unbound drug in the blood provides the driving force for distribu-
Carbamazepine 4–12 mcg/mL tion of the agent to body tissues. If unbound drug leaves the
Ethosuximide 40–100 mcg/mL bloodstream and distributes to tissue, it may become tissue-bound,
Phenobarbital 15–40 mcg/mL it may remain unbound in the tissue, or if the tissue can metabolize
Phenytoin 10–20 mcg/mL or eliminate the drug, it may be rendered inactive and/or eliminated
Primidone 5–12 mcg/mL from the body. If the drug becomes tissue-bound, it may bind to the
Valproic acid 50–100 mcg/mL receptor that causes its pharmacologic or toxic effect or to a
Theophylline 10–20 mcg/mL nonspecific binding site that causes no effect. Again, tissue binding
Cyclosporine 150–400 ng/mL (blood)
is usually reversible so that the tissue-bound drug is in equilibrium
a
Using a multiple-dose-per-day dosage schedule. with unbound drug in the tissue.
 11
Certain organs—such as the liver, gastrointestinal tract wall, and (absorption). The fraction of drug absorbed into the systemic
lung—possess enzymes that metabolize drugs. The resulting metab- circulation (F) after extravascular administration is defined as its

CHAPTER 5
olite may be inactive or have a pharmacologic effect of its own. The bioavailability and can be calculated after single intravenous and
blood also contains esterases, which cleave ester bonds in drug extravascular doses as1
molecules and generally render them inactive. D iv ( AUC 0 – ∞ )
Drug metabolism usually occurs in the liver through one or both F = ------------------------------------
D ( AUC iv, )
of two types of reactions. Phase I reactions generally make the drug 0–∞

molecule more polar and water soluble so that it is prone to where D and Div are the extravascular and intravenous doses, respec-
elimination by the kidney. Phase I modifications include oxidation, tively, and AUCiv,0-∞ and AUC0-∞ are the intravenous and extravas-
hydrolysis, and reduction. Phase II reactions involve conjugation to cular areas under the serum- or blood-concentration-versus-time

Clinical Pharmacokinetics and Pharmacodynamics

form glucuronides, acetates, or sulfates. These reactions generally curves, respectively, from time zero to infinity. The AUC represents
inactivate the pharmacologic activity of the drug and may make it the body’s total exposure to the drug and is a function of the
more prone to elimination by the kidney. fraction of the drug dose that enters the systemic circulation via the
Other organs have the ability to eliminate drugs or metabolites administered route and clearance (Fig. 5–2). When F is less than 1
from the body. The kidney can excrete drugs by glomerular filtra- for a drug administered extravascularly, either the dosage form did
tion or by such active processes as proximal tubular secretion. not release all the drug contained in it, or some of the drug was
Drugs also can be eliminated via bile produced by the liver or air eliminated or destroyed (by stomach acid or other means) before it
expired by the lungs. reached the systemic circulation.
When the extravascular dose is administered orally, part of the
LINEAR PHARMACOKINETICS dose may be metabolized by enzymes or removed by transport
proteins contained in the gastrointestinal tract wall or liver before it
 Most drugs follow linear pharmacokinetics: Serum drug concen- reaches the systemic circulation.2,3 This occurs commonly when
trations change proportionally with long-term daily dosing. For drugs have a high liver extraction ratio or are subject to gastrointes-
example, if a drug dose were doubled from 300 to 600 mg/day, the tinal tract wall metabolism because, after oral administration, the
patient’s serum drug concentration would double. drug must pass through the gastrointestinal tract wall and into the
When a drug is given by continuous intravenous infusion, serum portal circulation of the liver. Transport proteins are also present in
concentrations increase until an equilibrium is established between the gastrointestinal tract wall that can actively pump drug molecules
the drug dosage rate and the rate of drug elimination. At that point, that already have been absorbed back into the lumen of the
the rate of drug administration equals the rate of drug elimination, gastrointestinal tract. P-glycoprotein (P-gp) is the primary trans-
and the serum concentrations remain constant (Fig. 5–1). For port protein that interferes with drug absorption by this mecha-
example, if a patient were receiving a continuous intravenous nism. For example, if an orally administered drug is 100% absorbed
infusion of theophylline at 40 mg/h, the theophylline serum con- from the gastrointestinal tract but has a hepatic extraction ratio of
centration would increase until the patient’s body was eliminating 0.75, only 25% of the original dose enters the systemic circulation.
theophylline at 40 mg/h. When serum drug concentrations reach a This first-pass effect through the liver and/or gastrointestinal tract
constant value, steady state is achieved. wall is avoided when the drug is given by other routes of adminis-
If the drug is given at intermittent dosage intervals, such as 250 tration. The computation of F does not separate loss of oral drug
mg every 6 hours, steady state is achieved when the serum-concen- metabolized by the first-pass effect and drug not absorbed by the
tration-versus-time curves for each dosage interval are superimpos- gastrointestinal tract. Special techniques are needed to determine
able. The amount of drug eliminated during the dosage interval the fraction of drug absorbed orally for drugs with high liver
equals the dose. extraction ratios or substantial gut wall metabolism.
Two different dosage forms of the same drug are considered to be
BIOAVAILABILITY AND BIOEQUIVALENCE bioequivalent when the AUC0-∞, maximum serum or blood concen-
When drugs are administered extravascularly, drug molecules must 16
be released from the dosage form (dissolution) and pass through
several biologic barriers before reaching the vascular system  14

12
Concentration (mcg/mL)

10

6
AUC
C
4

0
0 5 10 15 20 25
Time (h)

FIGURE 5-2. Area under the concentration-versus-time curve (AUC)

after the administration of an extravascular dose. The AUC is a function of
t
the fraction of drug dose that enters the systemic circulation and
FIGURE 5-1. Normal serum concentration-time curve following a contin- clearance. AUCs measured after intravenous and extravascular doses can
uous intravenous infusion. be used to determine bioavailability for the extravascular dose.
 12
trations (Cmax), and the times that Cmax occurs (tmax) are neither Clearance changes will occur when blood flow to the clearing
clinically nor statistically different. When this occurs, the serum- organ changes (in conditions where blood flow is reduced, e.g.,
SECTION 1

concentration-versus-time curves for the two dosage forms should shock, congestive heart failure, or where blood flow is increased, e.g.,
be superimposable and identical. Bioequivalence studies have administration of medications such as vasodilators, resolution of
become very important as expensive drugs become available in less shock or congestive heart failure), binding in the blood changes (e.g.,
costly generic form. Most bioequivalence studies involve 18 to 25 if the concentration of binding proteins is low or highly protein-
healthy adults who are given the brand-name product and the bound drugs are displaced), or intrinsic clearance of unbound drug
generic product in a randomized, crossover study design. changes (e.g., when metabolizing enzymes are induced or inhibited
by other drug therapy or functional organ tissue is destroyed by
CLEARANCE disease processes).
Foundation Issues

If CLint is large (enzymes have a high capacity to metabolize the

 Clearance (CL) is the most important pharmacokinetic parame- drug), the product of fb and CLint is much larger than Q. When
ter because it determines the steady-state concentration for a given fb(CLint) is much greater than Q, the sum of Q and fb(CLint) in the
dosage rate. When a drug is given at a continuous intravenous denominator of the clearance equation almost equals fb(CLint):
infusion rate equal to k0, the steady-state concentration (Css) is
determined by the quotient of k0 and CL (Css = k0/CL). If the drug f b ( CL int ) ≈ Q + f b ( CL int )
is administered as individual doses (D) at a given dosage interval
(τ), the average steady-state concentration (Css) over the dosage Substituting this expression in the denominator of the clearance
interval is given by the equation4 equation and canceling common terms leads to the following
F(D ⁄ τ) expression for drugs with a large CLint: CL ≈ Q. In this case,
C ss = ------------------- clearance of the drug is equal to blood flow to the organ; such drugs
CL
are called high-clearance drugs and have large extraction ratios.
where F is the fraction of dose absorbed into the systemic vascular Propranolol, verapamil, morphine, and lidocaine are examples of
system. The average steady-state concentration over the dosage high-clearance drugs. High-clearance drugs such as these typically
interval is the steady-state concentration that would have occurred exhibit high first-pass effects when administered orally.
had the same dose been given as a continuous intravenous infusion If CLint is small (enzymes have a limited capacity to metabolize the
(e.g., 300 mg every 6 hours would produce an average Css equivalent drug), Q is much larger than the product of fb and CLint. When Q is
to the actual Css produced by a continuous infusion administered at much greater than fb(CLint), the sum of Q and fb(CLint) in the
a rate of 50 mg/h). denominator of the clearance equation becomes almost equal to Q: Q
Physiologically, clearance is determined by (a) blood flow (Q) to ≈ Q + fb(CLint). Substituting this expression in the denominator of the
the organ that metabolizes (liver) or eliminates (kidney) the drug clearance equation and canceling common terms leads to the follow-
and (b) the efficiency of the organ in extracting the drug from the ing expression for drugs with a small CLint: CL ≈ fb(CLint). In this case,
bloodstream.5 Efficiency is measured using an extraction ratio (E), clearance of the drug is equal to the product of the fraction unbound
calculated by subtracting the concentration in the blood leaving the in the blood and the intrinsic ability of the organ to clear unbound
extracting organ (Cout) from the concentration in the blood entering drug from the blood; such drugs are known as low-clearance drugs and
the organ (Cin) and then dividing the result by Cin: have small extraction ratios. Warfarin, theophylline, diazepam, and
C in – C out phenobarbital are examples of low-clearance drugs.
E = ------------------------ As mentioned previously, the concentration of unbound drug in
C in
the blood is probably more important pharmacologically than the
Clearance for that organ is calculated by taking the product of Q and total (bound plus unbound) concentration. The unbound drug in
E (CL = QE). For example, if liver blood flow equals 1.5 L/min and the blood is in equilibrium with the unbound drug in the tissues and
the drug’s extraction ratio is 0.33, hepatic clearance equals 0.5 L/min. reflects the concentration of drug at its site of action. Therefore, the
Total clearance is computed by summing all the individual organ pharmacologic effect of a drug is thought to be a function of the
clearance values. Clearance changes occur in patients when the blood concentration of unbound drug in the blood. The unbound steady-
flow to extracting organs changes or when the extraction ratio state concentration (Css,u) can be calculated by multiplying Css and fb:
changes. Vasodilators such as hydralazine or nifedipine increase liver Css,u = Cssfb. The effect that changes in Q, fb, and CLint have on Css,u
blood flow, whereas congestive heart failure and hypotension can and therefore on the pharmacologic response of a drug depends on
decrease hepatic blood flow. Extraction ratios can increase when whether a high- or low-clearance drug is involved. Because CL = Q
enzyme inducers increase the amount of drug-metabolizing enzyme. for high-clearance drugs, a change in fb or CLint does not change CL
Extraction ratios may decrease if enzyme inhibitors inhibit drug- or Css (Css = k0/CL). However, a change in unbound drug fraction
metabolizing enzymes or necrosis causes loss of parenchyma. does alter Css,u (Css,u = fbCss), thereby affecting the pharmacologic
response. Plasma-protein-binding displacement drug interactions
INTRINSIC CLEARANCE can be very important clinically, but they are also dangerous because
the changes in Css,u are not reflected in changes in Css for high-
The extraction ratio also can be thought of in terms of the unbound clearance drugs. Because laboratories usually measure only total
fraction of drug in the blood (fb), the intrinsic ability of the concentrations (concentrations of unbound drug are difficult to
extracting organ to clear unbound drug from the blood (CLint), and determine), the interaction is hard to detect. If CLint changes for high-
blood flow to the organ (Q)6,7: clearance drugs, CL, Css, Css,u, and pharmacologic response do not
f b ( CL int ) change. Changes in Q cause a change in CL; changes in Css, Css,u, and
E = -------------------------------- drug response are indirectly proportional to changes in CL.
Q + f b ( CL int )
For low-clearance drugs, total clearance is determined by
By substituting this equation for E, the clearance equation becomes unbound drug fraction and intrinsic clearance: CL = fb(CLint). A
change in Q does not change CL, Css, Css,u, or pharmacologic
Q [ f b( CL int )]
CL = -------------------------------- response. However, a change in fb or CLint does alter CL and Css (Css
Q + f b ( CL int ) = k0/CL). Changes in CLint will cause a proportional change in CL.
 13
Changes in Css, Css,u, and drug response are indirectly proportional metabolite eliminated in the urine is then determined. The fraction
to changes in CL. Altering fb for low-clearance drugs produces of the dose (in moles, because the molecular weights of the parent

CHAPTER 5
interesting results. A change in fb alters CL and Css (Css = k0/CL). drug and metabolites are not equal) eliminated by each metabolic
Because CL and Css change in opposite directions with changes in fb, pathway (fM1 = M1R/D and fM2 = M2R/D) can then be computed.
Css,u (Css,u = fbCss) and pharmacologic response do not change with Formation clearance for each pathway can be calculated using the
alterations in the fraction of unbound drug in the blood. For following equations: CLFM1 = fM1CLM and CLFM2 = fM2CLM, where
example, a low-clearance drug is administered to a patient until CLM is the metabolic clearance for the parent drug.
steady-state is achieved:
CL = f b ( CL int ) VOLUME OF DISTRIBUTION
k0  The volume of distribution (VD) is a proportionality constant

Clinical Pharmacokinetics and Pharmacodynamics

C ss = ------- that relates the amount of drug in the body to the serum concentra-
CL
tion (amount in body = CVD). VD is used to calculate the loading
Suppose that another drug is administered to the patient that
dose (LD) of a drug that will immediately achieve a desired Css (LD
displaces the first drug from plasma-protein-binding sites and
= CssVD). However, in practice, the patient’s own VD is not known
doubles fb (fb now equals 2fb). CL doubles because of the protein-
at the time the loading dose is administered. In this case, an average
binding displacement [2CL = 2fb(CLint)], and Css decreases by one-
VD is assumed and used to calculate a loading dose. Because the
half because of the change in clearance [1/2 (Css) = k0/(2Cl)]. Css,u does
patient’s VD is almost always different from the average VD for the
not change because even though fb is doubled, Css decreased by one-
drug, a loading dose does not attain the calculated Css, but it
half (Css,u= fbCss). The potential for error in this situation is that
hopefully achieves a therapeutic concentration. As usual, steady-
clinicians may increase the dose of a low-clearance drug after a
state conditions are achieved in three to five half-lives for the drug.
protein-binding displacement interaction because Css decreased.
The numeric value for the volume of distribution is determined
Because Css,u and the pharmacologic effect do not change, the dose
by the physiologic volume of blood and tissues and how the drug
should remain unaltered. Plasma protein binding decreases occur
binds in blood and tissues8:
commonly in patients taking phenytoin. Low albumin concentra-
tions (as in trauma or pregnant patients), high concentrations of V D = V b + ( f b ⁄ f t )V t
endogenous plasma protein-binding displacers (as with high con-
centrations of bilirubin), or plasma protein-binding drug interac- where Vb and Vt are the volumes of blood and tissues, respectively,
tions (as with concomitant therapy with valproic acid) can result in and fb and ft are the fractions of unbound drug in blood and tissues,
subtherapeutic total phenytoin concentrations. Despite this fact, respectively.
unbound phenytoin concentrations usually are within the therapeu-
tic range, and often the patient is responding appropriately to HALF-LIFE
treatment. Thus, in these situations, unbound rather than total
phenytoin serum concentrations should be monitored and used to  Half-life (t1/2) is the time required for serum concentrations to
guide future therapeutic decisions. decrease by one-half after absorption and distribution are complete.
It takes the same amount of time for serum concentrations to drop
CLEARANCES FOR DIFFERENT ROUTES OF from 200 to 100 mg/L as it does for concentrations to decline from
ELIMINATION AND METABOLIC PATHWAYS 2 to 1 mg/L (Fig. 5–3).
Half-life is important because it determines the time required to
Clearances for individual organs can be computed if the excretion reach steady state and the dosage interval. It takes approximately
the organ produces can be obtained. For example, renal clearance three to five half-lives to reach steady-state concentrations during
can be calculated if urine is collected during a pharmacokinetic continuous dosing. In three half-lives, serum concentrations are at
experiment. The patient empties his or her bladder immediately approximately 90% of their ultimate steady-state values. Because
before the dose is given. Subsequent urine production is collected most serum drug assays have approximately a 10% error, it is
until the last serum concentration (Clast) is obtained. Renal clear- difficult to differentiate concentrations that are within 10% of each
ance (CLR) is computed by dividing the amount of drug excreted in
the urine by AUC0–t,last. Biliary and other clearance values are
computed in a similar fashion.
Clearances also can be calculated for each metabolite that is
C0
formed from the parent drug. This computation is particularly
useful in drug-interaction studies to determine which metabolic
pathway is stimulated or inhibited. In the following metabolic
12
scheme, the parent drug (D) is metabolized into two different
Slope = −k
metabolites (M1, M2) that subsequently are eliminated by the kidney
log C

2.303
(M1R, M2R):

CLFM1 kidney
D M1 M1
6
CLFM2 t1/2

M2 kidney M2R

t
To compute the formation clearance of M1 and M2 (CLFM1, CLFM2),
urine would be collected for five or more half-lives after a single FIGURE 5-3. Calculation of the half-life of a drug following intravenous
dose or during a dosage interval at steady state. The amount of bolus dosing.
 14
other. For this reason, many clinicians consider concentrations Nonlinear Protein Binding
obtained after three half-lives to be Css.
Another type of nonlinear kinetics can occur if Css and AUC
SECTION 1

Half-life is also used to determine the dosage interval for a drug.

increase less than expected after an increase in dose of a low-
For instance, it may be desirable to maintain maximum steady-state
clearance drug. This usually indicates that plasma protein-binding
concentrations at 20 mg/L and minimum steady-state concentra-
sites are starting to become saturated so that fb increases with
tions at 10 mg/L. In this case, it would be necessary to administer
increases in dose (see Fig. 5–4). For a low-clearance drug, CL
the drug every half-life because the minimum desirable concentra-
depends on the values of fb and CLint (CL = fbCLint). When a dosage
tion is one-half the maximum desirable concentration.
increase takes place, fb increases because nearly all plasma-protein-
Half-life is a dependent kinetic variable because its value depends
binding sites are occupied and no binding sites are available. If fb
on the values of CL and VD.8 The equation that describes the
increases, CL increases and Css increases less than expected with the
Foundation Issues

relationship among the three variables is t1/2 = 0.693VD/CL. Changes

dosage change (Css = k0/CL). However, Css,u increases proportion-
in t1/2 can result from a change in either VD or CL; a change in t1/2
ally with dose because Css,u depends on CLint for low-clearance drugs
does not necessarily indicate that CL has changed. Half-life can
(Css,u = k0/CLint). Valproic acid9 and disopyramide10 both follow
change solely because of changes in VD. The elimination rate
saturable protein-binding pharmacokinetics.
constant (k) is related to the half-life by the following equation: k =
0.693/t1/2. Both the half-life and elimination rate constant describe
how quickly serum concentrations decrease in the serum or blood. PHARMACOKINETIC MODELS
AND EQUATIONS
NONLINEAR PHARMACOKINETICS Pharmacokinetic models are useful to describe data sets, to
predict serum concentrations after several doses or different routes
Michaelis-Menten Kinetics
of administration, and to calculate pharmacokinetic constants such
 Some drugs do not follow the rules of linear pharmacokinetics. as CL, VD, and t1/2.11 Compartmental models depict the body as one
Instead of Css and AUC increasing proportionally with dose, serum or more discrete compartments to which drug is distributed and/or
concentrations change more or less than expected (Fig. 5–4). One from which drug is eliminated. The shape of the serum-concentra-
explanation for the greater-than-expected increase in Css and AUC tion-versus-time curve determines the number of compartments in
after an increase in dose is that the enzymes responsible for the the pharmacokinetic model and the equation used in computations
metabolism or elimination of the drug may start to become satu- (Fig. 5–5). First-order rate constants, known as microconstants,
rated. When this occurs, the maximum rate of metabolism (Vmax) describe the rate of transfer from one compartment to another.
for the drug is approached. This is called Michaelis-Menten kinetics. Each compartment also has its own VD. For clinical dosage adjust-
The serum concentration at which the rate of metabolism equals ment purposes using drug concentrations, a one-compartment
Vmax/2 is Km. Practically speaking, Km is the serum concentration at model is the most commonly used pharmacokinetic model.
which nonproportional changes in Css and AUC start to occur when
dose is increased. The Michaelis-Menten constants (Vmax and Km) One-Compartment Model
determine the dosage rate (DR) needed to maintain a given Css: DR
= VmaxCss/(Km + Css). Most drugs eliminated by the liver are The simplest case uses a single compartment to represent the entire
body (see Fig. 5–5). Drug enters the compartment by continuous
metabolized by enzymes but still appear to follow linear kinetics.
intravenous infusion (k0), absorption from an extravascular site with
The reason for this disparity is that the therapeutic range for most
drugs is well below the Km of the enzyme system that metabolizes an absorption rate constant of ka, or intravenous bolus (D). After an
intravenous bolus, serum concentrations decline in a straight line
the agent. The therapeutic range is higher than Km for some com-
when plotted on semilogarithmic coordinates (see Fig. 5–3). The slope
monly used drugs. The average Km for phenytoin is about 4 mg/L.
of the line is –k/2.303; t1/2 can be computed by determining the time
The therapeutic range for phenytoin is usually 10 to 20 mg/L.
Most patients experience Michaelis-Menten kinetics while taking required for concentrations to decrease by one-half (t1/2 = 0.693/k).
phenytoin. The equation that describes the data is C = (D/VD)e–kt. VD is calculated
by dividing the intravenous dose by the y intercept (the concentration
at time zero, C0) of the graph. CL is computed by taking the product
of k and VD. Once VD and k are known, concentrations at any time
after the dose can be computed [C = (D/VD)e–kt].
Linear
When an extravascular dose is given, one-compartment-model
Michaelis-Menten serum concentrations rise during absorption, reach Cmax, and then

1 compartment

ko,ka, or k
Css or AUC

1
IV bolus

Nonlinear protein binding

2 compartments
k12
ko,ka, or
1 2
IV bolus
k21
Dose k10
FIGURE 5-4. Relationship of dose and steady-state drug concentration
(Css) or area under the concentration-versus-time curve (AUC) under FIGURE 5-5. Visual representations of one- and two-compartment drug-
linear and nonlinear conditions. distribution models.
 15

CHAPTER 5
A DC infusion
log Css
residual −ka
Slope =
2.303

log C
t
10
log C

−k −k
Slope = Slope =
2.303 2.303

Clinical Pharmacokinetics and Pharmacodynamics

5
t
t 1/2 3–5 t 1/2

FIGURE 5-7. Achievement of steady-state serum concentrations after

three to five half-lives of a drug. Note the elimination phase after
t
discontinuance of the infusion.
FIGURE 5-6. Calculation of the half-life of a drug following oral, intra-
muscular, or other extravascular dosing route. only metabolizes and eliminates drug but also distributes drug to one
or more other compartments. Of these multicompartment models,
decrease in a straight line with a slope equal to –k/2.303. The the two-compartment model is encountered most commonly (see
equation that describes the data is C = {(FDka)/[VD(ka – k)]}(e–kt – Fig. 5–5). After an intravenous bolus injection, serum concentrations
e–kat), where F is the fraction of the dose absorbed into the systemic decrease in two distinct phases described by the equation:
circulation. The absorption rate constant (ka) is obtained using the
method of residuals. D ( α – k 21 ) –α t D ( k 21 – β ) –β t
C = ---------------------------- e + ---------------------------- e
The method of residuals is used to obtain the individual rate VD ( α – β ) VD ( α – β )
1 1
constants (Fig. 5–6). A is determined by extrapolating the terminal
slope to the y axis; ka can be obtained by calculating the slope or t1/2 or C = Ae–αt + Be–βt, where k21 is the first-order rate constant that
and using the formulas given for the intravenous bolus case. At each reflects the transfer of drug from compartment 2 to compartment 1,
time point in the absorption portion of the curve, the concentration VD1 is the VD of compartment 1, A = D(α – k21)/[VD1(α – β)] and B
value from the extrapolated line is noted and called the extrapolated = D(k21 – β)/[VD1(α – β)]. The rate constants α and β found in the
concentration. For each point, the actual concentration is subtracted exponents of the equations describe the distribution and elimina-
from the extrapolated concentration to compute the residual con- tion of the drug, respectively (Fig. 5–8). A and B are the y intercepts
centration. When the residual concentrations are plotted on semi- of the lines that describe drug distribution and elimination, respec-
logarithmic coordinates, a line with y intercept equal to A and slope tively, on the log concentration-versus-time plot.
equal to –ka/2.303 is obtained. When these values are calculated, The residual line is calculated as before using the method of
they can be placed into the equation (C = Ae–kt – Ae–kat, where A = residuals. The terminal line is extrapolated to the y axis, and
FDka/[VD(ka – k)]) and used to compute the serum concentration at extrapolated concentrations are determined for each time point.
any time after the extravascular dose. The intercepts and rate Because actual concentrations are greater in this case, residual
constants also can be used to compute CL and VD: CL = FD/(A/k – concentrations are calculated by subtracting the extrapolated con-
A/ka) and VD = CL/k, where F is the fraction of the dose absorbed centrations from the actual concentrations. When plotted on semi-
into the systemic circulation. logarithmic paper, the residual line has a y intercept equal to A. The
During a continuous intravenous infusion, the serum concentra- slope of the residual line is used to compute α (slope = –α/2.303).
tions in a one-compartment model change according to the follow- With the rate constants (α and β) and the intercepts (A and B),
ing function: C = (k0/CL)(1 – e–kt). If the infusion has been running concentrations can be calculated for any time after the intravenous
for more than three to five half-lives, the patient will be at steady
state, and CL can be calculated (CL = k0/Css). When the infusion is
discontinued, serum concentrations appear to decline in a straight A −α
5 Slope =
line when plotted on semilogarithmic paper with a slope of –k/ 2.303
log
2.303. VD is computed by dividing CL by k (Fig. 5–7). residual 2.5
t1/2α
Multicompartment Model
t
After an intravenous bolus dose, serum concentrations often decline
in two or more phases. During the early phases, drug leaves the
log C

bloodstream by two mechanisms: (a) distribution into tissues and B 20 −β

Slope =
(b) metabolism and/or elimination. Because the drug is leaving the 2.303
bloodstream through these two mechanisms, serum concentrations 10
decline rapidly. After tissues and blood are in equilibrium, only
metabolism and/or elimination remove drug from the blood. Dur- t1/2β
ing this terminal phase, serum concentrations decline more slowly.
The half-life is measured during the terminal phase by determining
the time required for concentrations to decline by one-half.
t
After an intravenous bolus dose, serum concentrations decrease as
if the drug were being injected into a central compartment that not FIGURE 5-8. Calculation of α and β half-lives following intravenous dosing.
 16
drug distribution changes during pharmacokinetic or drug-interac-
R
Slope = −α
tion experiments.
SECTION 1

7 2.303
log
residual
Multiple Dosing and Steady-State Equations
3.5
3.5
Any of these compartmental equations can be used to determine
t1/2α
serum concentrations after multiple doses. The multiple-dosing
t factor (1 – e–nKτ)/(1 – e–Kτ), where n is the number of doses, K is the
appropriate rate constant, and τ is the dosage interval, is simply
log C

−β multiplied by each exponential term in the equation, substituting

Slope =
2.303
the rate constant of each exponent for K. Time (t) is set at 0 at the
Foundation Issues

6 beginning of each dosage interval. For example, a single-dose two-

S
3 compartment intravenous bolus is calculated as follows: C = Ae–αt +
Be–βt. Thus the equation for a multiple-dose two-compartment
t1/2β
intravenous bolus is
– n ατ – n βτ
–α t 1 –e –β t 1 – e
C = Ae – ατ
- + Be ---------------------
--------------------- – βτ
-
t 1–e 1–e
DC infusion
A single-dose one-compartment intravenous bolus is calculated
FIGURE 5-9. Calculation of α and β half-lives following a steady-state as C = (D/VD)e–kt. For a multiple-dose one-compartment intrave-
infusion.
nous bolus, the concentration is C = (D/VD)e–kt[(1 – e nkτ)/(1 – e–kτ)].
At steady state, the number of doses becomes large, e–nKτ
approaches zero, and the multiple-dosing factor equals 1/(1 – e–Kτ).
bolus dose (C = Ae–αt + Be–βt), or pharmacokinetic constants can be Therefore, the steady-state versions of the equations are simpler
computed: CL = D/[(A/α) + (B/β)], VD,β = CL/β, VD,ss = {D[(A/α 2) than their multiple-dose counterparts:
+ (B/β 2)]}/[(A/α) + (B/β)]2. –α t –β t
If serum concentrations of a drug given as a continuous intravenous Ae Be
C = ------------------
– ατ
- + ------------------
– βτ
-
infusion decline in a biphasic manner after the infusion is discontin- 1–e 1–e
ued, a two-compartment model describes the data set (Fig. 5–9).12,13
and
In this instance, the postinfusion concentrations decrease according –k t
( D ⁄ V D )e
to the equation C = Re–α t' + Se –β t', where t' is the postinfusion time C = -----------------------------
–k τ
(t' = 0 when infusion is discontinued) and R, S, α, and β are 1–e
determined from the postinfusion concentrations using the method of
for a steady-state two-compartment intravenous bolus and a steady-
residuals with the y axis set at t' = 0. R and S are used to compute A
state one-compartment intravenous bolus, respectively.
and B. A and B are the y intercepts that would have occurred had the
total dose given during the infusion (D = k0T) been administered as an
intravenous bolus dose. USE OF PHARMACOKINETIC CONCEPTS FOR
RD α INDIVIDUALIZATION OF DRUG THERAPY
A = -----------------------------
–α T
-
k0 ( 1 – e )
Many factors must be taken into consideration when deciding on
the best drug dose for a patient. For example, the age of the patient
SD β
B = -----------------------------
–β T
- is important because the dose (in milligrams per kilogram) for
k0 ( 1 – e ) pediatric patients may be higher and for geriatric patients may be
lower than the typically prescribed dose for young adults. Gender
where T is the duration of infusion. Once A, B, α, and β are known,
also can be a factor because males and females metabolize and
the equations for an intravenous bolus are used to compute the
eliminate some drugs differently. Patients who are significantly obese
pharmacokinetic constants. Often, when a drug is given as an intrave-
or cachectic also may require different drug doses because of clear-
nous bolus or continuous intravenous infusion, a two-compartment
ance and volume of distribution changes. Other drug therapy that
model is used to describe the data, but when the same agent is given
could cause drug interactions needs to be considered. Disease states
extravascularly, a one-compartment model applies.14 In this case,
and conditions may alter the drug-dosage regimen for a patient.
distribution occurs during the absorption phase, so a distribution
Three disease states that deserve special mention are congestive heart
phase is not observed.
failure, renal disease, and hepatic disease. Renal and hepatic diseases
cause loss of organ function and decreased drug elimination and
Volumes of Distribution in metabolism. Congestive heart failure causes decreased blood flow to
Multicompartment Models organs that clear the drug from the body.
Two different VD values are needed as proportionality constants for Many drug compounds are racemic mixtures of stereoisomers. In
drugs that require multicompartment models to describe the serum- most cases, one of the isomers is more pharmacologically active
concentration-versus-time curve. The VD that is used to compute the than the other isomer, and each isomer may exhibit different
amount of drug in the body during the terminal (β) portion of the pharmacokinetic properties. Warfarin, propranolol, verapamil, and
curve is called VD,β (amount of drug in body = VD,β C). During a ibuprofen are all racemic mixtures of stereoisomers. Some drug
continuous intravenous infusion at steady state, VD,ss is used to interactions inhibit or increase the elimination of only one stereo-
compute the amount of drug in the body (amount of drug in body = isomer. The importance of the drug interaction depends on which
VD,ssC). VD,ss is also the VD that can be computed using the physio- isomer is affected. Other drugs, such as dextromethorphan, levo-
logic volumes of blood and tissues and the ratio of unbound drug in floxacin, and diltiazem, are composed of just one stereoisomer.
blood to that in tissues [VD,ss = Vb + (fb/ft)Vt]. Because the value of  Genetics also plays a role in drug metabolism. Cytochrome P450
VD,β changes when CL changes, VD,ss should be used to indicate if is a generic term for the group of enzymes that are responsible for
 17
most drug metabolism oxidation reactions. Several cytochrome P450 lation. Approximately 7% of the white population are poor metabo-
(CYP) isozymes have been identified that are responsible for the lizers for CYP2C9 substrates.

CHAPTER 5
metabolism of many important drugs (Table 5–3). CYP2C19 is Other cytochrome P450 isozymes have been isolated.15 CYP1A2 is
responsible for aromatic hydroxylation of (S)-mephenytoin, and the enzyme that is responsible for the demethylation of caffeine and
CYP2D6 oxidizes debrisoquine.15 These subsets of the cytochrome theophylline; CYP2C9 metabolizes phenytoin, tolbutamide, losartan,
P450 enzyme family are also responsible for the metabolism of and ibuprofen; some antiretroviral protease inhibitors, cyclosporine,
several other drugs (CYP2D6: many tricyclic antidepressants, nifedipine, lovastatin, simvastatin, and atorvastatin are metabolized
codeine, (S)-metoprolol; CYP2C19: most proton pump inhibitors, by CYP3A4; and ethanol is a substrate for CYP2E1. It is important to
sertraline, voriconazole). CYP2C9, CYP2C19, and CYP2D6 isozymes recognize that a drug may be metabolized by more than one cyto-
appear to be under genetic control. As a consequence, there are chrome P450 isozyme. Although most tricyclic antidepressants are

Clinical Pharmacokinetics and Pharmacodynamics

“poor metabolizers” who have a defective mutant gene for the hydroxylated by CYP2D6, N-demethylation probably is mediated by
isozyme, cannot manufacture a fully functional isozyme, and there- a combination of CYP2C19, CYP1A2, and CYP3A4. Acetaminophen
fore cannot metabolize the drug substrate very well. “Extensive appears to be metabolized by both CYP1A2 and CYP2E1. The 4-
metabolizers” have the standard gene for the isozyme and metabolize hydroxy metabolite of propranolol is produced by CYP2D6, but side-
the drugs normally. Poor metabolizers usually are a minority of the chain oxidation of propranolol is probably a product of CYP2C19.
general population. They may achieve toxic concentrations of drug The CYP3A enzyme family comprises approximately 90% of the
when usual doses are prescribed for them or, if the active drug drug-metabolizing enzyme present in the intestinal wall but only
moiety is a metabolite, may fail to have any pharmacologic effect approximately 30% of the drug-metabolizing enzyme found in the
from the drug. The ethnic background of the patient can affect the liver. The remainder of hepatic drug-metabolizing enzyme is approx-
likelihood that the patient will be a poor metabolizer.15 For example, imately 20% for the CYP2C family, approximately 13% for CYP1A2,
the incidence of poor metabolizers for CYP2D6 is approximately 5% approximately 7% for CYP2E1, and approximately 2% for CYP2D6.
to 10% for whites and approximately 0% to 1% for Asians, whereas Understanding which cytochrome P450 isozyme is responsible
for CYP2C19, poor metabolizers make up approximately 3% to 6% for the metabolism of a drug is extraordinarily useful in predicting
of the white population and approximately 20% of the Asian popu- and understanding drug interactions. Some drug-metabolism
inhibitors and inducers are highly selective for certain cytochrome
TABLE 5-3 Cytochrome P450 (CYP) Enzyme Family and P450 isozymes.15 Quinidine is an extremely potent inhibitor of the
Selected Substrates CYP2D6 enzyme system15; a single 50-mg dose of quinidine can
change a rapid metabolizer of debrisoquine into a poor metabolizer.
CYP1A2 CYP2E1 Ciprofloxacin and zileuton inhibit, whereas tobacco or marijuana
Acetaminophen Enflurane
smoke induce, CYP1A2. Some drugs that are enzyme inhibitors are
Caffeine Ethanol
also substrates for that same enzyme system and appear to cause
Ondansetron Halothane
Tacrine Isoflurane drug interactions by being a competitive inhibitor. For example,
Theophylline CYP3A4 erythromycin is both a substrate for and an inhibitor of CYP3A4.
R-Warfarin Alfentanil Obviously, if one knows that a new drug is metabolized by a given
Zileuton Alprazolam cytochrome P450 enzyme system, it is logical to assume that the new
CYP2C9 Astemizole drug will exhibit drug interactions with the known inducers and
Candesartan Carbamazepine inhibitors of that cytochrome P450 isozyme.
Diclofenac Cyclosporine  The importance of transport proteins in drug bioavailability
Ibuprofen Diltiazem and elimination is now better understood. A principal transport
Losartan Erythromycin protein involved in the movement of drugs across biologic mem-
Naproxen Felodipine
branes is P-gp. P-gp is present in many organs, including the
Phenytoin Itraconazole
gastrointestinal tract, liver, and kidney. If a drug is a substrate for P-
Tolbutamide Ketoconazole
Valsartan Lidocaine
gp, its oral absorption may be decreased when P-gp transports drug
S-Warfarin Lovastatin molecules that have been absorbed back into the gastrointestinal
CYP2C19 Midazolam tract lumen. In the liver, some drugs are transported by P-gp from
Diazepam Nifedipine the blood into the bile, where the drug is eliminated by biliary
Lansoprazole Quinidine secretion. Similarly, some drugs eliminated by the kidney are trans-
(S)-Mephenytoin Simvastatin ported from the blood into the urine by P-gp. Digoxin is a substrate
Nelfinavir Tacrolimus of P-gp. Other possible mechanisms for drug interactions are when
Omeprazole Verapamil two drugs that are substrates for P-gp compete for transport by the
Pantoprazole Ziprasidone protein and when a drug is an inhibitor or inducer of P-gp. Drug
Voriconazole
interactions involving inhibition of P-gp decrease drug transporta-
CYP2D6
tion in these organs and potentially can increase gastrointestinal
Carvedilol
Codeine
absorption of orally administered drug, decrease biliary secretion of
Debrisoquine the drug, or decrease renal elimination of drug molecules. The drug
Dextromethorphan interaction between amiodarone and digoxin probably involves all
Encainide three of these mechanisms, and this explains why digoxin concentra-
Fluoxetine tions increase so dramatically in patients receiving amiodarone.
Haloperidol Many drugs that are metabolized by CYP3A4 are also substrates for
(S)-Metoprolol P-gp, and some of the drug interactions attributed to inhibition of
Paroxetine CYP3A4 may be a result of decreased drug transportation by P-gp.
Propafenone Drug interactions involving induction of P-gp have the opposite
Risperidone effect in these organs and may decrease gastrointestinal absorption of
Thioridazine
orally administered drug, increase biliary secretion of the drug, or
Venlafaxine
increase renal elimination of drug molecules.
 18

SELECTION OF INITIAL DRUG DOSES chronic hepatitis often retain relatively normal or slightly decreased
hepatic drug-metabolism capacity. In the absence of specific phar-
SECTION 1

When deciding on initial doses for drugs that are eliminated macokinetic dosing guidelines for a medication, a Child-Pugh score
renally, the patient’s renal function should be assessed. A common, equal to 8 to 9 is grounds for a moderate decrease (approximately
useful way to do this is to measure the patient’s serum creatinine 25%) in initial daily drug dose for agents that are metabolized
concentration and convert this value into an CLcr est. Serum creati- primarily (≥60%) hepatically, and a score of 10 or greater indicates
nine values alone should not be used to assess renal function that a significant decrease in initial daily dose (approximately 50%)
because they do not include the effects of age, body weight, or is required for drugs that are metabolized mostly by the liver. As in
gender. The Cockcroft-Gault equation16 is probably the most widely any patient with or without liver dysfunction, initial doses are meant
used method to estimate creatinine clearance (in milliliters per as starting points for dosage titration based on patient response and
Foundation Issues

minute) in adults (age 18 years or older) who are within approxi- avoidance of adverse effects.
mately 30% of their ideal body weight and have stable renal Because there are no good markers of liver function, clinicians
function: have come to rely on pharmacokinetic parameters derived in
various patient populations to compute initial doses of drugs that
( 140 – age )BW
Male: CL cr est = -------------------------------------- are eliminated hepatically. Table 5–4 contains average pharmacoki-
S cr × 72
netic parameters for theophylline in several disease states. Initial
0.85 ( 140 – age )BW doses of many liver-metabolized drugs are computed by determin-
Female: CL cr est = -------------------------------------------------
S cr × 72 ing which disease states and/or conditions the patient has that are
known to alter the kinetics of the drug and by using these average
where BW is body weight (in kilograms), age is the patient’s age (in
pharmacokinetic constants to calculate doses. The patient is then
years), 0.85 is a correction factor to account for lower muscle mass
monitored for therapeutic and adverse effects, and drug serum
in females, and Scr is serum creatinine (in milligrams per deciliter).
concentrations are obtained to ensure that concentrations are
For children, the following estimation equations are available
appropriate and to adjust doses, if necessary. The following compu-
according to the age of the child17: age 0 to 1 years: CLcr est (in mL/
tations illustrate the estimated intravenous loading dose and the
min/1.73 m2) = (0.45 × Lt)/Scr; age 1 to 20 years: CLcr est (in mL/min/
intravenous continuous infusion necessary to achieve a theophyl-
1.73 m2) = (0.55 × Lt)/Scr, where Lt is patient length in centimeters.
line concentration of 10 mg/L for a 55-year-old, 70-kg male with
Other methods to determine CLcr est for obese adults18 and patients
liver cirrhosis (mean kinetic parameters obtained from Table 5–4):
with rapidly changing renal function19 are available. Creatinine is a
by-product of muscle breakdown in the body, so none of these VD = (0.5 L/kg)(70 kg) = 35 L
estimation methods work well in patients with muscle disease, such
as multiple sclerosis, or diseases that alter muscle mass, such as LD = Css VD = (10 mg/L)(35 L)
cachexia, malnutrition, cancer, or spinal cord injury. Nomograms = 350 mg theophylline infused over 20 to 30 min
that adjust initial doses according to a patient’s renal function are
available for several drugs, including digoxin,20 vancomycin,21 and ( 0.35 mL/min/kg ) ( 70 kg ) ( 60 min/h )
the aminoglycoside antibiotics.22 CL ( in L/h ) = ------------------------------------------------------------------------------------------
1000 mL/L
For drugs that are eliminated primarily by the kidney (≥60% of
= 1.5 L/h
the administered dose), some agents will need minor dosage adjust-
ments for CLcr est between 30 and 60 mL/min, moderate dosage k0 = CssCL = (10 mg/L)(1.5 L/h)
adjustments for CLcr est between 15 and 30 mL/min, and major
dosage adjustments for CLcr est less than 15 mL/min. Specific recom- = 15 mg/h of theophylline to begin after loading dose
mendations for dosage adjustments of other drugs for patients with is given
renal disease are available.23,24 Supplemental doses of some medica- If theophylline is to be given as the aminophylline salt form, each
tions also may be needed for patients receiving hemodialysis if the dose would need to be changed to reflect the fact that aminophylline
drug is removed by the artificial kidney or for patients receiving contains only 85% theophylline (LD = 350 mg of theophylline/0.85
hemoperfusion if the drug is removed by the hemofilter.24 = 410 mg of aminophylline infused over 20 to 30 minutes, k0 = 15
 A similar assessment of liver function should be made for drugs mg/h of theophylline/0.85 = 18 mg/h of aminophylline to begin
that are metabolized hepatically. Unfortunately, there is no single after loading dose is given).
test that can estimate liver drug-metabolism capacity accurately, and Heart failure is often overlooked as a disease state that can alter
those that are used do not always prove accurate. High aminotrans- drug disposition. Severe heart failure decreases cardiac output and
ferase (aspartate aminotransferase [AST] and alanine aminotransfer- therefore reduces liver blood flow. Theophylline,26 lidocaine,27 and
ase [ALT]) and alkaline phosphatase concentrations usually indicate
acute hepatic cellular damage and do not establish poor liver drug
metabolism reliably. Abnormal values for three tests that usually TABLE 5-4 Theophylline Pharmacokinetic Parameters for
indicate that drugs will be metabolized poorly by the liver are high Selected Disease States/Conditions
serum bilirubin concentration, low serum albumin concentration, Mean Clearance Mean Dose
and a prolonged prothrombin time. Bilirubin is metabolized by the Disease State/Condition (mL/min/kg) (mg/kg/h)
liver, and albumin and clotting factors are manufactured by the liver, Children age 1–9 y 1.4 0.8
so aberrant values for all three of these tests are a more reliable Children age 9–12 y or adult smokers 1.25 0.7
indicator of abnormal liver drug metabolism. The Child-Pugh Adolescents age 12–16 y or elderly smok- 0.9 0.5
score,25 a widely used clinical classification for liver disease that ers (>65 y)
incorporates clinical signs and symptoms (ascites and hepatic Adult nonsmokers 0.7 0.4
encephalopathy) in addition to these three laboratory tests, can be Elderly nonsmokers (age >65 y) 0.5 0.3
used as an indicator of a patient’s ability to metabolize drugs that are Decompensated congestive heart failure, 0.35 0.2
eliminated by the liver. A score in excess of 10 suggests very poor cor pulmonale, cirrhosis
liver function. As a general rule, patients with cirrhosis have the most Mean volume of distribution = 0.5 L/kg.
severe decreases in liver drug metabolism. Patients with acute or Adapted from reference 49.
 19
drugs with high extraction ratios are compounds whose clearance 10
Cmax,ss
declines with decreased liver blood flow. Initial dosages of these

CHAPTER 5
drugs should be reduced in patients with moderate to severe heart t1/2

Concentration (μg/mL)
failure (New York Heart Association class III or IV) by 25% to 50%
until steady-state concentrations and response can be determined.

USE OF STEADY-STATE
1
Cmin,ss
∗
Cmin,ss (extrapolated)
DRUG CONCENTRATIONS
Serum drug concentrations are readily available to clinicians to use

Clinical Pharmacokinetics and Pharmacodynamics

as guides for the individualization of drug therapy. The therapeutic 0.1
ranges for several drugs have been identified, and it is likely that new 0 1 2 3 4 5 6 7 8 9 10
drugs also will be monitored using serum concentrations. Although Time (h)
several individualization methods have been advocated for specific FIGURE 5-10. When a patient has received enough doses to be at
 drugs, one simple, reliable method is used commonly. For drugs steady state, steady-state maximum (Cmax,ss) and minimum (Cmin,ss)
that exhibit linear pharmacokinetics, Css changes proportionally concentrations can be used to compute clearance, volume of distribution,
with dose. To adjust a patient’s drug therapy, a reasonable starting and half-life. At steady state, consecutive Cmin,ss values are equal, so the
dose is administered for an estimated three to five half-lives. A predose value can be extrapolated to the time before the next dose and
serum concentration is obtained, assuming that it will reflect Css. be used to calculate half-life (dashed line).
Independent of the route of administration, the new dose (Dnew)
needed to attain the desired Css (Css,new) is calculated: Dnew = centration. Under steady-state conditions, serum concentrations
Dold(Css,new/Css,old), where Dold and Css,old are the old dose and old Css, after each dose are identical, so the predose minimum concentra-
respectively. To use this method, Css,old must reflect steady-state tion is the same before each dose (Fig. 5–10). This situation allows
conditions. Often patients are noncompliant with regard to their the predose concentration to be used to compute both the patient’s
drug dosage and therefore are not at steady state. This occurs not t1/2 and V. If the drug was given extravascularly or has a significant
only in outpatients but also in hospital inpatients. Inpatients can distribution phase, the postdose concentration should be deter-
spit out oral doses or alter the infusion rates on intravenous pump mined after absorption or distribution is finished. To ensure that
rates after the nurse leaves the hospital room. Doses also can be steady-state conditions have been achieved, the patient needs to
missed if the patient is absent from his or her room at the time receive the drug on schedule for at least three to five estimated half-
medications are to be administered. If Css,old is much larger or lives. To make sure that this is the case, inpatients should have their
smaller than expected for the Dold the patient is taking, one should medication administration records checked, and the patient’s nurse
suspect noncompliance and repeat the serum concentration deter- should be consulted regarding missed or late doses. Outpatients
mination after another three to five half-lives or change the patient’s should be interviewed about compliance with the prescribed dosage
dose cautiously and monitor for signs of toxicity or lack of effect. regimen. When compliance with the dosage regimen has been
verified, steady-state conditions reasonably can be assumed.
MEASUREMENT OF PHARMACOKINETIC If the patient is not at steady state, an additional postdose serum
concentration determination should be done to compute the
PARAMETERS IN PATIENTS patient’s pharmacokinetic parameters. Ideally, the third concentra-
 If it is necessary to determine the kinetic constants for a patient tion (C3) should be acquired approximately one estimated half-life
to individualize his or her dose, a small kinetic evaluation is after the postdose maximum concentration. Determining serum
conducted in the individual. In these cases, the number of serum concentrations too close together will hamper the drug assay’s
concentrations obtained from the patient is held to the minimum ability to measure differences between them, and getting the third
needed to calculate accurate pharmacokinetic parameters and sample too late could result in a concentration too low for the assay
doses. The reason for using fewer serum drug concentration deter- to detect. In this situation, the predose minimum and postdose
minations is to be as cost-effective as possible because these labora- maximum concentrations are used to compute V, and both post-
tory tests generally cost $20 to $50 each. dose concentrations are used to calculate t1/2 (Fig. 5–11).
Although many drugs follow two-compartment-model pharma-
cokinetics (especially after intravenous administration), a one- 10
Cmax
compartment model is used to compute kinetic parameters in
patients because too many serum concentration determinations t1/2
Concentration (μg/mL)

would be needed to determine accurately both the distribution and

elimination phases found in the two-compartment model. Because
of this, serum concentrations usually are not measured in patients C3
1
during the distribution phase. Another important reason serum Cmin
concentrations are not measured during the distribution phase for
therapeutic drug-monitoring purposes in patients is that drug in the
blood and drug in the tissues are not in equilibrium during this time
so that serum concentrations do not reflect tissue concentrations. 0.1
When drug serum concentrations are obtained in patients for the 0 1 2 3 4 5 6 7 8 9 10
purpose of assessing efficacy or toxicity, it is important that they be Time (h)
measured in the postdistribution phase when drug in the blood is in FIGURE 5-11. If a patient has not received enough doses to be at steady
equilibrium with drug at the site of action. state, or doses have been given on an irregular schedule, the minimum
In the case where the patient has received enough doses to be at concentration (Cmin), maximum concentration (Cmax), and an additional
steady state, pharmacokinetic parameters can be computed using a postdose concentration (C3) can be used to compute clearance, volume
predose minimum concentration and a postdose maximum con- of distribution, and half-life.
 20
After CL, V, and t1/2 have been computed for a patient, the dose Appropriate Cmax,ss and Cmin,ss values are selected for the patient
and dosage interval necessary to achieve desired steady-state serum based on the site and severity of the infection and the sensitivity of
SECTION 1

concentrations can be calculated using one-compartment-model the known or suspected pathogen, as well as avoidance of adverse
equations. Specific examples of these methods to calculate initial effects. For example, Cmax,ss values of 8 to 10 mg/L generally are
doses and individualized doses using serum concentrations are selected for gram-negative pneumonia patients, whereas Cmin,ss
discussed later in this chapter for the aminoglycoside antibiotics, values of less than 2 mg/L usually are chosen to avoid aminoglyco-
vancomycin, digoxin, theophylline, phenytoin, and cyclosporine. side-induced nephrotoxicity when tobramycin and gentamicin are
prescribed using conventional multiple-daily-dosing regimens.
COMPUTER PROGRAMS Once appropriate steady-state serum concentrations are selected,
the dosage interval required to achieve those concentrations is
Computer programs that aid in the individualization of therapy are calculated, and τ is rounded to a clinically acceptable value (e.g., 8,
Foundation Issues

available for many different drugs. The most sophisticated pro- 12, 18, 24, 36, or 48 hours): τ = [(ln Cmax,ss – ln Cmin,ss)/k] + T.
grams use nonlinear regression to fit CL and VD to actual serum Finally, a dose is computed for the patient using the one-compart-
concentrations obtained in a patient.28 After drug doses and serum ment-model intermittent intravenous infusion equation at steady
concentrations are entered into the computer, nonlinear least- state, and the dose is rounded off to the nearest 5 to 10 mg:
squares regression programs adjust CL and VD until the sum of the –k τ
1–e
squared error between actual (Cact) and computer-estimated con- D = TkV D C max, ss ------------------
– kT
-
centrations (Cest) is at a minimum [∑ (Cest – Cact)2]. Once estimates 1–e
of CL and VD are available, doses are calculated easily. The Hull and Sarrubi aminoglycoside dosage nomogram (Table
Many programs also take into account what the CL and VD should 5–5) is based on this dosage-calculation method and includes precal-
be on the basis of disease states and conditions present in the culated doses and dosage intervals for a variety of creatinine clearance
patient.29 Incorporation of expected population-based parameters
allows the computer to use a limited number of serum concentra-
tions (one or two) to provide estimates of CL and VD. This type of TABLE 5-5 Aminoglycoside Dosage Chart
computer program is called Bayesian because it incorporates por- 1. Compute patient’s creatinine clearance (CLcr ) using Cockcroft-Gault method: CLcr
tions of Bayes’ theorem during the fitting routine.30 Bayesian phar- = [(140 – age)BW ]/(Scr × 72). Multiply by 0.85 for females.
macokinetic dosing programs are used widely to adjust the dose of a 2. Use patient’s weight if within 30% of IBW; otherwise use adjusted dosing weight
variety of drugs. In the case of renally eliminated drugs (e.g., = IBW + [0.40(TBW – IBW )].
aminoglycosides, vancomycin, and digoxin), population estimates 3. Select loading dose in mg/kg to provide peak serum concentrations in range
for kinetic parameters are generated by entering the patient’s age, listed below for the desired aminoglycoside antibiotic:
weight, height, gender, and serum creatinine concentration into the Expected Peak Serum
computer program. For hepatically eliminated drugs (e.g., theophyl- Aminoglycoside Usual Loading Doses Concentrations
line and phenytoin), population estimates for kinetic parameters are Tobramycin 1.5 to 2.0 mg/kg 4 to 10 mcg/mL
computed using the patient’s age, weight, and gender, as well as other Gentamicin
factors that might change hepatic clearance, such as the presence or Netilmicin
absence of disease states (e.g., cirrhosis or congestive heart failure) or Amikacin 5.0 to 7.5 mg/kg 15 to 30 mcg/mL
other drug therapy that might cause a drug interaction. The Bayesian Kanamycin
estimates of the pharmacokinetic parameters are then modified 4. Select maintenance dose (as percentage of loading dose) to continue peak serum
using nonlinear least-squares regression fits of serum concentrations concentrations indicated above according to desired dosage interval and the
to result in individualized parameters for the patient. The individu- patient’s creatinine clearance. To maintain usual peak to trough ratio, use dosage
alized parameters are used to compute doses for the patient that will intervals in unshaded areas below.
result in desired steady-state concentrations of the drug. Percentage of Loading Dose Required for Dosage Interval Selected
Estimated
Aminoglycosides CLcr (mL/min) Half-Life (h) 8 h (%) 12 h (%) 24 h (%)
Although aminoglycoside pharmacokinetics follow multicompart- >90 2–3 90 — —
90 3.1 84 — —
ment models,31 a one-compartment model appears sufficient to
80 3.4 80 91 —
individualize doses in patients.32 Aminoglycosides usually are given
70 3.9 76 88 —
as short-term intermittent intravenous infusions and administered 60 4.5 71 84 —
as a single daily dose or multiple doses per day. Initial doses for 50 5.3 65 79 —
aminoglycosides can be computed using estimated kinetic parame- 40 6.5 57 72 92
ters derived from population pharmacokinetic data. The elimination 30 8.4 48 63 86
rate constant is estimated using the patient’s creatinine clearance in 25 9.9 43 57 81
the following formula: k (in h–1) = 0.00293(CLcr) + 0.014, where CLcr 20 11.9 37 50 75
is the measured or estimated creatinine clearance in milliliters per 17 13.6 33 46 70
minute. The volume of distribution is estimated using the average 15 15.1 31 42 67
population value for normal-weight (within 30% of ideal weight) 12 17.9 27 37 61
individuals equal to 0.26 L/kg [V = 0.26(Wt), where Wt is the 10a 20.4 24 34 56
7a 25.9 19 28 47
patient’s weight] or for obese individuals (over 30% of ideal
5a 31.5 16 23 41
weight)33 by taking into account the patient’s excess adipose tissue: V 2a 46.8 11 16 30
= 0.26[IBW + 0.4(TBW – IBW)], where TBW is total body weight, 0a 69.3 8 11 21
IBW is ideal body weight [IBWmales (in kilograms) = 50 + 2.3(Ht –
60) or IBWfemales (in kilograms) = 45 + 2.3(Ht – 60), and Ht is the BW, body weight; CLcr, creatine clearance; IBW, ideal body weight; Scr, serum creatinine; TBW, total
body weight.
patient’s height in inches]. Additional volume of distribution popu- a
Note: Dosing for patients with CLcr ≤10 mL/min should be assisted by measuring serum
lation estimates are available for other disease states and conditions concentrations.
such as cystic fibrosis,34 ascites,35 and neonates.36 Adapted from reference 22.
 21
22
values. The nomogram assumes that VD = 0.26 L/kg and should not Assuming a one-compartment model, the following equation is
be used to compute doses for disease states with altered VD. used to compute VD32:

CHAPTER 5
For extended-interval therapy, Cmax,ss values of 20 to 30 mg/L and – kT
(D ⁄ T)(1 – e )
Cmin,ss values less than 1 mg/L generally are accepted as appropriate V D = -----------------------------------------------
– kT
-
for gram-negative pneumonia patients. A minimum 24-hour dos- k ( C max – C min e )
age interval is chosen for this dosing technique, and the dosing
interval is increased in 12- to 24-hour increments for patients with where D is dose and T is duration of infusion. Once these are
renal dysfunction. known, the dose and dosage interval (τ) can be calculated for any
An example of this initial dosage scheme for a typical case is desired maximum Css (Cmax,ss) and minimum Css (Cmin,ss):
provided to illustrate the use of the various equations. Mr. JJ is a 65-
lnC max,ss – lnC min,ss

Clinical Pharmacokinetics and Pharmacodynamics

year-old, 80-kg, 6-ft-tall man with the diagnosis of gram-negative τ = ------------------------------------------------- + T
pneumonia. His serum creatinine concentration is 2.1 mg/dL and is k
stable. Compute a conventional gentamicin dosage regimen (infused –k τ
1–e
over 1 hour) that would provide approximate peak and trough D = TkV D C max,ss ------------------
– kT
-
concentrations of Cmax,ss = 8 mg/L and Cmin,ss = 1.5 mg/L, respectively. 1–e
The patient is within 30% of his ideal body weight [IBWmale = 50 + The dose and dosage interval should be rounded to provide
2.3(72 in – 60) = 78 kg] and has stable renal function, so the clinically accepted values (every 8, 12, 18, 24, 36, and 48 hours for
Cockcroft-Gault creatinine clearance estimation equation can be dosage interval, nearest 5 to 10 mg for conventional dosing or every
used: CLcr est = [(140 – 65 y)80 kg]/[72(2.1 mg/dL)] = 40 mL/min. The 24, 36, and 48 hours for dosage interval, nearest 10 to 25 mg for
patient’s weight and estimated creatinine clearance are used to com- extended interval dosing). This method also has been used to
pute his V and k, respectively: V = 0.26 L/kg(80 kg) = 20.8 L; k = individualize intravenous theophylline dosage regimens.37
0.00293(40 mL/min) + 0.014 = 0.131 h–1 or t1/2 = 0.693/0.131 h–1) = To provide an example of this technique, the problem given
5.3 h. The dosage interval and dose for the desired serum concentra- previously will be extended to include steady-state concentrations.
tions would then be calculated: τ = [(ln 8 mg/L – ln 1.5 mg/L)/0.131 h–1] Mr. JJ was prescribed gentamicin 140 mg every 12 hours (infused
+ 1 h = 13.7 h rounded to 12 h; D = (1 h)(0.131 h–1)(20.8 L)(8 mg/L) over 1 hour) for the treatment of gram-negative pneumonia.
[1 – e–(0.131h–1(12h)/1 – e–(0.131h–1(1h)] = 140 mg. Thus the prescribed dose Steady-state trough (Cmin,ss) and peak (Cmax,ss) values were obtained
would be gentamicin 140 mg every 12 hours administered as a 1-hour before and after the fourth dose was given (more than three to five
infusion. If a loading dose were deemed necessary, it would be given estimated half-lives), respectively, and equaled Cmin,ss = 2.8 mg/L
as the first dose [LD = (20.8 L)(8 mg/L) = 166 mg rounded to 170 mg and Cmax,ss = 8.5 mg/L. Clinically, the patient was improving with
infused over 1 hour], and the first maintenance dose would be decreased white blood cell counts and body temperatures and a
administered 12 hours (e.g., one dosage interval) later. Using the Hull resolving chest radiograph. However, the serum creatinine value
and Sarrubi nomogram for the same patient, the loading dose is 160 had increased to 2.5 mg/dL. Because of this, a new dosage regimen
mg (gentamicin loading dose for serious gram-negative infection is 2 with a similar peak (to maintain high intrapulmonary levels) but
mg/kg: 2 mg/kg × 80 kg = 160 mg), and the maintenance dose is 115 lower trough (to decrease the risk of drug-induced nephrotoxicity)
mg every 12 hours (for a 12-hour dosage interval and CLcr est = 40 mL/ concentrations was suggested. The patient’s elimination rate con-
min, maintenance dose is 72% of the loading dose: 0.72 × 160 mg = stant and half-life can be computed using the following formulas: k
115 mg). = (ln 8.5 mg/L – ln 2.8 mg/L)/(12 h – 1 h) = 0.101 h–1 and t1/2 =
0.693/0.101 h–1 = 6.9 h. The patient’s volume of distribution can be
calculated using the following equation:
CLINICAL CONTROVERSY
–1
– ( 0.101h ) ( 1h )
Some clinicians use conventional dosing or extended-interval ( 140 mg ⁄ 1 h ) 1 – e
dosing exclusively for patients requiring aminoglycosides, V = --------------------------------------------------------------------------------------------------------------------------------- = 22.3L
whereas others use a mix of both approaches according to the –1 ⎧ – (0.101h ) (1h) ⎫
–1

perceived benefit to the patient. Definitive, authoritative recom- (0.101 h )⎨ 8.5 mg ⁄ L – (2.8 mg ⁄ L)e ⎬
⎩ ⎭
mendations to guide the choice of one method of aminoglyco-
side dosing over the other are not available.
Thus the patient’s volume of distribution was larger and half-life
was longer than originally estimated, and this led to higher serum
If appropriate aminoglycoside serum concentrations are avail- concentrations than anticipated. To achieve the desired serum
able, kinetic parameters can be calculated at any point in therapy. concentrations (Cmin,ss = 1.5 mg/L and Cmax,ss = 8 mg/L), the
When the patient is not at steady state, serum aminoglycoside patient’s actual kinetic parameters are used to compute a new dose
concentrations are obtained before a dose (Cmin), after a dose and dosage interval: τ = [(ln 8 mg/L – ln 1.5 mg/L)/0.101 h–1] + 1 h
administered as an intravenous infusion of about 1 hour or as a 30- = 17.6 h, rounded to 18 h and
minute infusion followed by a 30-minute waiting period to allow for –1
drug distribution (Cmax), and at one additional postdose time (C3) ⎛ 1 – e –( 0.101h ) ( 18h )⎞
–1 ⎝ ⎠
approximately one estimated half-life after Cmax. The t1/2 and k D = ( 1 h) ( 0.101 h ) ( 22.3L ) ( 8 mg ⁄ L) ---------------------------------------------------
values are computed using Cmax and C3: k = (ln Cmax – ln C3)/Δ t and ⎛ 1 – e –( 0.101h ) ( 1h )⎞
–1

t1/2 = 0.693/k, where Δt is the time that expired between the times ⎝ ⎠
Cmax and C3 were obtained. If the patient is at steady state, serum = 157 mg, round to 160 mg
aminoglycoside concentrations are obtained before a dose (Cmin,ss)
and after a dose administered as an intravenous infusion of about 1 Thus the new dose would be gentamicin 160 mg every 18 hours and
hour or as a 30-minute infusion followed by a 30-minute waiting infused over 1 hour; the first dose of the new dosage regimen would
period to allow for drug distribution (Cmax,ss). The t1/2 and k values be given 18 hours (e.g., the new dosage interval) after the last dose
are computed using Cmax,ss and Cmin,ss: k = (ln Cmax,ss – ln Cmin,ss)/(τ of the old dosage regimen.
– T) and t1/2 = 0.693/k, where τ is the dosage interval and T is the Because aminoglycoside antibiotics exhibit concentration-depen-
dose infusion time or dose infusion time plus waiting time. dent bacterial killing and the postantibiotic effect is longer with higher
 22
concentrations, investigators studied the possibility of giving a higher
dose of aminoglycoside using an extended-dosage interval (24 hours or 14
SECTION 1

longer, depending on renal function). Generally, these studies have 13

12
shown comparable microbiologic and clinical cure rates for many

Concentration (mcg/mL)
infections and about the same rate of nephrotoxicity (approximately 11
10
5% to 10%) as with conventional dosing. Ototoxicity has not been
9
monitored using audiometry in most of these investigations, but loss of q 48 h
8
hearing in the conversational range, as well as signs and symptoms of
7
vestibular toxicity, usually has been assessed and found to be similar to q 36 h
6
that with aminoglycoside therapy dosed conventionally. Based on these
5
Foundation Issues

data, clinicians are using extended-interval dosing in selected patients. q 24 h

4
For Pseudomonas aeruginosa infections where the organism has an 3
expected minimum inhibitory concentration (MIC) ≈ 2 mg/L, peak 2
concentrations between 20 and 30 mg/L and trough concentrations of 6 7 8 9 10 11 12 13 14
less than 1 mg/L for gentamicin or tobramycin have been suggested.38 Time between start of infusion and sample draw (h)
At the present time, there is no consensus on how to approach
1. Administer 7 mg/kg gentamicin with initial dosage interval:
concentration monitoring using this mode of administration. Some
clinicians obtain steady-state peak and trough concentrations and
use the kinetic equations given earlier to adjust the dose and dosage Estimated CLcr (mL/min) Initial dosage interval
interval in order to attain appropriate target levels. Other clinicians ≥60 mL/min q 24 h
measure only trough concentrations, trusting that the large doses
administered to patients achieve adequate peak concentrations. 40–59 mL/min q 36 h
Also, a nomogram that adjusts extended-interval doses based on 20–39 mL/min q 48 h
a single postdose concentration to achieve these steady-state con-
centration goals has been proposed (Fig. 5–12). The dose is 7 mg/kg <20 mL/min Monitor serial concentrations
of gentamicin or tobramycin. The initial dosage interval is set and administer next dose when
<1 mcg/mL.
according to the patient’s creatinine clearance (see Fig. 5–12). The
Hartford nomogram includes a method to adjust doses based on
serum concentrations. This portion of the nomogram contains 2. Obtain timed serum concentration 6 to 14 hours after dose
(ideally first dose).
average serum concentration time lines for gentamicin or tobramy-
cin in patients with creatinine clearances of 60, 40, and 20 mL/min. 3. Alter dosage interval to that indicated by the nomogram
A serum concentration is measured 6 to 14 hours after the first dose zone (above q 48 h zone, monitor serial concentrations
and administer next dose when <1 mcg/mL)
is given, and this concentration/time point is plotted on the graph
(see Fig. 5–12). The modified dosage interval is indicated by which
FIGURE 5-12. Hartford nomogram for extended-interval aminoglyco-
zone the serum concentration/time point falls in. Because cystic sides. (Adapted with permission from reference 38.)
fibrosis patients have a different volume of distribution (0.35 L/kg)
than assumed by this dosing technique and extended-interval dos- peak serum concentrations are obtained after the distribution phase
ing has not been tested adequately in patients with endocarditis, the is completed (usually 30 minutes to 1 hour after a 1-hour intravenous
Hartford nomogram should not be used in these situations. infusion), a one-compartment model can be used for patient dosage
To illustrate how the nomogram is used, the same patient example calculations. Also, because vancomycin has a relatively long half-life
used previously will be repeated for this dosage approach. Mr. JJ is an compared with the infusion time, only a small amount of drug is
80-kg man with a CLcr est of 40 mL/min. Using the Hartford eliminated during infusion, and it is usually unnecessary to use more
nomogram, the patient would receive gentamicin 560 mg every 36 complex intravenous infusion equations. Thus simple intravenous
hours (7 mg/kg × 80 kg = 560 mg; the initial dosage interval for bolus equations can be used to calculate vancomycin doses for most
CLcr est = 40 mL/min is 36 hours). Ten hours after the first dose was patients. Although a recent review paper 39 questioned the clinical
given, the serum gentamicin concentration is 8.2 mg/L. According to usefulness of measuring vancomycin concentrations on a routine
the graph contained in the nomogram, the dosage interval should be basis, research articles40,41 have shown potential benefits in obtaining
changed to 48 hours. The new dose is 560 mg every 48 hours. vancomycin concentrations in selected patient populations. Some
clinicians advocate monitoring only steady-state trough concentra-
tions of vancomycin.42 The decision to conduct vancomycin concen-
CLINICAL CONTROVERSY tration monitoring should be made on a patient-by-patient basis.
“Trough only” measurement of steady-state vancomycin concen- Initial doses of vancomycin can be computed for adult patients
trations is a mainstream method to monitor therapy. The exact using estimated kinetic parameters derived from population phar-
range for this value is uncertain. Some clinicians recommend 5 to macokinetic data. Clearance is estimated using the patient’s creati-
10 mcg/mL, whereas others suggest 5 to 15 mcg/mL. For some sites nine clearance in the following equation41: CL (in mL/min/kg) =
of infection with specific organisms (such as hospital-acquired 0.695(CLcr in mL/min/kg) + 0.05. The volume of distribution is
pneumonia caused by multidrug-resistant organisms) guidelines computed assuming the standard value of 0.7 L/kg: VD = 0.7(Wt),
suggest vancomycin trough concentrations as high as 15 to 20 mcg/ where Wt is the patient’s weight. In the case of obese patients, actual
mL may be necessary. Some clinicians continue to measure both or total body weight is used in the calculation of clearance, but ideal
steady-state peak and trough vancomycin concentrations. body weight is used to compute volume of distribution.44 The
elimination rate constant is calculated using clearance and volume
of distribution estimates, correcting for possible differences in units
Vancomycin for these parameters: k = CL/VD. A nomogram that uses this type of
Vancomycin requires multicompartment models to completely approach for vancomycin therapy is available to determine initial
describe its serum-concentration-versus-time curves. However, if doses rapidly for patients (Table 5–6).45
 23

TABLE 5-6 Vancomycin Dosage Chart as the first dose, and the first maintenance dose would be adminis-
tered 48 hours (one dosage interval) later. Using the Matzke

CHAPTER 5
1. Compute patient’s creatinine clearance (CLcr) using Cockcroft-Gault method: CLcr
nomogram for the same patient, the loading dose would be 1,700
= [(140 – age)BW]/(Scr × 72). Multiply by 0.85 for females.
mg (vancomycin loading dose is 25 mg/kg: 25 mg/kg × 68 kg = 1,700
2. Use patient’s total body weight to compute doses.
3. Dosage chart designed to achieve peak serum concentrations of 30 μg/mL and
mg), followed by a maintenance dose of 1,300 mg every 48 hours
trough concentrations of 7.5 μg/mL. (for CLcr est = 30 mL/min, maintenance dose is 19 mg/kg every 2
4. Compute loading dose of 25 mg/kg. days: 19 mg/kg × 68 kg = 1,292 mg, rounded to 1,300 mg).
5. Compute maintenance dose of 19 mg/kg given at the dosage interval listed in the If appropriate vancomycin serum concentrations are available,
following chart for the patient’s CLcr: kinetic parameters can be computed at any point in therapy. When
CLcr (mL/min) Dosage Interval (Days) the patient is not at steady state, serum vancomycin concentrations

Clinical Pharmacokinetics and Pharmacodynamics

≥120 0.5 are obtained before a dose (Cmin), after a dose administered as an
100 0.6 intravenous infusion of 1 hour followed by a 30-minute to 1-hour
80 0.75 waiting period to allow for drug distribution (Cmax), and at one
60 1.0 additional postdose time (C3) approximately one estimated half-life
40 1.5 after Cmax. The t1/2 and k values are computed using Cmax and C3: k =
30 2.0 (ln Cmax – ln C3)/Δ t and t1/2 = 0.693/k, where Δt is the time that
20 2.5 expired between the times Cmax and C3 were obtained. If the patient
10 4.0 is at steady state, serum vancomycin concentrations are obtained
5 6.0
before a dose (Cmin,ss) and after a dose administered as an intrave-
0 12.0
nous infusion of about 1 hour followed by a 30-minute to 1-hour
Adapted from reference 45. waiting period to allow for drug distribution (Cmax,ss). The t1/2 and k
values are computed using Cmax,ss and Cmin,ss: k = (ln Cmax,ss – ln
Steady-state peak and trough concentrations are chosen for the Cmin,ss)/(τ – Tmax) and t1/2 = 0.693/k, where τ is the dosage interval
patient based on the site and severity of the infection, as well as the and Tmax is the dose infusion time plus waiting time.
known or suspected pathogen and avoidance of potential side Assuming a one-compartment model, the following equation is
effects. Cmax,ss values of between 20 and 40 mg/L and Cmin,ss values of used to compute VD:
between 5 and 15 mg/L typically are used for patients with moderate
D
to severe methicillin-resistant Staphylococcus aureus, Staphylococcus V D = -----------------------------
C max – C min
epidermidis, or penicillin-resistant enterococcal infections. After
appropriate steady-state concentrations are chosen, the dosage where D is dose. Once these are known, the dose and dosage interval
interval required to attain those concentrations is computed, and τ (τ) can be calculated for any desired maximum Css (Cmax,ss) and
is rounded to a clinically acceptable value (12, 18, 24, 36, 48, or 72 minimum Css (Cmin,ss):
hours): τ = (ln Cmax,ss – ln Cmin,ss)/k. Finally, the maintenance dose ln Cmax,ss – ln Cmin,ss
is computed for the patient using a one-compartment-model intra- τ = -------------------------------------------------
venous bolus equation at steady state, and the dose is rounded off to k
the nearest 100 to 250 mg: –k τ
D = C max,ss V D ( 1 – e )
–kτ
D = Cmax,ss VD (1– e )
The dose and dosage interval should be rounded to provide clini-
If desired, a loading dose can be computed using the following cally accepted values (every 12, 18, 24, 36, 48, or 72 hours for dosage
equation: interval, nearest 100 to 250 mg for dose).
To provide an example for this dosage-calculation method, the
LD = VD Cmax,ss preceding problem will be extended to include steady-state concen-
The following case will illustrate the use of this dosage methodol- trations. Ms. HJ was prescribed vancomycin 1,200 mg every 48
ogy. Ms. HJ is a 65-year-old, 68-kg, 5-ft 4-in tall patient who has hours (infused over 1 hour) for the treatment of a surgical wound
developed a surgical wound infection with S. aureus the suspected infection. Steady-state trough (Cmin,ss) and peak (Cmax,ss) values
pathogen. Her serum creatinine concentration is 1.8 mg/dL and (Cmax,ss obtained 1 hour after the end of the infusion) were obtained
stable. Compute a vancomycin dosage regimen that would provide before and after the third dose was given (more than three to five
approximate peak (obtained 1 hour after a 1-hour infusion) and estimated half-lives), respectively, and equaled Cmin,ss = 2.5 mg/L
trough concentrations of 30 and 7 mg/L, respectively. The patient is and Cmax,ss = 22.4 mg/L. Clinically, the patient had improved
within 30% of her ideal body weight [IBWfemale = 45 + 2.3(64 in – somewhat, but her white blood cell count was still elevated, and the
60) = 54 kg] and has stable renal function, so the Cockcroft-Gault patient was still febrile. Because of this, a modified dosage regimen
creatinine clearance estimation formula can be used: CLcr est = with a Cmax,ss = 30 mg/L and Cmin,ss = 7 mg/L was suggested to
0.85[(140 – 65 y)68 kg]/[72(1.8 mg/dL)] = 33 mL/min. The maintain trough concentrations three to five times above the MIC
patient’s weight and estimated creatinine clearance are used to for the suspected pathogen. The patient’s actual elimination rate
calculate her estimated CL, VD, and k, respectively: CL = 0.695 (33 constant and half-life can be calculated using the following for-
mL/min/68 kg) + 0.05 = 0.387 mL/min/kg; VD = 0.7 L/kg(68 kg) = mulas: k = (ln 22.4 mg/L – ln 2.5 mg/L)/(48 h – 2 h) = 0.048 h–1 and
48 L; and k = [(0.387 mL/min/kg)(68 kg)(60 min/h)]/[(48 L)(1,000 t1/2 = 0.693/0.048 h–1 = 14.4 h. The patient’s volume of distribution
mL/L)] = 0.033 h–1 or t1/2 = 0.693/0.033 h–1 = 21 h. The dosage can be calculated using the following equation:
interval, maintenance dose, and loading dose for the desired serum 1,200mg
concentrations then can be computed: τ = (ln 30 mg/L – ln 7 mg/ V D = --------------------------------------------------------- = 60 L
22.4 mg ⁄ L – 2.5 mg ⁄ L
L)/0.033 h–1 = 44 h, rounded to 48 h; D = (30 mg/L) (48 L)(1 –
e–(0.033h-1)(48h)) = 1,145 mg, rounded to 1,200 mg; LD = (48 L)(30 Thus the patient’s volume of distribution was larger and half-life
mg/L) = 1,440 mg, rounded to 1,450 mg. Therefore, the prescribed shorter than originally estimated, and this led to lower serum
doses would be vancomycin 1,200 mg every 48 hours administered concentrations than anticipated. To achieve the desired serum
as a 1-hour infusion. If a loading dose was used, it would be given concentrations (Cmax,ss = 30 mg/L and Cmin,ss = 7 mg/L), the
 24
patient’s actual kinetic parameters are used to calculate a new dose Digoxin
and dosage interval:
Digoxin pharmacokinetics are best described by a two-compart-
SECTION 1

ln 30 mg ⁄ L – ln 7 mg ⁄ L ment model. However, because digoxin has a long half-life com-

τ = ------------------------------------------------------------
-
0.048h –1 pared with its dosage interval and a very long distribution phase,
simple pharmacokinetic equations can be used to individualize
= 30 h, rounded to 36 h dosing when postdistribution serum concentrations are used.
–1
– ( 0.048h ) ( 36h )⎞ Digoxin can be given as an intravenous injection and orally as elixir
D = ( 30 mg ⁄ L ) ( 60L ) ⎛ 1 – e
⎝ ⎠ (F = 0.8), tablets (F = 0.7), or capsules (F = 0.9). When given orally,
the appropriate bioavailability fraction must be used to compute the
= 1,480 mg, rounded to 1,500 mg
correct dose. Initial doses of digoxin can be computed using
Foundation Issues

The new dose would be vancomycin 1,500 mg every 36 hours population pharmacokinetic data obtained from published studies.
(infused over 1 hour); the first dose of the new dosage regimen Digoxin clearance is estimated using the patient’s creatinine clear-
would be given 36 hours (the new dosage interval) after the last dose ance in the following formula20: CL (in milliliters per minute) =
of the old dosage regimen. 1.303(CLcr in milliliters per minute) + CLm, where CLm is metabolic
Many clinicians measure only steady-state vancomycin trough clearance and equals 40 mL/min for patients with no or mild heart
concentrations in patients. The justification for this approach is that failure or 20 mL/min for patients with moderate to severe heart
because vancomycin exhibits time-dependent bacterial killing, the failure. The volume of distribution decreases with declining renal
minimum concentration is the most important with regard to function and is estimated using the following equation20: VD (in
therapeutic outcome. Vancomycin pharmacokinetics also support liters) = 226 + [298(CLcr in milliliters per minute)]/(29.1 + CLcr in
this approach because the volume of distribution is relatively stable milliliters per minute). The elimination rate constant can be com-
and is not changed by many disease states or conditions. Because of puted by taking the product of CL and VD: k = CL/VD. For obese
this important point, it is difficult to attain peak steady-state concen- individuals, digoxin dosing should be based on ideal body weight.46
trations in the toxic range when the steady-state vancomycin trough Appropriate Css values are chosen for the patient based on the
is in the therapeutic range if typical doses are used (15 mg/kg or disease state being treated, the goal of therapy, and avoidance of
≈1,000 mg for average-weight individuals). Also, toxic peak concen- adverse effects. The inotropic effects of digoxin occur at lower
trations (generally greater than 80 to 100 mg/L) are quite a bit higher concentrations than do the chronotropic effects. Therefore, initial
than therapeutic peak concentrations, which adds a safety margin serum concentrations of digoxin for the treatment of heart failure
between effective concentrations and those yielding adverse drug generally are 1 ng/mL or less and for the treatment of atrial
effects. fibrillation are 1 to 1.5 ng/mL. Once the appropriate Css is selected,
Coupled with trough-only vancomycin concentration monitoring a dose is computed for the patient: D/τ = (CssCL)/F.
is a widening of the therapeutic steady-state trough concentration An example of this initial dosage scheme is provided in the
range from 5 to 15 mg/L. The justification for increasing the top of following case. Mr. PO is a 72-year-old, 83-kg, 5-ft 11-in tall man
the range from 10 to 15 mg/L comes from limited retrospective41 and admitted to the hospital for the treatment of community-acquired
prospective42 studies, and until more clinical evidence is available, pneumonia. While in the hospital, Mr. PO develops atrial fibrilla-
should be reserved for severely ill patients, infections caused by tion, and the decision is made to treat him with digoxin to provide
bacteria with higher MICs, and patients who are not responding to ventricular rate control. His serum creatinine concentration is 2.5
trough concentrations within the usual 5- to 10-mg/L range. Trough mg/dL and stable. Calculate an intravenous loading dose and oral
concentrations in the range of 15 to 20 mg/L should only be used for maintenance dose that will achieve a Css of 1.5 ng/mL. The Cock-
specific clinical situations, such as hospital-acquired pneumonia croft-Gault equation can be used to estimate the patient’s creatinine
caused by multidrug-resistant organisms.56 clearance because his serum creatinine concentration is stable and he
When trough-only monitoring of vancomycin concentrations is is within 30% of his ideal weight [IBWmale = 50 + 2.3(71 in – 60) =
chosen by a clinician, a simple variant of linear pharmacokinetics 75 kg]: CLcr = [(140 – 72 y)83 kg]/[72(2.5 mg/dL)] = 31 mL/min.
can be used to adjust the dose (D) and dosage interval (τ): (Dnew/ Using the estimated CLcr, both CL and VD can be computed:
τnew) = (Dold/τold)(Css,new/Css,old), where new and old indicate the new
target trough concentration and the old measured trough concen- CL = 1.303 ( 31 mL ⁄ min ) + 40 = 80 mL ⁄ min
tration, respectively. In practice, the dose (typically 1,000 mg) is 298 ( 31 mL ⁄ min )
held constant and only the dosage interval is changed. This equation V D = 226 + ---------------------------------------------- = 380 L
29.1 + 31 mL ⁄ min
is an approximation of the actual new steady-state trough concen-
tration that will be attained in the patient because, mathematically, The maintenance dose will be given as digoxin tablets, so F = 0.7
Css,new is an exponential function of τ. in the dosing equation: D/τ = [(1.5 mcg/L)(80 mL/min)(60 min/
An example of this approach is given in the following case. Mr. MK h)(24 h/day)]/[0.7(1,000 mL/L)] = 247 mcg/day, rounded to 250
(72 years old, 72-kg weight, 5 ft 9 in tall) was prescribed vancomycin mcg/day. The loading dose will be given intravenously as a digoxin
1,000 mg every 12 hours (infused over 1 hour) for the treatment of an injection: LD = (1.5 mcg/L)(380 L) = 570 mcg, rounded to 500 mcg.
S. epidermidis central venous catheter infection. A steady-state trough The loading dose would be given 50% now (250 mcg), 25% (125
(Cmin,ss) value was obtained before the fifth dose was given (more than mcg) in 4 to 6 hours after monitoring the patient’s heart rate and
three to five estimated half-lives), and Cmin,ss equaled 19 mg/L. blood pressure and assessing the patient for digoxin adverse effects,
Clinically, the patient was improving, but the trough concentration and the final 25% (125 mcg) 4 to 6 hours later after monitoring the
was judged to be too high. Because of this, a modified dosage regimen same clinical parameters. The first maintenance dose would be
with a Cmin,ss = 10 mg/L was suggested to maintain trough concentra- given one dosage interval (in this case 24 hours) after the first part
tions three to five times above the MIC for the suspected pathogen: of the loading dose was given.
(Dnew/τnew) = (1,000 mg/12 h)(10 mg/L/19 mg/L) = 44 mg/h. Because Adjustment of digoxin doses using steady-state concentrations is
the patient is near his ideal weight, the same dose of 1,000 mg can be accomplished using linear pharmacokinetics and dosage ratios: Dnew =
used (Dnew), and the new dosage interval (τnew) can be computed: τ = Dold(Css,new/Css,old). For example, Mr. PO’s atrial fibrillation
1,000 mg/44 mg/h = 23 h, rounded to 24 h. The new prescribed dose responded to digoxin therapy, and he was discharged after resolu-
for the patient would be 1,000 mg every 24 hours. tion of his pneumonia. A month later he was followed up in the
 25
clinic with moderate nausea, possibly a result of digoxin toxicity. 2 ( 15 mg ⁄ h )
CL = -------------------------------------------------------------
His heart rate was 51 beats per minute. A steady-state digoxin 10.9 mg ⁄ L + 12.3 mg ⁄ L

CHAPTER 5
concentration was determined and reported by the clinical labora- 2 ( 0.5 L ⁄ kg × 70 kg ) ( 10.9 mg ⁄ L – 12.3 mg ⁄ L )
tory as 2.2 mcg/L. Compute a new dose for the patient to achieve a + -------------------------------------------------------------------------------------------------------------------- = 0.59 L ⁄ h
( 10.9 mg ⁄ L + 12.3 mg ⁄ L ) ( 16 – 10 h )
Css of 1.5 mcg/L. The digoxin Css and old dose would be used to
calculate a new dose using the linear pharmacokinetic equation: k 0 = C ss CL = ( 15 mg ⁄ L ) ( 0.59 L ⁄ h ) = 9 mg ⁄ h theophylline
Dnew = 250 mcg/day[(1.5 mcg/L)/(2.2 mcg/L)] = 170 mcg/day. This
If theophylline is to be given as the aminophylline salt form, the
approximate average daily dose could be achieved by having the
doses would need to be changed to reflect the fact that aminophylline
patient alternate take two 125-mcg tablets (250 mcg) and one 125-
contains only 85% theophylline (k0 = 9 mg/h theophylline/0.85 = 11
mcg tablet daily, giving an average dose equal to 187.5 mcg/day
mg/h aminophylline).

Clinical Pharmacokinetics and Pharmacodynamics

[(250 mcg + 125 mcg)/2 = 187.5 mcg/day].
If continuous intravenous infusions or oral dosage regimens are
given long enough for steady state to occur (three to five estimated
Theophylline half-lives based on previous studies conducted in similar patients),
Theophylline disposition is described most accurately by nonlinear linear pharmacokinetics can be used to adjust doses for either route
kinetics.47,48 However, at the usual doses, theophylline acts as if it of administration: Dnew = Dold (Css,new/Css,old). For example, a patient
obeys linear kinetics in most patients. Initial theophylline doses are receiving 200 mg of sustained-release oral theophylline every 12
computed by taking a detailed medical history of the patient and hours with a theophylline steady-state serum concentration of 9.5
noting disease states and conditions that are known to change mcg/mL can have the dose required to achieve a new steady-state
theophylline disposition. Age, smoking of tobacco-containing concentration equal to 15 mcg/mL computed by applying linear
products, heart failure, and liver disease are among the important pharmacokinetics: Dnew = 200 mg[(15 mcg/mL)/(9.5 mcg/mL)] =
factors that alter theophylline kinetic parameters and dosage 316 mg, rounded to 300 mg. Thus the new theophylline dose would
requirements. Once the patient has been assessed, average theophyl- be 300 mg every 12 hours.
line kinetic parameters obtained from the literature for patients
similar to the one being currently treated are used to compute either Phenytoin
oral or intravenous doses. Dosage guidelines that take into account
Phenytoin doses are very difficult to individualize because the drug
most common disease states and conditions that change theoph-
follows Michaelis-Menten kinetics, and there is a large amount of
ylline kinetic parameters are available (see Table 5–4).49 Once
interpatient variability in Vmax and Km. Initial maintenance doses of
theophylline is administered, the patient is monitored for the
phenytoin in adults usually range between 4 and 7 mg/kg per day,
therapeutic effect and potential adverse effects. Theophylline con-
yielding starting doses of 300 to 400 mg/day in most individuals. If
centrations then are used to individualize the theophylline dose that
needed, loading doses of phenytoin or fosphenytoin (a prodrug of
the patient receives. An example of this approach was given previ-
phenytoin used intravenously) can be administered in adults at a
ously for a patient in the section on drug dosing in patients with
dose of 15 mg/kg, which is approximately 1,000 mg in many
liver disease.
individuals. Loading doses of phenytoin can be given orally but
Continuous intravenous infusions of theophylline (or its salt,
need to be administered in divided doses separated by several hours
aminophylline) can be individualized rapidly by determining the
in order to avoid decreased bioavailability and gastrointestinal
patient’s CL before steady state occurs.50 Assuming that the patient
intolerance (400 mg, 300 mg, and then 300 mg with each dose
receives theophylline only by continuous intravenous infusion (pre-
separated by 4 to 6 hours). Since phenytoin is metabolized hepati-
vious doses of sustained-release oral theophylline are completely
cally, decreased doses may be needed in patients with liver disease.
absorbed), two serum theophylline concentration determinations
Because phenytoin follows dose-dependent pharmacokinetics, the
are done 4 hours or more apart. The infusion rate (k0) cannot be
half-life of phenytoin increases for a patient as the maintenance
changed between the times the samples are drawn. With one-
dose increases. Therefore, the time to steady-state phenytoin con-
compartment model equations, the first (C1) and second (C2)
centrations increases with dose. On average, at a phenytoin dose of
theophylline concentrations are used to calculate theophylline CL:
300 mg/day, it takes approximately 5 to 7 days to achieve steady
2k 0 2V D ( C 1 – C 2 ) state; at a dose of 400 mg/day, it takes approximately 10 to 14 days
CL = ------------------- + -------------------------------------------- to achieve steady state; and at a dose of 500 mg/day, it takes
C1 + C2 ( C1 + C2 ) ( t2 – t1 )
approximately 21 to 28 days to achieve steady state. It should be
VD is assumed to be 0.5 L/kg, and t1 and t2 are the times at which C1 noted that the injectable and capsule dosage forms of phenytoin are
and C2, respectively, are obtained. Once CL is known, k0 can be phenytoin sodium, and the labeled dosage amounts contain 92% of
computed easily for any desired Css (Css = k0/CL). This method active phenytoin (300-mg phenytoin sodium capsules contain 276
probably can be applied to other drugs that are administered as mg [300 mg × 0.92 = 276 mg] of active phenytoin). Unbound
continuous intravenous infusions, such as intravenous antiarrhyth- phenytoin concentrations are useful in patients with hypoalbumin-
mics, when rapid individualization of drug dosage is desirable. emia (e.g., liver disease, nephrotic syndrome, pregnancy, cystic
An example of this approach can be obtained by continuing the fibrosis, burns, trauma, and malnourishment, as well as in the
theophylline patient case from the section on drug dosing in liver elderly), in patients in whom displacement with endogenous com-
disease. In this example, a 55-year-old, 70-kg man with liver pounds is possible (e.g., hyperbilirubinemia, liver disease, or end-
cirrhosis was prescribed a loading dose of theophylline 350 mg stage renal disease), and in patients receiving other drugs that may
intravenously over 20 to 30 minutes, followed by a maintenance displace phenytoin from plasma protein-binding sights (e.g., val-
dose of 15 mg/h of theophylline as a continuous infusion. The proic acid, aspirin therapy of more than 2 g/day, warfarin, and
infusion began at 9 AM, blood samples were obtained at 10 AM and nonsteroidal antiinflammatory drugs with high albumin binding).57
4 PM, and the clinical laboratory reported the theophylline serum After steady state has occurred, phenytoin serum concentrations
concentrations as 10.9 and 12.3 mg/L, respectively. The patient’s can be obtained as an aid to dosage adjustment. A simple, easy way
theophylline clearance and revised continuous infusion to maintain to approximate new serum concentrations after a dosage adjust-
a Css of 15 mg/L can be computed as follows (patient’s VD estimated ment with phenytoin is to temporarily assume linear pharmacoki-
at 0.5 L/kg): netics and then add 15% to 33% for a dosage increase or subtract
 26
15% to 33% for a dosage decrease to account for Michaelis-Menten initial cyclosporine doses for various situations is warranted.
kinetics. To avoid large disproportionate changes in phenytoin Indeed, most transplant centers use doses that are determined
SECTION 1

concentrations when using this empirical method, dosage adjust- employing a locally derived cyclosporine dosage protocol. The
ments should be limited to 50 to 100 mg/day. This technique is only original computations of these doses were based on the pharmaco-
intended to provide a rough approximation of the resulting pheny- kinetic dosing methods described in preceding sections and subse-
toin steady-state concentration after an appropriate dosage adjust- quently modified based on clinical experience. In general, the
ment has been made. expected cyclosporine steady-state concentration used to compute
For example, Ms. PP is a 35-year-old, 65-kg patient with grand these doses depends on the type of transplanted tissue and the
mal seizures who is receiving phenytoin capsules 300 mg orally at posttransplantation time line. Generally speaking, initial oral doses
bedtime. A steady-state concentration of 9.2 mcg/mL is measured. of 8 to 18 mg/kg per day or intravenous doses of 3 to 6 mg/kg per
Foundation Issues

It is observed that her seizure frequency decreased by only approxi- day (one-third the oral dose to account for approximately 30% oral
mately 15% and that she has had no adverse effects as a consequence bioavailability) are used and vary greatly from institution to institu-
of phenytoin treatment. Because of this, her phenytoin dose is tion. For obese individuals (more than 30% over ideal body weight),
increased to 400 mg orally at bedtime. The expected phenytoin ideal body weight should be used to compute initial doses.
steady-state concentration would be estimated using linear pharma- It is likely that doses computed using patient population character-
cokinetics [Cnew = (Dnew/Dold)Cold = (400 mg/300 mg)/(9.2 mcg/ istics will not always produce cyclosporine concentrations that are
mL) = 12.3 mcg/mL] and then increased by 15% to 33% to account expected or desirable. Additionally, there is a very high amount of
for nonlinear kinetics [Cnew = 1.15(12.3 mcg/mL) = 14.1 mcg/mL or interday variation in cyclosporine concentrations. Because of phar-
Cnew = 1.33 (12.3 mcg/mL) = 16.4 mcg/mL]. Thus the patient would macokinetic variability, the narrow therapeutic index of cyclosporine,
be expected to have a steady-state phenytoin concentration of and the severity of cyclosporine adverse side effects, measurement of
approximately 14 to 16 mcg/mL as a consequence of the dosage cyclosporine concentrations is mandatory for patients to ensure that
increase. An alternative approach would be to use a graphic Bayes- therapeutic, nontoxic levels are present. When cyclosporine concen-
ian method that allows an estimate of Vmax and Km from one steady- trations are measured in patients and a dosage change is necessary,
state phenytoin concentration and the prediction of new steady- clinicians should seek to use the simplest, most straightforward
state concentrations when doses are changed.51 method available to determine a dose that will provide safe and
Other methods used to individualize phenytoin doses involve effective treatment. In most cases, a simple dosage ratio can be used
rearrangements of the Michaelis-Menten equation [DR = VmaxCss/ to change cyclosporine doses using steady-state concentrations and
(Km + Css), in which DR is the dosage rate at steady state] so that two assuming that the drug follows linear pharmacokinetics:
or more doses and Css values can be used to obtain graphic solutions
C ss,new
for Vmax and Km. One rearrangement52 is DR = –Km(DR/Css) + Vmax. D new = D old ----------------
C
When DR is plotted on the y axis and DR/Css is plotted on the x axis ss,old
of Cartesian graph paper, a straight line with a y intercept of Vmax
For example, LK is a 50-year-old, 75-kg, 5-ft 11-in male renal
and slope equal to –Km is found (Fig. 5–13). To use this method,
transplant recipient who is receiving oral cyclosporine 400 mg every
patients are prescribed an initial phenytoin dose, and Css is
12 hours. The current steady-state blood cyclosporine concentra-
obtained. The phenytoin dose is then changed, and a second Css
tion is 375 ng/mL. To compute a cyclosporine dose that will provide
from the new dose is obtained. Each dose is divided by its respective
a steady-state concentration of 200 ng/mL, linear pharmacokinetic
Css to derive DR/Css values. The DR/Css and Css values are plotted on
equations can be used. The new dose to attain the desired concen-
the graph to calculate Vmax (y intercept) and Km (minus slope). The
tration should be proportional to the old dose that produced the
steady-state Michaelis-Menten equation can be used to compute Css
measured concentration (total daily dose = 400 mg/dose × 2 doses/
for a given DR or a DR for any Css.
day = 800 mg/day):
Cyclosporine C ss,new 200 ng ⁄ mL
D new = D old ---------------- = 800 mg ⁄ day ----------------------------
C ss,old 375 ng ⁄ mL
Because of the large amount of variability in cyclosporine pharma-
cokinetics, even when concurrent disease states and conditions are = 427 mg ⁄ day, round to 400 mg ⁄ day
identified, many clinicians believe that the use of standardized
The new suggested dose would be 400 mg/day or 200 mg every 12
hours of cyclosporine capsules to be started at the next scheduled
Vmax dosing time.

CLINICAL PHARMACODYNAMICS
Slope = −Km  Pharmacodynamics is the study of the relationship between the
concentration of a drug and the response obtained in a patient.
DR

Originally, investigators examined the dose–response relationship

of drugs in humans but found that the same dose of a drug usually
resulted in different concentrations in individuals because of phar-
macokinetic differences in clearance and volume of distribution.
Examples of quantifiable pharmacodynamic measurements include
changes in blood pressure during antihypertensive drug therapy,
decreases in heart rate during β-blocker treatment, and alterations
DR/Css
in prothrombin time or international normalized ratio during
warfarin therapy.
FIGURE 5-13. Relationship between dosage rate (DR) and steady-state For drugs that exhibit a direct and reversible effect, the following
serum concentrations (Css). diagram describes what occurs at the level of the drug receptor:
 27
Drug + receptor ↔ drug – receptor complex ↔ response When this is the case, the sigmoid Emax equation may be superior to
the Emax model:

CHAPTER 5
According to this scheme, there is a drug receptor located within n
the target organ or tissue. When a drug molecule “finds” the E max × C
E = -------------------------
n
-
n
receptor, it forms a complex that causes the pharmacologic response EC 50 + C
to occur. The drug and receptor are in dynamic equilibrium with
the drug-receptor complex. where n is an exponent that changes the shape of the concentration–
effect curve. When n >1, the concentration–effect curve is S- or
sigmoid-shaped at lower serum concentrations. When n <1, the
THE EMAX AND SIGMOID EMAX MODELS concentration–effect curve has a steeper slope at lower concentra-
The mathematical model that comes from the classic drug receptor tions (Fig. 5–15).

Clinical Pharmacokinetics and Pharmacodynamics

theory shown previously is known as the Emax model: With both the Emax and sigmoid Emax models, the largest changes
in drug effect occur at the lower end of the concentration scale.
E max × C Small changes in low serum concentrations cause large changes in
E = -----------------------
EC 50 + C effect. As serum concentrations become larger, further increases in
serum concentration result in smaller changes in effect. Using the
where E is the pharmacologic effect elicited by the drug, Emax is the Emax model as an example and setting Emax = 100 units and EC50 =
maximum effect the drug can cause, EC50 is the concentration 20 mg/L, doubling the serum concentration from 5 to 10 mg/L
causing one-half the maximum drug effect (Emax/2), and C is the increases the effect from 20 to 33 units (a 67% increase), whereas
concentration of drug at the receptor site. EC50 can be used as a doubling the serum concentration from 40 to 80 mg/L only
measure of drug potency (a lower EC50 indicating a more potent increases the effect from 67 to 80 units (a 19% increase). This is an
drug), whereas Emax reflects the intrinsic efficacy of the drug (a important concept for clinicians to remember when doses are being
higher Emax indicating greater efficacy). If pharmacologic effect is titrated in patients.
plotted versus concentration in the Emax equation, a hyperbola
results with an asymptote equal to Emax (Fig. 5–14). At a concentra- LINEAR MODELS
tion of zero, no measurable effect is present.
When dealing with human studies in which a drug is administered When serum concentrations obtained during a pharmacodynamic
to a patient and pharmacologic effect is measured, it is very difficult experiment are between 20% and 80% of Emax, the concentration–
to determine the concentration of drug at the receptor site. Because effect curve may appear to be linear (Fig. 5–16). This occurs often
of this, serum concentrations (total or unbound) usually are used as because lower drug concentrations may not be detectable with the
the concentration parameter in the Emax equation. Therefore, the analytic technique used to assay serum samples, and higher drug
values of Emax and EC50 are much different than if the drug were concentrations may be avoided to prevent toxic side effects. The
added to an isolated tissue contained in a laboratory beaker. equation used is that of a simple line: E = S × C + I, where E is the
The result is that a much more empirical approach is used to drug effect, C is the drug concentration, S is the slope of the line,
describe the relationship between concentration and effect in and I is the y intercept. In this situation, the value of S can be used
clinical pharmacology studies. After a pharmacodynamic experi- as a measure of drug potency (the larger the value of S, the more
ment has been conducted, concentration–effect plots are gener- potent the drug). The linear model can be derived from the Emax
ated. The shape of the concentration–effect curve is used to model. When EC50 is much greater than C, E = (Emax/EC50)C = S ×
determine which pharmacodynamic model will be used to describe C, where S = Emax/EC50.
the data. Because of this, the pharmacodynamic models used in a The linear model allows a nonzero value for effect when the
clinical pharmacology study are deterministic in the same way that concentration equals zero. This may be a baseline value for the effect
the shape of the serum-concentration-versus-time curve deter- that is present without the drug, the result of measurement error
mines which pharmacokinetic model is used in clinical pharmaco- when determining effect, or model misspecification. Also, this
kinetic studies. model does not allow the prediction of a maximum response.
Sometimes a hyperbolic function does not describe the concen- Some investigators have used a log-linear model in pharmacody-
tration–effect relationship at lower concentrations adequately. namic experiments: E = S × (log C) + I, where the symbols have the

100 100

80 80

60 60
Effect

Effect

40 40

20 20

0 50 100 150 200 250 300 350 0 50 100 150 200 250 300 350
Concentration Concentration

FIGURE 5-14. The Emax model [E = (Emax × C)/(EC50 + C )] has the FIGURE 5-15. The sigmoid Emax model [E = (Emax × C n)/(EC n50 + C n)]
shape of a hyperbola with an asymptote equal to Emax. EC50 is the has an S-shaped curve at lower concentrations. In this example, Emax and
concentration where effect = Emax/2. EC50 have the same values as in Fig. 5–14.
 28
80 as a model parameter. This approach can lead to better estimates of
the remaining model parameters.55 Using the linear model as an
SECTION 1

example, the equation used would be E – E0 = S × C.

60 If the drug decreases the baseline value, the drug effect is sub-
tracted from E0 in the pharmacodynamic models:
E max × C
E = E 0 – ---------------------
-
Effect

40 IC 50 + C
n
E max × C
E = E 0 – ------------------------
n n
20 IC 50 + C
Foundation Issues

E = E0 – S × C
where Emax represents the maximum reduction in effect caused by
0 10 20 30 40 50 60 70 80 the drug, and IC50 is the concentration that produces a 50%
Concentration inhibition of Emax. These forms of the equations have been called the
FIGURE 5-16. The linear model (E = S × C + I ) is often used as a inhibitory Emax and inhibitory sigmoidal Emax equations, respectively.
pharmacodynamic model when the measured pharmacologic effect is In this arrangement of the pharmacodynamic model, E0 is a model
20% to 80% of Emax. In this situation, the determination of Emax and EC50 parameter and can be estimated. If the baseline effect is well known
is not possible. To illustrate this, effect measurements from Fig. 5–14 and has little measurement error, the effect in the presence of the
between 20% and 80% of Emax are graphed using the linear pharmaco- drug can be subtracted from the baseline effect and not estimated as
dynamic model. a model parameter. Using the inhibitory Emax model as an example,
the formula would be E0 – E = (Emax × C)/(IC50 + C).
same meaning as in the linear model. The advantages of this model When using the inhibitory Emax model, a special situation occurs
are that the concentration scale is compressed on concentration– if the baseline effect can be obliterated completely by the drug (e.g.,
effect plots for experiments where wide concentration ranges were decreased premature ventricular contractions during antiarrhyth-
used, and the concentration values are transformed so that linear mic therapy). In this situation, Emax = E0, and the equation simpli-
regression can be used to compute model parameters. The disad- fies to a rearrangement known as the fractional Emax equation:
vantages are that the model cannot predict a maximum effect or an C ⎞
⎛
effect when the concentration equals zero. With the increased E = E 0 ⎝ 1 – --------------------
IC 50 + C⎠
-
availability of nonlinear regression programs that can compute the
parameters of nonlinear functions such as the Emax model easily, use This form of the model relates drug concentration to the fraction of
of the log-linear model has been discouraged.53 the maximum effect.
An alternative approach to the pharmacodynamic modeling of
BASELINE EFFECTS drugs that alter baseline effects is to transform the effect data so that
they represent a percentage increase or decrease from the baseline
At times, the effect measured during a pharmacodynamic study has value.55 For drugs that increase the effect, the following transforma-
a value before the drug is administered to the patient. In these cases, tion equation would be used: percent effectt = [(treatmentt –
the drug changes the patient’s baseline value. Examples of these baseline)/baseline] × 100. For drugs that decrease the effect, the
types of measurements are heart rate and blood pressure. In addi- following formula would be applied to the data: percent inhibitiont =
tion, a given drug may increase or decrease the baseline value. Two [(baseline – treatmentt)/baseline] × 100. The subscript indicates the
basic techniques are used to incorporate baseline values into phar- treatment, effect, or inhibition that occurred at time t during the
macodynamic data. One way incorporates the baseline value into experiment. If the study included a placebo control phase, baseline
the pharmacodynamic model; the other way transforms the effect measurements made at the same time as treatment measurements (i.e.,
data to take baseline values into account. heart rate determined 2 hours after placebo and 2 hours after drug
Incorporation of the baseline value into the pharmacodynamic treatment) could be used in the appropriate transformation equa-
model involves the addition of a new term to the previous equa- tion.55 The appropriate model (excluding E0) then would be used.
tions. E0 is the symbol used to denote the baseline value of the effect
that will be measured. The form that these equations takes depends HYSTERESIS
on whether the drug increases or decreases the pharmacodynamic
effect. When the drug increases the baseline value, E0 is added to the Concentration–effect curves do not always follow the same pattern
equations: when serum concentrations increase as they do when serum con-
E max × C centrations decrease. In this situation, the concentration–effect
E = E 0 + ----------------------
- curves form a loop that is known as hysteresis. With some drugs the
EC 50 + C
effect is greater when serum concentrations are increasing, whereas
n with other drugs the effect is greater while serum concentrations are
E max × C
E = E 0 + -------------------------- decreasing (Fig. 5–17). When individual concentration–effect pairs
n n
EC 50 + C are joined in time sequence, this results in clockwise and counter-
E = S × C + E0 clockwise hysteresis loops.
Clockwise hysteresis loops usually are caused by the development
When E0 is not known with any better certainty than any other of tolerance to the drug. In this situation, the longer the patient is
effect measurement, it should be estimated as a model parameter exposed to the drug, the smaller is the pharmacologic effect for a
similar to the way that one would estimate the values of Emax, EC50, given concentration. Therefore, after an extravascular or short-term
S, or n.54,55 If the baseline effect is well known and has only a small infusion dose of the drug, the effect is smaller when serum concen-
amount of measurement error, it can be subtracted from the effect trations are decreasing compared with the time when serum con-
determined in the patient during the experiment and not estimated centrations are increasing during the infusion or absorption phase.
 29

80 2. Gibaldi M, Boyes RN, Feldman S. Influence of first pass effect on availabil-

ity of drugs on oral administration. J Pharm Sci 1971;60:1338–1340.

CHAPTER 5
70 3. Wu C-Y, Benet LZ, Hebert MF, et al. Differentiation of absorption and
first-pass gut and hepatic metabolism in humans: Studies with cyclo-
60 sporine. Clin Pharmacol Ther 1995;58:492–497.
4. Wagner JG, Northam JI, Alway CD, et al. Blood levels of drug at the
50 equilibrium state after multiple dosing. Nature 1965;207:1301–1302.
5. Rowland M, Benet LZ, Graham GG. Clearance concepts in pharmaco-
Effect

40
kinetics. J Pharmacokinet Biopharm 1973;1:123–136.
30 6. Wilkinson GR, Shand DG. A physiological approach to hepatic drug
clearance. Clin Pharmacol Ther 1975;18:377–390.

Clinical Pharmacokinetics and Pharmacodynamics

20 7. Nies AS, Shand DG, Wilkinson GR. Altered hepatic blood flow and
drug disposition. Clin Pharmacokinet 1976;1:135–155.
10 8. Gibaldi M, Koup JR. Pharmacokinetic concepts: Drug binding, appar-
ent volume of distribution and clearance. Eur J Clin Pharmacol
0 20 40 60 80 100 120 140
1981;20:299–305.
9. Bowdle TA, Patel IH, Levy RH, et al. Valproic acid dosage and plasma
Concentration
protein binding and clearance. Clin Pharmacol Ther 1980;28:486–492.
FIGURE 5-17. Hysteresis occurs when effect measurements are different 10. Lima JJ, Boudonlas H, Blanford M. Concentration-dependence of
at the same concentration. This is commonly seen after short-term disopyramide binding to plasma protein and its influence on kinetics
intravenous infusions or extravascular doses where concentrations increase and dynamics. J Pharmacol Exp Ther 1981;219:741–747.
and subsequently decrease. Counterclockwise hysteresis loops are found 11. Gibaldi M, Perrier D. Pharmacokinetics, 2d ed. New York: Marcel
when concentration–effect points are joined as time increases (shown by Dekker, 1980.
arrows) and effect is larger at the same concentration but at a later time. 12. Gibaldi M. Estimation of the pharmacokinetic parameters of the two-
Clockwise hysteresis loops are similar, but the concentration–effect points compartment open model from post-infusion plasma concentration
are joined in clockwise order and the effect is smaller at a later time. data. J Pharm Sci 1969;58:1133–1135.
13. Loo JCK, Riegelman S. Assessment of pharmacokinetic constants from
postinfusion blood curves obtained after IV infusion. J Pharm Sci
Accumulation of a drug metabolite that acts as an antagonist also 1970;59:53–55.
can cause clockwise hysteresis. 14. Wagner JG. Model-independent linear pharmacokinetics. Drug Intell
Counterclockwise hysteresis loops can be caused by the accumu- Clin Pharm 1976;10:179–180.
lation of an active metabolite, sensitization to the drug, or delay in 15. Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to
Patient Management, 2007 ed. Freeland, WA: H&H Publications, 2007.
time in equilibration between serum concentration and concentra-
16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
tion of drug at the site of action. Combined pharmacokinetic- serum creatinine. Nephron 1976;16:31–41.
pharmacodynamic models have been devised that allow equilibra- 17. Traub SL, Johnson CE. Comparison of methods of estimating creati-
tion lag times to be taken into account. nine clearance in children. Am J Hosp Pharm 1980;37:195–201.
18. Salazar DE, Corcoran GB. Predicting creatinine clearance and renal
drug clearance in obese patients from estimated fat-free body mass.
CONCLUSIONS Am J Med 1988;84:1053–1060.
19. Jelliffe RW, Jelliffe SM. A computer program for estimation of creati-
The availability of inexpensive, rapidly achievable serum drug con- nine clearance from unstable serum creatinine levels, age, sex, and
centrations has changed the way clinicians monitor drug therapy in weight. Math Biosci 1972;14:17–24.
patients. The therapeutic range for many drugs is known, and it is 20. Koup JR, Jusko WJ, Elwood CM, Kohli RK. Digoxin pharmacoki-
likely that more drugs will be monitored using serum concentrations netics: Role of renal failure in dosage regimen design. Clin Pharmacol
in the future. Clinicians need to remember that the therapeutic range Ther 1975;18:9–21.
is merely an average guideline and to take into account interindivid- 21. Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinet-
ics of vancomycin in patients with various degrees of renal function.
ual pharmacodynamic variability when treating patients. Individual
Antimicrob Agents Chemother 1984;25:433–437.
patients may respond to smaller concentrations or require concen-
22. Sarubbi FA, Hull JH. Amikacin serum concentrations: Predictions of
trations that are much greater to obtain a therapeutic effect. Con- levels and dosage guidelines. Ann Intern Med 1978;89:612–618.
versely, patients may show toxic effects at concentrations within or 23. Sivan SK, Bennett WM. Drug dosing guidelines in patients with renal
below the therapeutic range. Serum concentrations should never failure. West J Med 1992;156:633–638.
replace clinical judgment. 24. Brier ME, Aronoff GR. Drug Prescribing in Renal Failure, 5th ed.
Three kinetic constants determine the dosage requirements of Philadelphia: American College of Physicians, 2007.
patients. Clearance determines the maintenance dose (MD = 25. Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transection of the
CLCss), volume of distribution determines the loading dose (LD = oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646–649.
VDCss), and half-life determines the time to steady state and the 26. Jusko WJ, Gardner MJ, Mangione A, et al. Factors affecting theophyl-
line clearances: Age, tobacco, marijuana, cirrhosis, congestive heart
dosage interval. Several methods are available to compute these
failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and
parameters.
ethanol. J Pharm Sci 1979;68:1358–1366.
Methods available to individualize drug therapy range from 27. Thomson PD, Melmon KL, Richardson JA, et al. Lidocaine pharmaco-
clinical pharmacokinetic techniques using simple mathematical kinetics in advanced heart failure, liver disease, and renal failure in
relationships that hold for all drugs that obey linear pharmacokinet- humans. Ann Intern Med 1973;78:499–508.
ics to very complex computer programs that are specific to one 28. Koup JR, Killen T, Bauer LA. Multiple-dose nonlinear regression
drug. analysis program: Aminoglycoside dose prediction. Clin Pharmacoki-
net 1983;8:456–462.
29. Sheiner LB, Beal S, Rosenberg B, et al. Forecasting individual pharma-
REFERENCES cokinetics. Clin Pharmacol Ther 1979;26:294–305.
30. Sheiner LB, Beal SL. Bayesian individualization of pharmacokinetics:
1. Koup JR, Gibaldi M. Some comments on the evaluation of bioavail- Simple implementation and comparison with non-Bayesian methods.
ability data. Drug Intell Clin Pharm 1980;14:327–330. J Pharm Sci 1982;71:1344–1348.
 30
31. Schentag JJ, Jusko WJ. Renal clearance and tissue accumulation of 45. Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinet-
gentamicin. Clin Pharmacol Ther 1977;22:364–370. ics of vancomycin in patients with various degrees of renal function.
SECTION 1

32. Sawchuk RJ, Zaske DE, Cipolle RJ, et al. Kinetic model for gentamicin Antimicrob Agents Chemother 1984;25:433–437.
dosing with the use of individual patient parameters. Clin Pharmacol 46. Abernethy DR, Greenblatt DJ, Smith TW. Digoxin disposition in obe-
Ther 1977;21:362–369. sity: Clinical pharmacokinetic investigations. Am Heart J 1981;102:740–
33. Bauer LA, Edwards WAD, Dellinger EP, Simonowitz DA. Influence of 744.
weight on aminoglycoside pharmacokinetics in normal weight and 47. Sarrazin E, Hendeles L, Weinberger M, et al. Dose-dependent kinetics
morbidly obese patients. Eur J Clin Pharmacol 1983;24:643–647. for theophylline: Observations among ambulatory asthmatic children.
34. Bauer LA, Piecoro JJ, Wilson HD, Blouin RA. Gentamicin and tobra- J Pediatr 1980;97:825–828.
mycin pharmacokinetics in patients with cystic fibrosis. Clin Pharm 48. Tang-Liu DDS, Williams RL, Riegelman S. Nonlinear theophylline
1983;2:262–264. elimination. Clin Pharmacol Ther 1982;31:358–369.
Foundation Issues

35. Sampliner R, Perrier D, Powell R, Finley P. Influence of ascites on 49. Edwards DJ, Zarowitz BJ, Slaughter RL. Theophylline In: Evans E,
tobramycin pharmacokinetics. J Clin Pharmacol 1984;24:43–46. Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics: Principles of
36. Zank KE, Miwa L, Cohen JL, et al. Effect of body weight on gentamicin Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics,
pharmacokinetics in neonates. Clin Pharm 1984;3:170–173. 1992, 13-1 through 13-38.
37. Pancorbo S, Sawchuk RJ, Dashe C, et al. Use of a pharmacokinetic 50. Vozeh S, Kewitz G, Wenk M, et al. Rapid prediction of steady-state
model for individual intravenous doses of aminophylline. Eur J Clin serum theophylline concentrations in patients treated with intrave-
Pharmacol 1979;16:251–254. nous aminophylline. Eur J Clin Pharmacol 1980;18:473–477.
38. Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once- 51. Vozeh S, Muir KT, Sheiner LB, Follath F. Predicting individual
daily aminoglycoside program administered to 2184 adult patients. phenytoin dosage. J Pharmacokinet Biopharm 1991;9:131–146.
Antimicrob Agents Chemother 1995;39:650–655. 52. Ludden TM, Allen JP, Valutsky WA, et al. Individualization of pheny-
39. Cantu TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concen- toin dosage regimens. Clin Pharmacol Ther 1977;21:287–293.
trations: Reappraisal of their clinical value. Clin Infect Dis 1994;18:533–543. 53. Holford NHG, Sheiner LB. Understanding the dose-effect relation-
40. Welty TE, Copa AK. Impact of vancomycin therapeutic drug monitor- ship: Clinical application of pharmacokinetic-pharmacodynamic
ing on patient care. Ann Pharmacother 1994;28:1335–1339. models. Clin Pharmacokinet 1981;6:429–453.
41. Zimmermann AE, Katona BG, Plaisance KI. Association of vancomy- 54. Schwinghammer TL, Kroboth PD. Basic concepts in pharmacody-
cin serum concentrations with outcomes in patients with gram- namic modeling. J Clin Pharmacol 1988;28:388–394.
positive bacteremia. Pharmacotherapy 1995;15:85–91. 55. Sheiner LB, Stanski DR, Vozeh S, et al. Simultaneous modeling of
42. Karam CM, McKinnon PS, Neuhauser MM, Rybak MJ. Outcome pharmacokinetics and pharmacodynamics: Application to d-tubocu-
assessment of minimizing vancomycin monitoring and dosage adjust- rarine. Clin Pharmacol Ther 1979;25:358.
ments. Pharmacotherapy 1999;19:257–266. 56. Niederman MS, Craven DE. Guidelines for the management of adults
43. Moellering RC Jr, Krogstad DJ, Greenblatt DJ. Vancomycin therapy in with hospital-acquired, ventilator-associated, and healthcare-associ-
patients with impaired renal function: A nomogram for dosage. Ann ated pneumonia. Am J Respir Crit Care Med 2005;171(4):388–416.
Intern Med 1981;94:343–346. 57. Bauer LA. Use of mixed-effect modeling to determine the influence of
44. Blouin RA, Bauer LA, Miller DD, et al. Vancomycin pharmacokinetics in albumin, bilirubin, valproic acid, warfarin, and aspirin on phenytoin
normal and morbidly obese subjects. Antimicrob Agents Chemother unbound fraction and pharmacokinetics. J Am Pharm Assoc 2004;44:236–
1982;21:575–580. 237.
 31

C HAP T E R

6 Pharmacogenetics

LARISA H. CAVALLARI AND Y.W. FRANCIS LAM

(CYP450) and other drug-metabolizing enzymes now are well-recog-

KEY CONCEPTS nized causes of interindividual differences in plasma concentrations
of certain drugs. These variations may have serious implications for
 Genetic variations contribute to interpatient differences in drug drugs with a narrow therapeutic index, such as warfarin, phenytoin,
response. and mercaptopurine.2–4 More recent interest focuses on associations
 Genetic variations occur for drug metabolism, drug transporter, between drug response and variations in genes for drug transporters
and drug target proteins as well as for disease-associated genes. such as P-glycoprotein and drug targets such as receptors, enzymes,
and proteins involved in intracellular signal transduction. Genetic
 Genetic polymorphisms may be linked to drug efficacy and toxicity. variations of drug-metabolizing enzymes and drug transporter pro-
 Pharmacogenetics is the study of the impact of genetic poly- teins may influence pharmacokinetic drug properties, thus altering
morphisms on drug response. drug disposition. Drug target genes may alter pharmacodynamic
mechanisms by affecting sensitivity to a drug at its target site. Finally,
 The goals of pharmacogenetics are to optimize drug efficacy genes associated with disease severity have been correlated with drug
and limit drug toxicity based on an individual’s DNA. efficacy despite having no direct effect on pharmacokinetic or phar-
 Single nucleotide polymorphisms are the most common varia- macodynamic mechanisms.
tions in the human genome.
 Gene therapy aims to cure disease caused by genetic defects PHARMACOGENETICS: A DEFINITION
by changing gene expression.
  Pharmacogenetics involves the search for genetic variations
Inadequate gene delivery and expression and serious adverse that lead to interindividual differences in drug response. The term
effects are obstacles to successful gene therapy. pharmacogenetics often is used interchangeably with the term phar-
macogenomics. However, pharmacogenetics generally refers to mono-
genetic variants that affect drug response, whereas pharmacogenomics
Individuals vary greatly in their response to drug therapy, and
refers to the entire spectrum of genes that interact to determine drug
predicting how effective or safe a medication will be for a particular
efficacy and safety. For example, a pharmacogenetic study would
patient often is difficult. For example, when treating a patient with
examine the influence of the β1-adrenergic receptor gene on blood
hypertension, several agents or a combination of agents may be
pressure response to carvedilol. A pharmacogenomic study might
attempted before adequate blood pressure control with acceptable
examine the interaction between CYP2D6 and β1-, β2-, and α1-
tolerability is achieved. A number of nongenetic factors influence
adrenergic receptor genes on carvedilol effects. To date, most studies
drug response, including pharmacokinetics, age, and concomitant
of gene–drug responses are pharmacogenetic in nature. However,
drug use. However, considering these factors alone often is insuffi-
given that multiple proteins are involved in determining the ultimate
cient for predicting the likelihood of drug efficacy or safety for a
response to most drugs, many investigators are taking a more phar-
given patient. For instance, identical antihypertensive therapy in two
macogenomic approach to elucidating genetic contributions to drug
patients with similar demographic characteristics, medical histories,
response. For simplicity, this chapter treats pharmacogenetics and
and concomitant drug therapy may produce inadequate blood pres-
pharmacogenomics as synonymous.
sure reduction in one patient and symptomatic hypotension in the
 The goals of pharmacogenetics are to optimize drug therapy
other.
and limit drug toxicity based on an individual’s genetic profile.
  The observed interpatient variability in drug response may
Thus, pharmacogenetics aims to use genetic information to choose
result largely from genetically determined differences in drug metab-
a drug, drug dose, and treatment duration that will have the greatest
olism, drug distribution, and drug target proteins. The influence of
likelihood of achieving therapeutic outcomes with the least poten-
heredity on drug response was demonstrated as early as 1956 with the
tial for harm in a given patient. The results of pharmacogenetic
discovery that an inherited deficiency of glucose-6-phosphate dehy-
research ultimately will provide opportunities for clinicians to use
drogenase was responsible for hemolytic reactions to the antimalarial
genetic tests to predict individual responses to drug treatments,
drug primaquine.1 Variations in genes encoding cytochrome P450
specifically to select medications for patients based on DNA profiles
and to develop novel strategies for disease treatment and prevention
based on an understanding of genetic control of cellular functions.
Learning objectives, review questions, Although there has been considerable interest in genetic influ-
and other resources can be found at ences of drug response in recent years, pharmacogenetics is not a
www.pharmacotherapyonline.com. new area. In 1957, shortly after the discovery of a genetic predispo-
sition toward primaquine-induced toxicity, Arno Motulsky pro-

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 32

1953: Watson and Crick describe DNA’s double helix.

SECTION 1

1956: Investigators discover a genetic link to hemolytic reactions to primaquine.

1957: Motulsky proposes that “inheritance might explain many individual differences
in the efficacy of drugs and in the occurrence of adverse drug reactions.”

1959: Fredrich Vogel introduces the term “pharmacogenetics.”

Human Genome Project is started.

1950 1960 1970 1980 1990 2000

Foundation Issues

2003: Human Genome

Project is completed.

Renewed interest in pharmacogenetics FIGURE 6-1. Time line of genomic

discoveries.

posed that inheritance might underlie much of the disparity in drug genes. Two purine nucleotide bases, adenine (A) and guanine (G),
response among individuals (Fig. 6–1).5 Two years later, Fredrich and two pyrimidine nucleotide bases, cytosine (C) and thymidine
Vogel introduced the term pharmacogenetics.6 With the advent of (T), are present in DNA. Purines and pyrimidines always pair
the Human Genome Project in 1990 came a resurgence of interest together as A-T and C-G in the two strands that make up the DNA
in determining genetic contributions to drug response. structure. Most nucleotide base pairs are identical from person to
person, with only 0.1% contributing to individual differences.
According to the central dogma, when one strand of DNA is
HUMAN GENOME PROJECT transcribed into RNA and translated to make proteins, three con-
secutive nucleotides form a codon. Each codon specifies an amino
In 1988, Congress commissioned the Department of Energy and the acid or amino acid chain termination. For example, the nucleotide
National Institutes of Health to plan and implement the Human sequence, or codon, GGA specifies the amino acid glycine. The
Genome Project. The goal of the Human Genome Project was to genetic code has substantial redundancy, in that two or more
determine the entire sequence of the human genome by 2005. codons code for the same amino acid. For example, GGC, GGG,
Mapping of the human genome, which officially began in 1990, has and GGT also code for glycine. Amino acids are the basic constitu-
led to a better understanding of genetic contributions to disease ents of proteins, which mediate all cellular functions. Only 20
susceptibility. To encourage research and ultimately maximize the different amino acids, in various arrangements, form the basic units
societal benefits of the Human Genome Project, sequence data from of all the proteins in the human body.
the Human Genome Project have been deposited into a freely A gene is a series of codons that specifies a particular protein.
accessible database run by the National Center for Biotechnology Genes contain several regions: exons that encode for the final protein,
Information (www.ncbi.nlm.nih.gov). As a consequence of these introns that consist of intervening noncoding regions, and regulatory
shared data, research efforts in the 1990s accelerated the discovery of regions that control gene transcription. In most cases, an individual
genetic variations affecting treatment response and the development carries two alleles, one from each parent, at each gene locus. An allele
of new treatments and preventive strategies for human disease. is defined as the sequence of nucleic acid bases at a given gene
Largely because of advances in biotechnology, the initial working chromosomal locus. Two identical alleles make up a homozygous
draft of the human genome sequence was completed in 2000, well genotype. Two different alleles make up a heterozygous genotype. The
ahead of schedule.7 In April 2003, 50 years after James Watson and phenotype refers to the outward expression of the genotype.
Francis Crick described the double-helix structure of DNA and more
than 2 years ahead of schedule, researchers announced the comple-
tion of the Human Genome Project.8 The final version contains 99% TYPES OF GENETIC VARIATIONS
of the gene-containing sequence, with 99.9% accuracy.
Following completion of the Human Genome Project, the Genetic variations occur as either rare defects or polymorphisms.
National Human Genome Research Institute announced its vision Polymorphisms are defined as variations that occur at a frequency of
for the future of genomic research with the goal of improving at least 1% in the human population. For example, the genes encod-
human health and well-being.9 One of the challenges set forth to ing the CYP450 enzymes CYP2A6, CYP2C9, CYP2C19, CYP2D6, and
meet this goal is to develop genome-based approaches to predict CYP3A4 are polymorphic, with functional mutations of >1% occur-
drug response. This challenge involves the accurate, unbiased deter- ring in different ethnic groups. In contrast, rare mutations occur in
mination of genetic variants linked to drug response, advanced <1% of the population and cause inherited diseases such as cystic
technology to efficiently determine genotype, and appropriate inte- fibrosis, hemophilia, and Huntington’s disease. Common diseases,
gration of genetic testing into the therapeutic decision process. The such as essential hypertension and diabetes mellitus, are polygenic in
National Human Genome Research Institute also challenges inves- that multiple genetic polymorphisms likely interact with environ-
tigators to develop new, gene-based approaches to disease manage- mental factors to contribute to the disease susceptibility.
ment, which will require a thorough understanding of genetic  Single nucleotide polymorphisms (SNPs; pronounced
determinants of disease susceptibility and progression. “snips”) are the most common genetic variations in human DNA,
occurring approximately once in every 100 to 300 base pairs. To
date more than four million SNPs have been mapped in the human
GENETIC CONCEPTS genome. SNPs occur when one nucleotide base pair replaces
another (Fig. 6–2). Thus, SNPs are single-base differences that exist
The human genome contains approximately three billion nucleotide between individuals. Nucleotide substitution results in two possible
bases, which code for approximately 20,000 to 25,000 protein-coding alleles. One allele, typically either the most commonly occurring
 33
• Aberrant splice site, in which processing of the protein occurs at
A. “Wild-type” allele an alternate site

CHAPTER 6
Codon 13 14 15 16 17 18 19 • Premature stop codon polymorphisms, in which there is prema-
ture termination of the polypeptide chain by a stop codon
Nucleotide . . . GCA CCC AAT AGA AGC CAT GCG . . . (specific sequence of three nucleotides that do not code for an
Amino acid Ala Pro Asn Arg Ser His Ala amino acid but rather specify polypeptide chain termination)
SNPs may occur in exon, intron, or regulatory regions of a gene.
Those occurring in exon regions may alter the function of a protein,
B. “Variant” allele
whereas those in regulatory regions may alter the amount of protein
that is produced. Variations in the intron region often are silent

Pharmacogenetics
Codon 13 14 15 16 17 18 19
unless they affect intron splicing. Multiple SNPs may be in linkage
Nucleotide . . . GCA CCC AAT GGA AGC CAT GCG . . . disequilibrium with each other, meaning that two or more SNPs are
Amino acid Ala Pro Asn Gly Ser His Ala
inherited together more frequently than expected based on chance
alone. For example, if two SNPs, A46T and G72C, are possible in a
given gene and if a T at position 46 always occurs with a C at
FIGURE 6-2. Nucleotide sequence of the β2-adrenergic receptor gene from
position 72, the two SNPs are said to be in complete linkage
codons 13 through 19. A. Nucleotide sequence of the wild-type allele with
adenine (A) at nucleotide position 46 (underlined) located in codon 16 of
disequilibrium. A set of SNPs that are inherited together is called a
the β2-adrenergic receptor gene. The AGA codon designates the amino acid haplotype. For more detailed information about genetic concepts,
arginine (Arg), with an average frequency of 39% in the human population. refer to the recommended genetics textbook.11
B. Nucleotide sequence of the variant allele with guanine (G) at nucleotide Most common diseases are polygenic in nature. For example,
position 46 (underlined), located in codon 16. The GGA codon designates genes for numerous proteins involved in the renin–angiotensin
the amino acid glycine (Gly), which occurs at an average frequency of 61%. system, sympathetic nervous system, and renal sodium transport
Although the Arg16 polymorphism occurs less commonly than the Gly16 have been associated with the risk for essential hypertension.12
polymorphism, it is referred to as the wild type because it was identified first. Environmental factors are well-known risk factors for diseases such
as hypertension and often interact with genetic factors to influence
allele or the allele originally sequenced, is considered the wild type; disease susceptibility and progression. Given the complex patho-
the alternative allele is considered the variant allele. physiology of most common diseases, genes linked to disease suscep-
A SNP may change the codon resulting in amino acid substitu- tibility are not discussed in this chapter. Rather, this chapter focuses
tion, which may or may not alter the amount or function of the on genetic variations linked to responses to pharmacologic agents.
encoded protein. For example, in Fig. 6–2, guanine (G) is substi-
tuted for adenine (A) at nucleotide 46 in the β2-adrenergic receptor
gene. This results in the substitution of glycine for arginine at amino POLYMORPHISMS IN GENES FOR
acid position (codon) 16 and alterations in receptor downregulation DRUG-METABOLIZING ENZYMES
upon prolonged exposure to β2-receptor agonists.10 SNPs such as
this that result in amino acid substitution are referred to as nonsyn-  Polymorphisms in the drug-metabolizing enzymes represent the
onymous. SNPs that do not result in amino acid substitution are first recognized and the most documented examples of genetic
called synonymous. Referring to a previous example of redundancy variants with consequences in drug response and toxicity. The
in the genetic code, replacement of adenine (A) with cytosine (C) in major phase I enzymes are the CYP450 superfamily of isoenzymes.
the codon AGA is an example of a synonymous SNP because the N-acetyltransferase, uridine diphosphate glucuronosyltransferase
resulting amino acid still is glycine. Synonymous SNPs usually are (UGT), and glutathione S-transferase are examples of phase II
abbreviated based on the nucleotides involved and the nucleotide metabolizing enzymes that exhibit genetic polymorphisms. Thiopu-
base position. For example, A1166C or A1166→C indicates that rine S-methyltransferase (TPMT) and dihydropyrimidine dehydro-
cytosine is substituted for adenine at nucleotide position 1166 of a genase (DPD) are examples of nucleotide base-metabolizing
given gene region. Nonsynonymous SNPs usually are designated by enzymes. Table 6–1 lists selected examples of polymorphic metabo-
the amino acids and codon involved. For example, Arg16Gly or lizing enzymes, corresponding drug substrates, and consequences of
Arg16→Gly indicates that glycine is substituted for arginine at altered enzyme function as a result of gene variation.
codon 16. If a SNP changes the amount or function of a protein that
contributes to drug response, it may alter a patient’s sensitivity to a CYTOCHROME P450 ENZYMES
drug or predispose the patient to adverse reactions to drug therapy.
Other examples of genetic variants include the following: Currently, 57 different CYP450 isoenzymes have been documented
to be present in humans, with 42 involved in the metabolism of
• Insertion–deletion polymorphisms, in which a nucleotide or exogenous xenobiotics and endogenous substances such as steroids
nucleotide sequence either is added to or deleted from a DNA and prostaglandins.12 Fifteen of these isoenzymes are known to be
sequence involved in the metabolism of drugs, but significant interindividual
• Tandem repeats, in which a nucleotide sequence repeats in tandem variabilities in enzyme activity exist as a result of induction, inhibi-
(e.g., if “AG” is the nucleotide repeat unit, “AGAGAGAGAG” is a tion, and genetic inheritance. Functional genetic polymorphism has
five-tandem repeat) been discovered for CYP2A6, CYP2C9, CYP2C19, CYP2D6,13 and,
• Frameshift mutation, in which there is an insertion/deletion more recently, CYP3A4/5.14,15 A polymorphism in the regulatory
polymorphism and the number of nucleotides added or lost is region of the gene encoding for CYP1A2 has been identified,16 but
not a multiple of three, resulting in disruption of the gene’s its functional importance remains to be determined.
reading frame
CYP2D6
• Defective splicing, in which an internal polypeptide segment is
abnormally removed, and the ends of the remaining polypep- Polymorphisms in the CYP2D6 gene are the best characterized of
tide chain are joined the CYP450 variants. At least 48 gene variants and 53 alleles in the
 34

TABLE 6-1 Selected Examples of Genetic Polymorphisms in Drug-Metabolizing Enzymes and Response to Drug Therapy
SECTION 1

Genetic Variants/Genes Drug Drug Effect Associated with Polymorphism

CYP2D6*4, CYP2D6*5 Perhexiline Neuropathy18
Codeine Significant reduction in analgesic effect 22,23
Tramadol
CYP2D6*2 (n > l) Tricyclic antidepressants (e.g., desipramine, Inadequate antidepressant response30,31
nortriptyline)
CYP2D6*10 Antipsychotics (e.g., haloperidol) Elevated plasma concentrations and exaggerated responses34
CYP2CP*2, CYP2C9*3 Warfarin Hemorrhage 2
CYP2C9, CYP2C19 Phenytoin Phenytoin toxicity3
Foundation Issues

CYP2C19 Omeprazole Improved cure rates for Helicobacter pylori 42

Glutathione-S-transferase Primaquine Hemolytic reactions1
Thiopurine methyltransferase Mercaptopurine Bone marrow depression4
N-Acetyltransferase slow acetylator Isoniazid More prone to peripheral neuropathy105
Procainamide More prone to development of systemic lupus erthematosus-like
Hydralazine syndrome106,107
Sulfonamides Increased hematologic and gastrointestinal adverse reactions 108
Uridine diphosphate glucuronosyltransferase Irinotecan Increased severity of diarrhea and neutropenia in carrier of (TA)7TAA allele 62

CYP2D6 gene have been identified.17 Nevertheless, the CYP2D6 abuse among CYP2D6 PMs, investigators have used daily doses of
extensive-metabolizer (EM) and poor-metabolizer (PM) pheno- fluoxetine 20 mg, a CYP2D6 inhibitor, as adjunctive therapy in the
types (outward expression of genotypes) can be predicted with up management of opiate abuse to “metabolically convert” drug abus-
to 99% confidence with six genotypic variants. CYP2D6*1 is consid- ers who are EMs to PMs.26
ered the wild-type variant and exhibits normal enzyme activity. The potential and magnitude of drug interactions involving
CYP2D6*2 has the same activity as CYP2D6*1 but is capable of competitive inhibition of CYP2D6 are much greater in EMs versus
duplication or amplification. Both variants are present in EMs. The PMs, who have either deficient or absent enzyme activity.27,28 For
CYP2D6*4 (defective splicing) and CYP2D6*5 (gene deletion) vari- example, Hamelin et al.29 showed that hemodynamic responses to
ants are predominantly found in white PMs (5% to 10% of the metoprolol (a CYP2D6 substrate) were pronounced and prolonged
Caucasian population)17 and result in an inactive enzyme and an during concomitant diphenhydramine administration in EMs but
absence of enzyme, respectively. The predominant variants in peo- not in PMs. Thus, potent CYP2D6 inhibitors may reduce the
ple of Asian and African heritage are CYP2D6*10 (Pro34Ser) and metabolic capacity of EMs significantly so that EMs appear pheno-
CYP2D6*17 (Arg296Cys), respectively. Both result in a single amino typically as PMs.
acid substitution and consequent reduction in enzyme activity. Patients who are EMs have a wide range of CYP2D6 activity, with
Poor CYP2D6 metabolizers carry two defective alleles, such as ultrarapid metabolizers (UMs) on one end of the spectrum and
CYP2D6*3, CYP2D6*4 (more common), CYP2D6*5, and CYP2D6*6, subjects with diminished activity on the other end. Both have clinical
resulting in a total absence of active enzyme and an impaired ability implications in terms of dosage adjustment for CYP2D6 substrates.
to metabolize CYP2D6-dependent substrates. Examples of CYP2D6 UMs carry a duplicated or amplified mutant allele, resulting in two
substrates include neuroleptic medications, antidepressants such as or multiple copies of the functional CYP2D6*1 or CYP2D6*2 allele,
tricyclic antidepressants and mianserin, antiarrhythmic drugs such as and therefore show very high CYP2D6 activity. Nontherapeutic
propafenone, and β-adrenergic antagonists such as metoprolol (see plasma concentrations of nortriptyline, a CYP2D6 substrate, were
Table 6–1). Depending on the importance of the affected CYP2D6 observed in a UM given normal doses of the drug.30 The CYP2D6
pathway to overall drug metabolism and the drug’s therapeutic index, enzyme converts nortriptyline to 10-hydroxynortriptyline, and one
clinically significant side effects may occur in PMs as a result of study demonstrated a directly proportional relationship between the
elevated parent drug concentrations. For example, compared with number of functional CYP2D6 genes and the concentration of 10-
EMs, PMs develop neuropathy after treatment with the antianginal hydroxynortriptyline after nortriptyline administration.31 A patient
agent perhexiline18 and have experienced more adverse effects with with three copies of CYP2D6*2 required nortriptyline doses three-
propafenone19 and neuroleptic agents such as perphenazine.20,21 fold to fivefold higher than normally recommended to achieve
The therapeutic implication of CYP2D6 polymorphism is differ- therapeutic plasma concentrations (50 to 150 mcg/mL).30,32 In the
ent if the substrate in question is a prodrug. In this case, PMs would same report, another patient with duplicated CYP2D6*2 required
not be able to convert the drug into the therapeutically active twice the usual recommended daily dose (300 mg versus 25 to 150
metabolite. Two examples of prodrugs dependent on CYP2D6- mg) to achieve adequate therapeutic response.32 On the other hand,
mediated conversion to active forms are codeine and tramadol. UMs administered the usual therapeutic dose of codeine might
Codeine and tramadol are converted by CYP2D6 to morphine and exhibit symptoms of narcotic overdose associated with high mor-
O-desmethyltramadol, respectively; thus, poor CYP2D6 metaboliz- phine concentration. The UM genotype also has been reported to
ers experience little or no analgesic relief after taking these drugs.22,23 affect the potential for drug interaction with paroxetine, a CYP2D6
Another example is CYP2D6-catalyzed conversion of tamoxifen to substrate as well as a potent CYP2D6 inhibitor.33
the more potent antiestrogen metabolite 4-hydroxytamoxifen.24 The high prevalence of CYP2D6*10 (associated with lower enzyme
Although PMs are at a disadvantage from the standpoint of drug activity) in the Asian population provides a biologic and molecular
toxicity for most CYP2D6 substrates and lack of efficacy for explanation for the higher drug concentrations and/or lower dosage
CYP2D6 prodrugs, data suggest that they may be “protected” from requirements of neuroleptic medications and mianserin in people of
abusing opiates such as codeine, oxycodone, and hydrocodone. This Asian heritage.34,35 The widespread presence of the CYP2D6*17
idea is primarily based on the observation that no PMs were found variant among people of African heritage suggests that native African
among opiate-dependent subjects, which likely reflects their inabil- populations metabolize CYP2D6 substrates at a slower rate than do
ity to convert these drugs of abuse into their respective “pharmaco- other ethnic or racial groups.36,37 However, no current genotype- and
logically active” moieties.25 Given the reduced potential for opiate phenotype-based data document the need for prescribing lower
 35
doses of psychotropics and other CYP2D6 substrates in native homozygotes compared with subjects homozygous for the wild-type
African populations. allele.51 In another study, an overrepresentation of CYP2C9 variant

CHAPTER 6
In addition to the therapeutic implications of genetic polymor- alleles was observed in 81% of patients requiring low-dose warfarin
phisms, one study showed that the CYP2D6 polymorphism has an therapy (≤1.5 mg/day).2 The low-dose group was reported to have
economic impact.38 The annual cost of treating UMs and PMs more difficulty with warfarin induction, requiring longer hospital
(carriers of two nonfunctional CYP2D6 alleles) was $4,000 to $6,000 stays to stabilize the warfarin regimen and experiencing a higher
higher than the cost of treating EMs or intermediate metabolizers incidence of bleeding complications. In addition, a profound thera-
(carriers of one nonfunctional allele and one allele associated with peutic response to usual doses of warfarin was observed in a patient
diminished activity). The cost of genotyping can be considerably less homozygous for the CYP2C9*3 allele, necessitating dose reduction to
than that incurred in a patient with a serious adverse drug reaction. 0.5 mg/day.52

Pharmacogenetics
Brockmoller et al.39 suggested how CYP2D6 genotyping can be used
to achieve higher therapeutic success with the CYP2D6 substrate CYP2A6
haloperidol. Along these lines, the Food and Drug Administration
A polymorphism has been characterized for CYP2A6, with identifi-
(FDA) approved the AmpliChip CYP450 Test (Roche Diagnostics)
cation of several variants—CYP2A6*1 (wild type), CYP2A6*2 (sin-
for analyzing 27 CYP2D6 alleles in addition to the CYP2C19*1, *2,
gle amino acid substitution), CYP2A6*3 (gene conversion)—and
and *3 alleles (discussed below) to assist clinicians in individualizing
three gene-deletion alleles—CYP2A6*4A, CYP2A6*4B, and
therapy with drugs metabolized through the CYP2D6 and CYP2C19
CYP2A6*4D.53 Deletion of the CYP2A6 gene is very common in
pathways.
Asian patients,53,54 which likely accounts for the dramatic difference
in the frequency of PMs in Asian (20%) versus European and white
CYP2C19 populations (≤1%). Nicotine is metabolized by CYP2A6, and the
The principal defective alleles for the CYP2C19 genetic polymor- clinical relevance of the CYP2A6 polymorphism lies in management
phism are CYP2C19*2 (aberrant splice site) and CYP2C19*3 (prema- of tobacco abuse.55 Investigators reported that nonsmokers were
ture stop codon), which result in inactive CYP2C19 enzymes and the more likely to carry the defective CYP2A6 allele than were smokers.
PM phenotype. Clinical implication of the CYP2C19 polymorphism Smokers who had the defective CYP2A6 allele smoked fewer ciga-
has not been examined as extensively as that of the CYP2D6 poly- rettes and were more likely to quit.55 The inability to metabolize
morphism. However, PMs for the CYP2C19 polymorphism showed nicotine, secondary to the presence of a defective CYP2A6 allele,
a more than 12-fold increase in the area under the curve (AUC) of likely leads to enhanced nicotine tolerance and increased adverse
the CYP2C19 substrate omeprazole compared with EMs.40 In a effects from nicotine. Based on these observations, CYP2A6 inhibi-
separate study, the steady-state AUC of omeprazole and other tion may have a role in the management of tobacco dependency.56
CYP2C19 substrate proton pump inhibitors was five-fold higher in
PMs versus EMs.41 CYP3A4/5
The presence of a defective CYP2C19 allele has been associated
Within the CYP3A subfamily, at least three isoenzymes, namely,
with improved Helicobacter pylori cure rates after dual (omeprazole
CYP3A4, CYP3A5, and CYP3A7, have been characterized. Despite
and amoxicillin)42 or triple therapy (omeprazole, amoxicillin, and
as much as 40-fold interindividual variability in its expression,
clarithromycin) with omeprazole43 as well as with lansoprazole.44
functional CYP3A4 is expressed in most adults, with intestinal
This difference likely reflects the higher achievable intragastric pH
expression playing a significant role in the first-pass metabolism of
in the PM group.45 The cure rate achieved with dual therapy was
numerous drugs. CYP3A4 variants with amino acid substitutions in
100% in PMs compared with 60% and 29% in heterozygous and
exons 7 and 12 have been associated with altered catalytic activity
homozygous EMs, respectively.42 In two studies, EMs had H. pylori
for the CYP3A4 substrate nifedipine.14 The clinical importance of
eradication rates of 41% with dual therapy and 74% to 83% with
this finding needs further elucidation and confirmation.
triple therapy.43,44 In contrast, both dual- and triple-therapy regi-
CYP3A5 is reported to be polymorphic in 60% of African Amer-
mens produced 100% cure rates in all 15 PMs included in the same
icans and 33% of white people. In contrast to individuals with the
studies. Interestingly, EMs who did not respond to initial triple
CYP3A5*1 allele, subjects with variant alleles such as CYP3A5*3
therapy (lansoprazole, clarithromycin, and amoxicillin) and were
(aberrant splice site) in intron 3 have no functional CYP3A5
retreated with high-dose lansoprazole (30 mg four times daily) and
enzyme.15 With overlapping substrate specificities, whether there
amoxicillin achieved 97% H. pylori eradication.46
are clinically used drugs that are substrates for CYP3A5 but not
Similar to the CYP2D6 polymorphism, people of Asian heritage
CYP3A4 and vice versa is unknown. Although variability exists
also metabolize most CYP2C19 substrates at a slower rate than do
between dose-adjusted concentration and CYP3A5 genotypes, stud-
white people.47 This reflects the higher prevalence of both PMs
ies have shown a correlation between pharmacokinetics of tacroli-
(13% to 20% versus 2% to 6% in white people) and heterozygotes
mus and CYP3A5 genetic constitution.57,58
for the defective CYP2C19 allele in Asians.48 This genotypic differ-
ence may explain the practice of prescribing lower diazepam dos-
ages for patients of Chinese heritage.49 PHASE II AND NUCLEOTIDE-BASE
METABOLIZING ENZYMES
CYP2C9 The clinical relevance of genetic polymorphisms in TPMT, DPD,
Warfarin, phenytoin, and tolbutamide are examples of drugs with a and UGT enzymes has been demonstrated in the treatment of
narrow therapeutic index that are metabolized by CYP2C9. Warfarin cancer.4,59,60 The TPMT gene has three mutant alleles: TPMT*3A
is a racemic mixture, and the S-isomer, which possesses about three (the most common), TPMT*2, and TPMT*3C. Patients who are
times the anticoagulant effects of the R-isomer, is metabolized by homozygous or heterozygous for the TPMT mutant alleles are at
CYP2C9. CYP2C9*2 and CYP2C9*3 are the two most common higher risk for developing serious anemias during mercaptopurine
CYP2C9 variants. Both exhibit single amino acid substitutions at treatment.4 DPD mediates the metabolism of 5-fluorouracil, and
positions critical for enzyme activity.50 This could have clinically patients with a defective allele of the DPD gene cannot metabolize
important consequences in warfarin-treated patients. For example, a 5-fluorouracil and thus may experience enhanced drug-related
90% reduction in S-warfarin clearance was reported in CYP2C9*3 neurotoxicity.59 The camptothecin derivative irinotecan (CPT-11)
 36
is activated by carboxylesterase to SN-38, which is a potent topo- Anthracyclines
isomerase I inhibitor. SN-38 is inactivated by glucuronidation via Vinca alkaloids
SECTION 1

the polymorphic UGT1A1 enzyme, which may play a role in CPT- Digoxin
11–related toxicity. A polymorphism in the promoter region of the Cyclosporine
Protease inhibitors
UGT1A1 gene results in the (TA)7TAA allele, which possesses lower Dexamethasone
enzyme activity than the wild-type (TA)6TAA allele. A patient Extracellular
homozygous for the (TA)7TAA allele had impaired SN-38 glucu-
ronidation.60 Abnormally high SN-38 concentrations have been
associated with neutropenia and severe diarrhea.61 Diarrhea likely
Plasma
results from increased SN-38 excretion into the gut lumen, predis- membrane
Foundation Issues

posing patients with the (TA)7TAA allele to developing diarrhea

with usual CPT-11 doses. This observation was confirmed in a NH2 COOH
prospective clinical trial that demonstrated more severe diarrhea
and neutropenia in irinotecan-treated patients who are homozy-
gous or heterozygous carriers of the (TA)7TAA allele.62 The FDA Intracellular
approved the Invader UGT1A1 Molecular Assay (Third Wave
Technologies) to genotype for UGT1A1 alleles and revised the
labeling for irinotecan to recommend therapy adjustment for indi- P-glycoprotein
viduals who are homozygous for the (TA)7TAA allele.
FIGURE 6-3. Active transport of drugs out of the cell by P-glycoprotein.

healthy volunteers.63 These data imply that the ABCB1 genotype is

POLYMORPHISMS IN DRUG useful in predicting digoxin concentrations in patients with atrial
TRANSPORTER GENES arrhythmias or heart failure and in appropriate selection of initial
digoxin doses.
Certain membrane-spanning proteins facilitate drug transport
The ABCB1 exon 26 polymorphism also has been associated with
across the gastrointestinal tract, drug excretion into the bile and
plasma concentrations and clinical effects of protease inhibitors in
urine, and drug distribution across the blood–brain barrier. Genetic
patients infected with the human immunodeficiency virus (HIV).64
variations for drug transport proteins may affect the distribution of
Specifically, following 6 months of therapy with efavirenz or nelfin-
drugs that are substrates for these proteins and alter drug concen-
avir, a greater rise in CD4 cell counts was observed in individuals
trations at their therapeutic sites of action. P-glycoprotein is one of
with the exon 26 TT genotype compared with CC homozygotes.
the most recognized of the drug transport proteins that exhibit
This finding suggests a role for ABCB1 genotyping in predicting
genetic polymorphism. P-glycoprotein is an energy-dependent
hematologic responses to protease inhibitors and individualizing
transmembrane efflux pump encoded by the ABCB1 gene (also
antiretroviral drug therapy for HIV-infected patients.
known as the multidrug resistance-1 [MDR1] gene), which is a
Other examples of polymorphic drug transporter proteins
member of the ATP-binding cassette (ABC) transporter superfam-
include the dipeptide transporter, organic anion and cation trans-
ily. P-glycoprotein was first recognized for its ability to actively
porters, and L-amino acid transporter. Their effects on drug distri-
export anticancer agents from cancer cells and promote multidrug
bution are the focus of ongoing research.
resistance to cancer chemotherapy. P-glycoprotein later was discov-
ered to be widely distributed on normal cell types, including
intestinal enterocytes, hepatocytes, renal proximal tubule cells, and
endothelial cells lining the blood–brain barrier. At these locations,
POLYMORPHISMS IN DRUG TARGET GENES
P-glycoprotein serves a protective role by transporting toxic sub-  Genetic polymorphisms occur commonly for drug target pro-
stances or metabolites out of cells. P-glycoprotein affects the distri- teins, including receptors, enzymes, ion channels, and intracellular
bution of some nonchemotherapeutic agents, including digoxin, the signaling proteins. Drug target genes may work in concert with
immunosuppressants cyclosporine and tacrolimus, and antiretrovi- genes that affect pharmacokinetic properties to contribute to overall
ral protease inhibitors (Fig. 6–3). Increased intestinal expression of drug response. Table 6–2 provides examples of drug target genes
P-glycoprotein can limit the absorption of P-glycoprotein sub- linked to drug response in clinical studies. The following section
strates, thus reducing their bioavailability and preventing attain- highlights some of the receptor, enzyme, ion channel, and cell-
ment of therapeutic plasma concentrations. Conversely, decreased signaling protein genes that influence the efficacy and safety of
P-glycoprotein expression may result in supratherapeutic plasma various pharmacologic agents.
concentrations of relevant drugs and drug toxicity.
RECEPTOR GENOTYPES AND
CLINICAL CONTROVERSY DRUG RESPONSE
Much of the data on individual variations in the ABCB1 gene and The β1- and β2-adrenergic receptor genes have been the focus of
response to P-glycoprotein substrates are inconsistent, even con- much research into genetic determinants of responses to β-adrener-
flicting, and require clarification. The combination of multiple gic receptor agonists and antagonists. β1-Receptors are located in the
variations in the ABCB1 gene eventually may prove to be a heart and kidney, where they are involved in the regulation of heart
stronger predictor of drug response than any individual variation. rate, cardiac contractility, and blood pressure. Two common non-
synonymous SNPs in the β1-receptor gene are located at codons 49
A number of polymorphisms have been identified in the pro- (Ser→Gly) and 389 (Arg→Gly), and there is evidence of their
moter and exon regions of the ABCB1 gene. Common SNPs occur involvement in blood pressure control.10 Investigators have exam-
in exons 12 (C1236T), 21 (G2677T), and 26 (C3435T). The exon 21 ined the influence of the β1-receptor gene on blood pressure
and 26 SNPs have been associated with intestinal ABCB1 expres- response to β1-receptor blockade with metoprolol. Hypertensive
sion, P-glycoprotein activity, and digoxin plasma concentrations in patients who were homozygous for both the Ser49 and Arg389 alleles
 37

TABLE 6-2 Genetic Polymorphisms in Drug Targets and Response to Drug Therapy

CHAPTER 6
Gene Drug /Drug Class Drug Effect Associated with Polymorphism
α-Adducin Hydrochlorothiazide Blood pressure reduction78
ACE ACE inhibitors Blood pressure reduction, regression of left ventricular hypertrophy,
renoprotective effects77,78
Epithelial sodium channel Amiloride Blood pressure reduction83
Angiotensinogen ACE inhibitors Blood pressure reduction78
β1-Adrenergic receptor β -Blockers Blood pressure lowering65
β2-Adrenergic receptor β2-Agonists Bronchodilation68
Cyclooxygenase-1 Aspirin Antiplatelet effects109

Pharmacogenetics
Dopamine D3 receptor Levodopa, neuroleptics Tardive dyskinesia84
3-Hydroxy-3-methylglutaryl-coenzyme A reductase Statins Magnitude of cholesterol lowering110
Inhibitory GTP-binding protein β3-subunit Antidepressants Antidepressant response80
5-Lipoxygenase Leukotriene modifier Change in FEV1111
Combination of H2, 5-HT2A, 5-HT2C, 5-HT transporter Clozapine Response in schizophrenia70
Serotonin transporter Selective serotonin reuptake inhibitors Antidepressant response80
Stimulatory GTP-binding protein α-subunit β -Blockers Blood pressure lowering78
Vitamin K epoxide reductase complex subunit-1 Warfarin Dose requirements73
ACE, angiotensin-converting enzyme; H, histamine; FEV1, forced expiratory volume in the first second of expiration; 5-HT, serotonin.

had greater reductions in diastolic blood pressure with metoprolol the data are inconsistent.71 In a more recent study, a combination of
monotherapy compared with carriers of the Gly49 and/or Gly389 six polymorphisms in the histamine and serotonin 2A and 2C
alleles.65 These data suggest that β1-receptor genotype may be an receptor genes and the serotonin transporter gene were 77% predic-
important determinant of blood pressure response to β-blockers in tive of antipsychotic response to clozapine.70 These findings imply
the management of hypertension. Given that a significant percentage that, similar to other drug target gene–drug response relationships,
of hypertensive patients fail to derive adequate blood pressure a combination of polymorphisms, rather than any single polymor-
reduction with β-blocker monotherapy,66 the ability to predict the phism, provides more accurate prediction of clozapine response.
likelihood of response based on genotype would have important
clinical implications. Specifically, β-blockers could be started in ENZYME GENES AND DRUG RESPONSE
patients expected to respond well to this drug class based on their β1-
receptor genotype, whereas other classes of antihypertensive agents Vitamin K epoxide reductase (VKOR) is an example of an enzyme
could be used in patients expected to respond poorly to β-blockers. with genetic contributions to drug response. Warfarin exerts its
β2-Receptors are located on bronchial smooth muscle cells, where anticoagulant effects by inhibiting VKOR, thus preventing carboxyla-
they mediate bronchodilation upon exposure to the β2-receptor tion of clotting factors II, VII, IX, and X. The vitamin K epoxide
agonists. Inhaled β2-agonists are the most effective agents for acute reductase complex subunit-1 gene (VKORC1) encodes for VKOR.
reversal of bronchospasm; however, the magnitude of their effects Mutations in the VKORC1 coding region cause rare cases of warfarin
varies substantially among asthmatic patients.67 More than 11 SNPs resistance. Carriers of these mutations either require exceptionally
have been identified in the β2-receptor gene, three of which occur high warfarin doses (>100 mg/wk) to achieve effective anticoagula-
frequently and result in amino acid changes. Two common nonsyn- tion or fail to respond to any dose of warfarin.72
onymous SNPs are found in the gene’s coding block region, at Aside from rare cases of warfarin resistance, among patients there
codons 16 and 27, and a third occurs upstream from the coding is substantial variability with regard to the dose of warfarin necessary
block in the gene’s promoter region. to produce optimal anticoagulation, defined as an international
A number of studies have examined the association between the normalized ratio of 2.0 to 3.0 for most indications. Common SNPs
codon 16 or 27 polymorphisms and bronchodilatory response to in the VKORC1 promoter and intron regions have been identified
β2-receptor agonists in asthma; however, the results of these studies and found to contribute to the interpatient variability in warfarin
have been largely inconsistent.68 More recently, investigators found dose requirements.73 These SNPs are in linkage disequilibrium (i.e.,
that the combination of SNPs in the gene’s coding block and inherited together) and form several haplotypes. VKORC1 haplo-
promoter region was a better determinant of β2-agonist response type, together with CYP2C9 genotype, explains approximately 30%
than any individual SNP.69 These data suggest that an individual to 40% of the interpatient variability in warfarin dose require-
SNP in the β2-receptor gene is an insufficient predictor of β2-agonist ments.74 Much of the remainder of the variability is believed to be
effects and that multiple receptor gene variations more accurately due to differences in demographic characteristics and dietary habits.
correlate with bronchodilatory response to β2-agonists. Warfarin dosing algorithms that incorporate both genetic and non-
Clozapine is an example of a drug for which evidence indicates genetic (e.g., age, body size) factors have been developed, and their
that multiple receptor genes interact to influence the drug’s effects. accuracy in prospectively predicting warfarin dose is being tested.75,76
Clozapine is an atypical antipsychotic used for the treatment of In the future, it may be possible to use these algorithms to accurately
schizophrenia. Because of its potential to produce agranulocytosis predict warfarin dose requirements for a given patient, thus reducing
in 0.5% to 2% of treated patients, clozapine is reserved for schizo- the patient’s risk for thrombosis and bleeding associated with sub-
phrenic patients who are unresponsive to other drug therapies. therapeutic or supratherapeutic anticoagulation, respectively.
However, only 30% to 60% of patients with refractory schizophre- The angiotensin-converting enzyme (ACE) gene is probably the
nia respond to clozapine.70 Clozapine’s effects are believed to be most widely studied of the enzyme genes. An insertion/deletion (I/
mediated through dopaminergic, serotoninergic, adrenergic, and D) polymorphism in intron 16 of the ACE gene results in the
histaminergic receptors in the central nervous system. Although presence or absence of a 287-base-pair fragment. This polymor-
several studies have demonstrated relationships between single phism has been linked consistently to plasma concentrations of
genetic variants for these receptor subtypes and clozapine response, ACE, the enzyme responsible for conversion of angiotensin I to the
 38

Angiotensinogen (78)
SECTION 1

Bradykinin B1
Renin (27) receptor (36)

Angiotensin I Bradykinin
Bradykinin B2
ACE (101) ACE inhibitor receptor (86)
Angiotensin II Inactive
fragments
Foundation Issues

AT1 receptor (131) ARB

FIGURE 6-4. Single nucleotide poly-

G-protein morphisms (SNPs) identified for renin–
signaling pathways
angiotensin system genes. The number
(numerous)
of polymorphisms identified for each
protein is shown in parentheses after
the protein name (http://snp.cshl.org).
Cellular response (ACE, angiotensin-converting enzyme;
ARB, angiotensin receptor blocker.)

potent vasoconstrictor angiotensin II.77 Given its association with GENES FOR INTRACELLULAR SIGNALING
ACE concentrations, a number of investigators have examined PROTEINS, ION CHANNELS, AND
whether the I/D polymorphism contributes to the interpatient DRUG RESPONSE
variability in ACE inhibitor response. However, much of the data
with the I/D polymorphism and blood pressure response to ACE Cellular responses to many drugs are mediated through GTP-
inhibitors are inconsistent and even conflicting, with some studies binding proteins, also called G proteins. The β1-adrenergic receptor
demonstrating greater response with the DD genotype but others is an example of a G-protein–coupled receptor in which a stimula-
showing greater response with the II genotype.78 In the largest tory G (Gs) protein couples the receptor to intracellular signaling
pharmacogenetic study (including nearly 38,000 patients) to date, mechanisms to elicit a cellular response (Fig. 6–5). Receptor-coupled
no association has been found between the ACE I/D genotype and Gs proteins contain α-, β -, and γ-subunits that mediate the activa-
either blood pressure response or cardiovascular or renal outcome tion of adenylyl cyclase and the generation of cyclic AMP following
with antihypertensive therapy.79 receptor stimulation. A SNP in the α-subunit of Gs protein has been
The negative findings with regard to the ACE gene and ACE linked to the blood pressure response to β -blockers.78 Whether the
inhibitor response are not surprising given that numerous proteins Gs protein α-subunit gene interacts with the β1-adrenergic receptor
are involved in the complex signaling pathway of the renin– gene or other intracellular signaling-protein genes to determine β -
angiotensin system (Fig. 6–4). Multiple genetic polymorphisms blocker response remains to be determined.
have been identified for many of these proteins. Thus, one explana- Disturbances in G-protein–mediated signal transduction have
tion for the lack of an association between the ACE gene and ACE been implicated in the response to antidepressant drugs.80 A com-
inhibitor response is that a single polymorphism contributes little to mon SNP (C825T) occurs in the gene for the inhibitory G (Gi)
the overall response to an ACE inhibitor. Rather, response to ACE protein β3-subunit and has been associated with enhanced intracel-
inhibition may be best determined by a combination of multiple lular signal transduction.81 The TT genotype has been correlated
polymorphisms occurring in multiple genes involved in the renin– with greater improvement in depression symptoms among patients
angiotensin pathway. Indeed, other renin–angiotensin system genes, treated with either a tricyclic antidepressant or serotonin reuptake
including the gene for angiotensinogen and aldosterone synthase,
have been correlated with antihypertensive responses to ACE inhib-
itors and angiotensin receptor blockers,78 suggesting that genes for
ACE, angiotensinogen, aldosterone synthase, and probably other ȕ-blocker
renin–angiotensin system proteins interact to influence ACE inhib-
itor response. Thus, before genotype can be used as a predictor of
response to renin–angiotensin antagonists, the combination of
genetic variants in the renin–angiotensin system that best deter-
mines drug response first must be elucidated. Cell
There is evidence of racial differences in response to ACE inhibi- membrane ȕ-receptor
tors as well as many other pharmacologic agents. Specifically, Adenylyl
African Americans in general are believed to have diminished cyclase
Ȗ ȕ
antihypertensive responses to ACE inhibitors compared with white
people.66 The frequencies of many SNPs in the renin–angiotensin Gs protein Į
system vary between African American and white populations and
may contribute to the observed racial differences in ACE inhibitor ATP cAMP
response. Indeed, most racial differences in drug response probably FIGURE 6-5. β1-receptor coupled to intracellular signaling mechanisms
can be attributed to racial differences in genotype frequencies, by a stimulatory G (Gs) protein.
although this is yet to be determined.
 39
inhibitor, implying that the Gi protein β3-subunit gene may have
80
numerous noncardiovascular agents can induce torsade de pointes,
a role in therapeutic decisions for depression management. and many have been withdrawn from the market as a result. Such

CHAPTER 6
The epithelial sodium channel (ENaC) is an example of an ion drugs include the antihistamines terfenadine and astemizole, the
channel with genetic contributions to drug response. The ENaC is fluoroquinolone antibiotic grepafloxacin, and the motility agent
located in the distal renal tubule and collecting duct of the nephron, cisapride. Given the serious and unpredictable nature of torsade de
where it serves as the final site for sodium reabsorption. The channel pointes, there has been great interest in identifying genetic markers
is composed of α-, β-, and γ-subunits. Mutations in the β- or γ- that predispose individuals to its occurrence.
subunit cause excessive sodium reabsorption and an inherited form Abnormalities in ion flux across the cardiac cell membrane
of hypertension called Liddle syndrome. The more common variant resulting in an excess of intracellular positive ions and delayed
Thr594Met occurs exclusively in blacks and is associated with high ventricular repolarization are characteristic of long QT syndromes.

Pharmacogenetics
blood pressure in this population.82 Amiloride blocks the ENaC but Mutations in genes for the pore-forming channel proteins that
is a relatively weak diuretic with minimal effects on blood pressure affect potassium and sodium transport across the cardiac cell
when used as monotherapy in most hypertensive individuals. How- membrane underlie congenital long QT syndromes.86 There is
ever, evidence indicates that amiloride monotherapy is as effective as evidence that these mutations also may increase the risk for drug-
combination therapy with more potent agents in blacks carrying the induced torsade de pointes.86 The ability to screen for mutations
Thr594Met variant.83 These data suggest that genotyping for the associated with drug-induced torsade de pointes would be of
Thr594Met polymorphism may be appropriate for black patients clinical significance, so that individuals with a genetic predisposi-
whose blood pressure is resistant to traditional antihypertensive tion for this life-threatening arrhythmia could be spared exposure
drugs, in whom treatment with amiloride could be instituted if the to potentially causative agents and treated with alternative therapies.
polymorphism is present.
The examples of drug target genes given thus far relate to drug CORONARY DISEASE PROGRESSION GENE
efficacy. There are also examples of drug target genes linked to drug AND RESPONSE TO STATIN THERAPY
toxicity. One example is the Ser9Gly polymorphism of the dopamine
D3 receptor gene, which has been associated with neuroleptic- Several large clinical trials in patients with coronary heart disease,
induced tardive dyskinesia.84 Tardive dyskinesia is a debilitating including the Scandinavian Simvastatin Survival Study (4S), have
adverse effect that occurs in up 30% of patients treated with typical demonstrated significant reductions in coronary events and mor-
antipsychotics. Genetic influences of adverse effects that occur less tality with β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA)
frequently, such as ACE inhibitor–induced angioedema, are more reductase inhibitors, or statins.87 The gene for apolipoprotein E has
difficult to delineate because of the large sample size needed to been correlated with hepatic cholesterol uptake and the risk for
establish a definite genetic cause. Investigators for many multicenter coronary heart disease.88 Its contribution to coronary heart disease
clinical drug trials now are asking participants to provide consent for progression and statin response was examined in the 4S popula-
the collection of genetic material so that genetic contributions to rare tion.89 Investigators found that the variant ε4 allele was associated
but serious adverse drug effects can be elucidated in future studies. with increased risk for all-cause mortality among placebo-treated
study participants. However, no such association was observed in
DISEASE-ASSOCIATED GENES the simvastatin group, suggesting that simvastatin abolished the
excess mortality risk associated with the ε4 allele.
Numerous genes have been correlated with disease outcomes, and Several other genes have been associated with responses to statins
many of these have been found subsequently to influence response in coronary heart disease. These include the genes for the choles-
to pharmacologic disease management. These gene–drug response teryl ester transfer protein, which is involved in the metabolism of
associations often occur despite the lack of a direct effect on high-density lipoprotein cholesterol; β-fibrinogen, which influences
pharmacokinetic or pharmacodynamic drug properties. Examples plasma fibrinogen concentrations; and stromelysin-1, which is
of disease-associated genes are given in the following. involved in remodeling of the extracellular matrix of atherosclerotic
plaques.88 In each case, the gene linked to worse disease progression
FACTOR V AND PROTHROMBIN GENES AND or clinical outcomes also was associated with the greatest response
ORAL CONTRACEPTION to statin therapy. These data imply that genotype is useful in
identifying which coronary heart disease patients are at increased
Use of oral contraceptives is associated with an increased risk for risk for coronary events and death, in whom treatment with a statin
developing thromboembolic disorders, including deep-vein throm- would be of particular benefit.
bosis, pulmonary embolism, and thrombotic stroke. Variations in the
genes for the coagulation factors prothrombin and factor V Leiden NOVEL SITES FOR DRUG DEVELOPMENT
also have been identified as risk factors for thromboembolic disor-
ders.85 In case-control studies, the presence of a factor V Leiden or The discovery of genes that confer disease has led to an improved
prothrombin gene variation markedly increased the risk for deep- understanding of the molecular mechanisms involved in disease
vein thrombosis and cerebral vein thrombosis among oral contracep- pathophysiology. Once associations between genes and diseases are
tive users.85 These data suggest that women who are known to carry a discovered, scientists can elucidate the functions of the encoded
prothrombin or factor V Leiden mutation should use alternative birth proteins and more clearly define the consequences of genetic muta-
control measures. tions. Insight into the genetic control of cellular functions may
reveal new strategies for disease treatment and prevention.
CONGENITAL LONG QT SYNDROME AND For example, overexpression of the human epidermal growth factor
DRUG-INDUCED TORSADES DE POINTES receptor-2 (HER2) secondary to HER2 gene amplification occurs in
20% to 30% of metastatic breast cancers and is associated with
Drug-induced QT-interval prolongation may precipitate the seri- decreased survival.90 The discovery of HER2 overexpression and its
ous, potentially life-threatening arrhythmia called torsades de effects on cancer prognosis led to the development of trastuzumab, a
pointes. It is well recognized that many antiarrhythmic drugs can recombinant monoclonal antibody that targets and blocks HER2. The
cause QT-interval prolongation and torsade de pointes. In addition, addition of trastuzumab to cancer chemotherapy significantly slows
 40
the progression of cancer and improves tumor response rates in genes to recipient cell targets. Disease-causing genes are replaced
women with HER2-positive tumors.90 Testing for HER2 overexpres- with the desired therapeutic genes; the viral genes that control
SECTION 1

sion is necessary to determine which patients may benefit from delivery mechanisms are retained.
trastuzumab. The FDA has approved several tests that detect HER2 The first viral vectors introduced were retroviruses, which are
overexpression either directly by measuring the amount of protein or RNA viruses that integrate into the host cell genome and replicate
indirectly by measuring gene amplification. during cell division. Thus, retroviral gene transfer is capable of
The discovery that the apolipoprotein E gene is strongly linked to permanently altering gene expression. Retroviruses can be used to
Alzheimer’s disease91 and that the α-synuclein gene is associated with deliver genes through either direct infusion into target organs or ex
Parkinson’s disease92 raises the possibility of examining these genes as vivo manipulation of harvested cells followed by reinfusion into the
targets for drug therapy for psychiatric and neurologic diseases. recipient. The disadvantages of retroviral vectors are the limited size
Foundation Issues

of the gene they can carry, relatively low efficiency, and risk of
insertional mutagenesis. In fact, the FDA temporarily halted retro-
GENE THERAPY viral gene delivery into hematopoietic tissue in early 2003 after
 Gene therapy has emerged as a possible approach to treating and leukemia developed as a result of insertional mutagenesis in two of
curing disease by altering gene expression. Initially, the focus of gene 11 SCID-affected children treated with retroviral gene therapy.94 A
therapy was treatment of inherited disorders such as cystic fibrosis, third child later developed cancer.
sickle cell anemia, hemophilia, and adenosine deaminase deficiency. Since research with retroviral gene therapy has resumed, some
Gene therapy trials later were expanded to include patients with success with this mode of gene delivery has been reported in the area
acquired diseases such as cancer and heart disease. The goal of gene of oncology. In 2003, the FDA granted orphan drug status for a
therapy for inherited diseases is to correct genetic defects permanently retroviral gene therapy that targets the cyclin G1 gene in the
and thereby restore normal cellular function. Gene therapy for acquired treatment of pancreatic cancer. Retroviruses also have been used in
diseases aims to cure disease by targeting pathogenic processes. the development of recombinant cancer vaccines designed to stim-
Most gene therapy techniques for inherited diseases attempt to ulate the immune system to recognize and destroy cancer cells. One
replace defective genes with normally functioning ones. Exogenous such vaccine was associated with regression of metastatic lesions in
genes, called transgenes, can be transferred into either somatic two of 15 patients with advanced melanoma.95
(body) or germ-line (egg or sperm) cells of the recipient. In somatic
cell gene transfer, genetic changes do not affect future generations. ADENOVIRAL GENE DELIVERY
In contrast, germ-line cell transfer, which currently is prohibited by
the FDA, results in the passage of genetic alterations to offspring. Unlike retroviruses, adenoviruses do not integrate into the host
The first clinical gene therapy trial for treatment of adenosine genome and thus do not replicate. As a result, genes delivered by
deaminase deficiency began in 1990.93 B and T lymphocytes fail to adenoviruses are active only temporarily. Adenoviral-mediated
develop in this autosomal recessive disease, resulting in a severe gene therapy is used commonly in cancer patients because perma-
combined immunodeficiency syndrome (SCID) made famous by nent gene expression is unnecessary in this patient population.
the “bubble boys” whose lives were confined to tents in an effort to Tumor cells have been infused with adenoviral vectors carrying
keep them in a germ-free environment. Only two patients were the herpes simplex virus-1 thymidine kinase gene and then exposed
included in this trial, and although both boys continued to demon- to ganciclovir as a mode of cancer chemotherapy.96 Thymidine
strate clinical improvement 10 years later, gene therapy did not cure kinase converts ganciclovir to its active, cytotoxic form, which is
the disease, as investigators had hoped. incorporated in the DNA of tumor cells, leading to their death.
Since then, the FDA has approved more than 700 clinical gene Adenoviruses can be grown in high titers and do not carry the risk
therapy trials (www.clinicaltrials.gov). Most of these trials involve cancer of insertional mutagenesis. The major disadvantage of adenoviruses
patients; however, a number of studies also target inherited disorders. is their immunogenic potential, which has resulted in one death and
The results of gene therapy trials to date have been disappointing, with prompted federal oversight of gene therapy trials.97
reports of serious toxicities and few therapeutic successes.
OTHER MEANS OF GENE DELIVERY
OBSTACLES TO SUCCESS
Adeno-associated viruses are human DNA-containing viruses that
Reasons for limited success with gene therapy include inefficient do not appear to trigger immune responses upon injection. Similar
gene delivery to target cells, inadequate gene expression, and unac- to retroviruses, adeno-associated viruses are incapable of carrying a
ceptable adverse effects.93 large amount of genetic material, and their use entails the risk of
Sufficient amounts of the transgene must be inserted into a insertional mutagenesis. Investigators have reported some success
sufficient number of recipient cells to produce a therapeutic in treating hemophilia B using intramuscular injections of an
response. In addition, the transgene must be inserted into the adeno-associated virus vector that expresses the human coagulation
correct chromosomal position of the correct cell nucleus so as not factor IX gene.98
to disrupt normal gene function and expression. Incorrect chromo- Scientists are experimenting with nonviral delivery methods such
somal insertion of the transgene is a problem referred to as inser- as the use of direct DNA injection, liposomes, and electroporation.
tional mutagenesis. Once the therapeutic gene is integrated correctly Some success with intramyocardial transfection of plasmid DNA
into host DNA, it must be expressed at adequate levels and at encoding for vascular endothelial growth factor into patients with
appropriate times to restore normal cell function. Finally, the gene severe, intractable angina has been reported.99 Initially, the proce-
delivery system and delivery technique should lack any potential to dure improved myocardial perfusion and angina in this patient
cause unwanted effects in the transgene recipient. population, with few major adverse events. One year later, patients
continued to report some improvement in anginal symptoms.100
RETROVIRAL GENE DELIVERY Scientists have enjoyed few successes with gene therapy for
inherited diseases. Improvements in gene delivery techniques and a
Because of their efficiency in integrating into human DNA, better understanding of molecular processes controlling gene
viruses are the most common vectors used to deliver therapeutic expression are necessary before gene therapy can correct genetic
 41
defects successfully and thus cure associated diseases without induc- nosuppressants cyclosporine and tacrolimus are believed to be sub-
ing adverse effects. Because of limited success with traditional strates for both P-glycoprotein and the CYP450, CYP3A4, and

CHAPTER 6
approaches to gene therapy, scientists are exploring other strategies, possibly CPY3A5 enzymes.112 Thus, it is possible that genes for both
such as repairing or regulating (“turning off”) defective genes rather MDR1 and CYP450 enzymes interact to influence cyclosporine and
than replacing them.101 Scientists have reported more success with tacrolimus distribution and plasma concentrations.
gene therapy for acquired diseases, such as cancer, and a number of Pharmacists are broadly trained in a number of medication-
phase II and III clinical trials in this area are underway. While gene related areas, including pharmacology, pharmacokinetics, and phar-
therapy research is evolving, much progress is needed before effec- macodynamics. This training places pharmacists in a unique posi-
tive and safe therapies are available. tion to deal with the complexities of the drug-decision process in the
age of pharmacogenetics. Pharmacists will be in key positions to

Pharmacogenetics
interpret the results of genetic tests, determine the ultimate effects of
ETHICAL CONSIDERATIONS multiple genetic variations on drug response, and choose the most
appropriate drug for a given patient based on the individual’s DNA.
PHARMACOGENETICS Thus, it will be essential for pharmacists to stay abreast of significant
discoveries in genotype–drug response relationships and understand
Traditionally, genetic testing refers to screening human genetic mate-
how best to incorporate this genomic information into pharmaco-
rial to identify genotypes associated with disease susceptibility or
therapeutic decisions.
carrier status for inherited diseases, such as Huntington’s disease,
Recognizing the challenges in healthcare delivery with advancing
Alzheimer’s disease, and breast cancer. This kind of testing can have
genetic discoveries, the National Coalition for Health Professional
profound legal, ethical, and social implications. For example, knowl-
Education in Genetics established core competencies related to genet-
edge that a patient is at risk for developing a genetic disorder could
ics for healthcare professionals that are available through the coali-
result in discrimination by employers or insurance companies. In
tion’s website (www.nchpeg.org). The objective of these competencies
addition, this information likely would cause emotional distress for
is to encourage clinicians to incorporate genetics knowledge, skills,
the individual at risk and his or her family members.
and attitudes into their clinical practices. Subsequently, the American
Within the context of pharmacogenetics, however, testing
Association of Colleges of Pharmacy developed recommendations to
involves searching for genetic variations linked to drug efficacy or
guide academic institutions on how to instill these competencies in
toxicity rather than to disease susceptibility. In many instances, this
future pharmacists so that pharmacists will be prepared to provide
form of testing will carry little risk for ethical, legal, and social
appropriate pharmacotherapy in the age of genomics.102
concerns. For example, knowledge that a person has a genotype
associated with poor blood pressure response to a β-blocker is of
little consequence because a number of alternative therapies are
available. However, more serious implications may arise if a person APPLICATION OF PHARMACOGENETIC DATA
is predicted to respond poorly to a drug based on genotype, and TO DISEASE MANAGEMENT
treatment options are limited. Thus, ethical considerations associ-
ated with pharmacogenetic testing may need to be addressed before Pharmacogenetics has the potential to greatly improve the pharma-
testing is widely accepted by the public. cologic management of disease. Clinicians may be able to predict
the likelihood that an individual will respond to a particular
medication based on the patient’s genotype. Medications may be
GENE THERAPY
avoided or prescribed in lower doses with careful monitoring in
Many of the ethical concerns with gene therapy center on transgenic patients genetically predisposed to the drugs’ adverse effects. This
manipulation of somatic versus germ-line cells. Somatic gene ther- would be of particular benefit for drugs with a narrow therapeutic
apy only affects the recipient, that is, genetic alterations introduced index. For example, warfarin may be initiated at lower doses, with
by gene therapy are not passed on to future generations. In contrast, closer monitoring in patients with a VKORC1 haplotype associated
with manipulation of germ-line cells, alterations are passed on to with increased warfarin sensitivity or a CYP2C9 allele associated
children of the treated patient. Some argue that this is unethical with reduced warfarin metabolism.
because it violates the rights of future generations. Thus, it appears With pharmacogenetics, it may be possible to eliminate the trial-
that most gene therapy in the foreseeable future will focus on and-error approach to drug prescribing for many diseases. Instead,
somatic gene transfer. clinicians may be able to use genetic information to match the right
drug to the right patient at the right dose while minimizing adverse
effects. For example, the current approach to hypertension manage-
ROLE OF PHARMACISTS ment involves the trial of various antihypertensives until blood
pressure goals are achieved with acceptable drug tolerability. Com-
Although pharmacogenetics provides opportunities to improve drug monly, the initial agent fails to lower blood pressure to goal or
therapy outcomes, it likely will increase the complexity of drug produces intolerable adverse effects (Fig. 6–6). Trials of additional or
prescribing. In addition to considering factors such as age, concom- alternative antihypertensive medications must be undertaken until
itant drug therapy, and renal and hepatic function, prescribers will treatment is deemed successful. In the interim, the patient remains
have to interpret the results of genetic analyses when making drug hypertensive and at risk for hypertension-related target-organ dam-
therapy decisions. The FDA has already incorporated genetic infor- age. With pharmacogenetics, clinicians may choose the antihyper-
mation into the package insert for a number of drugs, including tensive drug expected to provide the greatest response with the best
irinotecan, azathioprine, mercaptopurine, fluoxetine, and celecoxib. tolerability for a particular patient based on his or her DNA.
Further complicating the drug-prescribing process are many med- New drugs may be developed based on knowledge about genetic
ications whose effects are not determined by single polymorphisms control of cellular functions. For example, the discovery that
in single genes. Rather, pharmacologic effects for most medications chronic myeloid leukemia was caused by chromosome transloca-
likely are determined by the interaction of polymorphisms in multi- tion and consequent production of an enzyme capable of producing
ple genes that encode proteins involved in the various pathways of life-threatening lymphocyte levels led to accelerated FDA approval
drug metabolism, distribution, and effects. For example, the immu- of Gleevec (also known as STI-571), an inhibitor of the transloca-
 42

Same therapy for Individualized therapy based

SECTION 1

all patients on genotype

Adverse effects:
Initiate alternative therapy
Foundation Issues

Therapeutic success: Population with a Therapeutic success:

Continue current therapy given disease Continue current therapy

Nonresponders:
Initiate alternative therapy

FIGURE 6-6. Current and future approaches to pharmacologic management of disease.

tion-created enzyme, for treatment of chronic myeloid leukemia.103 FDA: Food and Drug Administration
In addition, future drug development may focus on treating specific G: guanine
genetic subgroups instead of broadly treating all individuals with a
HIV: human immunodeficiency virus
particular disease. Along these lines, the FDA is encouraging phar-
maceutical companies to submit pharmacogenetic data during the I/D: insertion/deletion
drug development process.104 Ultimately, pharmacogenetics may MDR1: multidrug resistance-1
improve the quality and reduce the overall costs of healthcare by PM: poor metabolizer
decreasing the number of treatment failures and the number of
adverse drug reactions and leading to the discovery of new genetic SCID: severe combined immunodeficiency syndrome
targets and therapeutic interventions for disease management. SNPs: single nucleotide polymorphisms
T: thymidine
TPMT: thiopurine S-methyltransferase
CLINICAL CONTROVERSY UGT: uridine diphosphate glucuronosyltransferase
For many drugs, such as warfarin, variations in genes affecting UM: ultrarapid metabolizer
both pharmacokinetic and pharmacodynamic drug properties
may interact to determine the ultimate effects of drug therapy.
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reduces smoking. Nature 1998;393:750. 79. Arnett DK, Davis BR, Ford CE, et al. Pharmacogenetic association of
Foundation Issues

56. Sellers EM, Tyndale RF. Mimicking gene defects to treat drug depen- the angiotensin-converting enzyme insertion/deletion polymorphism
dence. Ann N Y Acad Sci 2000;909:233–246. on blood pressure and cardiovascular risk in relation to antihyperten-
57. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic sive treatment: The Genetics of Hypertension-Associated Treatment
polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and (GenHAT) study. Circulation 2005;111:3374–3383.
pharmacokinetics of the calcineurin inhibitors cyclosporine and tac- 80. Serretti A, Benedetti F, Zanardi R, Smeraldi E. The influence of Serotonin
rolimus. Clin Pharmacol Ther 2003;74:245–254. Transporter Promoter Polymorphism (SERTPR) and other polymor-
58. Zheng H, Zeevi A, Schuetz E, et al. Tacrolimus dosing in adult lung phisms of the serotonin pathway on the efficacy of antidepressant treat-
transplant patients is related to cytochrome P4503A5 gene polymor- ments. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1074–1084.
phism. J Clin Pharmacol 2004;44:135–140. 81. Siffert W, Rosskopf D, Moritz A, et al. Enhanced G protein activation
59. Lu Z, Zhang R, Carpenter JT, Diasio RB. Decreased dihydropyrimidine in immortalized lymphoblasts from patients with essential hyperten-
dehydrogenase activity in a population of patients with breast cancer: sion. J Clin Invest 1995;96:759–766.
Implication for 5-fluorouracil-based chemotherapy. Clin Cancer Res 82. Su YR, Menon AG. Epithelial sodium channels and hypertension.
1998;4:325–329. Drug Metab Dispos 2001;29:553–556.
60. Ando Y, Saka H, Asai G, Sugiura S, Shimokata K, Kamataki T. 83. Baker EH, Duggal A, Dong Y, et al. Amiloride, a specific drug for hyperten-
UGT1A1 genotypes and glucuronidation of SN-38, the active metabo- sion in black people with T594M variant? Hypertension 2002;40:13–17.
lite of irinotecan. Ann Oncol 1998;9:845–847. 84. de Leon J, Susce MT, Pan RM, Koch WH, Wedlund PJ. Polymorphic
61. Wasserman E, Myara A, Lokiec F, et al. Severe CPT-11 toxicity in patients variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine
with Gilbert’s syndrome: Two case reports. Ann Oncol 1997;8:1049–1051. D2 and D3 receptors and their association with tardive dyskinesia in
62. Iyer L, Das S, Janisch L, et al. UGT1A1*28 polymorphism as a severe mental illness. J Clin Psychopharmacol 2005;25:448–456.
determinant of irinotecan disposition and toxicity. Pharmacogenom- 85. Martinelli I, Battaglioli T, Mannucci PM. Pharmacogenetic aspects of
ics J 2002;2:43–47. the use of oral contraceptives and the risk of thrombosis. Pharmacoge-
63. Johne A, Kopke K, Gerloff T, et al. Modulation of steady-state kinetics netics 2003;13:589–594.
of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin 86. Roepke TK, Abbott GW. Pharmacogenetics and cardiac ion channels.
Pharmacol Ther 2002;72:584–594. Vasc Pharmacol 2006;44:90–106.
64. Fellay J, Marzolini C, Meaden ER, et al. Response to antiretroviral 87. Executive Summary of The Third Report of The National Cholesterol
treatment in HIV-1–infected individuals with allelic variants of the Education Program (NCEP) Expert Panel on Detection, Evaluation,
multidrug resistance transporter 1: A pharmacogenetics study. Lancet and Treatment of High Blood Cholesterol in Adults (Adult Treatment
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65. Johnson JA, Zineh I, Puckett BJ, McGorray SP, Yarandi HN, Pauly DF. 88. Maitland-van der Zee AH, Klungel OH, Stricker BH, et al. Genetic
Beta 1-adrenergic receptor polymorphisms and antihypertensive response polymorphisms: Importance for response to HMG-CoA reductase
to metoprolol. Clin Pharmacol Ther 2003;74:44–52. inhibitors. Atherosclerosis 2002;163:213–222.
66. Materson BJ, Reda DJ, Cushman WC. Department of Veterans Affairs 89. Gerdes LU, Gerdes C, Kervinen K, et al. The apolipoprotein ε4 allele
single-drug therapy of hypertension study. Revised figures and new determines prognosis and the effect on prognosis of simvastatin in
data. Department of Veterans Affairs Cooperative Study Group on survivors of myocardial infarction: A substudy of the Scandinavian
Antihypertensive Agents. Am J Hypertens 1995;8:189–192. simvastatin survival study. Circulation 2000;101:1366–1371.
67. Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly 90. Harries M, Smith I. The development and clinical use of trastuzumab
scheduled with as-needed use of albuterol in mild asthma. Asthma (Herceptin). Endocr Relat Cancer 2002;9:75–85.
Clinical Research Network. N Engl J Med 1996;335:841–847. 91. Brickell KL, Steinbart EJ, Rumbaugh M, et al. Early-onset Alzheimer’s
68. Litonjua AA. The significance of β2-adrenergic receptor polymor- disease in families with late-onset Alzheimer’s disease: A potential important
phisms in asthma. Curr Opin Pulm Med 2006;12:12–17. subtype of familial Alzheimer’s disease. Arch Neurol 2006;63:1307–1311.
69. Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and 92. Mizuno Y, Hattori N, Yoshino H, et al. Progress in familial Parkinson’s
coding region β2-adrenergic receptor haplotypes alter receptor expres- disease. J Neural Transm Suppl 2006:191–204.
sion and predict in vivo responsiveness. Proc Natl Acad Sci USA 93. Fibison WJ. Gene therapy. Nurs Clin North Am 2000;35:757–772.
2000;97:10483–10488. 94. Marshall E. Gene therapy. Second child in French trial is found to have
70. Arranz MJ, Munro J, Birkett J, et al. Pharmacogenetic prediction of leukemia. Science 2003;299:320.
clozapine response. Lancet 2000;355:1615–1616. 95. Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in
71. Masellis M, Basile VS, Ozdemir V, Meltzer HY, Macciardi FM, patients after transfer of genetically engineered lymphocytes. Science
Kennedy JL. Pharmacogenetics of antipsychotic treatment: Lessons 2006;314:126–129.
learned from clozapine. Biol Psychiatry 2000;47:252–266. 96. Morris JC, Ramsey WJ, Wildner O, Muslow HA, Aguilar-Cordova E,
72. Rost S, Fregin A, Ivaskevicius V, et al. Mutations in VKORC1 cause Blaese RM. A phase I study of intralesional administration of an adenovi-
warfarin resistance and multiple coagulation factor deficiency type 2. rus vector expressing the HSV-1 thymidine kinase gene (AdV.RSV-TK) in
Nature 2004;427:537–541. combination with escalating doses of ganciclovir in patients with cutane-
73. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on ous metastatic malignant melanoma. Hum Gene Ther 2000;11:487–503.
transcriptional regulation and warfarin dose. N Engl J Med 2005;352:2285– 97. Marshall E. Gene therapy death prompts review of adenovirus vector.
2293. Science 1999;286:2244–2245.
74. Carlquist JF, Horne BD, Muhlestein JB, et al. Genotypes of the 98. Jiang H, Pierce GF, Ozelo MC, et al. Evidence of multiyear factor IX
cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reduc- expression by AAV-mediated gene transfer to skeletal muscle in an
tase complex subunit 1 conjointly determine stable warfarin dose: A individual with severe hemophilia B. Mol Ther 2006;14:452–455.
prospective study. J Thromb Thrombolysis 2006;22:191–197. 99. Symes JF, Losordo DW, Vale PR, et al. Gene therapy with vascular
75. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and endothelial growth factor for inoperable coronary artery disease. Ann
VKORC1 genetic polymorphism and patient characteristics upon Thorac Surg 1999;68:830–836.
 45
100. Fortuin FD, Vale P, Losordo DW, et al. One-year follow-up of direct special regard to ANF and SLE in fast and slow acetylators. Acta Med
myocardial gene transfer of vascular endothelial growth factor-2 using Scand 1975;198:475–482.

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naked plasmid deoxyribonucleic acid by way of thoracotomy in no- 107. Strandberg I, Boman G, Hassler L, Sjoqvist F. Acetylator phenotype in
option patients. Am J Cardiol 2003;92:436–439. patients with hydralazine-induced lupoid syndrome. Acta Med Scand
101. Sullenger BA. Targeted genetic repair: An emerging approach to 1976;200:367–371.
genetic therapy. J Clin Invest 2003;112:310–311. 108. Pullar T, Hunter JA, Capell HA. Effect of acetylator phenotype on
102. Johnson JA, Bootman JL, Evans WE, et al. Pharmacogenomics: A efficacy and toxicity of sulfphasalazine in rheumatoid arthritis. Ann
scientific revolution in pharmaceutical sciences and pharmacy prac- Rheum Dis 1985;44:831–837.
tice. Report of the 2001–2002 Academic Affairs Committee. Am J 109. Maree AO, Curtin RJ, Chubb A, et al. Cyclooxygenase-1 haplotype modu-
Pharm Educ 2002;66:12S–15S. lates platelet response to aspirin. J Thromb Haemost 2005;3:2340–2345.
103. Johnson JR, Bross P, Cohen M, et al. Approval summary: Imatinib 110. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP Jr,

Pharmacogenetics
mesylate capsules for treatment of adult patients with newly diagnosed Ridker PM. Pharmacogenetic study of statin therapy and cholesterol
Philadelphia chromosome-positive chronic myelogenous leukemia in reduction. JAMA 2004;291:2821–2827.
chronic phase. Clin Cancer Res 2003;9:1972–1979. 111. Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association
104. Ratner M. FDA pharmacogenomics guidance sends clear message to between ALOX5 promoter genotype and the response to anti-asthma
industry. Nat Rev Drug Discov 2005;4:359. treatment. Nat Genet 1999;22:168–170.
105. Devadatta S, Gangadharam PRJ, Andrews RH. Peripheral neuritis due 112. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic
to isoniazid. Bull World Health Organ 1960;23:587–598. polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and
106. Henningsen NC, Cederberg A, Hanson A, Johansson BW. Effects of pharmacokinetics of the calcineurin inhibitors cyclosporin and tacroli-
long-term treatment with procaine amide. A prospective study with mus. Clin Pharmacol Ther 2003;74:245–254.
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 47

C HAP T E R

7 Pediatrics

MILAP C. NAHATA AND CAROL TAKETOMO

ture; those between 1 day and 1 month of age are neonates; 1 month
KEY CONCEPTS to 1 year are infants; 1 to 11 years are children; and 12 to 16 years are
adolescents. This chapter covers notable examples of problems in
 Children are not just “little adults,” and lack of data on impor- pediatrics, pharmacokinetic differences in pediatric patients, drug
tant pharmacokinetic and pharmacodynamic differences has efficacy and toxicity in this patient group, and various factors
led to several disastrous situations in pediatric care. affecting pediatric pharmacotherapy. Specific examples of problems
 Variations in absorption of medications from the gastrointesti- and special considerations in pediatric patients are cited to enhance
nal tract, intramuscular injection sites, and skin are important in understanding.
pediatric patients, especially in premature and other newborn  Infant mortality has declined from 200 per 1,000 births in the
infants. 19th century to 75 per 1,000 births in 1925 to 6.79 per 1,000 births in
2004.1 This success has resulted largely from improvements in identi-
 The rate and extent of organ function development and the fication, prevention, and treatment of diseases once common during
distribution, metabolism, and elimination of drugs differ not delivery and the period of infancy. Although most marketed drugs are
only between pediatric versus adult patients but also among used in pediatric patients, only one fourth of the drugs approved by
pediatric age groups. the Food and Drug Administration (FDA) have indications specific
 The effectiveness and safety of drugs may vary among various for use in the pediatric population. Data on the pharmacokinetics,
age groups and from one drug to another in pediatric versus pharmacodynamics, efficacy, and safety of drugs in infants and
adult patients. children are scarce. Lack of this type of information led to disasters
such as gray baby syndrome from chloramphenicol, phocomelia from
 Concomitant diseases may influence dosage requirements to thalidomide, and kernicterus from sulfonamide therapy. Gray baby
achieve a targeted effect for a specific disease in children. syndrome was first reported in two neonates who died after excessive
 The myth that neonates and young infants do not experience doses of chloramphenicol (100–300 mg/kg/day); the serum concen-
pain has led to inadequate pain management in this pediatric trations of chloramphenicol immediately before death were 75 and
population. 100 mcg/mL. Patients with gray baby syndrome usually have abdom-
inal distension, vomiting, diarrhea, a characteristic gray color, respi-
 Special methods of drug administration are needed for infants ratory distress, hypotension, and progressive shock.
and young children. Thalidomide is well known for its teratogenic effects. Clearly
implicated as the cause of multiple congenital fetal abnormalities
Many medicines needed for pediatric patients are not available
(particularly limb deformities), thalidomide also can cause poly-
in appropriate dosage forms; thus, the dosage forms of drugs
neuritis, nerve damage, and mental retardation. Isotretinoin (Accu-
marketed for adults may require modification for use in infants
tane) is another teratogen. Because it is used to treat severe acne
and children, necessitating assurance of potency and safety of
vulgaris, which is common in teenage patients who may be sexually
drug use.
active but not willing to acknowledge that activity to healthcare

The pediatric medication-use process is complex and error- professionals, isotretinoin has presented a difficult problem in
prone because of the multiple steps required in calculating, patient education since its marketing in the 1980s.
verifying, preparing, and administering doses. Kernicterus was reported in neonates receiving sulfonamides,
which displaced bilirubin from protein-binding sites in the blood to
cause a hyperbilirubinemia. This results in deposition of bilirubin in
Remarkable progress has been made in the clinical management of the brain and induces encephalopathy in infants.
disease in pediatric patients. This chapter highlights important Another area of concern in pediatrics is identifying an optimal
principles of pediatric pharmacotherapy that must be considered dosage. Dosage regimens cannot be based simply on body weight or
when the diseases discussed in other chapters of this book occur in surface area of a pediatric patient extrapolated from adult data.
pediatric patients, defined as those younger than 18 years. Newborn Bioavailability, pharmacokinetics, pharmacodynamics, efficacy, and
infants born before 37 weeks of gestational age are termed prema- adverse-effect information can differ markedly between pediatric
and adult patients, as well as among pediatric patients, because of
differences in age, organ function, and disease state. Significant
Learning objectives, review questions, progress has been made in the area of pediatric pharmacokinetics
and other resources can be found at during the last 2 decades, but few such studies have correlated
www.pharmacotherapyonline.com. pharmacokinetics with the outcomes of efficacy, adverse effects, or
quality of life.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 48
Several additional factors should be considered in optimizing INTRAMUSCULAR SITES
pediatric drug therapy. Many drugs prescribed widely for infants
SECTION 1

and children are not available in suitable dosage forms. For exam- Drug absorption from an intramuscular site may be altered in
ple, extemporaneous liquid dosage forms of amiodarone, captopril, premature infants. Differences in relative muscle mass, poor perfu-
omeprazole, and spironolactone are prepared for infants and chil- sion to various muscles, peripheral vasomotor instability, and insuf-
dren who cannot swallow tablets or capsules, and injectable dosage ficient muscular contractions in premature infants compared with
forms of aminophylline, methylprednisolone, morphine, and phe- older children and adults can influence drug absorption from the
nobarbital are diluted to accurately measure small doses for infants. intramuscular site. The net effect of these factors on drug absorption
Alteration (dilution or reformulation) of dosage forms intended for is impossible to predict; phenobarbital has been reported to be
adult patients raises questions about the bioavailability, stability, absorbed rapidly,10 whereas diazepam absorption may be delayed.11
Foundation Issues

and compatibility of these drugs. Because of low fluid volume Thus, intramuscular dosing is used rarely in neonates except in
requirements and limited access to intravenous sites, special meth- emergencies or when an intravenous site is inaccessible.
ods must be used for delivery of intravenous drugs to infants and
children. As simple as it may seem, administration of oral drugs to
young patients continues to be a difficult task for nurses and
SKIN
parents. Similarly, ensuring adherence to pharmacotherapy in pedi- Percutaneous absorption may be increased substantially in newborns
atric patients poses a special challenge. because of an underdeveloped epidermal barrier (stratum corneum)
Finally, the need for additional pharmacologic or therapeutic and increased skin hydration. Furthermore, because the ratio of total
research brings up the issue of ethical justification for conducting body surface area to total body weight is highest in the youngest
research. Investigators proposing studies and institutional review group, the relative systemic exposure of topically applied drugs,
committees approving human studies must assess the risk-to- including corticosteroids, may be higher in infants and young
benefit ratio of each study to be fair to children who are not in a children than in adults. The increased exposure can produce toxic
position to accept or reject the opportunity to participate in the effects after topical use of hexachlorophene soaps and powders,12
research project. salicylic acid ointment, and rubbing alcohol.13 Interestingly, a study
Enormous progress in pharmacokinetics has been made in pedi- has shown that a therapeutic serum concentration of theophylline
atric patients. Two factors have contributed to this progress: (a) the can be achieved for control of apnea in premature infants less than 30
availability of sensitive and specific analytic methods to measure weeks’ gestation after topical application of gel containing a standard
drugs and their metabolites in small volumes of biologic fluids and dose of theophylline.14 Use of this route of administration may
(b) awareness of the importance of clinical pharmacokinetics in minimize the unpredictability of oral and intramuscular absorption
optimization of drug therapy. Absorption, distribution, metabo- and the complications of intravenous drug administration for cer-
lism, and elimination of many drugs are different in premature tain drugs. A transdermal patch formulation of methylphenidate has
infants, full-term infants, and older children, and this topic is been approved for use in children 6 to 12 years of age for treatment
discussed in detail in the next few sections. of attention-deficit/hyperactivity disorder (ADHD). The patch can
be applied once daily and can remain on during normal activities
such as bathing, swimming, and exercising.
ABSORPTION
GASTROINTESTINAL TRACT DISTRIBUTION
 Two factors affecting the absorption of drugs from the gas-  Drug distribution is determined by the physicochemical properties
trointestinal tract are pH-dependent passive diffusion and gastric of the drug itself (pKa, molecular weight, partition coefficient) and the
emptying time. Both processes are strikingly different in premature physiologic factors specific to the patient. Although the physicochem-
infants compared with older children and adults. In a full-term ical properties of the drug are constant, the physiologic functions
infant, gastric pH ranges from 6 to 8 at birth but declines to 1 to 3 often vary in different patient populations. Some important patient-
within 24 hours.2 In contrast, gastric pH remains elevated in specific factors include extracellular and total body water, protein
premature infants because of immature acid secretion.3 binding by the drug in plasma, and presence of pathologic conditions
In premature infants, higher serum concentrations of acid-labile modifying physiologic function. Total body water, as a percentage of
drugs, such as penicillin,4 ampicillin,5 and nafcillin,6 and lower serum total body weight, has been estimated to be 94% in fetuses, 85% in
concentrations of a weak acid such as phenobarbital7 can be premature infants, 78% in full-term infants, and 60% in adults.14
explained by higher gastric pH. Because of a lack of extensive data Extracellular fluid volume also is markedly different in premature
comparing serum concentration–time profiles after oral versus infants compared with older children and adults; the extracellular
intravenous drug administration, differences in the bioavailability fluid volume may account for 50% of body weight in premature
of drugs in premature infants are poorly understood. Although little infants, 35% in 4- to 6-month-old infants, 25% in children 1 year old,
is known about the influence of developmental changes with age on and 19% in adults.15 This conforms to the observed gentamicin
drug absorption in pediatric patients, a few studies with drugs (e.g., distribution volumes of 0.48 L/kg in neonates and 0.20 L/kg in
digoxin and phenobarbital) and nutrients (e.g., arabinose and adults.16 Studies have shown that the distribution volume of tobramy-
xylose) have suggested that the processes of both passive and active cin is largest in the most premature infants and decreases with
transport may be fully developed by approximately 4 months of increases in gestational age and birth weight of the infant.17
age.8 Little is known about the development and expression of the Binding of drugs to plasma proteins is decreased in newborn
efflux transporter P-glycoprotein and the intestinal drug-metaboliz- infants because of decreased plasma protein concentration, lower
ing enzymes and their impact on drug absorption and bioavailabil- binding capacity of protein, decreased affinity of proteins for drug
ity in infants and children. binding, and competition for certain binding sites by endogenous
Studies have shown that gastric emptying is slow in a premature compounds such as bilirubin. The plasma protein binding of many
infant.9 Thus, drugs with limited absorption in adults may be drugs, including phenobarbital, salicylates, and phenytoin, is signifi-
absorbed efficiently in a premature infant because of prolonged cantly less in the neonate than in the adult.18 The decrease in plasma
contact time with gastrointestinal mucosa. protein binding of drugs can increase their apparent volumes of
 49
distribution. Therefore, premature infants require a larger loading should be noted. First, in premature infants receiving theophylline
dose than do older children and adults to achieve a therapeutic serum for treatment of apnea, a significant amount of its active metabolite

CHAPTER 7
concentration of drugs such as phenobarbital19 and phenytoin.20 caffeine may be present, unlike the case in older children and
The consequences of increased concentrations of free or unbound adults.18 Second, theophylline clearance in children 1 to 9 years of
drug in the serum and tissues must be considered. Pharmacologic age exceeds the values in infants as well as adults. Thus, a child with
and toxic effects are related directly to the concentration of free asthma often requires markedly higher doses on a weight basis of
drug in the body. Increases in free drug concentrations may result theophylline compared with an adult.31 Because of decreased metab-
directly from decreases in plasma protein binding or indirectly olism, doses of drugs such as theophylline, phenobarbital, pheny-
from, for example, drug displacement from binding sites. The toin, and diazepam should be decreased in premature infants.
increased mortality from the development of kernicterus secondary The clearance of unbound S-warfarin, a substrate of CYP2C9,

Pediatrics
to displacement of bilirubin by sulfisoxazole in neonates is well was substantially greater in prepubertal children than among puber-
documented.21 However, because drug bound to plasma proteins tal children and adults even after adjustment for total body weight.32
cannot be eliminated by the kidney, an increase in free drug concen- Finally, clearance of caffeine, metabolized by demethylation,
tration also may increase its clearance.22 declines to adult values when girls reach Tanner stage II (early
The amount of body fat is substantially lower in neonates than in puberty) and boys reach Tanner stages IV and V (late puberty).33
adults, which may affect drug therapy. Certain highly lipid-soluble The knowledge of pharmacogenetics and pharmacogenomics now
drugs are distributed less widely in infants than in adults. The is being applied to patient care in some instances. 6-Mercaptopur-
apparent volume of distribution of diazepam has ranged from 1.4 to ine (6-MP), a drug commonly used in pediatric leukemias, under-
1.8 L/kg in neonates and from 2.2 to 2.6 L/kg in adults.23 In recent goes catabolism that is facilitated by thiopurine methyltransferase
years, the numbers of mothers breast-feeding their infants has (TPMT). The inherited deficiency (an autosomal recessive trait),
climbed. Thus, certain drugs distributed in breast milk may pose which occurs in 6% to 11% of patients, is primarily explained by three
problems for the infants. The American Academy of Pediatrics polymorphisms in the TPMT gene (*2, *3A, and *3C). Children
recommends that bromocriptine, cyclophosphamide, cyclosporine, homozygous for one of the variant alleles require 6-MP dose reduc-
doxorubicin, ergotamine, lithium, methotrexate, phenindione, and tion of approximately 90%, and heterozygotic children need a dose
all drugs of abuse (e.g., amphetamine, cocaine, heroin, marijuana, reduction of approximately 50% to achieve survival rates observed
and phencyclidine [PCP]) not be used during breast-feeding. Use of in patients receiving full doses in the absence of TPMT deficiency.
nuclear medicines should be stopped temporarily during breast- Thus, TPMT screening is recommended to identify patients with
feeding.24 Note that these recommendations are based on limited genotypes associated with TPMT deficiency who may benefit from
data; other drugs taken over a prolonged period by the mother also dose reductions to prevent toxicity.34
may be toxic to the infant. For example, acebutolol, aspirin, atenolol,
clemastine, phenobarbital, primidone, sulfasalazine, and 5-aminosal-
icylic acid have been associated with adverse effects in some nursing ELIMINATION
infants.24,25 Unless the benefits outweigh the risks, the mother should
avoid using any drug during pregnancy and while breast-feeding. Drugs and their metabolites are often eliminated by the kidney. The
glomerular filtration rate (GFR) may be as low as 0.6 to 0.8 mL/min
per 1.73 m2 in preterm infants and approximately 2 to 4 mL/min
METABOLISM per 1.73 m2 in term infants. The processes of glomerular filtration,
tubular secretion, and tubular reabsorption determine the efficiency
Drug metabolism is substantially slower in infants than in older of renal excretion. These processes may not develop fully for several
children and adults. There are important differences in the matura- weeks to 1 year after birth.
tion of various pathways of metabolism within a premature infant. Studies in infants have shown that tobramycin clearance during
For example, the sulfation pathway is well developed but the glucu- the first postnatal week may increase with an increase in gestational
ronidation pathway is undeveloped in infants.26 Although acetamino- age.17 In infants up to 1 month after birth, postnatal age also was
phen metabolism by glucuronidation is impaired in infants compared correlated directly with aminoglycoside clearance.29 Thus, prema-
with adults, it is partly compensated for by the sulfation pathway. ture infants require a lower daily dose of drugs eliminated by the
The cause of the tragic chloramphenicol-induced gray baby syn- kidney during the first week of life; the dosage requirement then
drome in newborn infants is decreased metabolism of chloram- increases with age.
phenicol by glucuronyltransferases to the inactive glucuronide Because of immature renal elimination, chloramphenicol succi-
metabolite.27 This metabolic pathway appears to be age related28 and nate can accumulate in premature infants. Although chlorampheni-
may take several months to 1 year to develop fully, as evidenced by col succinate is inactive, this accumulation may be the reason for an
the increase in clearance with age up to 1 year.29 increased bioavailability of chloramphenicol in premature infants
Interestingly, higher serum concentrations of morphine are required compared with older children.28 These data indicate that dose-
to achieve efficacy in premature infants than in adults, in part because related toxicity may result from an underdeveloped glucuronida-
infants are not able to metabolize morphine adequately to its 6- tion pathway as well as increased bioavailability of chloramphenicol
glucuronide metabolite (20 times more active than morphine).30 This is in premature infants.
balanced to some degree by the fact that the clearance of morphine
quadruples between 27 and 40 weeks of postconceptional age.
Metabolism of drugs such as theophylline, phenobarbital, and DRUG EFFICACY AND TOXICITY
phenytoin by oxidation also is impaired in newborn infants. How-
ever, the rate of metabolism is more rapid with phenobarbital and  Besides the pharmacokinetic differences previously identified
phenytoin than with theophylline, perhaps because of the involve- between pediatric and older patients, factors related to drug efficacy
ment of different cytochrome P450 isozymes. Total clearance of and toxicity also should be considered in planning pediatric phar-
phenytoin by CYP2C9 and, to a lesser extent, by CYP2C19 surpasses macotherapy. Unique pathophysiologic changes occur in pediatric
adult values by 2 weeks of age, whereas theophylline clearance is not patients with some disease states.
fully developed for several months.18 Two additional observations Examples of pathophysiologic and pharmacodynamic differences
about theophylline metabolism by CYP1A2 in pediatric patients are numerous. Clinical presentation of chronic asthma differs in
 50
children and adults.35 Children present almost exclusively with a
reversible extrinsic type of asthma, whereas adults have nonspecific, CLINICAL CONTROVERSY
SECTION 1

nonatopic bronchial irritability.35 This explains the value of adjunctive Are antidepressants safe and effective in children and adoles-
hyposensitization therapy in the management of pediatric patients cents? Because of observations of increased suicidality among
with extrinsic asthma.36,37 adolescents (and adults, for that matter), experts are questioning
The maintenance dose of digoxin is substantially higher in infants whether these medications merely bring out an increased suicide
than in adults. This is explained by a lower binding affinity of risk that the patient has suppressed or has been too depressed to
receptors in the myocardium for digoxin and increased digoxin- act on, or these medications actually increase the risk per se
binding sites on neonatal erythrocytes compared with adult eryth- through some pharmacologic effect. Some selective serotonin
rocytes.38 Insulin requirement is highest during adolescence because reuptake inhibitors (SSRIs)—fluoxetine, sertraline, and fluvox-
Foundation Issues

of the individual’s rapid growth. Growth hormone therapy has amine—are approved for use in pediatric patients in the United
allowed children with growth hormone deficiency to attain greater States. The British regulatory agency banned the use of another
adult height. However, a study has shown that in “normal” short SSRI, paroxetine, in 2003 after analysis of the data indicated the
children (without growth hormone deficiency), early and rapid occurrence of suicidal thoughts or episodes of self-harm at a rate
pubertal progression by growth hormone therapy may lead to a 1.5 to 3.2 times higher than that with placebo. Subsequently, the
shorter final adult height than may have been attained naturally.39 FDA added a black-box warning about the use of and need for
This finding emphasizes the need for identifying specific indications monitoring SSRI therapy in pediatric patients, and FDA action
for the effective and safe use of drugs in pediatric patients. has continued in this arena.
Certain adverse effects of drugs are most common in the newborn
period, whereas other toxic effects may continue to be important for Some drugs may be less toxic in pediatric patients than in adults.
many years of childhood. Promethazine now is contraindicated for Aminoglycosides appear to be less toxic in infants than in adults. In
use in children younger than 2 years because of the risk of severe adults, aminoglycoside toxicity is related to both peripheral com-
respiratory depression. Chloramphenicol toxicity is increased in new- partment accumulation and the individual patient’s inherent sensi-
borns because of immature metabolism and enhanced bioavailability. tivity to these tissue concentrations.45 Although neonatal peripheral
Similarly, propylene glycol, which is added to many injectable drugs,
tissue compartments for gentamicin have been reported to closely
including phenytoin, phenobarbital, digoxin, diazepam, vitamin D,
resemble those of adults with similar renal function,16 gentamicin
and hydralazine, to increase their stability, can cause hyperosmolality
rarely is nephrotoxic in infants. This dissimilarity in the incidence
in infants.40 Benzyl alcohol was a popular preservative used in intra-
of nephrotoxicity implies that newborn infants have less inherent
vascular flush solutions until a syndrome of metabolic acidosis, tissue sensitivity for toxicity than do adults.
seizures, neurologic deterioration, gasping respirations, hepatic and The differences in efficacy, toxicity, and protein binding of drugs
renal abnormalities, cardiovascular collapse, and death was described in pediatric versus adult patients raise an important question about
in premature infants. A decline in both mortality and the incidence of the acceptable therapeutic range in children. Therapeutic ranges for
major intraventricular hemorrhage was documented after use of drugs are first established in adults and often are applied directly to
solutions containing benzyl alcohol was stopped in low-birth-weight pediatric patients, but specific studies should be conducted in
infants.41 pediatric patients to define optimal therapeutic ranges of drugs.
Tetracyclines are contraindicated for use in pregnant women, nurs-
ing mothers, and children younger than 8 years because these drugs
can cause dental staining and defects in enamelization of deciduous FACTORS AFFECTING PEDIATRIC THERAPY
and permanent teeth, as well as a decrease in bone growth.42 However,
the Centers for Disease Control and Prevention has recommended the DISEASES
use of doxycycline for initial prophylaxis following suspected bioter-
rorism related exposure to Bacillus anthracis (anthrax); the potential  Because most drugs are either metabolized by the liver or eliminated
benefits outweigh potential risks among infants and children. by the kidney, hepatic and renal diseases are expected to decrease the
dosage requirements in patients. Nevertheless, not all diseases require
lower doses of drugs. For instance, patients with cystic fibrosis require
CLINICAL CONTROVERSY larger doses of certain drugs to achieve therapeutic concentrations.46
Are fluoroquinolones safe in pediatric patients younger than 1
year? Antibiotics of the fluoroquinolone class (e.g., ciprofloxacin) Hepatic Disease
are generally not recommended for pediatric patients or pregnant Because the liver is the main organ for drug metabolism, drug
women because of an association between these drugs and the clearance usually is decreased in patients with hepatic disease.
development of permanent lesions of the cartilage of weight- However, most studies on the influence of hepatic disease on dosage
bearing joints and other signs of arthropathy in immature animals requirements have been performed in adults, and these data may
of various species.43 However, there are exceptions. The manufac- not be extrapolated uniformly to pediatric patients.
turer states that ciprofloxacin can be used in pediatric patients only Drug metabolism by the liver depends on complex interactions
for inhalation anthrax (postexposure) or for treatment of compli- among hepatic blood flow, ability of the liver to extract the drug
cated urinary tract infections and pyelonephritis caused by suscep- from the blood, drug binding in the blood, and both type and
tible Escherichia coli. The American Academy of Pediatrics and severity of hepatic disease. Routine hepatic function tests, such as
Infectious Disease Society of America suggest that their use may be determinations of serum aspartate aminotransferase, serum alanine
justified for certain other conditions (e.g., endocarditis and multi- aminotransferase, alkaline phosphatase, and bilirubin levels, have
drug-resistant gram-negative infections). Reversible arthralgia, not correlated consistently with drug pharmacokinetics. Further-
sometimes accompanied by synovial effusion, was associated with more, because of different pathologic changes in various types of
ciprofloxacin therapy in 1.8% of pediatric patients with cystic hepatic diseases, patients with acute viral hepatitis may have different
fibrosis.44 Although these drugs are used to treat certain infections abilities to metabolize drugs than patients with alcoholic cirrhosis.47
in pediatric populations, additional safety data are needed before On the basis of hepatic extraction characteristics, drugs can be
these drugs can be prescribed routinely, especially in infants. divided into two categories. The first category consists of drugs with
 51
a high hepatic extraction ratio (>0.7; such drugs include morphine, doses of certain drugs. Studies have reported higher clearance of
meperidine, lidocaine, and propranolol). Clearance of these drugs is drugs such as gentamicin, tobramycin, netilmicin, amikacin,

CHAPTER 7
affected by hepatic blood flow. A decreased hepatic blood flow in dicloxacillin, cloxacillin, azlocillin, piperacillin, and theophylline in
the presence of disease states such as cirrhosis and congestive heart patients with cystic fibrosis compared with patients without the
failure is expected to decrease the clearance of drugs with high disease. The apparent volume of distribution of certain drugs also
extraction ratios. The second category consists of drugs with a low may be altered in cystic fibrosis.51 Severity of the illness may
extraction ratio (<0.2) and a low affinity for plasma proteins. influence the change in dosage requirements, but this is not certain.
Metabolism of these drugs (e.g., theophylline, chloramphenicol, Chapter 32 reviews these changes in detail.
and acetaminophen) is influenced mainly by hepatocellular func-
tion and not as much by changes in hepatic blood flow or plasma Other Diseases

Pediatrics
protein binding. One report suggested that theophylline clearance
Although specific dosage guidelines are not available, pediatric
may decrease by 45% in a child with acute viral hepatitis.48 Because
patients with gastrointestinal disease (e.g., celiac disease, gastroen-
of a lack of specific data on dosage adjustment in hepatic disease,
teritis, and severe malabsorption) may require dosage adjust-
drug therapy should be monitored closely in pediatric patients to
ments.46 Hypoxemia also has been shown to decrease the elimination
avoid potential toxicity from excessive doses, particularly for drugs
of amikacin in low-birth-weight infants.52 Critically ill adult and
with narrow therapeutic indices.
pediatric patients with severe head trauma require higher than
normal doses of phenytoin in part because of increased intrinsic
Renal Disease clearance.53
Renal failure decreases the dosage requirement of drugs eliminated
by the kidney. Once again, because of limited studies, dosage adjust-
ments in pediatric patients are based largely on data obtained in ISSUES IN PEDIATRIC DRUG THERAPY
adults. For many important drugs, such as aminoglycoside antibi-
otics, renal clearance or rate of elimination is directly proportional to PAIN MANAGEMENT
the GFR, as measured by endogenous renal creatinine clearance.
 For many years, the term pain could not be found in the index of
In clinical practice, GFR can be estimated from prediction equa-
any major pediatric medicine or pediatric surgical textbooks.54 The
tions such as the Schwartz formula, which takes into account serum
prevailing wisdom was that neonates did not experience pain
creatinine concentration and the patient’s height, gender, and age.
because of their inadequately developed neuroendocrine systems
The advantage of estimating GFR using the Schwartz equation is
and nerve pathways. During the last years of the 20th century,
rapid determination and the avoidance of a cumbersome 24-hour
however, many research and clinical studies have been performed in
urine collection.49,50 The following formula is used to estimate GFR:
the areas of pain management and assessment of neonates, infants,
GFR = K × L / SCr (7–1) children, and adolescents. Today, results of these discoveries have
been incorporated into clinical practice, making effective pain
where GFR is expressed in milliliters per minute per 1.73 m2, K = therapy a standard of care and pain assessment the fifth vital sign in
age-specific constant of proportionality (see below), L = child’s modern pediatric practice.55
length in centimeters, and SCr = serum creatinine concentration in The basic mechanisms of pain perception in infants and children
milligrams per deciliter. are similar to those of adults, except that pain impulse transmission
in neonates occurs primarily along slow-conducting, nonmyeli-
Age K nated C fibers rather than along myelinated Aδ fibers. In addition,
pain signal transmission in the spinal cord is less precise, and
<1 year of age, low-birth-weight infant 0.33
<1 year of age, full-term infant 0.45
descending inhibitory neurotransmitters are lacking. As a result,
2- to 12-year-old child 0.55 neonates and young infants may perceive pain more intensely and
13- to 21-year-old female 0.55 be more sensitive to pain than are older children or adults.56,57 It is
13- to 21-year-old male 0.70 now known that previous pain experience leads to long-term
consequences such as alterations in response to a subsequent
painful event.58 Taddio et al.59,60 reported that boys circumcised
Studies comparing the Schwartz-predicted GFR versus measured
with the topical anesthetic eutectic mixture of local anesthetics
GFR noted that the Schwartz formula overestimated GFR in
(EMLA) had a lower pain response to subsequent immunizations
patients with decreasing GFR. The formula may not provide an
than those who were circumcised without topical anesthesia. An
accurate estimation of GFR in patients with rapidly changing serum
inadequately treated initial painful procedure may decrease the
creatinine concentrations, as seen in the critical care setting, in
effect of adequate analgesia in subsequent procedures as a result of
infants younger than 1 week, and in patients with obesity, malnutri-
altered pain response patterns.
tion, or muscle wasting. Factors that interfere with serum creatinine
Children consistently report that needles and shots are what they
measurement also may cause errors in estimation of GFR.
fear most. However, with the current immunization schedule that
Serum drug concentrations should be monitored for drugs with
recommends 14 to 33 injections before adolescence, interventions
narrow therapeutic indices and eliminated largely by the kidney
to decrease injection pain need to be performed (Table 7–1).
(e.g., aminoglycosides and vancomycin) to optimize therapy in
Pharmacologic pain management for medical conditions and
pediatric patients with renal dysfunction. For drugs with wide
surgical and postoperative events has progressed considerably over
therapeutic ranges (e.g., penicillins and cephalosporins), dosage
the past decade with the use of continuous opioid infusions,
adjustment may be necessary only in patients with moderate-to-
epidural anesthesia, peripheral nerve blockade, local anesthetics,
severe renal failure.
nonsteroidal antiinflammatory drugs, different routes for tradi-
tional agents (i.e., transmucosal and transdermal), and nonopioid
Cystic Fibrosis adjuvant drugs (Table 7–2). New pain management techniques,
Drug therapy in pediatric patients with cystic fibrosis has been education, research, and increasing awareness of pain management
reviewed.51 For unknown reasons, these patients require increased options have helped to improve the quality of life in children.
 52

TABLE 7-1 Techniques for Minimizing Pain Caused by Injection TABLE 7-2 Opioid Administration for Acute and Severe Pain
SECTION 1

Pharmacologic methods Intermittent IV or PO Weak opioids (e.g., codeine, hydrocodone, oxycodone)

EMLA61 (eutectic mixture Advantages: Penetrates the skin to provide anesthe- bolus administration often are combined with acetaminophen or a nonster-
of lidocaine and sia to a depth of 5 mm; effective in decreasing the (not as needed) oidal antiinflammatory agent (NSAID) for moderate
prilocaine) pain of IM and subcutaneous injections, venipunc- pain. With dose escalation of combination oral prod-
ture, IV cannulation, lumbar puncture, circumci- ucts, be aware that the dose does not exceed recom-
sion, skin-graft harvesting, and laser dermal mended daily amounts for acetaminophen or
therapy; safe and effective in newborns >37 ibuprofen. IV administration of codeine has been asso-
weeks’ gestation. ciated with allergic reactions related to histamine
Disadvantages: Requires 1 hour before onset of release. Parenteral administration of codeine is not
adequate anesthesia, has a vasoconstrictive effect recommended. Intermittent opioid administration is
Foundation Issues

that may make starting IV catheters difficult, may associated with wide fluctuation between peak and
induce methemoglobinemia. trough levels, so the patient may alternate between
Numby Stuff (lidocaine Advantages: Provides dermal anesthesia to a depth peak blood levels associated with untoward effects and
iontophoresis)62 of 10 mm within 10–20 min; effective in decreas- trough levels associated with inadequate pain relief
ing the pain of IM injection, IV cannulation, when being treated for severe pain.
venipuncture, lumbar puncture, skin biopsy, and Oxycodone and morphine are available in a sustained-
bone marrow aspiration. release formulation for use with chronic pain (not acute
Disadvantage: Tingling, itching, or burning sensa- pain). Tablet must be swallowed whole and cannot be
tion from the electric current used to transport administered to patients through gastric tubes.
drug to the tissues. Intravenous continu- Loading dose is administered to achieve rapidly a thera-
Vapocoolant sprays (ethyl Advantages: Vapocoolant is sprayed directly onto ous infusion68,69 peutic blood level and pain relief (i.e., morphine
chloride or dichlorodiflu- the skin or applied to a cotton ball that is held on loading dose of 0.05–0.15 mg/kg in children; 0.1 mg/kg
oromethane)63 the area to be anesthetized; provides local anes- infused over 90 min in neonates). Loading dose is
thesia within 15 seconds; effective in reducing followed by a maintenance continuous infusion. Doses
injection pain in children 4–6 years of age. that are considered safe in children can cause respira-
Disadvantages: Brief duration of action, so proce- tory depression and seizures in neonates because of
dure should be completed in 1 or 2 min; may not decreased clearance, immature blood–brain barrier at
be effective in reducing injection pain in infants birth that is more permeable to morphine, and an
aged 2–6 months. increased unbound fraction of morphine that increases
Local anesthetic Advantage: Reduces the pain of subsequent needle CNS effects of the drug.
(lidocaine)64 insertion. Patient-controlled Gives patient some control over his/her pain therapy. PCA
Disadvantage: Local anesthetic injection itself is analgesia (PCA)70 allows the patient to self-administer small opioid doses.
associated with pain and burning sensation. The PCA-Plus (Abbott, Chicago, IL) pump allows the
Pacifier with sucrose65,66 For preterm neonates: 0.1–0.4 mL of a 12%–24% patient to receive a continuous infusion together with a
sucrose solution (place on pacifier or the tongue set number of self-administered doses per hour. PCA
2 min before procedure). For term neonates: 1–2 helps to eliminate wide peak and trough fluctuations so
mL of a 12%–24% sucrose solution (place on that levels remain in a therapeutic range. Children as
pacifier or the tongue 2 min before procedure). young as 6 or 7 years of age can master the use of PCA.
Advantage: Noninvasive method to reduce pain Epidural and Effective in the management of severe postoperative,
associated with needle insertion in infants. intrathecal chronic, or cancer pain. Spinal opioids can be adminis-
Disadvantage: Sucrose solution’s effect in reducing analgesia71 tered by a single bolus injection into the epidural or
pain gradually decreases over time. subarachnoid space or by continuous infusion via an
Other techniques indwelling catheter. Dosage requirement by these
Site selection67 For children older than 18 months: Use of the deltoid routes is significantly less than with IV administration
muscle for IM injections is associated with less pain (epidural opioid doses: 10-fold lower than IV doses;
than injections administered in the thigh. For chil- intrathecal opioid doses: 100-fold lower than IV doses).
dren older than 3 years: Use of the ventrogluteal Morphine, hydromorphone, fentanyl, and sufentanil
area for injection is associated with less pain than are effective when administered intrathecally. Bupiv-
the anterior thigh or dorsogluteal area. acaine is the most commonly used local anesthetic in
Z-tract technique Z-tract intramuscular injection technique is less pain- continuous epidural infusions. Fentanyl, morphine, or
ful (pull skin taut at the injection site, give injec- hydromorphone usually is combined with bupivacaine
tion, then release the skin); use a higher-gauge for epidural infusions.
needle when the injectable solution is not viscous. Transmucosal Fentanyl lozenge is absorbed transmucosally. It is useful
Behavioral Use of distraction methods (e.g., blowing bubbles, administration for providing analgesia during painful procedures.
providing music by headphones, relaxation, imag- Advantages include rapid onset of action (within 15
ery, self-hypnosis, or having parents present for min), short duration of action (60–90 min), and pain-
the procedure) can be helpful. less administration because no injection is needed. A
common side effect is vomiting and mild-to-moderate
oxygen desaturation. Doses of 10–15 mcg/kg provide
DRUG ADMINISTRATION blood levels equivalent to 3–5 mcg/kg IV.
 Drugs often are given by the intravenous route to seriously ill
patients. Syringe pumps are widely used for administration of turers; offer extensive delivery mode combinations including milli-
intravenous drugs. Important steps in successfully administering liters per hour, body weight, mass, volume over time, custom
intravenous drugs include selecting the drug, calculating the dose, dilution and intermittent, loading dose, bolus dose, standby, vol-
preparing the infusion, programming the infusion pump, and ume limit; wide-ranging flow rates and rate to keep vein open; and
delivering the infusion. Use of “smart” pumps is preferred because adequate internal battery capacity.
they can recognize syringes and have drug libraries and dose limits No single infusion system is ideal for delivery of all drugs in all
as safety features. The pumps should be accurate; precise; easy to institutions for all patients. Each facility must be cognizant of
use; accept syringes and administration sets from various manufac- problems of drug delivery and develop specific guidelines for
 53
intravenous infusions. At our institution, specific guidelines are ate the importance of understanding and following the prescribing
provided for administration of each drug. These guidelines take into information.

CHAPTER 7
account various infusion rates and provide consistency of delivery In one study, medication adherence was considered to be a
with each dose. As long as the time for actual delivery is known, problem in nearly 60% of adolescents (age 12 to 15 years) with
times to obtain blood samples for measurement of drug concentra- asthma. Approximately 40% of patients had severe denial regarding
tion can be adjusted accordingly to generate meaningful data. their asthma and its severity. Nearly 80% of patients had prevent-
able asthma exacerbations.75
ALTERATION OF DOSAGE FORMS Among the factors that can negatively affect adherence are poor
communication between the physician and patient or parent; insuf-
Many drugs used in pediatric patients are not available in ficient prescribing information; lack of understanding about the

Pediatrics
suitable dosage forms. This necessitates dilution of high concentra- severity of illness by the patient or parent; lack of interest (e.g.,
tions of drugs intended for adult patients. Examples of these drugs among adolescents); fear of side effects; failure of the patient or
include atropine, carbamazepine, diazepam, digoxin, epinephrine, parent to remember to administer the drugs; inconvenient dosage
hydralazine, insulin, morphine, phenobarbital, and phenytoin. Vol- forms or dosing schedules involving administration of three or
umes ranging from 0.01 to 0.1 mL must be measured to dispense more doses daily; and unpalatability of drug products.76 Studies in
these drugs for use in infants. This obviously can be associated with pediatric volunteers have compared the palatability of antibiotics,77
large errors in measurements, and such errors have caused intoxica- and the data may have important implications for adherence in
tion with digoxin72 and morphine73 in infants. One solution to this children.
problem is to dilute these concentrated products, but such alter-
ations can influence the stability or compatibility of these drugs. DOSE REQUIREMENTS
Because of limited data, pharmacists justifiably may be reluctant to
alter dosage forms of certain drugs. Medication doses often are based on the body weight of neonates,
Selection of the appropriate vehicle to dilute the adult dosage infants, and children, for example, milligrams per kilogram of body
forms for use in pediatric patients can be difficult. Phenobarbital weight per day to be given in one or more portions daily. However,
sodium contains propylene glycol in the original product to improve certain drugs, including antineoplastic agents, may be given based
drug stability. Because propylene glycol can cause hyperosmolality in on body surface area, for example, milligrams per square meter in
infants,40 further addition of this vehicle may not be wise. Because of one or more doses daily. In either case, the total amount of weight-
limited access to intravenous sites in pediatric patients, drugs must or surface area-based individual or daily dose in a pediatric patient,
be administered through the same site; however, data on drug especially an adolescent, should not exceed the amount of drug
compatibilities often are missing. Newborn infants often require indicated in an adult patient.
aminoglycosides for presumed or proven sepsis and calcium gluco- An additional challenge in managing pediatric drug therapy is
nate for correction of hypocalcemia. Tobramycin and calcium gluco- understanding the effects of obesity on a population that relies on
nate have been found to be compatible, at least during a 1-hour weight-based dosing. According to the Centers for Disease Control
administration at the same site.73 and Prevention, the prevalence of overweight and obese children in
Administration of oral drugs continues to challenge parents and the United States nearly doubled from 15% during 1976 to 1980 to
nurses. Alteration of these drugs by crushing or mixing, refusal of more than 30% during 1999 to 2002.78 Using ideal body weight
patients to accept the medication, and loss of drug during adminis- versus total body weight to calculate a weight-based dose or to
tration are some factors that can affect pediatric therapy. A common determine body surface area can result in a large variance in obese
practice is to mix medications in applesauce, syrup, ice cream, or patients. Additional pharmacokinetic studies are needed to study
other vehicles just before administration to make the drugs palatable. the effects of obesity on drug distribution, protein binding, and
A number of extemporaneous formulations for oral, intravenous, clearance and to identify whether dosing should be adjusted accord-
and rectal administration are included in a compilation of products ing to total body weight or ideal body weight to achieve consistent
for use in pediatric patients.74 However, a specific reference on the drug exposure for individual drugs.79,80 Generally, the highest drug
stability of many drug formulations is lacking and emphasizes the dose recommended for a child is the maximum dose approved for
need for continued research in this area. adults. However, determining the highest dose of certain drugs for
Drug administration into the middle ear, nose, or eye of a child use in children without a known maximum dose for adults (e.g.,
requires special attention. Certain drugs (e.g., sodium valproate and intravenous immunoglobulin, infliximab, rituximab, and liposomal
morphine) can be administered rectally to infants who have limited amphotericin B [AmBisome]) can be difficult.
access for intravenous drug administration or if oral drug adminis-
tration cannot be accomplished. DRUG INTERACTIONS
Transdermal drug delivery can be used in pediatric patients (a) to
avoid problems of drug absorption from the oral route and compli- Drug interaction studies in pediatric age groups generally are
cations from the intravenous route and (b) to maximize duration lacking. The data often are extrapolated from studies in adult
of effect and minimize adverse effects of drugs. As discussed earlier populations. Special attention should be given to adolescents, who
in this chapter, methylphenidate (Daytrana) now is available as a may concurrently use alcohol, recreational/illicit drugs, or other
transdermal patch for children with ADHD. Unfortunately, the prescription or nonprescription medications without the knowl-
commercially available transdermal dosage forms (e.g., clonidine edge of the primary healthcare provider, who must attempt to
and scopolamine) are not intended for pediatric patients; these determine their use to avoid drug interactions.
would deliver doses much higher than needed for infants and
children. COMPLEMENTARY AND
ALTERNATIVE THERAPY
MEDICATION ADHERENCE
In a study of patients between 3 weeks and 18 years (mean 5.3 years)
The issue of medication adherence is more complex in pediatric of age, 45% of caregivers were giving a product to the children; 27%
patients than in adults. Caregivers of young patients must appreci- had given three or more products in the past year. The most
 54
commonly used products were aloe plant/juice (44% of those clinical and economic outcomes and on quality of life in pediatric
reporting use of herbal therapies), echinacea (33%), and sweet oil patients are needed.
SECTION 1

(25%). The most dangerous combination was ephedra (which was The development of new drugs has contributed to improved
withdrawn from the U.S. market in 2004) with albuterol given to patient care. The new FDA regulations (Best Pharmaceuticals for
adolescents with asthma. Most caregivers did not recognize poten- Children Act of 2002) can require the industry to conduct studies
tial adverse effects or drug interactions associated with herbs. and seek labeling of important drugs for use in pediatric patients. As
Friends or relatives were the main source of information for 80% of an incentive, a 6-month patent extension and waiver of supplemen-
caregivers.81 tal new drug application fee are offered to the industry. This should
Little is known about the efficacy of herbal products in infants, encourage the industry to develop and market more drugs for the
children, and adolescents. Healthcare professionals must ask care- pediatric population. However, greater emphasis also should be
Foundation Issues

givers specifically about the use of complementary and alternative placed on disease prevention. Millions of children die because of
treatments to minimize the adverse effects and costs associated with preventable diseases, particularly in developing countries of the
ineffective therapies. world. Administration of vaccines and control of diarrhea alone
could save millions of these lives annually. However, the developed
MEDICATION SAFETY countries face different problems. The infant mortality rate in the
United States is nearly twice as high among blacks as whites.

The Institute of Medicine reported that between 44,000 and Improved prenatal care, educational programs, and avoidance of
98,000 Americans each year die as a result of medical errors in alcohol, smoking, and drugs of abuse during pregnancy may
hospitals.82 According to this report, the vast majority of medical decrease mortality as well as morbidity from illnesses, including
errors that cause harm to patients are preventable. Healthcare acquired immunodeficiency syndrome.
professionals have a responsibility for creating a safe medication Finally, efforts should be made to offer evidence-based pharmaco-
environment and reducing risk to a vulnerable pediatric population. therapy. This often is difficult in pediatric populations when the drugs
Pediatric medication errors commonly occur at the medication- must be used outside the guidelines and indications approved by the
ordering step because of the multiple calculations required for FDA. Institutions should develop guidelines for the use of drugs in
weight-based dosing and the adjustments needed for providing specific diseases and for the use of high-cost drugs such as colony-
therapy to the developing pediatric patient.83–85 The United States stimulating factors, monoclonal antibodies, dornase-alfa, epoetin-
Pharmacopeia (USP) Center for the Advancement of Patient Safety alfa, immunoglobulins, surfactants, and growth hormones.
states that risk to patients when performing repeated calculations Although much needs to be learned about the optimization of
involving multiple steps can be minimized using computer-based therapy, it is encouraging to witness the continued growth of
algorithms.86 Since the medication-preparation step is also a high- knowledge in this area that has improved the quality of life and
hazard point owing to the need for dilution or manipulation of survival from pharmacotherapy in pediatric patients.
commercially available products only available in adult doses, the
USP recommends that compounded pediatric medications be pre-
pared and labeled in the pharmacy and verified by a pharmacist. ABBREVIATIONS
Among drug administration–related errors, wrong dose, wrong
technique, and wrong drug are the three most common errors and FDA: Food and Drug Administration
may be related to an inability to access pediatric drug information. GFR: glomerular filtration rate
In 2001, the Agency for Healthcare Research and Quality (AHRQ)
SSRI: selective serotonin reuptake inhibitor
published an evidence-based assessment of patient safety practices
that prevent or reduce medication errors.87 Risk-reduction strate- USP: United States Pharmacopeia
gies include placing a clinical pharmacist on pediatric wards in
hospitals, simplifying the medication-use system, ordering stan-
dardized concentrations and doses, implementing computerized REFERENCES
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CONCLUSIONS infants and children of various age groups. J Pediatr 1953;42:657–
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11. Morselli PL. Serum levels and pharmacokinetics of anticonvulsants in 39. Kawai M, Momoi T, Yorifuji, T, et al. Unfavorable effects of growth
the management of seizure disorders. In: Merkin B, ed. Clinical hormone therapy on the final height of boys with short stature not
Pharmacology. Chicago: Mosby Year Book, 1978:89. caused by growth hormone deficiency. J Pediatr 1997;130:205–209.
12. Tyrala FF, Hillman LS, Hillman RE, et al. Clinical pharmacology of 40. Glasgow AM, Boeckx RL, Miller MK, et al. Hyperosmolality in small
hexa-chlorophene in newborn infants. J Pediatr 1977;91:481–486. infants due to propylene glycol. Pediatrics 1983;72:353–355.
13. McFadden S, Haddow JE. Coma produced by topical application of 41. Hiller JL, Benda GI, Rahatzad M, et al. Benzyl alcohol toxicity: Impact
isopropanol. Pediatrics 1969;43:622–623. of mortality and intraventricular hemorrhage among very low birth
14. Evans NJ, Rutter N, Hadgraft J, et al. Percutaneous administration of weight infants. Pediatrics 1986;77:500–506.

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theophylline in preterm infant. J Pediatr 1985;107:307–311. 42. Grossman ER, Walchek A, Freedman H. Tetracyclines and permanent
15. Friis-Hansen B. Body water compartments in children: Changes dur- teeth: The relation between dose and tooth color. Pediatrics 1971;47:567–
ing growth and related changes in body composition. Pediatrics 570.
1961;28:169–181. 43. Walker RC, Wright AJ. The quinolones. Mayo Clin Proc 1987;62:1007–
16. Haughey DB, Hilligoss DM, Grassi A, et al. Two-compartment gentami- 1012.
cin pharmacokinetics in premature neonates: A comparison to adults 44. Chysky V, Kapla M, Hullman R, et al. Safety of ciprofloxacin in children:
with decreased glomerular filtration rates. J Pediatr 1980;96:325–330. Worldwide clinical experience based on compassionate usage. Infection
17. Nahata MC, Powell DA, Durrell DE, et al. Effect of gestational age and 1991;19:289–296.
birth weight on tobramycin kinetics in newborn infants. J Antimicrob 45. Schentag JJ, Plaut ME, Cerra FB, et al. Aminoglycoside nephrotoxicity
Chemother 1984;14:59–65. in critically ill surgical patients. J Surg Res 1979;26:270–279.
18. Roberts RJ. Pharmacologic principles in therapeutics in infants. In: 46. Kauffman RE, Habersange R. Modification of dosage regimens in
Drug Therapy in Infants: Pharmacologic Principles and Clinical Expe- disease states of childhood. In: Mirking BL, ed. Clinical Pharmacology
rience. Philadelphia: WB Saunders, 1984:3–12. and Therapeutics: A Pediatric Perspective. Chicago: Mosby Year Book,
19. Pitlick W, Painter M, Pippenger C. Phenobarbital pharmacokinetics in 1978:73–88.
neonates. Clin Pharmacol Ther 1978;23:346–350. 47. Roberts RJ. Special considerations in drug therapy in infants. In: Drug
20. Painter MJ, Pippenger C, MacDonald H, et al. Phenobarbital and diphen- Therapy in Infants: Pharmacologic Principles and Clinical Experience.
ylhydantoin levels in neonates with seizures. J Pediatr 1978;92:315–319. Philadelphia: WB Saunders, 1984:25–35.
21. Silverman WA, Anderson DH, Blanc WA, et al. A difference in mortality 48. Feinstein RA, Miles MV. The effect of acute viral hepatitis on theophyl-
rate and incidence of kernicterus among premature infants allotted to line clearance. Clin Pediatr 1985;24:357–358.
two prophylactic antibacterial regimens. Pediatrics 1956;18:614–624. 49. Hogg RJ, Furth S, Lemley KV, et al. National Kidney Foundation’s
22. Odell GB. The dissociation of bilirubin from albumin and its clinical kidney disease outcomes quality initiative clinical practice guidelines
implications. J Pediatr 1959;55:268–279. for chronic kidney disease in children and adolescents: Evaluation,
23. Morselli PL. Clinical pharmacokinetics in neonates. Clin Pharmacoki- classification, and stratification. Pediatrics 2003;111:1416–1421.
net 1976;1:81–98. 50. Schwartz Gj, Brion LP, Spitzer A. The use of plasma creatinine
24. Committee on Drugs, American Academy of Pediatrics. The transfer of concentration for estimating glomerular filtration rate in infants,
drugs and other chemicals into human milk. Pediatrics 1994;93:137– children and adolescents. Pediatr Clin North Am 1987;34:571–590.
150. 51. Wallace CS, Hall M, Kuhn RJ. Pharmacologic management of cystic
25. Anderson PO. Drugs and breast milk. J Pediatr 1995;95:957. fibrosis. Clin Pharm 1993;12:657–674.
26. Rane A. Basic principles of drug disposition and action in infants and 52. Myers MG, Roberts JF, Mirhig NJ. Effect of gestational age, birth
children. In: Yaffe JF, ed. Pediatric Pharmacology: Therapeutic Princi- weight, and hypoxemia on the pharmacokinetics of amikacin in serum
ples in Practice. New York: Grune & Stratton, 1980:7–28. of infants. Antimicrob Agents Chemother 1977;11:1027.
27. Weiss CF, Glazko AJ, Weston JK. Chloramphenicol in the newborn 53. Bahal-O’Mara N, Jones R, Nahata MC, et al. Pharmacokinetics of phenytoin
infant: A physiologic explanation of its toxicity when given in excessive in children with acute neurotrauma. Crit Care Med 1995;23:1418–1424.
doses. N Engl J Med 1960;262:787–794. 54. Rana SR. Pain: A subject ignored [letter]. Pediatrics 1987;79:309.
28. Nahata MC, Powell DA. Comparative bioavailability and pharmacoki- 55. Franch LS, Greenberg CS, Stevens B. Pain assessment in infants and
netics of chloramphenicol after intravenous chloramphenicol succi- children. Pediatr Clin North Am 2000;47:487–512.
nate in premature infants and older patients. Dev Pharmacol Ther 56. Anand KJS. Consensus statement for the prevention and management
1983;6:23–32. of pain in the newborn. Arch Pediatr Adolesc Med 2001;155:173–180.
29. Kuhn R, Nahata MC, Powell DA, et al. Netilmicin pharmacokinetics in 57. American Academy of Pediatrics at Canadian Paediatric Society. Pre-
newborn infants. Eur J Clin Pharmacol 1986;29:635–637. vention and management of pain and stress in the neonate. Pediatrics
30. Cha PCW, Duffy BJ, Walker JS. Pharmacokinetic-pharmacodynamic 2000;105:454–461.
relationships of morphine in neonates. Clin Pharmacol Ther 1992;51:334– 58. Fitzgerald M, Anand KJS. Development neuroanatomy and neuro-
342. physiology of pain. In: Schechter NL, Berde CB, Yaster M, eds. Pain in
31. Edwards DJ, Zarowitz BJ, Slaughter RL. Theophylline. In: Evans WE, Infants, Children and Adolescents. Baltimore: Williams & Wilkins,
Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics, 3rd ed. Van- 1993:11–31.
couver, WA: Applied Therapeutics, 1992:1–47. 59. Taddio A, Katz J, Ilersich Al, et al. Effect of neonatal circumcision on pain
32. Takahashi H, Ishikawa S, Nomoto S, et al. Developmental changes in response during subsequent routine vaccination. Lancet 1997;349:559–603.
pharmacokinetics and pharmacodynamics of warfarin enantiomers in 60. Taddio A, Ohlsson A, Einarson T, et al. A systematic review of
Japanese children. Clin Pharmacol Ther 2000;68:541–555. lidocaine-prilocaine cream for neonatal circumcision pain. N Engl J
33. Lambert GH, Schoeller DA, Kotake AN, et al. The effect of age, gender, Med 1997;336:1197–1201.
and sexual maturation on the caffeine breath test. Dev Pharmacol Ther 61. Uhari M. Eutectic mixture of lidocaine and prilocaine for alleviating
1986;9:375–388. vaccination pain in infants. Pediatrics 1993;92:719–721.
34. McLeod HL, Krynetski ER, Relling MV, Evans WE. Genetic polymor- 62. Zempsky, WT, Anand KS, Sullivan KM, et al. Lidocaine iontophoresis
phism of thiopurine methyltransferase and its clinical relevance for for topical anesthesia before intravenous line placement in children. J
childhood acute lymphoblastic leukemia. Leukemia 2000;14:567–572. Pediatr 1998;132:1061–1063.
35. Leffert FL. The management of chronic asthma. J Pediatr 1980;97:875– 63. Reis EC, Holobukov R. Vapocoolant spray is equally effective as EMLA
885. cream in reducing immunization pain in school aged children. Pediat-
36. Johnston DE. Immunotherapy in children: Past, present, and future, rics 1997;100:5.
part I. Ann Allergy 1981;46:1–7. 64. Bartfield JM, Connis P, Barbera J, et al. Buffered versus plain lidocaine
37. Johnston DE. Immunotherapy in children: Past, present, and future, as a local anesthetic for simple laceration repair. Ann Emerg Med
part II. Ann Allergy 1981;46:59–66. 1990;19:1387–1390.
 56
65. Annand KHS; International Evidenced Based Group for Neonatal 79. Cheymol G. Effects of obesity on pharmacokinetics: Implications for
Pain. Consensus statement for the prevention and management of drug therapy. Clin Pharmacokinetics 2000;39:215–231.
SECTION 1

pain in the newborn. Arch Pediatr Adolesc Med 2001;155:173–180. 80. Vance-Bryan K, Guay DR, Gilliland SS, et al. Effect of obesity on
66. Schechter NL, Berde CB, Yaster M, et al. Pain in Infants, Children, and vancomycin pharmacokinetic parameters as determined by using a
Adolescents. Baltimore: Lippincott Williams & Wilkins, 2003. Bayesian forecasting technique. Antimicrob Agents Chemother
67. Keen MF. Comparison of intramuscular injection techniques to 1993;37:436–440.
reduce site discomfort and lesions. Nurs Res 1986;35:207–210. 81. Lanski SL, Greenwald M, Perkins A, et al. Herbal therapy use in a
68. Golianu B, Krane EJ, Galloway KS, et al. Pediatric acute pain manage- pediatric emergency department population: Expect the unexpected.
ment. Pediatr Clin North Am 2000;47:559–587. Pediatrics 2003;111:981–985.
69. Chay PCW, Duffy BJ, Walker JS. Pharmacokinetic–pharmacodynamic rela- 82. Institute of Medicine, Committee on Quality of Health Care in
tionship of morphine in neonates. Clin Pharmacol Ther 1992;51:334–342. American. To Err is Human: Building a Safer Health System. Washing-
Foundation Issues

70. Berde CB, Lehn BM, Yee JD, et al. Patient-controlled analgesia in ton, DC: National Academy Press, 2000.
children and adolescents: A randomized, prospective comparison with 83. Raju TN, Kecskes S, Thornton JP, et al. Medication errors in neonatal
intramuscular administration of morphine for postoperative analgesia. and paediatric intensive-care units. Lancet 1989;2:374–376.
J Pediatr 1991;118:460–466. 84. Folli HL, Poole RL, Benitz WE, et al. Medication error prevention by
71. Nichols DG, Yaster M, Lynn AM, et al. Disposition and respiratory effects clinical pharmacists in two children’s hospitals. Pediatrics 1987;79:718–
of intrathecal morphine in children. Anesthesiology 1993;79:733–738. 722.
72. Berman W. Whitman V, Marks KH, et al. Inadvertent overadministra- 85. Kaushal R, Bates DW, Landrigan C, et al. Medication errors and
tion of digoxin to low birth weight infants. J Pediatr 1978;92:1024. adverse drug events in pediatric inpatients. JAMA 2001;285:2114–
73. Zenk KE, Anderson S. Improving the accuracy of minivolume injec- 2120.
tions. Infusion 1982;Jan–Feb:7–11. 86. USP Center for the Advancement of Patient Safety. USP issues recom-
74. Nahata MC, Pai V, Hipple TF. Pediatric Drug Formulations, 5th ed. mendations for preventing medication errors in children. January 21,
Cincinnati, OH: Harvey Whitney Books, 2003:1–307. 2003.
75. Martin AJ, Campbell DA, Gluyas PA, et al. Characteristics of near-fatal 87. American Academy of Pediatrics Committee on Drugs and Committee
asthma in childhood. Pediatr Pulmonol 1995;20:1–8. on Hospital Care. Prevention of medication errors in pediatric inpa-
76. Boreus LO. Drug compliance. In: Yaffe SJ, ed. Principles of Pediatric tient setting. Pediatrics 2003;112:431–436.
Pharmacology. New York: Churchill-Livingstone, 1982:176–192. 88. Agency for Healthcare Research and Quality. Making Health Care
77. Matsui D, Barron A, Rieder MJ. Assessment of the palatability of Safer: A Critical Analysis of Patient Safety Practices. AHRQ Publica-
antistaphylococcal antibiotics in pediatric volunteers. Ann Pharmaco- tion No. 01-E058. Washington, DC: Agency for Healthcare Research
ther 1996;30:586–588. and Quality, 2001.
78. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight 89. Larsen GY, Parker HB, Cash J, et al. Standard drug concentrations and
and obesity among US children, adolescents and adults, 1999–2002. smart-pump technology reduce continuous-medication-infusion errors
JAMA 2004;291:2847–2850. in pediatric patients. Pediatrics 2005;116:21–25.
 57

C HAP T E R

8 Geriatrics

CATHERINE I. STARNER, SHELLY L. GRAY, DAVID R.P. GUAY, EMILY R. HAJJAR,

STEVEN M. HANDLER, AND JOSEPH T. HANLON

independence and dependence, and function and dysfunction that

KEY CONCEPTS make the available demographic and health status data relevant for
clinical practice. Understanding this diversity and growth of the
 The population of persons aged 65 years and older is increasing. older population will allow society to plan for the training, research,
 Age-related changes in physiology can affect the pharmacoki- and resources needed for future clinical practice and adequate
netics and pharmacodynamics of numerous drugs. healthcare.
In 2000, persons aged 65 and older accounted for 12.4% (35
 Improving and maintaining functional status is a cornerstone of million) of the total U.S. population.2 Among those older than 65
care for older adults. years, women outnumbered men and accounted for 58.8% of this
 Drug-related problems in older adults are common and cause segment of the population. The gender gap widens with increasing
considerable morbidity. age, with women accounting for 71.1% of the cohort aged 85 years
and older and 80% of centenarians.2
 Pharmacists can play a major role in optimizing drug therapy In 2011, the first baby boomers will turn 65 years old; this will
and preventing drug-related problems in older adults. mark a rapid increase in the older population in the years between
2010 and 2030. By 2030, the older population is projected to double
in size relative to the year 2000, with one in five (20%) Americans
Pharmacotherapy for older adults can cure or palliate disease as well older than 65 years. This 20% projection for persons aged 65 years
as enhance health-related quality of life (HRQOL). HRQOL consid- and older will remain relatively stable through 2050. However, the
erations for older adults include focusing on improvements in proportion of the oldest old (>85 years) will continue to grow. In
physical functioning (e.g., activities of daily living), psychological 2000, the oldest old represented 12.1% of the older population but
functioning (e.g., cognition, depression), social functioning (e.g., are projected to double by 2050. The increase in the number of
social activities, support systems), and overall health (e.g., general older persons is due not just to the higher post–World War II birth
health perception).1 Despite the benefits of pharmacotherapy, rate but also to the declining mortality rate and the overall better
HRQOL can be compromised by drug-related problems. The pre- health among older adults.2 The decline in early death and the better
vention of drug-related adverse consequences in older adults health of older adults arise for a variety of reasons: (a) public health
requires that health professionals become knowledgeable about a measures affecting all age groups (e.g., immunizations, prenatal
number of age-specific issues. To address these knowledge needs, care), (b) advances in medical technology, (c) promotion of a
this chapter discusses the epidemiology of aging; physiologic changes healthy lifestyle, and (d) improvements in living conditions.3 More
associated with aging, with emphasis on those changes that can affect relevant to providers of care to older Americans is life expectancy at
the pharmacokinetics and pharmacodynamics of drugs; clinical age 65 years. In 2000, white women 65 years of age can expect an
conditions commonly seen in older adult patients; epidemiology of average additional 19.2 years of life; black women, 17.4 years; white
drug-related problems in older adults; and an approach to reducing men, 16.3 years; and black men, 14.5 years.2 For a person who
drug-related problems through the provision of comprehensive survived to age 85 years in 2000, another 5.6 years of life can be
geriatric assessment. expected for men and 6.7 years for women. Given this increase in
life expectancy, the increase in the number of centenarians from
37,000 in 1990 to 50,000 in 2000 is not surprising.2
EPIDEMIOLOGY OF AGING Along with changes in the life expectancy of future older adults, the
older population will become more diverse in racial/ethnic composi-
 The older American population is highly diverse and heteroge-
tion. In 2000, an estimated 84% of persons aged 65 years and older
neous with respect to health status. The demographics and health
were non-Hispanic white, 8% were black, 5% were Hispanic, and
characteristics of persons aged 65 to 74 years are different from
2.3% were Asian. By 2050, the percent of non-Hispanic white older
those of persons 85 years of age and older, as are those of persons
adults is projected to decline to 61%, whereas Hispanics will account
who are institutionalized compared with those living in the com-
for 18% and Asians 8% of the older population.2
munity. It is teasing apart the various threads of wellness and illness,
Most older persons are self-sufficient and live in the community.
However, as they age in the community, the likelihood of living
alone increases, more so for women than for men. Only 4.5% of
Learning objectives, review questions, older persons reside in a long-term care facility, a decrease since
and other resources can be found at 1990 (5.1%). This decline may be due to the improved health of
www.pharmacotherapyonline.com. older adults or the use of alternative long-term care services (e.g.,
assisted-living facilities, in-home healthcare). Nursing homes resi-

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 58
dents are predominately 85 years and older (45%), followed by modification, such as diet and physical activity. The prevalence of
persons 75 to 84 years (33.5%), 65 to 74 years (12.2%), and younger select common conditions in 2003 to 2004 included hypertension
SECTION 1

than 65 years (9.5%).2 Oldest old women (>85 years) compose 42% (52%), arthritis (50%), heart disease (32%), any cancer (21%),
of nursing home residents. diabetes (17%), stroke (9%), and asthma (9%). Sensory impairments
Physical activity has many positive health benefits in adults, are common in older adults and pose challenges for maintaining
including disease reduction (e.g., cardiovascular disease), weight functional independence and interactions with healthcare providers.
maintenance, and reduction in physical disability. Only 22% of In 2004, 40% of older adults reported some trouble hearing, and 17%
older adults engage in regular leisure-time physical activity, and this reported difficulties with vision. Furthermore, 13% of older adults
percentage decreases with increasing age.4 It is no surprise that have moderate or severe memory impairment, which is a major risk
obesity is a growing problem in both men (33%) and women (36%) factor for nursing home admission. The prevalence of memory
Foundation Issues

aged 65 to 74 years. The prevalence of obesity decreases to approxi- impairment increases dramatically (to 32%) for the oldest old.4
mately one in four for those older than 75 years.4 Chronic diseases are the primary cause of death in older adults.
An important goal in the care of older adults is allowing them to The leading causes of death among older adults have changed little
maintain independence and avoid the need for institutionalization for over the last 20 years. Fig. 8–1 illustrates the leading casues of death
as long as possible. Functional loss or disability often is a final common from 2004.4 Some important trends have emerged over the past 2
pathway of many clinical problems in older persons, especially among decades. First, the death rates for heart disease and stroke have
those older than 75 years. In 2000, 28.6% of older adults reported a decreased. This trend is secondary to the gains made in the preven-
physical disability (e.g., difficulty walking, climbing stairs, reaching, tion and treatment of these diseases. Second, death secondary to
lifting, carrying), and 9.5% reported disability with self-care or basic Alzheimer’s disease has increased rapidly in recent years. The
activities of daily living (ADLs; e.g., dressing, bathing, transferring, increased rate is due in part to improvements in the diagnosis and
feeding, toileting).5 Disability increases with increasing age and is awareness of Alzheimer’s disease in the medical community.4
higher in institutionalized older persons, among whom approximately Older adults are devoted consumers of medical and prescription
80% have some problems with mobility and 65% have difficulty with drug resources. With older persons accounting for 36% of all
bowel control.6 Segments of the population that are especially vulner- hospital stays and 49% of all days of care in hospitals, elders
able to disability include women, minorities, and those in lower consume almost one third of total U.S. healthcare expenditures.7 By
socioeconomic classes. Disability rates have declined significantly dur- 2030, healthcare spending by the U.S. population is projected to
ing the last 2 decades.2 The decline in late-life disability was greatest for increase by 25% simply because of aging demographics.7 Although
limitations in instrumental ADLs (e.g., housekeeping chores, shop- older persons compose 12.4% of the U.S. population, they account
ping, going outside, medication management) and physical disability. for 34% of all prescription drug expenditures.8 Overall in 2002,
Conflicting evidence exists for basic ADL disability, the most severe prescription drug spending was estimated to be between $91 and
type of disability that often leads to institutionalization. Multiple $117 billion.9 National estimates in 2002 indicated that individuals
factors likely are responsible for the decline in disability prevalence, older than 65 years filled nearly 32 prescriptions per year and that
including improved medical treatment, change in health behaviors their average annual expenditure for prescription drugs was $1,740.4
(e.g., reduced smoking), and widespread use of assistive devices.2 In 2003, approximately one fourth (27%) of older adults had no
Chronic diseases or impairments, such as heart disease, stroke, and prescription drug coverage, with the poor disproportionately
diabetes, are major causes of disability in older adults. An estimated affected (34%).10 The Medicare Prescription Drug, Improvement
80% of older adults have at least one chronic health condition, and and Modernization Act (MMA) began offering coverage to the 43
more than half have at least two concomitant conditions. Many million Medicare beneficiaries as of January 1, 2006, and this has
chronic conditions can be prevented or improved with behavioral improved prescription drug coverage for older adults. However, as

Leading Causes of Death in 2004 for Older Adults

600,000 Alzheimer’s Disease

Influenza & Pneumonia

500,000
Diabetes Mellitus
400,000 Cerebrovascular

Number of deaths 300,000 Chronic Lower

in 2004 Respiratory Disease

200,000 Heart Disease

Malignant Neoplasms
100,000

0
65–74 75–84 85+
Age ranges
Centers for Disease Control and Prevention, National Center for Injury Prevention and
Control. 2007, http://webappa.cdc.gov/saswb/ncipc/leadcaus10.html

FIGURE 8-1. Leading causes of death in 2004, by age group. (Data from Centers for Disease Control and Prevention,
National Center for Injury Prevention and Control. 2007, http://webappa.cdc.gov/sasweb/ncipc/leadcaus10.htm.)
 59
11,12
of June 2006, five million beneficiaries still did not have coverage ity. The cardiovascular, musculoskeletal, and central nervous
under MMA or other sources of credible coverage.9 systems appear to be most affected.12 Examples of homeostatic

CHAPTER 8
mechanisms that may become impaired include postural or gait
stability, orthostatic blood pressure responses, thermoregulation,
HUMAN AGING AND CHANGES cognitive reserve, and bowel and bladder function. An event resulting
IN DRUG PHARMACOKINETICS in functional impairment may involve an insult for which the body
AND PHARMACODYNAMICS cannot compensate, and relatively small stresses may result in major
morbidity and mortality.11–13
 There is a progressive functional decline in many organ systems A number of age-related physiologic changes occur that could affect
with advancing age. Table 8–1 reviews some common physiologic drug pharmacokinetics and pharmacodynamics (see Table 8–1).
changes associated with aging, with an emphasis on those changes

Geriatrics
Unfortunately, data on the pharmacokinetics and pharmacodynam-
that can affect pharmacotherapy. For more detailed information, ics of individual drugs commonly used in older adults are limited.
readers are referred to excellent reviews.11,12 This information gap may improve with implementation of Food
Age-associated physiologic changes may cause reductions in func- and Drug Administration guidelines calling for pharmacokinetic
tional reserve capacity (i.e., ability to respond to physiologic chal- studies by pharmaceutical companies for new molecular entities
lenges or stresses) and the ability to preserve homeostasis, thus likely to be used in older adults.14
making elders susceptible to decompensation in stressful situa-
tions.11–13 To deal with physiologic challenges or stresses, older
ALTERED PHARMACOKINETICS
individuals may require up to 95% of their remaining reserve capac-
Table 8–2 and the following discussion summarize what is known
TABLE 8-1 Physiologic Changes with Aging about the effect of aging on each of the four major facets of pharmaco-
kinetics.13,15 Of interest, when multivariate population pharmacoki-
Organ System Manifestation
netic analyses are conducted, age by itself seldom is a significant
Body composition ↓ Total body water predictor of individual pharmacokinetic parameters (e.g., clearance).
↓ Lean body mass
Aging-associated changes in drug absorption, distribution, metabo-
↑ Body fat
lism, and elimination are more important predictors of altered phar-
↔ or ↓ Serum albumin
↑ α1-Acid glycoprotein (↔ or ↑ by several disease states)
macokinetics than is aging, per se.
Cardiovascular ↓ Myocardial sensitivity to β-adrenergic stimulation
↓ Baroreceptor activity Absorption
↓ Cardiac output
Most drugs are taken orally; thus, a number of age-related changes in
↑ Total peripheral resistance
gastrointestinal physiology could affect the absorption of medica-
Central nervous ↓ Weight and volume of the brain
system Alterations in several aspects of cognition
tions. Fortunately, most drugs are absorbed via passive diffusion, and
Endocrine Thyroid gland atrophies with age age-related physiologic changes appear to have little influence on
Increased incidence of diabetes mellitus, thyroid disease drug bioavailability.16 A few drugs require active transport for absorp-
Menopause tion, so their bioavailability may be reduced (e.g., calcium in the
Gastrointestinal ↑ Gastric pH setting of hypochlorhydria). However, there is evidence for a
↓ Gastrointestinal blood flow decreased first-pass effect on hepatic and/or gut wall metabolism that
Delayed gastric emptying results in increased bioavailability and higher plasma concentrations
Slowed intestinal transit of drugs such as propranolol and morphine.16 Increased drug bio-
Genitourinary Atrophy of the vagina due to decreased estrogen availability also may be seen with the concurrent ingestion of grape-
Prostatic hypertrophy due to androgenic hormonal changes fruit juice. Constituents of this product inhibit cytochrome P450
Age-related changes may predispose to incontinence
(CYP450) isoenzyme CYP3A4, thus decreasing first-pass metabolism
Immune ↓ Cell-mediated immunity
Liver ↓ Hepatic size
and resulting in exaggerated pharmacologic effects.17
↓ Hepatic blood flow
Oral Altered dentition TABLE 8-2 Age-Related Changes in Drug Pharmacokinetics
↓ Ability to taste sweetness, sourness, bitterness
Pulmonary ↓ Respiratory muscle strength Pharmacokinetic Phase Pharmacokinetic Parameters
↓ Chest wall compliance Gastrointestinal absorption Unchanged passive diffusion and no change in
↓ Total alveolar surface bioavailability for most drugs
↓ Vital capacity ↓ Active transport and ↓ bioavailability for some
↓ Maximal breathing capacity drugs
Renal ↓ Glomerular filtration rate ↓ First-pass extraction and ↑ bioavailability for
↓ Renal blood flow some drugs
↑ Filtration fraction Distribution ↓ Volume of distribution and ↑ plasma concentra-
↓ Tubular secretory function tion of water-soluble drugs
↓ Renal mass ↑ Volume of distribution and ↑ terminal disposi-
Sensory ↓ Accommodation of the lens of the eye, causing tion half-life (t1/2) for fat-soluble drugs
farsightedness ↑ or ↓ Free fraction of highly plasma protein-
Presbycusis (loss of auditory acuity) bound drugs
↓ Conduction velocity Hepatic metabolism ↓ Clearance and ↑ t1/2 for some oxidatively metab-
Skeletal Loss of skeletal bone mass (osteopenia) olized drugs
Skin/hair Skin dryness, wrinkling, changes in pigmentation, epithelial ↓ Clearance and ↑ t1/2 for drugs with high hepatic
thinning, loss of dermal thickness extraction ratios
↓ Number of hair follicles Renal excretion ↓ Clearance and ↑ t1/2 for renally eliminated drugs
↓ Number of melanocytes in hair bulbs and active metabolites
From Kane et al.11 and Masoro.12 From Cusack13 and Chapron.15
 60
Distribution documented, as many as one third of “normal” older adult subjects
may have no reduction as measured by creatinine clearance.13,15
The distribution of medications in the body depends on factors such
SECTION 1

Moreover, emerging information suggests that renal tubular secretion

as blood flow, plasma protein binding, and body composition, each of
may not decline in proportion to other renal processes.30 The estima-
which may be altered with age. For example, the volume of distribu-
tion of creatinine clearance, although not entirely accurate in individ-
tion of water-soluble drugs is decreased, whereas lipophilic drugs
ual patients, can serve as a useful screening approximation. Cockcroft
exhibit an increased volume of distribution.13,15 Changes in the vol-
and Gault31 created one of the most commonly used equations for
ume of distribution can have a direct impact on the amount of
adults with stable renal function whose actual weight is within 30% of
medication that must be given as a loading dose.
ideal body weight:
P-glycoprotein, a member of the multidrug resistance (MDR)-
associated protein family of efflux transporters, influences the transport (140 – Age) (Actual body weight)
Foundation Issues

Creatinine clearance = ---------------------------------------------------------------------------------------

of drugs across the blood–brain barrier. Studies using verapamil labeled 72 (Serum creatinine concentration)
with carbon-11 (a positron emitter) and positron emission tomogra-
phy have demonstrated decreased P-glycoprotein activity in the blood– where age is given in years, actual body weight in kilograms, and serum
brain barrier with aging. As a result of this, the brain of aged individuals creatinine concentration in milligrams per deciliter. For women,
may be exposed to higher than normal levels of drugs and toxins.18 multiply this result by 0.85. The Modified Diet in Renal Disease32
The two major plasma proteins to which medications can bind are equation has become more widely used for estimation of glomerular
albumin and α1-acid glycoprotein, and concentrations of these pro- filtration rate. However, dosing guidelines for medications that pri-
teins may change with concurrent pathologies seen with increasing marily are renally cleared still are based on estimated creatinine
age.19 For acidic drugs such as naproxen, phenytoin, tolbutamide, and clearance determined using the Cockcroft and Gault equation. In the
warfarin, decreased serum albumin may lead to an increase in free future, use of another protein, cystatin C, a low-molecular-mass
fraction. An increase in α1-acid glycoprotein induced by burns, cancer, protein that is produced by all nucleated cells, is freely filtered at the
inflammatory disease, or trauma may lead to a decreased free fraction glomerulus, and is not secreted by the renal tubules, may prove to be
of basic drugs such as lidocaine, propranolol, quinidine, and imip- superior to use of creatinine. This could be the case especially with
ramine. In the absence of compromise in excretory pathways, these coexisting conditions such as cachexia, sedentary lifestyle, malnutri-
potential changes are unlikely to have any deleterious clinical effect. tion, and hepatic disease, because creatinine clearance is a poor
However, they may be important to consider when interpreting serum predictor of glomerular filtration in the presence of these conditions.33
concentrations of these drugs because usually only total drug concen- Medications whose excretion is primarily renal and for which
trations (sum of free and protein-bound drug) are reported. there is evidence of age-related reduction in renal and total body
clearance include (but are not limited to) amantadine, aminoglyco-
Metabolism sides, atenolol, captopril, cimetidine, digoxin, lithium, and vanco-
mycin. Some hepatically metabolized medications can yield active,
The liver is the major organ responsible for drug metabolism, including primarily renally excreted metabolites, such as N-acetylprocaina-
phase I (oxidative) and phase II (conjugative) reactions.20 The most mide, normeperidine, and morphine-6-glucuronide, which can
remarkable characteristic of hepatic function in older adults is the accumulate with advancing age because of reduced renal function.
increase in interindividual variability compared with other age groups,
a feature that may obscure true age-related changes.20 Data suggest that
age-related declines in phase I metabolism more likely are the result of CLINICAL CONTROVERSY
reduced hepatic volume than reduced hepatic enzymatic activity.21
Decreased phase I metabolism (e.g., hydroxylation, dealkylation) pro- When using the Cockcroft and Gault equation to estimate creati-
ducing decreased drug clearance and increased terminal disposition nine clearance in older adults, some clinicians round the value up to
half-life (t1/2) has been reported in elders for medications such as 1 if the patient’s serum creatinine concentration is less than 1.
diazepam, piroxicam, theophylline, and quinidine. Phase II metabo- Rounding the serum creatinine concentration may provide an
lism (e.g., glucuronidation, acetylation) of medications such as underestimation of creatinine clearance and result in improper dose
lorazepam and oxazepam appears to be relatively unaffected by advanc- adjustment of renally eliminated medications. It is important to
ing age. Hepatic enzyme induction (e.g., by rifampin, phenytoin) or realize that the equation is merely an estimate, and attempts should
inhibition (e.g., by fluoroquinolone and macrolide antimicrobials, be made to determine creatinine clearance accurately when use of
cimetidine) does not appear to be affected by the aging process.20,22 certain medications (e.g., metformin) is being contemplated.
Age-related decreases in hepatic blood flow can decrease signifi-
cantly the metabolism of drugs with high hepatic extraction ratios, ALTERED PHARMACODYNAMICS
such as imipramine, lidocaine, morphine, and propranolol.20 The
There is some evidence of altered drug response or “sensitivity” in older
effect of aging on polymorphic drug metabolism has not been well
adults. Four possible mechanisms have been suggested: (a) changes in
studied. Advancing age has been reported both to have no significant
receptor numbers, (b) changes in receptor affinity, (c) postreceptor
effect and to reduce significantly the activity of the CYP450 isoenzyme
alterations, and (d) age-related impairment of homeostatic mecha-
CYP3A4.23,24 Other available data suggest that advancing age has no
nisms.13,34 For example, muscarinic, parathyroid hormone, β-adrener-
significant effect on drug acetylation or on CYP450 isoenzyme
gic, α1-adrenergic, and μ-opioid receptors exhibit reduced density with
CYP2D6 or CYP2C9 isoenzyme-mediated metabolism.25–28 A single-
increasing age.13,34 Evidence from epidemiologic and experimental
point blood sampling method for evaluating CYP450 isoenzyme
studies suggests that, independent of pharmacokinetic alterations, older
CYP3A4 activity in older adults has been described.29 A number of
adults are more sensitive to the central nervous system effects of
potential confounding factors, including race, sex, frailty, smoking,
benzodiazepines.13,34 Older adults exhibit a greater analgesic respon-
diet, and drug–drug interactions, may significantly affect hepatic
siveness to opioids compared with their younger counterparts, even
metabolism in older adults.20
when pharmacokinetic parameters are similar in the two groups.13,34 In
addition, older adults demonstrate an enhanced responsiveness to
Elimination anticoagulants such as warfarin and heparin as well as to thrombolytic
Renal excretion is the primary route of elimination for many drugs. therapy but not to the direct thrombin inhibitor ximelagatran.13,34,35 In
Although age-related reductions in glomerular filtration are well contrast, older adults exhibit decreased responsiveness to certain drugs
 61
(e.g., β-agonists/antagonists). 13,34
Reflex tachycardia, seen commonly TABLE 8-4 Atypical Disease Presentation in Older Adults
with vasodilator therapy, often is blunted in older adults, perhaps

CHAPTER 8
Disease Presentation
because of dampened baroreceptor function. For some drugs (e.g.,
calcium channel blockers), both enhanced responsiveness (as demon- Acute myocardial Only ~50% present with chest pain. In general, older
strated by greater reduction in blood pressure) and decreased respon- infarction adults present with weakness, confusion, syncope, and
siveness (as demonstrated by reduced atrioventricular nodal blockade) abdominal pain; however, electrocardiographic findings
can occur simultaneously in older adults.13,34 are similar to those in younger patients.
Congestive heart Instead of dyspnea, the older patient may present with
failure hypoxic symptoms, lethargy, restlessness, and confusion.
CLINICAL GERIATRICS Gastrointestinal bleed Although the mortality rate is ~10%, presenting symp-
toms are nonspecific, ranging from altered mental

Geriatrics
status to syncope with hemodynamic collapse. Abdom-
 Maintenance of independence and prevention of disability are
inal pain often is absent.
primary goals in the clinical care of persons 65 years of age and older.
Upper respiratory Older patients typically present with lethargy, confusion,
To achieve these goals, it is necessary that all healthcare professionals infection anorexia, and decompensation of a preexisting medical
understand the concept of functional status. Functional status is a condition. Fever, chills, and a productive cough may or
proxy measure of a patient’s ability to live independently and can be may not be present.
determined in part by inquiring about an older person’s ability to Urinary tract infection Dysuria, fever, and flank pain may be absent. More com-
perform specific tasks. As mentioned previously, the two types of monly, older adults present with incontinence, confusion,
functional measurements are basic ADLs and the more complex abdominal pain, nausea/vomiting, and azotemia.
instrumental ADLs.36,37 However, to fully assess functional status, the From Fried et al.,38 Jarrett et al.,39 and Merck Manual of Geriatrics, 3rd ed, Whitehouse Station, NJ.40
patient’s psychological state, financial resources, physical function,
and social circumstances also must be considered.1
One of the challenges of maintaining and improving functional DRUG-RELATED PROBLEMS IN
status in geriatric individuals is recognizing and managing conditions OLDER ADULTS
frequently seen in older adults. Problems found more commonly in
older persons sometimes are referred to as the “I’s of geriatrics” (Table  Although medications used by older adults can lead to improve-
8–3).11 These problems are often due to underlying disease processes ment in HRQOL, negative outcomes due to drug-related problems
that may or may not be diagnosed. Examples of diseases and syn- are considerable.41–43 Three important and potentially preventable
dromes that can present as common problems in older adults include negative outcomes due to drug-related problems that can occur in
Parkinson’s disease, falls, hip fractures, benign prostatic hypertrophy, older adults are adverse drug withdrawal events (ADWEs), which are
dementia, glaucoma, postherpetic neuralgia, and tuberculosis. clinically significant sets of symptoms or signs caused by the removal
Another factor contributing to the challenge of clinical geriatrics is of a drug; therapeutic failure (inadequate or inappropriate drug
that approximately 50% of older patients present with atypical symp- therapy and not related to the natural progression of disease); and
toms or complaints, so use of the classic medical model for diagnosis adverse drug reactions (ADRs), defined as reactions that are noxious
is difficult. For example, cardiac ischemia in an older person may and unintended and occur at dosages normally used in humans for
present as syncope or weakness rather than the typical presentation of prophylaxis, diagnosis, or therapy.41–43
chest pain. Confusion may be the presenting symptom of an acute Data on the prevalence of ADWEs and therapeutic failures in older
abdominal process rather than the expected severe pain, rigid abdom- adults are limited. Graves et al.44 reported ADWEs in 38 of 124 male
inal muscles, and leukocytosis. Serious adverse consequences may outpatients who had discontinued taking 238 medications. Kaiser et
result if a diagnosis is delayed or missed because of these atypical al.45 reported that 11% of hospital admissions in a group of older frail
presentations. Such unusual presentations may be due to age-related men were related to therapeutic failure. ADRs occur commonly in
physiologic changes, the presence of multiple comorbid illnesses or older adults, with reported rates ranging from 2.5% to 50.6% depend-
compromised function, and the presence of psychological stressors.38 ing on the study population and methodology used.41 In a large study
Table 8–4 lists other examples of medical illnesses that often present of more than 30,000 Medicare outpatients, Gurwitz et al.46 reported
atypically in older adults.38–40 For very frail older adults, delirium, that 5% experienced an ADR in a 1-year period, with more serious
falls, and nonspecific functional decline (e.g., failure to thrive) fre- reactions more likely to be preventable. In contrast, Hanlon et al.47
quently are presenting problems.38–40 reported that 33% of frail male outpatients had one or more ADRs in
Multiple coexisting chronic illnesses are another common threat to a 1-year period. A review suggests that ADRs are the most common
independence that distinguishes older adults from younger patients. type of medication-related problem in elderly nursing home patients.42
Older patients usually have multiple comorbidities, such as osteoar- ADRs and other drug-related problems (e.g., ADWEs, therapeutic
thritis, heart disease, and diabetes. Although multiple comorbidities failure) are major threats to the HRQOL of outpatient elders and
can have a substantial impact on a patient’s functional status, the account for billions of healthcare dollars per year.48 In the nursing home
mere existence of multiple diseases alone does not determine func- setting alone, a cost-of-illness study estimated that drug-related prob-
tional impairment. lems (including ADRs and therapeutic failure) cost $4 billion per year.49

TABLE 8-3 The I’s of Geriatrics: Common Problems in RISK FACTORS

Older Adults
Overuse
Immobility Instability
Isolation Intellectual impairment Polypharmacy can be defined as either the concomitant use of multiple
Incontinence Impotence drugs or the administration of more medications than are indicated
Infection Immunodeficiency clinically.50 Polypharmacy is common and increasing among older
Inanition (malnutrition) Insomnia adults. Community-based surveys reveal that older adults take an
Impaction Iatrogenesis average of two to nine prescription and nonprescription medications
Impaired senses each day.50–52 A study of community-dwelling older adults in Finland
From Kane et al.11 reported an increase in polypharmacy, with the largest growth among
 62
patients older than 85 years.53 Increased use of dietary supplements, health services use.61 Underuse of medication in general because of
such as herbal products, vitamins, and minerals, may add to the limiting access of Medicaid patients to medications more than dou-
SECTION 1

increase in polypharmacy. In a nationwide survey, Kaufman et al.54 bled the risk of admission to a nursing home.71 Tamblyn et al.72
found that 59% of women and 46% of men older than 65 years used a studied the effects of a deductible and a 25% coinsurance fee for
vitamin or mineral supplement and that 14% of these women and medications taken by elders in Canada. This reform led to a decrease
11% of these men used an herbal product. Outside of the community, in the number of essential medications (e.g., furosemide, anticoagu-
a nursing facility survey found that institutionalized older persons lants, angiotensin-converting enzyme inhibitors) used by older
took an average of 6.69 routine medications and 27.1% took nine or patients and increased costs owing to adverse events and emergency
more medications on a regular basis.55 Drug-use studies that defined department visits.
polypharmacy as use of one or more unnecessary medications showed
Foundation Issues

that polypharmacy occurs in 55% to 59% of older outpatients.56,57 A Medication Nonadherence

study of frail veterans at hospital discharge reported that 44% of
The World Health Organization (WHO) defines medication adher-
patients were taking one or more unnecessary medications, with 25%
ence as “the extent to which a person’s behavior—taking medica-
of patients starting the medication(s) during hospitalization.58 Multi-
tion…corresponds with agreed recommendations from a healthcare
ple medication use has been strongly associated with ADRs.41 Poly-
provider.”73 Given that definition, nonadherence could be defined as
pharmacy also is problematic for older adults because it may increase
not filling the prescription, stopping use of the medication before the
the risk of geriatric syndromes (e.g., falls, cognitive impairment),
entire supply is consumed, or taking more or less of the medication
diminished functional status, and healthcare costs.50,59,60
than stated by the label. The prevalence rate of medication nonadher-
ence in older adults ranges from 40% to 80% (mean approximately
Inappropriate Prescribing 50%).74,75 Older and younger patients have similar adherence when
Inappropriate prescribing can be defined as prescribing medications the number of drugs taken is similar.76 In fact, some evidence
outside the bounds of accepted medical standards.61 This phenom- indicates that adherence may be better in older adults for some
enon occurs commonly in older outpatients, as exemplified by one conditions.74,77,78 According to the AARP (formerly the American
study in which 92% of patients were taking at least one medication Association for Retired Persons) and a study in the Medicare popula-
with one or more inappropriate ratings based on clinical review tion, cost is a common reason why older adults do not fill their
applying explicit criteria.62 Studies using explicit drug-use review prescriptions.79,80 Older patients also may not adhere to their regi-
criteria have found that between 15% and 21% of community- mens because of possible adverse effects, an inability to read product
dwelling older adults take one or more medications that have a labels, or a lack of full understanding of information about the
dose, duration, duplication, or drug-interaction problem.63,64 prescribed medication.79,81
Alternatively, inappropriate prescribing can be defined as prescrib- Limited retrospective data suggest that nonadherence is associ-
ing drugs whose use should be avoided because their risk outweighs ated with increased health services use and ADRs. In a 2001 study,
their potential benefit.65 A European study found that 20% of older nonadherence was the possible cause of more than 10% of older
home-care patients used at least one inappropriate medicine as adult hospital admissions.82 A study by Col et al. 83 evaluated 315
defined by explicit criteria.66 A study of inappropriate drug use in U.S. consecutive older patients admitted to a hospital and determined
long-term care facilities found that 25% of residents took one or more that 11.4% of admissions resulted from nonadherence. Gurwitz et
inappropriate medications as defined by explicit criteria.67 al.46 found that 21% of preventable ADRs in elderly outpatients
were due to errors in patient adherence. On the positive side, a study
found that increased medication adherence was associated with
CLINICAL CONTROVERSY fewer hospitalizations and decreased cost in patients with certain
chronic medical conditions (e.g., diabetes, hypertension).84
At present, the best way to measure inappropriate prescribing is
not clear. The association between explicit criteria developed by
Beers et al. (known commonly as the Beers’ criteria)65 for
inappropriate prescribing or other measures of inappropriate
PROVISION OF COMPREHENSIVE
prescribing and health outcomes has been mixed.68 We recom- GERIATRIC ASSESSMENT
mend further studies of the predictive validity of evidence-based
 Given that drug-related problems are common, costly, and clini-
standards for measuring inappropriate prescribing of medica-
cally important, how can they be prevented/managed? A solution may
tions in older adults.
lie in comprehensive geriatric assessment. The term comprehensive
geriatric assessment has been applied to geriatric evaluation and
Underuse management (GEM), in which GEM clinicians (which often include
An important and increasingly recognized problem in elders is pharmacists) manage the patient. Comprehensive geriatric assess-
underuse, defined as the omission of drug therapy that is indicated ment has become a cornerstone in the care of older adults. A
for treatment or prevention of a disease or condition.61 A study of comprehensive review has summarized its effectiveness in improving
community-dwelling elders found that 50% of 372 vulnerable adults suboptimal prescribing and reducing ADRs.61
were not prescribed an indicated medication. The most common Pharmacists can independently play a significant role in optimiz-
problems were the lack of a gastroprotective agent for high-risk ing pharmacotherapy for older adults. The results from 13 random-
nonsteroidal antiinflammatory drug users, no angiotensin-convert- ized controlled studies show that clinical pharmacy interventions can
ing enzyme inhibitor for patients with diabetes and proteinuria, and reduce drug-related problems and improve health outcomes in older
no calcium and/or vitamin D for those with osteoporosis.69 A study adults.85 Subsequent published studies also have demonstrated the
of older adults in assisted-living facilities revealed that 62% of value of pharmacists in improving drug therapy for elders.61,86,87
residents with a diagnosis of heart failure did not take an angioten- The following subsections provide an approach to how pharma-
sin-converting enzyme inhibitor, and 61% of those with osteoporo- cists in any practice setting (especially those providing medication
sis did not take calcium supplements.70 therapy management services under the new Medicare Part D
Underuse may have an important relationship with negative health program) can optimize medication use through the provision of
outcomes in older adults, including functional disability, death, and comprehensive geriatric assessment.
 63

HISTORY TAKING TABLE 8-6 Centers for Medicare and Medicaid Services
Guidelines for Monitoring Medication Use

CHAPTER 8
Several difficulties may occur while taking medication histories
from older adults. They include (a) communication problems Drug Monitoring
(impaired hearing and vision), (b) underreporting (e.g., health Acetaminophen (>4 g/day) Hepatic function tests
beliefs, cognitive impairment), (c) reporting of vague or nonspecific Aminoglycosides Serum creatinine, drug levels
symptoms (altered presentation), (d) coexistence of multiple dis- Hypoglycemic agents Blood sugar levels
eases and/or use of multiple medications, (e) reliance on a caregiver Antiepileptic agents (older) Drug levels
for the history, and (f) lack of medical records to confirm findings. Angiotensin-converting enzyme Potassium levels
inhibitors
Despite these potential difficulties, health professionals should find
Antipsychotic agents Extrapyramidal adverse effects

Geriatrics
value in collecting this vital medication history information. Appetite stimulants Weight, appetite
The importance of inquiring about use of nonprescription medica- Digoxin Serum creatinine, drug levels
tions and dietary supplements in older adults cannot be overstressed. Diuretic Potassium levels
A national survey reported that half of community-dwelling older Erythropoiesis stimulants Blood pressure, iron and ferritin levels, com-
adults take one or more vitamins or minerals and another 12% take plete blood count
one or more herbal/botanical agents.54 Fibrates Hepatic function test, complete blood count
Asking older adults and their caregivers about methods they use Iron Iron and ferritin levels, complete blood count
to keep track of medicines is important. This will allow design of Lithium Drug levels
solutions to any problems detected and prevent repeating of ineffec- Niacin Blood sugar levels, hepatic function tests
tive, previously used methods. Statins Hepatic function tests
Theophylline Drug levels
Patients and caregivers should be asked about risk factors for
Thyroid replacement Thyroid function tests
prescribing problems (e.g., utilizing multiple physicians and phar- Warfarin Prothrombin time/international normalized
macies) and adherence problems (e.g., impaired hearing, vision, ratio
and/or cognition; inability to open safety caps, pay for medicines, or
From reference 91.
swallow medications).88 The drug history should end with an inquiry
about any past allergies to medications and whether patients cur- the appropriateness of the remaining medications. A variety of
rently or in the recent past experienced any adverse effects, unwanted approaches can be used.61 One standardized measure with demon-
reactions, or other problems with their medications.89 strated reliability and validity is the Medication Appropriateness Index
(MAI).68,92 The MAI consists of 10 questions that should be asked
ASSESSING AND MONITORING about each medication (Table 8–7). Some other factors to consider
DRUG THERAPY during drug regimen review include medication storage problems and
drug interactions with food and/or laboratory test results.
The first step in the assessment is to determine whether drug-related
problems are causing any of the patient’s symptoms/problems. In
particular, consider whether any current medications are causing any CLINICAL CONTROVERSY
geriatric syndrome (e.g., falls, urinary incontinence, cognitive impair-
An increasing number of clinical trials are enrolling older adult
ment). Table 8–5 lists medications for which there is evidence that use
patients. For example, we now have evidence supporting the car-
increases the risk of cognitive impairment.90 The next step is to match
diac benefits of pravastatin in older adults.93 Clinicians must weigh
the medical problem list with the drug list. If a drug does not have a
the risks and benefits of adding drug therapy to a patient’s drug
match with the problem list, the drug may not be needed. Conversively,
regimen because increasing the number of drugs may decrease
if the patient has a chronic condition and is not taking a medication,
adherence and lead to an increased risk for ADRs. Furthermore, a
consider whether the patient would benefit from an essential evidence-
clinician must decide whether adding drug therapy in patients who
based drug to treat the condition. Next, examine laboratory test results
may not live long enough to benefit from the medication is ethical.
and vital signs that can be used to monitor the efficacy and toxicity of
each medication. Table 8–6 lists laboratory monitoring recommenda-
tions for medications used in long-term care facilities.91 Finally, assess DOCUMENTING PROBLEMS AND
FORMULATING A THERAPEUTIC PLAN
TABLE 8-5 Drugs/Drug Classes Associated with Altered
Cognition and/or Cognitive Disorders The clinician must document the problems that have been detected,
develop a therapeutic plan to resolve them, and establish reasonable
Antiarrhythmic agents (e.g., disopyramide)
Antiemetic/antivertigo agents (e.g., meclizine) TABLE 8-7 Medication Appropriateness Index
Antihistamines (e.g., diphenhydramine, hydroxyzine)
Antiparkinsonian agents (e.g., benztropine, trihexyphenidyl) Questions to Ask About Each Individual Medication
Antipsychotic agents (e.g., thioridazine) 1. Is there an indication for the medication?
Antispasmodic agents (e.g., belladonna, flavoxate) 2. Is the medication effective for the condition?
Benzodiazepines 3. Is the dosage correct?
Central nervous system drugs, especially when several agents are used 4. Are the directions correct?
concomitantly (as in polypharmacy) 5. Are the directions practical?
Digoxin 6. Are there clinically significant drug–drug interactions?
Histamine H2 receptor antagonists 7. Are there clinically significant drug–disease/condition interactions?
Nonsteroidal antiinflammatory drugs 8. Is there unnecessary duplication with other medication(s)?
Opioid agonists (especially meperidine, pentazocine) 9. Is the duration of therapy acceptable?
Skeletal muscle relaxants (e.g., cyclobenzaprine) 10. Is this medication the least expensive alternative compared with others of equal
Tricyclic antidepressants (e.g., amitriptyline) utility?
Data from Kotylar M, Gray SL, Lindblad CI, Hanlon JT. Psychiatric Manifestations of Medications in Reprinted and adapted from J Clin Epidemiol, Vol. 45, Hanlon JT, Schmader KE, Samsa GP, et al. A
the Elderly. In Malletta G, Agronin M (editors). Principles and Practice of Geriatric Psychiatry, 1st ed. method for assessing drug therapy appropriateness, Pages 1045–1051, Copyright 1992, with
Philadelphia, PA: Lippincott Williams and Wilkins 2005;605–615. permission from Elsevier.
 64
therapeutic end points. Remember that what may be a reasonable high-risk drugs (e.g., anticoagulant, antidepressant, antiinfective, anti-
end point for a 40-year-old patient may not be as reasonable for an psychotic, anticonvulsant, opioid analgesic, sedative/hypnotic, skeletal
SECTION 1

80-year-old patient when comorbidities, functional status, and life muscle relaxant). Another study of geriatric experts identified 21 risk
expectancy are taken into consideration. factors for ADRs in ambulatory older adults.98 Other unique risk
factors include (a) medication-related issues (i.e., with anticholin-
CONSULTING THE PHYSICIAN REGARDING ergics, benzodiazepines, chlorpropamide, corticosteroids, nonster-
PROBLEMS AND CONCERNS oidal antiinflammatory drugs), (b) certain patient characteristics (e.g.,
multiple comorbidities, multiple prescribers, age 85 years and older,
In most cases, the pharmacist or other healthcare professional dementia, regular use of alcohol, decreased renal function), (c) use of
should contact a patient’s physician regarding problems and con- drugs with narrow therapeutic ranges (e.g., lithium, theophylline),
Foundation Issues

cerns that have been detected and documented. In discussing the (d) history of an ADR, and (e) recent hospitalization.
patient in this context, the importance of optimizing the prescribing
for the older adult patient before implementing strategies to
enhance his or her adherence cannot be overstressed. Otherwise, CONCLUSIONS
adherence intervention, if effective, may result in patient harm.
Similarly, in institutional settings, strategies to reduce medication The number of people older than 65 years is growing in the United
errors may not improve patient outcomes if prescribing is not States and around the world, and individuals older than 85 years are
improved beforehand. the fastest growing segment of the U.S. population. A number of
physiologic changes associated with age, especially hepatic metabo-
COUNSELING AND ADHERENCE AIDS lism and renal excretion, affect the pharmacokinetics and pharmaco-
dynamics of drugs. Improving and maintaining the patient’s
Before dispensing medication, consider some general factors that may functional status and managing the patient’s comorbidities are hall-
enhance adherence by older adults, such as modifying medication marks of clinical geriatrics. Certain medical conditions are restricted
schedules to fit patients’ lifestyles, prescribing generic agents to reduce to older adults, and drug-related problems represent a major concern
costs, and using easy-to-open bottles, easy-to-swallow dosage forms, for this group. Innovative approaches, such as the provision of
and larger type on direction and auxiliary labels.94 The WHO suggests comprehensive geriatric assessment by pharmacists and other health-
clinicians consider five dimensions when assessing medication adher- care professionals, are needed to decrease the occurrence of these
ence: social/economic factors (e.g., cultural beliefs), provider–patient/ drug-related problems.
healthcare system factors (e.g., provider–patient relationship), condi-
tion-related factors (e.g., chronic conditions), therapy-related factors
(e.g., regimen complexity), and patient-related factors (e.g., visual or ABBREVIATIONS
hearing impairment).73 Finally, when dispensing medications (partic-
ularly new medications or previously used medications that have ADL: activity of daily living
changed in appearance or directions for use), provide both written
ADR: adverse drug reaction
and oral drug information to the patient and caregiver.
To improve the likelihood of adherence, the healthcare professional ADWE: adverse drug withdrawal event
should recruit active patient and caregiver involvement, stress the CYP450: cytochrome P450
importance of adherence, and consider the use of adherence-enhanc- GEM: geriatric evaluation and management
ing aids (e.g., special packaging, a medication record, a drug calendar,
HRQOL: health-related quality of life
medication boxes, magnification for insulin syringes, dose-measuring
devices, and spacers for metered-dose inhalers).95,96 In institutional MAI: Medication Appropriateness Index
settings, discussion of special considerations (e.g., medications that MMA: Medicare Prescription Drug, Improvement and Moderniza-
can be crushed and given via feeding tube) with healthcare profession- tion Act
als responsible for medication administration is prudent. WHO: World Health Organization

DOCUMENTING INTERVENTIONS AND

MONITORING PATIENT PROGRESS REFERENCES
All interventions must be documented, and the steps just outlined 1. Rubenstein LZ, Rubenstein LV. Multidimensional geriatric assess-
must be repeated over time with older adult patients. During fol- ment. In: Tallis R, Fillit H, eds. Brocklehurst’s Textbook of Geriatric
lowup contacts, minimum inquiry should include asking patients Medicine, 6th ed. London: Churchill-Livingstone, 2003:291–299.
whether they have any questions or concerns regarding medicines 2. He W, Sengupta M, Velkoff VA, DeBarros KA. U.S. Census Bureau,
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lished have been achieved. To assess potential ADRs, ask patients Washington, DC: U.S. Government Printing Office, 2005.
whether they currently or recently have experienced any side effects, 3. Olshansky SJ. The demography of aging. In: Cassel CK, Leipzig RM,
unwanted reactions, or other problems with their medications. Cohen HJ, Larson EB, Meier DE, eds. Geriatric Medicine: An Evidence-
based Approach, 4th ed. New York: Springer-Verlag, 2003:37–44.
4. Centers for Disease Control and Prevention. National Center for Injury
TARGETING HIGH-RISK OLDER ADULTS Prevention and Control. 2007. Accessed at http://webappa.cdc.gov/
sasweb/ncipc/leadcaus10.html, October 19, 2007.
In busy practices, the approach outlined may not be feasible for every
5. Waldrop J, Stern SM. Disability Status, 2000. Census 2000 Brief. March
patient. Therefore, practitioners may consider targeting these activities
Report Number C2KBR-17. Washington, DC: U.S. Department of Com-
to patients at high risk for developing drug-related problems. Geriatric merce, Economics and Statistics Administration, U.S. Census Bureau, 2003.
experts have identified risk factors for preventable ADRs in older adult 6. National Center for Health Statistics. Health, United States, 2000.
nursing home patients.97 These include the following medication- Hyattsville, MD: U.S. Department of Health and Human Services, 2000.
related factors: (a) polypharmacy (i.e., use of seven or more medica- 7. National Center for Chronic Disease Prevention and Health Promo-
tions or more than three cardiac medications), and (b) taking specific tion. Healthy Aging: Preventing Disease and Improving Quality of Life
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27. Taioli E, Mari D, Franceschi C, et al. Polymorphisms of drug-metabo- older adults: A pilot study. Am J Geriatr Pharmacother 2005;3:196–204.
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28. Brenner SS, Herrlinger C, Dilger K, et al. Influence of age and 2002;55:809–817.
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29. Krupka E, Venisse N, Lafay C, et al. Probe of CYP3A by a single-point Slone Survey. JAMA 2002;287:337–344.
blood measurement after oral administration of midazolam in healthy 55. Tobias DE, Sey M. General and psychotherapeutic medication use in
elderly volunteers. Eur J Clin Pharmacol 2006;62:653–659. 328 nursing facilities: A year 2000 national survey. Consult Pharm
30. Ujhelyi MR, Bottorff MB, Schur M, et al. Aging effects on the organic 2001;16:54–64.
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Ther 1997;62:117–128. medication prescribing in ambulatory elderly patients. J Am Geriatr
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serum creatinine. Nephron 1976;16:31–41. 57. Lipton HL, Bird JA. The impact of clinical pharmacists’ consultations
32. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate on geriatric patients’ compliance and medical care use: A randomized,
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59. Montamat SC, Cusack B. Overcoming problems with polypharmacy A national survey 1 year before the medicare drug benefit. Arch Intern
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60. Hanlon JT, Schmader KE, Ruby CM, Weinberger M. Suboptimal 81. Moisan J, Gaudet M, Gregoire JP, et al. Non-compliance with drug
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64. Lindblad CI, Hanlon JT, Gross CR, et al. Clinically important drug- tion adherence on hospitalization and health care cost. Med Care
disease interactions and their prevalence in older adults. Clin Ther 2005;43:521–530.
2006;28:1133–1143. 85. Hanlon JT, Lindblad CI, Gray SL. Evidence that clinical pharmacy
65. Fick DM, Cooper JW, Wade WE, et al. Updating the Beers criteria for services can have a positive impact on drug-related problems and
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66. Fialova D, Topinkova E, Gambassi G, et al. Potentially inappropriate 86. Zermansky AG, Alldred DP, Petty DR, et al. Clinical medication review
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67. Briesacher B, Limcangco R, Simoni-Wastila L, et al. Evaluation of nation- 87. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on
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70. Sloane PD, Gruber-Baldini Al, Zimmerman S, et al. Medication under- community setting. J Am Geriatric Soc 2007;55:29–34.
treatment in assisted living settings. Arch Intern Med 2004;164;2031– 90. Kotylar M, Gray SL, Lindblad CI, Hanlon JT. Psychiatric manifesta-
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71. Soumerai SB, Ross-Degnan D, Avorn J, et al. Effects of Medicaid drug- Principles and Practice of Geriatric Psychiatry. Philadelphia: Lippin-
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72. Tamblyn R, Laprise R, Hanley JA, et al. Adverse events associated with Use (Tag F329) 2007, http://www.cms.hhs.gov/transmittals/downloads/
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74. Hughes CM. Medication non-adherence in the elderly: How big is the Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at
problem? Drugs Aging 2004;21:793–811. risk of vascular disease (PROSPER): A randomized, controlled trial.
75. American Society on Aging and American Society of Consultant Lancet 2002;360:1623–1630.
Pharmacists Foundation 2006. Medication adherence—Where are we 94. Ryan AA. Medication compliance and older people: A review of the
today? 2007, http://www.adultmeducation.com. literature. Int J Nurs Stud 1999;36:153–162.
76. German PS, Klein LE, McPhee SJ, et al. Knowledge of and compliance 95. van Eijken M, Tsang S, Wensing M, et al. Interventions to improve
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77. Park DC, Hertzog C, Leventhal H, et al. Medication adherence in rheuma- systematic review of the literature. Drugs Aging 2003;20:229–240.
toid arthritis patients: Older is wiser. J Am Geriatr Soc 1999;47:172–183. 96. Cramer JA. Enhancing patient compliance in the elderly: Role of
78. Buist DSM, LaCroix AZ, Black DM, et al. Inclusion of older women in packaging aids and monitoring. Drugs Aging 1998;12:7–15.
randomized clinical trials: Factors associated with taking study medication 97. Lapane, KL. Hughes, CM. Identifying nursing home residents at high
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Washington, DC: AARP, December 2004. 98. Hajjar E, Artz MB, Lindblad CI, et al. Risk factors and prevalence for
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 67

C HAP T E R

9 Pharmacoepidemiology

ANDY STERGACHIS, THOMAS K. HAZLET, AND DENISE BOUDREAU

once a drug is marketed. Benefits and risks learned following a drug’s

KEY CONCEPTS approval may range from relatively minor to clinically important
effects that seriously alter an individual drug’s risk-to-benefit profile.
 Risks and benefits are commonly identified only after a drug is The association between certain appetite-suppressant drugs and pri-
used widely by the general population. mary pulmonary hypertension and valvular heart disease, and between
 Observational study designs are essential for the study of risks some cyclooxygenase-2 inhibitors and cardiovascular events, are two
and benefits associated with marketed drugs. examples where serious adverse effects were discovered only after these
drugs had come into widespread use.1–4 These examples highlight the
 Not all associations represent a cause-and-effect relationship. inherent limitations of the drug development process, the limitations
 Regulatory agencies are under pressure to identify and re- of the regulatory framework for contemporary medical products
spond to postapproval drug safety issues. (drugs, biologics, and medical devices), and the need to study popula-
tions receiving medications obtained through usual clinical practice.
The liver toxicity seen with troglitazone and more recently, rosiglita-
 The practice of pharmacotherapy presents numerous challenges to zone, is another example of the valuable contribution of close moni-
clinicians as they apply knowledge of the benefits and risks of pharma- toring to drug safety. The first thiazolidinedione introduced for
ceuticals to individual and population-based patient care. A great deal treatment of type 2 diabetes mellitus in 1997, troglitazone was with-
of our understanding about the efficacy and short-term safety of drugs drawn from the market based on reports of serious hepatocellular
arises from well-controlled studies conducted during the drug devel- injury. In mid-2007, heart attacks and related deaths were observed in
opment and approval process. However, many additional risks and, pooled clinical trials data for some patients receiving rosiglitazone,
increasingly, additional benefits are only identified after the drug is another thiazolidinedione subsequently approved for diabetes.5 Medi-
used widely by the general population. Our gaps in knowledge of risks cal products must also be monitored closely following their introduc-
and benefits at the time a drug is marketed is a result of numerous tion into the marketplace, and this information has value when
characteristics of preapproval studies, including limited sample size, applied to clinical practice. This chapter describes the role of pharma-
relatively short study followup, restricted characteristics of persons coepidemiology in drug development and therapeutics and character-
studied, and differences in research settings from real-life conditions izes the primary methods and contemporary issues in this field.

The complete chapter,

learning objectives, and other
resources can be found at
www.pharmacotherapyonline.com.

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This page intentionally left blank
 69

C HAP T E R

10 Clinical Toxicology

PETER A. CHYKA

cases, detoxify a certain dose of a chemical; however, once a critical

KEY CONCEPTS threshold is exceeded, toxicity results. Poisoning can produce minor
local effects that can be treated readily in the outpatient setting or
 Poisoning can result from exposure to excessive doses of any systemic life-threatening effects that require intensive medical inter-
chemical, with medicines being responsible for most child- vention. This spectrum of toxicity is typical for many chemicals with
hood and adult poisonings. which humans come in contact. Virtually any chemical can become
 The total number and rate of poisonings have been increasing, a poison when taken in sufficient quantity, but the potency of some
but preventive measures, such as child-resistant containers, compounds leads to serious toxicity with small quantities (Table
have reduced mortality in young children. 10–1).1 Poisoning by chemicals includes exposure to drugs, indus-
trial chemicals, household products, plants, venomous animals, and
 Immediate first aid may reduce the development of serious agrochemicals. This chapter describes some examples of this spec-
poisoning, and consultation with a poison control center may trum of toxicity, outlines means to recognize poisoning risk, and
indicate the need for further therapy. presents principles of treatment.
 The use of ipecac syrup, gastric lavage, and cathartics has fallen
out of favor as routine therapies, whereas activated charcoal
and whole-bowel irrigation still are useful for gastric decontam-
EPIDEMIOLOGY
ination of appropriate patients.
Each year poisonings account for approximately 30,000 deaths and at
 Antidotes can prevent or reduce the toxicity of certain poisons, least 1.4 million emergency department visits in the United States.2,3
but symptomatic and supportive care is essential for all patients. Adults, 20 to 59 years of age are at greatest risk for a poisoning death,
and males have a twofold higher incidence of death than do females.
 Acute acetaminophen poisoning produces severe liver injury One fifth of all adult poisoning deaths are due to suicide. Poisoning
and occasionally kidney failure. A determination of serum acet- deaths in adults are most commonly caused by motor vehicle exhaust
aminophen concentration may indicate whether there is risk of (carbon monoxide), opioids, antidepressants, benzodiazepines, seda-
hepatotoxicity and the need for acetylcysteine therapy. tives, alcohol, and cocaine.3,4 Approximately 0.2% of poisoning deaths
 Anticholinesterase insecticides may produce life-threatening res- involve children younger than 5 years. The number and rates of
piratory distress and paralysis by all routes of exposure and can poisoning deaths from all circumstances have been increasing steadily,
be treated with symptomatic care, atropine, and pralidoxime. with a 50% increase from 1999 to 2004.3 Age-adjusted annual rates for
unintentional poisoning deaths increased from 4.4 per 100,000 popula-
An overdose of calcium channel antagonists will produce se- tion in 1999 to 7.1 in 2004 (63% increase).5 This increase in mortality is
vere hypotension and bradycardia and can be treated with sup- attributed to poisonings from drugs (primarily prescription opioids;
portive care, calcium, glucagon, and insulin with supplemental secondarily cocaine and prescription psychotherapeutic drugs, e.g.,
dextrose. sedatives), which increased by 68% compared to an increase of 1%

Poisoning with iron-containing drugs produces vomiting, gross from other substances.5
gastrointestinal bleeding, shock, metabolic acidosis, and coma  Several databases in the United States provide different levels
and can be treated with supportive care and deferoxamine. of insight into and documentation of the poisoning problem
(Table 10–2). Poisonings documented by U.S. poison centers are
 Overdoses of tricyclic antidepressants can cause arrhythmias, compiled in the annual report of the American Association of
such as prolonged QRS intervals and ventricular dysrhythmias, Poison Control Centers’ National Poison Data System (AAPCC-
coma, respiratory depression, and seizures and are treated with NPDS).6 Although it represents the largest database on poisoning, it
symptomatic care and intravenous sodium bicarbonate.

TABLE 10-1 Serious Toxicity in a Child Associated with Ingestion

Poisoning is an adverse effect from a chemical that has been taken of One Mouthful or One Dosage Unit
in excessive amounts. The body is able to tolerate and, in some Acidsa Cocaine
Anticholinesterase insecticidesa Colchicine
Caustics or alkalisa Cyanidea
Learning objectives, review questions, Cationic detergentsa Hydrocarbonsa
and other resources can be found at Chloroquine Methanola
www.pharmacotherapyonline.com. Clonidine Phencyclidine or LSD
a
Concentrated or undiluted form.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 70

TABLE 10-2 Comparison of Various Poisoning Databases TABLE 10-4 Examples of Products Requiring
Child-Resistant Closures
SECTION 1

Database (Abbreviation) Characteristics

Death certificates from state health Compiles all death certificates whether Acetaminophen Kerosene
departments compiled by the the cause of death was by disease Aspirin Methanol
National Center for Health Statistics or external forces. Data typically veri- Diphenhydramine Oral prescription drugsa
(NCHS) www.cdc.gov/ncipc/wisqars fied by laboratory and clinical obser- Ethylene glycol Permanent hair wave neutralizers con-
vations. Glue removers containing acetonitrile taining sodium bromate
National Electronic Injury Surveillance Surveys electronically all injuries, Ibuprofen Sodium hydroxide
System of U.S. Consumer Product including poisonings, treated daily at Iron pharmaceuticals Sulfuric acid
Safety Commission (NEISS) a sample of approximately 100 emer- Turpentine
Foundation Issues

www.cdc.gov/ncipc/wisqars gency departments. Used to identify a

With certain exceptions such as nitroglycerin and oral contraceptives.
product-related injuries.
Drug Abuse Warning Network (DAWN) Identifies substance abuse–related epi- for this economic estimate excluded poisoning from alcohol and
of the Federal Substance Abuse and sodes and deaths as reported to illicit drugs.
Mental Health Services Administra- approximately 420 hospitals and 120
tion www.dawninfo.samhsa.gov medical examiners.
(SAMHSA) POISON PREVENTION STRATEGIES
The American Association of Poison Represents largest database of poison-
Control Centers’-National Poison ings with high representation of chil-  The number of poisoning deaths in children has declined
Data System (AAPCC-NPDS) dren based on voluntary reporting to dramatically over the past three decades, due, in part, to the
www.aapcc.org poison control centers. implementation of several poison prevention approaches.7,8 These
include the Poison Prevention Packaging Act (PPPA) of 1970, the
evolution of regional poison control centers, the application of
is not complete because it relies on individuals voluntarily contacting prompt first aid measures, improvements in overall critical care,
a poison control center. The AAPCC-NPDS dataset captures approx- development of less toxic product formulations, better clarity in the
imately 5% of the annual number of deaths from poisoning tabulated packaging and labeling of products, and public education on the
in death certificates.4 Despite this shortcoming, AAPCC-NPDS pro- risks and prevention of poisoning.9 Although all these factors play a
vides valuable insight into the characteristics and frequency of poi- role in minimizing poisoning dangers, particularly in children, the
sonings. In the 2005 AAPCC-NPDS summary, 2,424,180 poisoning PPPA has perhaps had the most significant influence.8 The intent of
exposures were reported by 61 participating poison centers that the PPPA was to develop packaging that is difficult for children
served a population of 296 million people.6 Children younger than 6 younger than 5 years to open or to obtain harmful amounts within
years accounted for 51% of cases. The home was the site of exposure a reasonable period of time. However, the packaging was not to be
in 93% of the cases, and a single substance was involved in 91% of difficult for normal adults to use properly. Safety packaging is
cases. An acute exposure accounted for 92% of cases, 84% of which required for a number of products and product categories (Table
were unintentional or accidental exposures. Only 13% were inten- 10–4). Child-resistant containers are not totally childproof and may
tional. Fatalities accounted for 1,261 (0.05%) cases, of which 2% were be opened by children, which can result in poisoning. Despite the
children younger than 6 years. The distribution of substances most success of child-resistant containers, many adults disable the hard-
frequently involved in pediatric and adult exposures differed; how- ware or simply use no safety cap, thus placing children at risk.10
ever, medicines were the most frequently involved (51%) substances Fatigue of the packaging materials can occur, which underscores the
(Table 10–3). Seventy-four percent of the poison exposures were need for new prescription ware for refills, as required in the PPPA.11
treated at the scene, typically a home. In summary, children account Poison prevention requires constant vigilance because of new
for most of the reported poisonings with morbidity, but adults generations of families in which parents and grandparents must be
account for a greater proportion of mortality from poisoning. educated on poisoning risks and prevention strategies. New prod-
ucts and changes in product formulations present different poison-
ing dangers and must be studied to provide optimal management.
ECONOMIC IMPACT OF POISONING
Strategies to prevent poisonings should consider the various psy-
Poisoning accounted for a total lifetime cost of $12.6 billion chosocial circumstances of poisoning (Table 10–5), prioritize risk
annually in 2003 dollars.7 Estimates of the lifetime cost of injury groups and behaviors, and customize an intervention for specific
include related health care costs and lost lifetime earnings of the situations.12,13
victim; however, they do not include the costs of suffering, reduced
productivity of caregivers, or legal costs. The definition of poisoning TABLE 10-5 Psychosocial Characteristics of Poisoning Patients
Children Young Adults Elderly
TABLE 10-3 Poison Exposure by Age Group and Fatal Outcome, Act purposefully or are Intentional abuse or sui- Suicidal intent or unin-
Ranked in Decreasing Order poisoned by caretaker cidal intent is possible tentional misuse
or sibling Disregard or cannot read Confuse product identity
Pediatric Adult Fatal Outcome Act with developmen- directions and directions for use
Medicines Medicines Medicines tally appropriate curi- Do not recognize poi- Do not recognize poi-
Cosmetics and personal Cleaning substances Alcohols osity soning risk soning risk
care items Bites or envenomations Gases and fumes Attracted by product Reluctant to seek assis- Comorbid conditions
Cleaning substances Alcohols Chemicals appearance tance until ill complicate toxicity
Foreign bodies Pesticides Cleaning substances Ingest substances that Exaggerate or misrepre- Unable or unwilling to
Plants Cosmetics and personal Pesticides adults find unpleasant sent situation describe situation
Pesticides care items Automotive products React to stressful and Peer pressure to experi- Multiple drugs may lead
Arts and crafts or office Food products or food disrupted household ment with drugs to adverse reactions
supplies poisoning Imitate adult behaviors
(e.g., taking medicine)
From Lai et al.6
 71

TABLE 10-6 Considerations in Evaluating the Results of Some Common Immunoassays Used for Urine Drug Screening

CHAPTER 10
Drug Detection after Stopping Use Comments
Amphetamines 2–5 days Many sympathomimetic amines, such as pseudoephedrine, ephedra, phenylephrine, fenfluramine,
and phentermine, may cause positive results.
Up to 2 weeks with prolonged or heavy Other drugs, such as selegiline, chlorpromazine, trazodone, bupropion, and amantadine, may cause
use false-positive results depending on the assay.
Benzodiazepines Up to 2 weeks Ability to detect benzodiazepines varies by drug.
Up to 6 weeks with chronic use of
some drugs
Cannabinoid metabolite (mar- 7–10 days Extent and duration of use will affect detection time. Drugs such as ibuprofen and naproxen may

Clinical Toxicology
ijuana) Up to 1–2 months with prolonged or cause false-positive results depending on the assay.
heavy use
Cocaine metabolite 12–72 hours Cocaine is metabolized rapidly, and specific metabolites are typically the substance detected. False-
(benzoylecgonine) Up to 1–3 weeks with prolonged or positive results from “caine” anesthetics and other drugs are unlikely.
heavy use
Opioids 2–3 days Because the assay was made to detect morphine, detection of other opioids, such as codeine,
Up to 6 days with sustained-release oxycodone, hydrocodone, and other semisynthetic opioids, may be limited. Some synthetic
formulations opioids, such as fentanyl and meperidine, may not be detected. Drugs such as rifampin and some
Up to 1 week with prolonged or heavy fluoroquinolones may cause false-positive results depending on the assay.
use
Phencyclidine 2–10 days Drugs such as ketamine, dextromethorphan, diphenhydramine, and sertraline may cause false-
1 month or more with prolonged or positive results depending upon the assay.
heavy use

contain the greatest concentration of drug, but they are difficult to

RECOGNITION AND ASSESSMENT analyze. Blood or urine can be tested by qualitative screening in
order to detect a drug’s presence.18,19 The results of a qualitative drug
The clinician’s initial responsibility is to determine whether a poi-
screen can be misleading because of interfering or low-level sub-
soning has occurred or a potential for development of a poisoning
stances (Table 10–6); it rarely guides emergency therapy and thus has
exists. Some patients provide a clear account of an exposure that
questionable value for nonspecific, general screening purposes.18,19
occurred with a known quantity of a specific agent. Other patients
Consultation with the laboratory technician and review of the assay
appear with an unexplained illness characterized by nonspecific signs
package insert will help to determine the sensitivity and specificity of
and symptoms and no immediate history of ingestion. Exposure to
the assay. Quantitative determination of serum concentrations may
folk remedies, dietary supplements, and environmental toxins also
be important for the assessment of some poisonings, such as those
should be considered. Patients with suicide gestures can deliberately
containing acetaminophen, ethanol, methanol, iron, theophylline,
give an unclear history, and poisoning should be suspected routinely.
and digoxin.20
Poisoning and drug overdoses should be suspected in any patient
with a sudden, unexplained illness or with a puzzling combination of
signs and symptoms, particularly in high-risk age groups. Nearly any PHARMACOKINETICS OF OVERDOSE
symptom can be seen with poisoning, but some signs and symptoms
are suggestive of a particular toxin exposure.14 Compounds that The pharmacokinetic characteristics of drugs taken in overdose
produce characteristic clinical pictures (toxidromes), such as or– may differ from those observed following therapeutic doses (Table
ganophosphate poisoning with pinpoint pupils, rales, bradycardia, 10–7).21,22 These differences are the result of dose-dependent
central nervous system depression, sweating, excessive salivation, changes in absorption, distribution, metabolism, or elimination;
and diarrhea, are most readily recognizable.15 The recognition of
chemicals responsible for acute mass emergencies resulting from TABLE 10-7 Examples of the Influence of Drug
industrial disasters, hazardous materials accidents, or acts of terror- Overdosage on Pharmacokinetic and
ism may be aided by evaluating characteristic signs and symptoms.16 Pharmacodynamic Characteristics
Assessment of the patient may be aided by consultation with a
poison control center. The center can provide information on Effect of Overdosagea Examples
product composition, typical symptoms, range of toxicity, labora- Slowed absorption due to formation of Aspirin, lithium, phenytoin, sustained-
tory analysis, treatment options, and bibliographic references. Fur- poorly soluble concretions in the gas- release theophylline
thermore, the center will have specially trained physicians, trointestinal tract
pharmacists, nurses, and toxicologists on staff or available for con- Slowed absorption due to slowed gas- Benztropine, nortriptyline
trointestinal motility
sultation to assist with difficult cases. Consultation with a poison
Slowed absorption due to toxin- Procainamide
control center also may identify changes in recommended therapy. A induced hypoperfusion
nationwide toll-free poison center access number (1-800-222-1222) Decreased serum protein binding Lidocaine, salicylates, valproic acid
routes callers to the local poison control center. Increased volume of distribution asso- Salicylates
When the circumstances of a poison exposure indicate that it is ciated with toxin-induced acidemia
minimally toxic, many poisonings can be managed successfully at Slowed elimination due to saturation of Ethanol, phenytoin, salicylates, theo-
the scene of the poisoning.6,17 Poison control centers typically biotransformation pathways phylline
monitor the victim by telephone during the first 2 to 6 hours of the Slowed elimination due to toxin- Ethanol, propranolol
exposure to assess the patient’s status and outcome of first aid. induced hypothermia (<35°C)
Once a poisoning is suspected and confirmation of the diagnosis Prolonged toxicity due to formation of Carbamazepine, dapsone, gluteth-
longer-acting metabolites imide, meperidine
is needed for medical or legal purposes, appropriate biologic material
should be sent to the laboratory for analysis. Gastric contents may a
Compared to characteristics following therapeutic doses or resolution of toxicity.
 72
pharmacologic effects of the drug; or pathophysiologic consequences TABLE 10-8 First Aid for Poison Exposures
of the overdose. Dose-dependent changes may decrease the rate and
SECTION 1

Inhaled poison
extent of absorption, whereas the bioavailability of the agent may be
Immediately get the person to fresh air. Avoid breathing fumes. Open doors and
increased due to saturation of first-pass metabolism. The distribution
windows. If victim is not breathing, start artificial respiration.
of a compound may be altered due to saturation of protein-binding Poison on the skin
sites. Metabolism and elimination of a compound may be retarded Remove contaminated clothing and flood skin with water for 10 minutes. Wash
due to saturation of biotransformation pathways leading to nonlinear gently with soap and water and rinse. Avoid further contamination of victim or first
elimination kinetics. Delayed gastric emptying by anticholinergic aid providers.
drugs or as the result of general central nervous system depression Poison in the eye
caused by many drugs may alter the rate and extent of absorption. Flood the eye with lukewarm or cool water poured from a glass 2 or 3 inches from
the eye. Repeat for 10–15 continuous minutes. Keep eye open, but do not force
Foundation Issues

Patients with a drug overdose may inherently exhibit prolonged

gastric emptying and gastric hypomotility.23 The formation of con- the eyelid open.
Swallowed poison
cretions or bezoars of solid dosage forms may delay the onset, prolong
Unless the patient is unconscious, having convulsions, or cannot swallow, give 2–4
the duration, or complicate the therapy for an acute overdose.24 A
ounces of water immediately and then seek further help.
combination of pharmacokinetic and pharmacodynamic factors may
lead to delayed onset of toxicity of several toxins, such as thyroid
hormones, oral anticoagulants, acetaminophen, and drugs in sus- panel of North American and European toxicologists concluded that
tained-release dosage forms.25 Drug-induced hypoperfusion may its routine use in the emergency department should be abandoned.27
affect drug distribution and result in reduced hepatic or renal clear- In 2003 the American Academy of Pediatrics issued a policy statement
ance. Changes in blood pH may alter the distribution of weak acids indicating that ipecac syrup was no longer to be used routinely to
and bases. Drug-induced renal or hepatic injury also can decrease treat poisonings at home and that parents should discard any ipecac.28
clearance significantly. Implications of these changes for poisoning The key reason for the policy change was that research failed to show
management include delayed achievement of peak concentrations benefits in children who were treated with ipecac syrup. It likely will
with a corresponding longer period of opportunity to remove the take several years for these recommendations to be adopted fully by
drug from the gastrointestinal tract. The expected duration of effects parents and healthcare professionals, and rare exceptions may arise.
may be much greater than that observed with therapeutic doses In the 2005 AAPCC-NPDS report, 0.1% of 2.4 million cases received
because of continued absorption and impaired clearance. The appli- ipecac syrup, with or without poison center direction.6
cation of pharmacokinetic variables, such as percentage protein There are several contraindications to the use of ipecac syrup or
binding and volume of distribution, from therapeutic doses may not any form of induced emesis, such as gagging.27 If the patient is
be appropriate in poisoning cases.21 Data on toxicokinetics often are without a gag reflex; is lethargic, comatose, or convulsing; or is
difficult to interpret and compare because the doses and times of expected to become unresponsive within the next 30 minutes, emesis
ingestion are uncertain, the duration of sampling is inadequate, active should not be induced. If a fruitful emesis has occurred spontane-
metabolites may not be measured, protein binding typically is not ously shortly after ingestion, further emesis may not be necessary.
assessed, and the severity of toxicity may vary dramatically. Ingestions of caustics, corrosives, ammonia, and bleach are definite
contraindications to induced emesis. Ingestion of aliphatic hydrocar-
bons (e.g., gasoline, kerosene, and charcoal lighter fluid) typically
TREATMENT does not require emesis. When the agent is definitely known to be
nontoxic, induction of emesis is purposeless and potentially danger-
Clinical Toxicology ous. The rapid onset of coma or seizures or the potential to exaggerate
the toxic effects of the poison may preclude the induction of emesis.
Some examples include poisonings with diphenoxylate, pro-
GENERAL APPROACHES TO TREATMENT poxyphene, clonidine, tricyclic antidepressants, hypoglycemic agents,
OF THE POISONED PATIENT nicotine, strychnine, β-blocking agents, and calcium channel block-
ers. Debilitated, pregnant, and elderly patients may be further com-
promised by induction of emesis.
■ PREHOSPITAL CARE
First Aid ■ HOSPITAL TREATMENT
 The presence of adequate airway, breathing, and circulation should
be assessed, and cardiopulmonary resuscitation should be started if General Care
needed. The most important step in preventing a minor exposure from Supportive and symptomatic care is the mainstay of treatment of a
progressing to a serious intoxication is early decontamination of the poisoned patient. In the search for specific antidotes and methods
poison. Basic poisoning first aid and decontamination measures (Table to increase excretion of the drug, attention to vital signs and organ
10–8) should be instituted immediately at the scene of the poisoning. If functions should not be neglected. Establishment of adequate oxy-
there is any question about the potential severity of the poison expo- genation and maintenance of adequate circulation are the highest
sure, a poison control center should be consulted immediately (1-800- priorities. Other components of the acute supportive care plan
222-1222). While awaiting transport, placing the patient on the left side include the management of seizures, arrhythmias, hypotension,
may afford easier clearance of the airway if emesis occurs and may slow acid–base balance, fluid status, electrolyte balance, and hypoglyce-
absorption of drug from the gastrointestinal tract.26 mia. Placement of intravenous and urinary catheters is typical to
ensure delivery of fluids and drugs when necessary and to monitor
Ipecac Syrup urine production, respectively.
 Ipecac syrup, a nonprescription drug, has been used in the United
States for the past 50 years as a means to induce vomiting for Gastric Lavage
treatment of ingested poisons. Despite its widespread use, concerns Gastric lavage involves the placement of an orogastric tube and
about its effectiveness and safety have been raised recently. An expert washing out of the gastric contents through repetitive instillation
 73
and withdrawal of fluid. Gastric lavage may be considered only if a Whole-Bowel Irrigation
potentially toxic agent has been ingested within the past hour for

CHAPTER 10
Polyethylene glycol electrolyte solutions, such as GoLYTELY and
most patients. If the patient is comatose or lacks a gag reflex, gastric
Colyte, are used routinely as whole-bowel irrigants prior to colonos-
lavage should be performed only after intubation with a cuffed or
copy and bowel surgery.33 These solutions also can be used to
well-fitting endotracheal tube. The largest orogastric tube that can
decontaminate the gastrointestinal tract of ingested toxins.9,14,34
be passed (external diameter at least 12 mm in adults and 8 mm in
Large volumes of these osmotically balanced solutions are adminis-
children) should be used to ensure adequate evacuation, especially
tered continuously through a nasogastric or duodenal tube for 4 to
of undissolved tablets. Lavage should be performed with warm
12 hours or more. They quickly cause gastrointestinal evacuation
(37°C to 38°C) normal saline or tap water until the gastric return is
and are continued until the rectal discharge is relatively clear. This
clear; this usually requires 2 to 4 L or more of fluid. Relative
procedure may be indicated for certain patients in whom the

Clinical Toxicology
contraindications for gastric lavage include ingestion of a corrosive
ingestion occurred several hours prior to hospitalization and the
or hydrocarbon agent. Complications of gastric lavage include
drug still is suspected to be in the gastrointestinal tract, such as drug
aspiration pneumonitis, laryngospasm, mechanical injury to the
smugglers who swallow condoms filled with cocaine.35 In addition,
esophagus and stomach, hypothermia, and fluid and electrolyte
patients who have ingested delayed-release or enteric-coated drug
imbalance.29 Use of gastric lavage has declined in recent years as
formulations or have ingested substances such as iron that are not
evidenced by the finding that only 2.2% of 553,292 cases treated at
well adsorbed by activated charcoal may benefit from whole-bowel
a healthcare facility received gastric lavage.6
irrigation.34 It should not be used in patients with a bowel perfora-
tion or obstruction, gastrointestinal hemorrhage, ileus, or intracta-
Single-Dose Activated Charcoal ble emesis. Emesis, abdominal cramps, and intestinal bloating have
Reduction of toxin absorption can be achieved by administration of been reported with whole-bowel irrigation.34 During 2005, whole-
activated charcoal. It is a highly purified, adsorbent form of carbon bowel irrigation was used in 0.5% of 553,292 cases managed at a
that prevents gastrointestinal absorption of a drug by chemically healthcare facility.6
binding (adsorbing) the drug to the charcoal surface. There are no
toxin-related contraindications to its use, but it is generally ineffec-
tive for iron, lead, lithium, simple alcohols, and corrosives. It is not CLINICAL CONTROVERSY
indicated for aliphatic hydrocarbons because of the increased risk
Some clinicians believe that whole-bowel irrigation should be
for emesis and pulmonary aspiration. Activated charcoal is most
used more routinely as a rapid means to evacuate the gas-
effective when given within the first few hours after ingestion,
trointestinal tract. Others recognize that it does have a quick
ideally within the first hour.30 The recommended dose of activated
onset but point out that little proof indicates whole-bowel
charcoal for a child (1 to 12 years old) is 25 to 50 g; for an adolescent irrigation makes a difference in patient outcome.
or adult the recommended dose is 25 to 100 g. Children younger
than 1 year can receive 1 g/kg.9 Activated charcoal is mixed with
water to make a slurry, shaken vigorously, and administered orally Perspectives on Gastric Decontamination
or via a nasogastric tube. Activated charcoal is contraindicated when Although there are a variety of options for gastric decontamination,
the gastrointestinal tract is not intact. Activated charcoal is relatively two clinical toxicology groups (the American Academy of Clinical
nontoxic, but two identified risks are (a) emesis following adminis- Toxicology and the European Association of Poison Centers and
tration and (b) pulmonary aspiration of charcoal and gastric con- Clinical Toxicologists) have concluded that no means of gastric
tents leading to pneumonitis in patients with an unprotected airway decontamination should be used routinely for a poisoned patient
or absent gag reflex.30 Some activated charcoal products contain without careful consideration.27,29,30,32,34 They indicate that therapy
sorbitol, a cathartic that may be associated with an increased is most effective within the first hour and that effectiveness beyond
incidence of emesis following use.31 Single-dose activated charcoal this time cannot be supported or refuted with the available data. A
use has remained relatively steady during the past decade, with 4.9% clinical policy statement by the American College of Emergency
of 2.4 million cases having received it according to the 2005 Physicians concludes that although no definitive recommendation
AAPCC-NPDS report.6 can be made on the use of ipecac syrup, gastric lavage, cathartics, or
whole-bowel irrigation, activated charcoal is advocated for most
Cathartics patients when appropriate.36 The clinical policy also states that
ipecac syrup is rarely of value in the emergency department and that
Cathartics, such as magnesium citrate and sorbitol, were thought to the use of whole-bowel irrigation following ingestion of substances
decrease the rate of absorption by increasing gastrointestinal elimi- not well adsorbed by activated charcoal is not supported by evi-
nation of the poison and the poison-activated charcoal complex, dence. The efficacy of activated charcoal has been demonstrated for
but their value is unproven. Poisoned patients do not routinely many compounds,30 but a randomized, controlled clinical trial of
require a cathartic, and it is rarely, if ever, given without concurrent
poisoned patients indicated that charcoal therapy did not reduce
activated charcoal administration.32 If used, a cathartic should be
length of hospital stay or positively influence patient outcomes.37
administered only once and only if bowel sounds are present. Although gastric lavage can reduce drug absorption if performed
Infants, the elderly, and patients with renal failure should be given within 1 hour of ingestion, its use is not recommended rou-
saline cathartics cautiously, if at all.9,32 tinely.29,36,38 In recent years, the use of ipecac syrup has declined
markedly in part because of its apparent lower efficacy compared
with activated charcoal in minimizing drug absorption.6,27,30 The
CLINICAL CONTROVERSY American Academy of Pediatrics has recommended that ipecac
syrup no longer be used for treatment of poisonings at home and
Activated charcoal has been promoted for use at home as a
has called for its removal from the home.28 Recently, activated
replacement for ipecac syrup, but some have contended that
charcoal has been promoted for treatment of poisonings at home,
little evidence indicates activated charcoal can be used safely and
but issues of safety, patient compliance, and effectiveness have not
properly in this setting.
been proven in the home setting.28,39 Poison control centers may be
 74
a source of guidance on the contemporary application of gastric hours. Serious complications, such as pulmonary aspiration, occur
decontamination techniques for a specific patient. in <1% of patients.45 The risks of aspiration pneumonitis in
SECTION 1

obtunded or uncooperative patients and of intestinal obstruction in

Enhanced Elimination Numerous methods have been used to
patients prone to ileus following a period of bowel ischemia (e.g.,
increase the rate of excretion of poisons from the body. Of these,
after cardiopulmonary arrest in the elderly) may be higher.46 Con-
only diuresis, multiple-dose activated charcoal, and hemodialysis
traindications are the same as those for single-dose charcoal.
have demonstrated usefulness. These approaches should be consid-
ered only if the risks of the procedure are significantly outweighed Hemodialysis Hemodialysis may be necessary for certain severe
by the expected benefits or if the recovery of the patient is seriously cases of poisoning. Dialysis should be considered when the dura-
in doubt and the method has been shown to be helpful. tion of symptoms is expected to be prolonged, normal pathways of
excretion are compromised, clinical deterioration is present, the
Foundation Issues

Diuresis Diuresis can be used for poisons excreted predominantly

drug is dialyzable, and appropriate personnel and equipment are
by the renal route; however, most drugs and poisons are metabo-
available. Drugs that are hemodialyzable usually have a low molec-
lized, and only a good urine flow (e.g., 2 to 3 mL/kg/h) needs to be
ular weight, are not highly or tightly protein bound, and are not
maintained for most patients. Fluid and electrolyte balance should
highly distributed to tissues. The principles of hemodialysis for
be monitored closely. Ionized diuresis by altering urinary pH may
acutely ill individuals are described in Chap. 48. Hemodialysis and
increase excretion of certain chemicals that are weak acids or bases
charcoal hemoperfusion are efficient methods of dialysis, but both
by trapping ionized drug in the renal tubule and minimizing
pose serious risks related to anticoagulation, blood transfusions,
reabsorption.14 Alkalinization of the urine to achieve a urine pH of
loss of blood elements, fluid and electrolyte disturbances, and
7.5 or greater for poisoning by weak acids such as salicylates or
infection.47 Hemodialysis may be lifesaving for methanol and
phenobarbital can be achieved by intravenous administration of
ethylene glycol poisoning and effective for other poisons, such as
sodium bicarbonate 1 to 2 mEq/kg over a 1- to 2-hour period.
lithium, salicylates, ethanol, and theophylline.14,36 Charcoal hemo-
Complications of urinary alkalinization include alkalosis, fluid and
perfusion was popular in the 1970s and 1980s as a means to
electrolyte disturbances, and inability to achieve target urinary pH
remove toxins, but this approach has fallen out of favor because of
values.40 Acid diuresis may enhance the excretion of weak bases,
poor clinical results, inappropriate use for drugs with large vol-
such as amphetamines, but it is rarely, if ever, used because it risks
umes of distribution, and limited availability of charcoal hemoper-
worsening rhabdomyolysis commonly associated with ampheta-
fusion columns.48 Continuous hemofiltration transports drugs
mine overdose.14 Generally, diuresis or ionized diuresis is rarely
across a semipermeable membrane by convection in response to
indicated for poisoned patients because it is inefficient relative to
hydrostatic pressure gradients.14,47 Limited experience is reported
other methods of enhancing elimination, it is associated with a risk
with the use of hemofiltration for poisonings, but it may be
of unacceptable adverse effects, and renal elimination of most drugs
attractive for the hemodynamically unstable patient who cannot
is not enhanced dramatically.
tolerate hemodialysis.
Multiple-Dose Activated Charcoal Multiple doses of acti-
vated charcoal can augment the body’s clearance of certain drugs Antidotes
by enhanced passage from the bloodstream into the gastrointesti-
 The search for and use of an antidote should never replace good
nal tract and subsequent adsorption. This process, termed charcoal
supportive care.36 Specific systemic antidotes are available for many
intestinal dialysis or charcoal-enhanced intestinal exsorption, describes
common poisonings (Table 10–9). 49,50 Inadequate availability of
the attraction of drug molecules across the capillary bed of the
antidotes at acute care hospitals has been noted throughout the
intestine by activated charcoal in the intestinal lumen and subse-
United States and can complicate the care of a poisoned patient. An
quent adsorption of the drug to the charcoal.41 Furthermore, it may
evidenced-based consensus of experts has recommended minimum
interrupt the enterohepatic recirculation of certain drugs.14,41 Once
stocking requirements for 16 antidotes for acute care hospitals.51
the drug is adsorbed to the charcoal, it is eliminated with the
These recommendations may provide guidance to pharmacy and
charcoal in the stool. Systemic clearance of several drugs has been
therapeutics committees in establishing a hospital’s antidote needs.
shown to be enhanced up to severalfold.41,42 An international
Drugs used conventionally for nonpoisoning situations may act as
toxicology group’s position statement on multiple-dose activated
antidotes to reverse acute toxicity, such as glucagon for β-adrener-
charcoal concluded that it should be considered only if a patient has
gic blocker or calcium channel antagonist overdose and octreotide
ingested a life-threatening amount of carbamazepine, dapsone,
for sulfonylurea-induced hypoglycemia.52 As our understanding of
phenobarbital, quinine, or theophylline.42 Although a prospective,
drug toxicity increases, antidotes may have applications beyond
randomized study of the effects of multiple-dose activated charcoal
contemporary indications, such as for acetylcysteine, which has
on phenobarbital-overdosed patients demonstrated increased drug
shown promise for treating approximately 25 different poisonings
elimination, no demonstrable effect on patient outcome was
and adverse drug reactions.53 The use of toxin-specific antibodies
observed.43
(e.g., fragment antigen binding [Fab] antibody fragments for
This approach provides a rapid onset of action that is limited by
digoxin54 or crotalid snake venom55) has offered a new approach to
blood flow and a maximal “ceiling effect” related to the dose of
treatment of poisoning victims.
charcoal present in the intestine. The response to multiple-dose
activated charcoal is greatest for drugs with the following character-
istics: good affinity for adsorption by activated charcoal, low intrin- Assessing the Effectiveness of Therapies
sic clearance, sufficient residence time in the body (long serum half- Our knowledge of poisoning treatment is derived from case reports,
life), long distributive phase, and nonrestrictive protein binding. A clinical studies, human volunteer studies, animal investigations, and
small volume of distribution is desirable, but it has a marginal in vitro tests. Each of these approaches has limited applicability to
influence as an isolated characteristic,44 particularly if multiple-dose the care of humans who have been poisoned. Case reports often are
activated charcoal is instituted during the toxin’s distributive phase. difficult to assess because they are uncontrolled, the histories are
A typical dosage schedule is 15 to 25 g of activated charcoal every 2 uncertain, and multiple therapies frequently are used. However,
to 6 hours until serious symptoms abate or the serum concentration they can be useful to describe unique or new toxicities or character-
of the toxin is below the toxic range. This procedure has been used ize adverse effects associated with a therapy. Although clinical
in premature and full-term infants in doses of 1 g/kg every 1 to 4 studies may describe tens to hundreds of patients, they can exhibit
 75

TABLE 10-9 Systemic Antidotes Available in the United States and they illustrate the application of general treatment approaches
as well as some agent-specific interventions.

CHAPTER 10
Toxic Agent Antidote
Acetaminophen Acetylcysteine ACETAMINOPHEN
Anticholinesterase insecticides Atropine
Anticoagulants Phytonadione Clinical Presentation
Benzodiazepines Flumazenil
Botulism Botulism antitoxin  Acute acetaminophen poisoning characteristically results in
Carbon monoxide Oxygen hepatotoxicity56,57 and is the leading cause of acute liver failure in the
Cyanide Cyanide antidote kit (amyl nitrite, sodium United States.58 Clinical presentation (see below) is dependent on
nitrate, and sodium thiosulfate) the time since ingestion, presence of risk factors, and the ingestion of

Clinical Toxicology
Cyanide Hydroxocobalamin other drugs. During the first 12 to 24 hours after ingestion, nausea,
Digoxin Digoxin immune Fab vomiting, anorexia, and diaphoresis may be observed; however,
Ethylene glycol, methanol Ethanol
many patients are asymptomatic. During the next 1 to 3 days, which
Ethylene glycol, methanol Fomepizole
is a latent phase of lessened symptoms, patients often have an
Heavy metals (arsenic, inorganic Dimercaprol
mercury, lead, gold) asymptomatic rise in liver enzymes and bilirubin. Signs and symp-
Heavy metals (copper, lead) Penicillamine toms of hepatic injury become manifest 3 to 5 days after ingestion
Iron Deferoxamine and include right upper quadrant abdominal tenderness, jaundice,
Isoniazid Pyridoxine hypoglycemia, and encephalopathy. Prolongation of the prothrom-
Lead Calcium EDTA bin time worsens as hepatic necrosis progresses and may lead to
Lead Succimer disseminated intravascular coagulopathy. Patients with hepatic dam-
Methemoglobinemia Methylene blue age may develop hepatic coma and hepatorenal syndrome, and death
Opioids Nalmefene can occur.56,57,59 Even in patients with severe hepatotoxicity, usually
Opioids Naloxone
no residual functional or histologic abnormalities of the liver are
Organophosphate insecticides Pralidoxime
noted within 1 to 6 months of the incident.57
Radioactive americium, curium, Diethylenetriamene pentaacetate
plutonium
Radioactive iodine Potassium iodide CLINICAL PRESENTATION OF
Snake, coral Micrurus fulvius antivenin
ACUTE ACETAMINOPHEN POISONING
Snakes (rattlesnakes, cotton- Crotalidae polyvalent antivenin
mouth, copperhead) Crotalidae polyvalent immune Fab General
Spider, black widow Lactrodectus mactans antivenin ■ No or mild nonspecific symptoms within 6 hours of ingestion
Thallium Prussian blue
Symptoms
■ Nausea, vomiting, and abdominal discomfort within 1 to 12
serious shortcomings, such as weak randomization procedures, no
hours after ingestion
laboratory confirmation or correlation with history, insufficient
number of severe cases, no control group, and no quantitative ■ Right upper abdominal quadrant tenderness typically within
measure of outcome. Extrapolation of data from human volunteer 1 to 2 days
studies to patients who overdose is difficult because of potential or Signs
unknown variations in pharmacokinetics (e.g., differing dissolu- ■ Typically no signs present within first day
tion, gastric emptying, and absorption rates) seen with toxic as
■ Jaundice, scleral icterus, bleeding within 3 to 10 days
opposed to therapeutic doses,21,22 differences in time to institute
therapy in the emergency setting, and differences in absorption in ■ Oliguria occasionally within 2 to 7 days
fasted human volunteers compared with the full stomach of some ■ With severe poisoning, hepatic encephalopathy (delirium,
patients who overdose. However, these studies provide the most depressed reflexes, coma) within 5 to 10 days
controlled and objective measures of the efficacy of a treatment. Laboratory Tests
Experiences from animal studies cannot be applied directly to
■ Toxic serum acetaminophen concentration no earlier than 4
humans because of interspecies differences in toxicity and metabo-
lism. In vitro tests serve to screen the efficacy of some approaches, hours after ingestion by comparison with nomogram
such as activated charcoal adsorption, but they do not mimic ■ Elevated aspartate aminotransferase (AST), alanine amino-
physiologic conditions sufficiently to allow direct clinical applica- transferase (ALT), serum bilirubin, and international normal-
tion of the findings. Despite their limitations, these data compose ization ratio (INR); hypoglycemia within 1 to 3 days
the basis for the therapy of poisoned patients and are tempered with
■ Elevated serum creatinine and blood urea nitrogen (BUN)
the consideration of nonpoisoning-related factors such as a partic-
within 2 to 7 days
ular patient’s underlying medical condition, age, and need for
concurrent supportive measures.
Mechanism of Toxicity
Acetaminophen is metabolized in the liver primarily to glucuronide
CLINICAL SPECTRUM OF POISONING or sulfate conjugates, which are excreted into the urine with small
amounts (<5%) of unchanged drug. Approximately 5% of a thera-
Poisoning and drug overdose with acetaminophen, anticholinester- peutic dose is metabolized by the cytochrome P450 mixed-function
ase insecticides, calcium channel blockers, iron, and tricyclic antide- oxygenase system, primarily CYP2E1, to a reactive metabolite, N-
pressants are the focus of the remainder of this chapter because they acetyl-p-benzoquinoneimine (NAPQI). This metabolite normally is
represent commonly encountered poisonings for which pharmaco- conjugated with glutathione, a sulfhydryl-containing compound, in
therapy is indicated. These agents also were chosen because they the hepatocyte and excreted in the urine as a mercapturate conju-
represent common examples with different mechanisms of toxicity, gate (Fig. 10–1).59
 76
Nontoxic Chronic exposure to drugs that induce the cytochrome oxidase
mercapturate system—specifically isoenzyme CYP2E1, which is responsible for
SECTION 1

Sulfate conjugate metabolites

most of the formation of NAPQI—may increase the risk of aceta-
Cytochrome P-450 minophen hepatotoxicity. Poorer outcomes have been noted in
oxidase system
Adequate patients who chronically ingest alcohol and those receiving anticon-
Therapeutic glutathione
Glucuronide
vulsants, both known to induce CYP2E1.57,62 Patients with chronic
dose
conjugate Acetaminophen NAPQI alcoholism have a 3.5 greater odds of mortality with acute acetamin-
Acute
overdose Depleted
ophen poisoning.63 Concurrent acute ingestion of alcohol and
glutathione acetaminophen may decrease the risk of acetaminophen-induced
hepatotoxicity by ethanol acting as a competitive substrate for
Foundation Issues

Unchanged in urine Undetoxified

CYP2E1, thus reducing NAPQI formation.64 Ethanol coingestion is
Hepatocellular not advocated as a preventive measure, and it is difficult to account
reactive
necrosis
metabolite for its specific impact on care.
FIGURE 10-1. Pathway of acetaminophen metabolism and basis for Repeated ingestion of supratherapeutic doses of acetaminophen
hepatotoxicity. (NAPQI, N-acetyl-p-benzoquinoneimine, a reactive aceta- (defined for patients <6 years: ≥200 mg/kg over 8 to 24 hours, ≥150
minophen metabolite.) mg/kg/day for 2 days, ≥100 mg/kg/day for 3 days or longer; for
patients ≥6 years: ≥10 g or 200 mg/kg (whichever is less) over a
In an acute overdose situation, sulfate stores are depleted, shifting single 24-hour period, ≥6 g or 150 mg/kg (whichever is less) per 24-
more drug through the cytochrome system, thereby depleting the hour period for ≥48 hours) has been associated with hepatotoxi-
available glutathione used to detoxify the reactive metabolite. The city.57,61 Patients who are fasting or have ingested alcohol in the
reactive metabolite NAPQI then reacts with other hepatocellular preceding 5 days appear to be at greater risk.65 Young children who
sulfhydryl compounds such as those in the cytosol, cell wall, and receive repetitive supratherapeutic doses of acetaminophen have a
endoplasmic reticulum. This results in centrilobular hepatic necro- higher risk of developing hepatotoxicity, particularly when they
sis.59 Several other mechanisms, such as cytokine release and oxida- have been acutely fasting as the result of a febrile illness or gastroen-
tive stress, also may be initiated by the initial cellular injury.59 teritis.61,66 Patients with suspected risk factors, such as alcoholism,
In many cases of severe hepatotoxicity, renal injury also is isoniazid therapy, or prolonged fasting, should be referred for
present and may range from oliguria to acute renal failure. The medical evaluation if there is evidence that the ingestion exceeded 4
etiology of the renal injury may be a direct effect of the toxic g/day or 100 mg/kg/day, whichever is less.61
metabolite of acetaminophen, NAPQI, generated by renal cyto- The risk of developing hepatotoxicity may be predicted from a
chrome oxidase, or a consequence of hepatic injury resulting in nomogram (Fig. 10–2) based on the acetaminophen serum concen-
hepatorenal syndrome.60 tration and time after ingestion.56 The treatment line of the nomo-
gram (150 mcg/mL at 4 hours), which allows a margin of error in
Causative Agents laboratory analysis and time of ingestion, should be used to make
treatment decisions. The other lines on the nomogram indicate
Acetaminophen, also known as paracetamol, is available widely
differing levels of risk for hepatotoxicity based on a multicenter
without prescription as an analgesic and antipyretic. It is available in
study of 11,195 patients.56
various oral dosage forms, including extended-release preparations.
If the plasma concentration plotted on the nomogram falls above
Acetaminophen may be combined with other drugs, such as antihis-
the nomogram treatment line, indicating that hepatic damage is possi-
tamines or opioid analgesics, and marketed in cough and cold
ble, a full course of treatment with acetylcysteine is indicated. When the
preparations, menstrual remedies, and allergy products.
results of the acetaminophen determination will be available later than
8 hours after the ingestion, acetylcysteine therapy should be initiated
Incidence based on the history and later discontinued if the results indicate
Acetaminophen is one of the drugs most commonly ingested by nontoxic concentrations. The nomogram has not been evaluated and
small children and is used commonly in suicide attempts by adoles- thus is not useful for assessing chronic exposure to acetaminophen.
cents and adults. The 2005 AAPCC-NPDS report documented Some have advocated that patients with chronic alcoholism should be
67,393 nonfatal exposures and 138 deaths from acetaminophen, treated with acetylcysteine regardless of the risk estimation.63
with 49% of the exposures in children younger than 6 years.6
Age-based differences in the metabolism of acetaminophen Management of Toxicity
appear to be responsible for major differences in the incidence of
Therapy of an acute acetaminophen overdose depends on the
serious toxicity. Despite the common ingestion of acetaminophen
amount ingested, time after ingestion, and serum concentration of
by young children, few develop hepatotoxicity from acute overdos-
acetaminophen. When excessive amounts are ingested, the history
age.6 In children younger than 9 to 12 years, acetaminophen
is unclear, or an intentional ingestion is suspected, the patient
undergoes more sulfation and less glucuronidation. The reduced
should be evaluated at an emergency department and acetamino-
fraction available for metabolism by the cytochrome system may
phen serum concentrations obtained.61 No prehospital care gener-
explain the rare development of serious toxicity in young children
ally is indicated, and ipecac syrup typically is not recommended.61 If
who take large overdoses. Earlier treatment intervention and spon-
the patient presents to the emergency department within 4 hours of
taneous emesis also may reduce the risk of toxicity in children.
the ingestion or ingestion of other drugs is suspected, one dose of
activated charcoal can be administered.
Risk Assessment Acetylcysteine (also known as N-acetylcysteine), a sulfhydryl-
There is a risk of developing hepatotoxicity when patients 6 years or containing compound, replenishes the hepatic stores of glutathione
older acutely ingest at least 10 g or 200 mg/kg, whichever is less, of by serving as a glutathione surrogate that combines directly with
acetaminophen or when children younger than 6 years acutely ingest reactive metabolites or by serving as a source of sulfate, thus
200 mg/kg or more.61 Patients have survived much larger doses, preventing hepatic damage.67 It should be started within 10 hours of
particularly with early treatment. Initial symptoms, if present, do not the ingestion to be most effective.56 Initiation of therapy 24 to 36
predict how serious the toxicity eventually may become. hours after the ingestion may be of value in some patients, particu-
 77

4000 500 TABLE 10-10 Comparison of Intravenous and Oral Regimens

CHAPTER 10
3000 400
for Acetylcysteine in the Treatment of
Plasma acetaminophen concentration 2000 300 Acute Acetaminophen Poisoning
Lower limit for
1300 200 high-risk group Characteristic Intravenous Oral
1000 150
Regimen 150 mg/kg in 200 mL D5W 140 mg/kg, followed 4
100 Lower limit for
probable-risk group infused over 1 hour, hours later by 70 mg/kg
500 then 50 mg/kg in 500 every 4 hours for 17
50 mL D5W over 4 hours, doses diluted to 5%
followed by 100 mg/kg with juice or soft drinks
100 Nomogram in 1,000 mL D5W over

Clinical Toxicology
treatment line 16 hoursa
10
Total dose (mg/kg) 300 1,330
50
Duration (h) 21 72
Adverse effects Anaphylactoid reactions Nausea, vomiting
30 5 (rash, hypotension,
wheezing, dyspnea);
μmol/L μg/mL 4 8 12 16 20 24
acute flushing and ery-
Hours after acetaminophen ingestion thema in first hour of the
FIGURE 10-2. Nomogram for assessing hepatotoxic risk following acute infusion that typically
ingestion of acetaminophen. (Adapted from reference 56.) resolves spontaneously
Ancillary therapy, if Antihistamines and epi- Antiemetics, e.g., meto-
needed nephrine for severe ana- clopramide, ondanse-
larly those with measurable serum acetaminophen concentra- phylactic reactions tron, or droperidol
tions.67,68 Patients with fulminant hepatic failure may benefit Trade name Acetadote Mucomyst
through other mechanisms by the administration or initiation of Available strength 20% 10%, 20%
acetylcysteine several days after ingestion.67 a
For patients <40 kg and those requiring fluid restriction, the total volume for dilution should be
reduced as directed in the package insert.
D5W, 5% dextrose in water for injection.
CLINICAL CONTROVERSY
Although young children have an inherently lower risk of aceta-
The routine administration of acetylcysteine more than 24 hours
minophen-induced hepatotoxicity, these patients should be man-
after acetaminophen overdose has been proposed. Case reports
aged in the same manner as adults. When acetaminophen plasma
and animal studies indicate that it is relatively safe and that its
concentrations predict that toxicity is probable, young children
use may minimize hepatotoxicity. Although accepted criteria for
should receive acetylcysteine in the dosing regimen described previ-
its use are lacking, it may be considered for patients with
ously.66 If fulminant hepatic failure develops, the approaches
fulminant hepatoxicity, when acetaminophen is still measurable
described in Chap. 39 should be considered. In unresponsive
in the serum, or when the ingestion was not recognized within
patients, liver transplantation is a lifesaving option.57
24 hours and liver toxicity is apparent.
Monitoring and Prevention
Therapy should be initiated with acetylcysteine within 10 hours of
ingestion when indicated. The oral liquid was the only approved form Baseline liver function tests (AST, ALT, bilirubin, prothrombin
of acetylcysteine in the United States until 2004, when the Food and time), serum creatinine determination, and urinalysis should be
Drug Administration (FDA) approved an intravenous formulation.69 obtained on admission and repeated at 24-hour intervals until at
The dosage regimen for the intravenous form is based on one used in least 96 hours have elapsed for patients at risk. Most patients with
Europe for two decades, and outcomes similar to the 72-hour oral liver injury develop elevated transaminase concentrations within 24
regimen have been reported.53,70 A systematic review of the literature hours of ingestion. AST or ALT concentrations >1,000 international
indicated that acetylcysteine is superior to supportive care, but there units per liter commonly are associated with other signs of liver
is no clear evidence of which regimen is better.71 Although there are dysfunction and have been used as the threshold concentration in
several notable differences (Table 10–10),53,56,69,70 a clear preference outcome studies to define severe liver toxicity.56 The extent of
for the oral or intravenous form of acetylcysteine likely will not evolve transaminase elevation is not correlated directly with the severity of
until further experience with IV formulation accumulates. When hepatic injury, with nonfatal cases demonstrating peak concentra-
acetaminophen plasma concentrations are below the nomogram tions as high as 30,000 international units per liter between 48 and
treatment line, there is little risk of toxicity, protective therapy with 72 hours after ingestion.57
acetylcysteine is not necessary, and medical therapy likely is unneces- Prevention of acetaminophen poisoning is based on recognition of
sary.56 The acetaminophen blood sample should be drawn no sooner the maximum daily therapeutic doses, observance of general poison
than 4 hours after the ingestion to ensure that peak acetaminophen prevention practices, and early intervention in cases of suspected
concentrations have been reached. If a concentration is obtained less overdose. The frequent involvement of acetaminophen in poisonings
than 4 hours after ingestion, it is uninterpretable, and a second and overdoses, whether or not declared by the patient, has led to the
determination should be done at least 4 hours after ingestion. Serial routine determination of acetaminophen concentrations in patients
determinations of a serum concentration, 4 to 6 hours apart, typically admitted to emergency departments for any overdose.18
are unnecessary unless there is some evidence of slowed gastrointesti-
nal motility as the result of the ingestion of certain drugs (e.g.,
opioids, antihistamines, or anticholinergics) or unless an extended- ANTICHOLINESTERASE INSECTICIDES
release product is involved. Therapy with acetylcysteine is continued
if any concentration is above the treatment line of the nomogram,
Clinical Presentation
and provisional therapy is discontinued when both concentrations  The clinical manifestations of anticholinesterase insecticide poi-
are below the treatment line. soning include any or all of the following: pinpoint pupils, excessive
 78

TABLE 10-11 Effects of Acetylcholinesterase Inhibition at Other Diagnostic Tests

Muscarinic, Nicotinic, and CNS Receptors
■ Chest radiographs for progression of pulmonary edema or
SECTION 1

Muscarinic receptors Nicotinic–sympathetic neurons hydrocarbon pneumonitis in symptomatic patients

Diarrhea Increased blood pressure
■ Electrocardiogram (ECG) with continuous monitoring and
Urination Sweating and piloerection
Miosisa Mydriasisa
pulse oximetry for complications from toxicity and hypoxia
Bronchorrhea Hyperglycemia
Bradycardiaa Tachycardiaa Organophosphate poisoning has been associated with several resid-
Emesis Priapism ual effects, such as intermediate syndrome, extrapyramidal symptoms,
Lacrimation Nicotinic–neuromuscular neurons neuropsychiatric effects, and delayed chronic neuropathy. Intermedi-
Foundation Issues

Salivation Muscular weakness ate syndrome becomes manifest in some patients approximately 1 to 3
CNS receptors (mixed type) Cramps days after exposure. It is characterized by muscle weakness of proximal
Coma Fasciculations limbs, cranial nerve innervated muscles, and muscles of respiration.
Seizures Muscular paralysis The inability of the patient to raise his or her head is often an initial
a
Generally muscarinic effects predominate, but nicotinic effects can be observed. sign. It often follows resolution of cholinergic symptoms but typically
is unresponsive to further therapy with atropine or pralidoxime. It
generally resolves within weeks of onset without further treatment.
lacrimation, excessive salivation, bronchorrhea, bronchospasm and Extrapyramidal symptoms, which may develop 1 to 7 days after
expiratory wheezes, hyperperistalsis producing abdominal cramps exposure, usually resolve spontaneously within a few days of onset.
and diarrhea, bradycardia, excessive sweating, fasciculations and Neuropsychiatric effects, such as confusion, lethargy, memory impair-
weakness of skeletal muscles, paralysis of skeletal muscles (particu- ment, headache, and depression, typically begin weeks to months after
larly those involved with respiration), convulsions, and coma.72 exposure and may last for years. The etiology is unclear. Delayed
Symptoms of anticholinesterase poisoning and their response to chronic neuropathy often presents as cramping muscle pain in the legs
antidotal therapy depend on the action of excessive acetylcholinest- (upper extremities are sometimes involved), followed by rapidly pro-
erase at different receptor types (Table 10–11). gressive weakness and paralysis. Paresthesia and pain may be present.
The time of onset and severity of symptoms depend on the route The onset often is delayed by 1 to 5 weeks after recovery from the acute
of exposure, potency of the agent, and total dose received (see poisoning exposure. It is unresponsive to further atropine or prali-
presentation box below). Toxic signs and symptoms develop most doxime therapy. Improvement may be delayed for months to years,
rapidly after inhalation or intravenous injection and slowest after and in some cases the patient develops permanent disability. It is not
skin contact. Anticholinesterase insecticides are absorbed through associated with all organophosphates.72,74
the skin, lungs, conjunctivae, and gastrointestinal tract. Severe
symptoms can occur from absorption by any route. Most patients Mechanism of Toxicity
are symptomatic within 6 hours, and death may occur within 24
Anticholinesterase insecticides phosphorylate the active site of cho-
hours without treatment. Death typically is caused by respiratory
linesterase in all parts of the body.72,75 Inhibition of this enzyme
failure resulting from the combination of pulmonary and cardiovas-
leads to accumulation of acetylcholine at affected receptors and
cular effects (Fig. 10–3).72 Poisoning may be complicated by aspira-
results in widespread toxicity. Acetylcholine is the neurohormone
tion pneumonia, urinary tract infections, and sepsis.73
responsible for physiologic transmission of nerve impulses from
preganglionic and postganglionic neurons of the cholinergic (para-
CLINICAL PRESENTATION OF sympathetic) nervous system, preganglionic adrenergic (sympa-
ANTICHOLINESTERASE INSECTICIDE POISONING thetic) neurons, neuromuscular junction in skeletal muscles, and
General multiple nerve endings in the central nervous system (Fig. 10–4).
■ Mild symptoms may resolve spontaneously; life-threatening
Causative Agents
toxicity may develop with 1 to 6 hours of exposure
Anticholinesterase insecticides include organophosphate and car-
Symptoms
bamate insecticides. These insecticides are currently in widespread
■ Diarrhea, diaphoresis, excessive urination, miosis, blurred use throughout the world for eradication of insects in dwellings and
vision, pulmonary congestion, dyspnea, vomiting, lacrima- crops. Carbamates typically are less potent and inactivate cholines-
tion, salivation, and shortness of breath within 1 hour terase in a more reversible fashion through carbamylation com-
■ Headache, confusion, coma, and seizures possible within 1 to pared with organophosphates.72 The prototype anticholinesterase
6 hours agent is the organophosphate, which is the focus of this discussion.
Signs A large number of organophosphates are used as pesticides (e.g.,
dichlorphos disulfoton, malathion, mevinphos, phosmet), and sev-
■ Increased bronchial secretions, tachypnea, rales, and cyanosis
eral were specifically developed for use as potent chemical warfare
within 1 to 6 hours
agents (see Chap. 12).72,73,76,77 The chemical warfare agents act like
■ Muscle weakness, fasciculations, and respiratory paralysis organophosphate insecticides, but they are highly potent, are
within 1 to 6 hours quickly absorbed, and can be deadly to humans within minutes (see
■ Bradycardia, atrial fibrillation, atrioventricular block, and Chap. 12).77,78 An anticholinesterase insecticide typically is stored in
hypotension within 1 to 6 hours a garage, chemical storage area, or living area. Anticholinesterase
Laboratory Tests agents also can be found in occupational (e.g., pest exterminators)
or agricultural (e.g., crop dusters or farm workers) settings. These
■ Markedly depressed serum pseudocholinesterase activity
agents also have been used as a means for suicide or homicide.
below normal range
■ Altered arterial blood gases (acidosis), serum electrolytes, Incidence
BUN, and serum creatinine in response to respiratory distress
Anticholinesterase insecticides are among the most poisonous sub-
and shock within 1 to 6 hours
stances commonly used for pest control and are a frequent source of
 79

CHAPTER 10
Organophosphate insecticide effects after exposure

Neuromuscular paralysis Bronchorrhea CNS depression Cardiovascular effects,

e.g., bradycardia, hypotension

Clinical Toxicology
RESPIRATORY FAILURE CIRCULATORY FAILURE

Hypoxia ACIDOSIS Myocardial dysfunction

FIGURE 10-3. Pathogenesis of life-threatening effects of organophosphate poisoning. (CNS, central nervous system.)

serious poisoning in children and adults in rural and urban settings. of acute poisoning; thus, tabulated “toxic” doses generally are not
The 2005 AAPCC-NPDS report documented 9,942 nonfatal expo- helpful in assessing risk of toxicity. Generally, ingestion of a small
sures and 12 deaths from anticholinesterase insecticides alone or in mouthful (~5 mL) of the concentrated forms of an organophos-
combination with other pesticides, with 29% of exposures in chil- phate intended to be diluted for commercial or agricultural use will
dren younger than 6 years.6 produce serious, life-threatening toxicity, whereas a mouthful of an
already diluted household product, such as an aerosol insecticide for
Risk Assessment household use, typically does not produce serious toxic effects.76
Measurement of acetylcholinesterase activity at the neuronal
The triad of miosis, bronchial secretions, and muscle fasciculations
synapse is not feasible clinically. Cholinesterase activity can be
should suggest the possibility of anticholinesterase insecticide poison-
measured in the blood as the pseudocholinesterase (butylcholines-
ing and warrants a therapeutic trial of the antidote atropine. In cases
terase) activity of the plasma and acetylcholinesterase activity in the
of low-level exposure, failure to develop signs within 6 hours indicates
erythrocyte. Both cholinesterases will be depressed with anticholin-
a low likelihood of subsequent toxicity.72 Ruling out other chemical
esterase insecticide poisoning.72,79 Severity can be estimated roughly
exposures may be guided initially by symptoms at presentation.16
by the extent of depressed activity in relation to the low end of
Although the lethal dose for parathion is approximately 4 mg/kg,
normal values. Because there are several methods to measure and
as little as 10 to 20 mg can be lethal to an adult and 2 mg (0.1 mg/
report cholinesterase activity, each particular laboratory’s normal
kg) to a child. Small children may be more susceptible to toxicity
range must be considered. Clinical toxicity usually is seen only after
because less pesticide is required per body weight to produce
a 50% reduction in enzyme activity, and severe toxicity typically is
toxicity.72,76 Estimation of an exact dose is impossible in most cases
observed at levels 20% or less of the normal range.75,76,79 The
intrinsic activity of acetylcholinesterase may be depressed in some
Autonomic nervous system Somatic nervous system
individuals, but the absence of any manifestations in most people
Parasympathetic Sympathetic Neuromuscular tract
does not permit recognition of the relative deficiency in the general
Preganglionic
nerves
population. Therapy should not be delayed pending laboratory
confirmation when insecticide poisoning is clinically suspected.
ACh ACh−ase ACh ACh−ase ACh ACh−ase
N N N Management of Toxicity
Ganglion
People handling the patient should wear gloves and aprons to protect
themselves against contaminated clothing, skin, or gastric fluid of the
Postganglionic patient.72,76 Because many insecticides are dissolved in a hydrocar-
nerves bon vehicle, there is an additional risk of pulmonary aspiration of the
ACh ACh−ase NE
M
hydrocarbon leading to pneumonitis. The risks and benefits of
gastric decontamination (e.g., gastric lavage, activated charcoal)
should be considered carefully and should involve consultation with
Selected Heart Heart Skeletal muscles a poison control center or clinical toxicologist. Symptomatic cases of
effector Exocrine glands Blood vessels (includes muscles
organs GI smooth muscles Pupils of respiration) anticholinesterase insecticide exposure typically are referred to an
Lung smooth muscles emergency department for evaluation and treatment.
Pupils
If the poison has been ingested within the hour, gastric lavage
FIGURE 10-4. Organization of neurotransmitters of the peripheral ner- should be considered and followed by the administration of acti-
vous system and site of acetylcholinesterase action. (ACh, acetylcholine; vated charcoal. For the patient with skin contamination, contami-
ACh-ase, acetylcholinesterase; M, muscarinic receptor; N, nicotinic recep- nated clothing should be removed and the patient washed with
tor; NE, norepinephrine.) copious amounts of soap and water before he or she is admitted to
 80
the emergency department or other patient care area. An alcohol TABLE 10-12 Comparative Characteristics of Atropine and
wash may be useful for removing residual insecticide because of its Pralidoxime for Anticholinesterase Poisoning
SECTION 1

lipophilic nature. A surgical scrub kit for the hands, feet, and nails
Characteristic Atropine Pralidoxime
may be useful for exposure to those areas. Supportive therapy
should include maintenance of an airway (including bronchotra- Interaction Synergy with Reduces atropine dose
cheal suctioning), provision of adequate ventilation, and establish- pralidoxime requirement
ment of an intravenous line. Based on a history of an exposure and Indication Any anticholinesterase Typically needed for
agent organophosphates
presence of typical symptoms, the anticholinesterase syndrome
Primary sites of action Muscarinic, CNS Nicotinic > muscarinic >
should be recognized without difficulty. CNS
Pharmacologic management of organophosphate intoxication Adverse effects Coma, hallucinations, Dizziness, diplopia,
Foundation Issues

relies on the administration of atropine and pralidoxime.72,75,76 Atro- tachycardia tachycardia, headache
pine has no effect on inhibited cholinesterase, but it competitively Daily dosea 2–1,600 mg 1–12 g
blocks the actions of acetylcholine on cholinergic and some central Total dosea 2–11,422 mg 1–92 g
nervous system receptors. It thereby alleviates bronchospasm and a
Range of reported cases; higher doses may be required in rare cases.
reduces bronchial secretions. Although atropine has little effect on the
flaccid muscle paralysis or the central respiratory failure of severe
poisoning, it is indicated in all symptomatic patients and can be used MONITORING AND PREVENTION
as a diagnostic aid. It should be given intravenously and in larger than
conventional doses of 0.05 to 0.1 mg/kg in children younger than 12 Poisoned patients may require monitoring of vital signs, measure-
years and 2 to 5 mg in adolescents and young adults.76 It should be ment of ventilatory adequacy such as blood gases and pulse oxime-
repeated at 5- to 10-minute intervals until bronchial secretions and try, leukocyte count with differential to assess development of
pulmonary rales resolve. Therapy may require large doses over a pneumonia, and chest radiographs to assess the degree of pulmo-
period of several days until all absorbed organophosphate is metabo- nary edema or development of hydrocarbon pneumonitis. Workers
lized, and acetylcholinesterase activity is restored. involved in the formulation and application of pesticides should be
Restoration of enzyme activity is necessary for severe poisoning, monitored by periodic measurement of cholinesterase activity in
characterized by a reduction of cholinesterase activity to <20% of their bloodstream. Untreated, anticholinesterase-depressed acetyl-
normal, profound weakness, and respiratory distress. Pralidoxime cholinesterase activity returns to normal values in approximately
(Protopam), also called 2-PAM or 2-pyridine aldoxime methiodide, 120 days. Long-term followup for severe cases of poisoning may be
breaks the covalent bond between the cholinesterase and organo- necessary to detect the presence of delayed or persistent neuropsy-
phosphate and regenerates enzyme activity. Organophosphate- chiatric effects.
cholinesterase binding is reversible initially, but it gradually becomes Many anticholinesterase insecticide poisonings are unintentional
irreversible. Therefore, therapy with pralidoxime should be initiated as a result of misuse, improper storage, failure to follow instructions
as soon as possible, preferably within 36 to 72 hours of exposure.76 for mixing or application, or inability to read directions for use.
The drug should be given at a dose of 25 to 50 mg/kg up to 1 g Training and vigilant adherence to directions may minimize some
intravenously over 5 to 20 minutes. If muscle weakness persists or poisonings. Storing pesticides in original or labeled containers can
recurs, the dose can be repeated after 1 hour and again if needed. A minimize the risk of unintentional ingestion. Keeping pesticides out
continuous infusion of pralidoxime has been shown to be effective in of children’s reach may decrease the risk of childhood poisoning.84
adults when administered at 2 to 4 mg/kg/h preceded by a loading
dose of 4 to 5 mg/kg80 and in children at 10 to 20 mg/kg/h with a CALCIUM CHANNEL BLOCKERS
loading dose of 15 to 50 mg/kg.81 Both atropine and pralidoxime
should be given together because they have complementary actions Clinical Presentation
(Table 10–12). Systematic reviews of the literature indicate that the Overdosage with calcium channel blockers typically results in brady-
effectiveness of pralidoxime and similar oxime compounds in the cardia and hypotension (Fig. 10–5). Many patients become lethargic
treatment of organophosphate poisoning is inconclusive because of and may develop agitation and coma. If the degree of hypotension
problems with study design.82,83 Carbamate insecticide poisonings becomes severe or is prolonged, the secondary effects of seizures,
typically do not require the administration of pralidoxime. coma, and metabolic acidosis usually develop. Pulmonary edema,
nausea and vomiting, and hyperglycemia are frequent complica-
tions of calcium channel blocker overdoses. Paralytic ileus, mesen-
CLINICAL CONTROVERSY teric ischemia, and colonic infarction have been observed in
patients with severe hypotension. Many symptoms become mani-
Some references indicate that pralidoxime should be avoided
fest within 1 to 2 hours of ingestion (see presentation box below). If
in the treatment of carbamate (another type of anticholinester-
a sustained-release formulation is involved, the onset of overt
ase insecticide) poisoning because of reports of worsened
toxicity may be delayed by 6 to 18 hours from the time of ingestion.
toxicity in animals. Pralidoxime may be considered when
Severe poisoning can result in refractory shock and cardiac arrest.
exposure to carbamates is not known but an anticholinesterase
Death can occur within 3 to 4 hours of ingestion.85–88
is suspected based on symptoms or when respiratory paralysis
due to nicotinic effects is not managed sufficiently by mechan-
ical ventilation. CLINICAL PRESENTATION OF
CALCIUM CHANNEL BLOCKER POISONING
One of the pitfalls of therapy is the delay in administering General
sufficient doses of atropine or pralidoxime.72,76 The adverse effects ■ Life-threatening cardiac toxicity (bradycardia, depressed con-
of atropine and pralidoxime, predictable extensions of their anti- tractility, dysrhythmias) within 1 to 3 hours of ingestion,
cholinergic actions, are minimally important compared with the delayed by 12 to 18 hours if a sustained-release product is
life-threatening effects of severe anticholinesterase poisoning and involved
can be minimized easily by decreasing the dose.
 81

CHAPTER 10
Calcium channel blocker actions after absorption

Vasodilation Decreased contractility, automaticity, Suppressed insulin release

and conduction velocity

Clinical Toxicology
Hyperglycemia
Hypotension Bradycardia

Hypoperfusion Dysrhythmias Reduced myocardial

carbohydrate metabolism

Reduced Reduced cellular

contractility calcium exchange

Coma, Ischemic changes Metabolic Myocardial

seizures e.g., stroke, ischemic bowel acidosis dysfunction

FIGURE 10-5. Pathophysiologic changes associated with calcium channel blocker poisoning.

Symptoms tions, but these differences are less clear with overdosage.88 Calcium
channel blockers also inhibit insulin secretion, which results in
■ Nausea and vomiting within 1 hour hyperglycemia and changes in fatty acid oxidation in the myocar-
■ Dizziness, lethargy, coma, and seizures within 1 to 3 hours dium that alter myocardial calcium flow and reduce contractility.89
Signs Current experiences suggest that the signs and symptoms of calcium
channel blocker toxicity are similar among the drugs in this class.
■ Hypotension and bradycardia within 1 to 6 hours

■ Unresponsiveness and depressed reflexes within 1 to 6 hours Causative Agents

■ Atrioventricular block, intraventricular conduction defects, Approximately 10 calcium channel antagonists are marketed in the
and ventricular dysrhythmias on ECG United States for treatment of hypertension, certain dysrhythmias, and
Laboratory Tests some forms of angina. The calcium channel blockers are classified by
their chemical structure as phenylalkylamines (e.g., verapamil), ben-
■ Hyperglycemia typically resolves spontaneously if it occurs
zothiapines (e.g., diltiazem), and dihydropyridines (e.g., amlodipine,
■ Altered arterial blood gases (metabolic acidosis), serum elec- felodipine, nicardipine, and nifedipine). Several of these agents, namely,
trolytes, BUN, and serum creatinine in response to shock diltiazem, nicardipine, nifedipine, and verapamil, are formulated as
within 1 to 6 hours sustained-release oral dosage forms or have a slow onset of action and
Other Diagnostic Tests longer half-life (e.g., amlodipine90), allowing once-daily administration.
■ ECG with continuous monitoring and pulse oximetry to
monitor for toxicity and shock Incidence
■ Monitor for complications of pulmonary aspiration such as In 2005, the AAPCC-NPDS report documented 10,500 toxic expo-
hypoxia and pneumonia by physical findings and chest sures to a calcium channel blocker in 9,650 individuals; 384 patients
radiographs exhibited and survived major toxic effects, and 75 died.6 Poison
control center reports have shown a steady increase in the number
of cases of morbidity and mortality following calcium channel
Mechanism of Toxicity blocker overdosage.
Most toxic effects of calcium channel blockers are produced by
Risk Assessment
three basic actions on the cardiovascular system: vasodilation
through relaxation of smooth muscles, decreased contractility by Ingestion of doses near or in excess of 1 g of diltiazem, nifedipine, or
action on cardiac tissue, and decreased automaticity and conduc- verapamil may result in life-threatening symptoms or death in an
tion velocity through slow recovery of calcium channels. Calcium adult.85 Ingestion of an amount that exceeds the usual maximum
channel blockers interfere with calcium entry by inhibiting one or single therapeutic dose or a dose equal to or greater than the lowest
more of the several types of calcium channels and binding at one or reported toxic dose (whichever is less) warrants referral to a poison
more cellular binding sites. Selectivity of these actions varies with control center and/or an emergency department. The threshold doses
the calcium channel blocker and provides some therapeutic distinc- of several agents and dosage forms vary (e.g., diltiazem: adults, >120
 82
mg for immediate release and chewed sustained release, >360 mg for from calcium channel blocker toxicity or glucagon therapy typically
sustained release, >540 mg for extended release; children younger does not require treatment with insulin. Intravenous sodium bicar-
SECTION 1

than 6 years: >1 mg/kg).91 Patients on chronic therapy with these bonate, however, may be necessary to establish acid–base balance and
agents who acutely ingest an overdose may have a greater risk of correct the metabolic acidosis that is common with serious calcium
serious toxicity. Elderly patients and those with underlying cardiac channel blocker overdoses.
disease may not tolerate mild hypotension or bradycardia. Concur- For severe cases of calcium channel blocker toxicity refractory to
rent ingestion of β-adrenergic blocking drugs, digitalis, class I antiar- conventional therapy, an infusion of high-dose insulin with supple-
rhythmics, and other vasodilators may worsen the cardiovascular mental dextrose and potassium to produce a state of hyperinsuline-
effects of calcium channel blockers.86,88,91 mia and euglycemia should be considered.52,85,87–89 Case reports
suggest that an intravenous bolus of regular insulin (0.5 to 1 units/kg)
Foundation Issues

Management of Toxicity with 50 mL dextrose 50% (0.25 mg/kg for children) followed by a
continuous infusion of regular insulin (0.5 to 1 units/kg/h) may
There is no accepted specific prehospital care for calcium channel improve myocardial contractility. The effect of insulin is presently
blocker poisoning except to summon an ambulance for symptomatic unclear, but it may improve myocardial metabolism that is adversely
patients. Ipecac syrup should be avoided because of the risks of affected by calcium channel blocker overdoses, such as decreased
seizures and coma.91 The therapeutic options for management of cellular uptake of glucose and free fatty acids and a shift from fatty
calcium channel blocker poisoning include supportive care, gastric acid oxidation to carbohydrate metabolism.85,87,89 This insulin regi-
decontamination, and adjunctive therapy for the cardiovascular and
men is titrated to improvement in systolic blood pressure over 100
metabolic effects. Supportive care consists of airway protection,
mm Hg and heart rate over 50 beats/min. Serum glucose concentra-
ventilatory support, intravenous hydration to maintain adequate
tions should be monitored closely to maintain euglycemia. Patients
urine flow, and maintenance of electrolyte and acid–base balance.
with serum potassium concentrations <2.5 mEq/L may need supple-
Maintaining vital organ perfusion is critical for successful therapy in
mental potassium (see Chap. 54). The insulin infusion rate can be
order to allow time for calcium channel blocker toxicity to resolve.87,88
reduced gradually as signs of toxicity resolve. Therapies with glucagon
Gastric lavage and a single dose of activated charcoal should be and insulin are based on animal studies and case reports; clinical trials
administered if instituted within 1 to 2 hours of ingestion. Besides demonstrating effectiveness have not been performed to date.52,85,87–89
exhibiting a slower onset of symptoms, sustained-release formula-
Several lifesaving options may be warranted for patients with
tions can form concretions in the intestine.87,88 Whole-bowel irriga-
cardiogenic shock that is refractory to conventional therapy. Electri-
tion with polyethylene glycol electrolyte solution may accelerate cal cardiac pacing may restore an acceptable heart rate in patients
rectal elimination of the sustained-release tablets and should be with severe bradycardia.88 Intraaortic balloon counterpulsation or
considered routinely for ingestion of sustained-release calcium
cardiopulmonary bypass may improve shock in patients unrespon-
channel blocker formulations.34,92
sive to other therapies.52,88,94,95
Adjunctive therapy is focused on treating hypotension, bradycar- Measures to enhance elimination from the bloodstream by
dia, and resulting shock. Hypotension is treated primarily by cor- hemodialysis or multiple-dose activated charcoal have not been
rection of coexisting dysrhythmias (e.g., bradycardia, heart block) shown to be effective and are not indicated for calcium channel
and implementation of conventional measures to treat decreased blocker poisoning.42,86,88,96
blood pressure. Infusion of normal saline and placement of the
patient in the Trendelenburg position are initial therapies. Further
fluid therapy should be guided by central venous pressure monitor-
ing. Dopamine and epinephrine in conventional doses for cardio- CLINICAL CONTROVERSY
genic shock should be considered next. If hypotension persists, Some clinicians believe that hyperinsulinemia/euglycemia or
dysrhythmias are present, or other signs of serious toxicity are glucagon therapy for calcium channel blocker poisoning should
present, calcium should be administered intravenously.85,88 be used early in the course of therapy. Others reserve it for life-
A calcium chloride bolus test dose (10 to 20 mg/kg up to 1 to 3 g) threatening symptoms not responsive to other therapy. More
is the preferred therapy for patients with serious toxicity. In adults, safety and effectiveness data are needed to define the place of
calcium chloride 10% can be diluted in 100 mL normal saline and these two agents in therapy.
infused over 5 minutes through a central venous line. If a positive
cardiovascular response is achieved with this test dose, a continuous
infusion of calcium chloride (20 to 50 mg/kg/h) should be started.
Monitoring and Prevention
Calcium gluconate is less desirable to use because it contains less Regular monitoring of vital signs and ECG is essential in suspected
elemental calcium per milligram of final dosage form. Intravenous calcium channel blocker poisoning. Determinations of serum elec-
calcium salts can produce vomiting and tissue necrosis on extrava- trolytes, serum glucose, arterial blood gases, urine output, and renal
sation.52,88 Atropine also may be considered for treatment of brady- function are indicated to assess and monitor symptomatic patients.
cardia, but it is seldom sufficient as a sole therapy.87 If serious toxicity is likely to develop, overt symptoms will manifest
If the bradycardia and hypotension are refractory to the foregoing within 6 hours of ingestion.91 For ingestions of sustained-release
therapy, a bolus infusion of glucagon (0.05 to 0.20 mg/kg, initial adult products in toxic doses, observation for 24 hours in a critical care
dose is 3 to 5 mg over 1 to 2 minutes) should be considered. Benefit unit may be prudent because the onset of symptoms may be slow
typically is observed within 5 minutes of administration and can be and delayed up to 12 to 18 hours after ingestion.85,91,92,96,97 Serum
sustained with a continuous intravenous infusion (0.05 to 0.1 mg/kg/h) concentrations of these agents in overdose patients do not correlate
titrated to clinical response.93 Glucagon possesses chronotropic and well with the ingested dose, degree of toxicity, or outcome.
inotropic effects in part by stimulating adenyl cyclase and increasing Poisonings resulting from these agents are likely to increase as
cyclic adenosine monophosphate, which may promote intracellular their therapeutic indications and use increase. These poisonings
entry of calcium through calcium channels. It thereby may improve may be the result of an intentional suicide or unintentional inges-
hypotension and bradycardia.52 Vomiting is not uncommon with tion by young children. Prevention of calcium channel blocker
these large doses of glucagon, and the airway should be protected to poisonings in children rests with the education of patients receiving
prevent pulmonary aspiration. Hyperglycemia may occur or be exac- these agents, particularly of grandparents and those who have
erbated in those patients receiving glucagon therapy. Hyperglycemia children visit their homes infrequently, of their dangers on overdos-
 83
98,100
age. Safe storage and use of child-resistant closures may reduce the iron in the body. Iron is irritating to the gastric and duodenal
opportunities for unintentional poisonings by children.86 mucosa, which may result in hemorrhage and occasional perfora-

CHAPTER 10
tions. Once absorbed, iron is taken up by tissues, particularly the
IRON liver, and acts as a mitochondrial poison. It occasionally causes
hepatic injury. Iron may inhibit aerobic glycolysis and perturb the
Clinical Presentation electron transport system. Further, iron may shunt electrons away

In the first few hours after ingestion of toxic amounts of iron, from the electron transport system, thereby reducing the efficiency
symptoms of gastrointestinal irritation (e.g., nausea, vomiting, and of oxidative phosphorylation. These biochemical factors, along with
diarrhea) are common (see presentation box below). In certain severe the cardiovascular effects of iron, lead to metabolic acidosis. The
cases, acidosis and shock can become manifest within 6 hours of pathogenesis of shock is not well understood but may include the

Clinical Toxicology
ingestion. Some have observed a quiescent phase between 6 and 48 development of hypovolemia and lactic acidosis, release of endoge-
hours after ingestion when symptoms improve or abate, but this nous vasodilators, and the direct vasodepressant effects of iron and
phenomenon is poorly characterized.98 Continued gastrointestinal ferritin on the circulation (Fig. 10–6).
symptoms, poor perfusion, and oliguria should suggest the develop-
ment of severe toxicity, with other effects still to become manifest. Causative Agents
Generally, within 24 to 36 hours of the ingestion, central nervous Iron poisoning results from the ingestion and absorption of exces-
system involvement with coma and seizures; hepatic injury character- sive amounts of iron from iron tablets, multiple vitamins with iron,
ized by jaundice, increased prothrombin time, increased bilirubin, and and prenatal vitamins. Different iron salts and formulations contain
hypoglycemia; cardiovascular shock; and acidosis also develop.98,99 varying amounts of elemental iron (see Chap. 104). Generally,
Adult respiratory distress syndrome (ARDS) may develop in patients children’s chewable vitamins are less likely to produce systemic iron
with severe cardiovascular shock and further compromise recovery.100 poisoning in part because of their lower iron content.103
Coagulopathy with decreased thrombin formation is one of the early
direct effects of excessive iron concentrations, and later disturbances of Incidence
coagulation (after 24 to 48 hours of ingestion) are a consequence of
hepatotoxicity.101 Mucosal injury, an iron-rich circulation, or deferox- Acute iron poisoning can produce death in children and
amine therapy may promote septicemia with Yersinia enterocolitica adults.102,103 The 2005 AAPCC-NPDS report documented 3,635
during iron overdose; other bacteria or viruses also may cause septice- nonfatal and 4 fatal cases, respectively, of iron poisoning, with 54%
mia.98 Two to four weeks after the exposure, a few rare patients of the exposures in children younger than 6 years. Multiple vitamins
experience persistent vomiting from gastric outlet obstruction as the with iron were involved in 24,599 cases, with 84% of ingestions
result of pyloric and duodenal stenosis from the earlier gastric mucosal occurring in those younger than 6 years. No deaths were associated
necrosis. Autopsy findings in children indicate prominent iron depo- with these products.6
sition in intestinal mucosa and periportal necrosis of the liver that
correlate with the primary symptoms of serious iron poisoning.102 Risk Assessment
A patient who exhibits lethargy, paleness, persistent or bloody
CLINICAL PRESENTATION OF ACUTE emesis, or diarrhea should be immediately referred to an emergency
IRON POISONING department.103 Ingestion of 10 to 20 mg/kg elemental iron usually
General elicits mild gastrointestinal symptoms. Ingestion of 20 to 40 mg/kg
is not likely to produce systemic toxicity, and typically these patients
■ Gastrointestinal symptoms shortly after ingestion with possi-
can be conservatively managed at home. Ingestions of 40 mg/kg or
ble rapid progression to shock and coma
more of elemental iron are often associated with serious toxicity and
Symptoms require immediate medical attention.103 Psychiatric as well as med-
■ Vomiting, abdominal pain, and diarrhea within 1 to 6 hours ical intervention is indicated for adults and adolescents who inten-
■ Lethargy, coma, seizures, bloody vomiting, bloody diarrhea,
tionally ingest iron as a suicide gesture.98,100,103
and shock within 6 to 24 hours An abdominal radiograph may help to confirm the ingestion of
iron tablets and indicate the need for aggressive gastrointestinal
Signs evacuation with whole-bowel irrigation. An abdominal radiograph
■ Hypotension and tachycardia within 6 to 24 hours is most useful within 2 hours of ingestion. The visualization of
radiopaque iron tablets is confounded by the presence of other
■ Liver dysfunction and failure possible in 2 to 5 days
hard-coated tablets and some extended-release tablets that also are
Laboratory Tests radiopaque. Furthermore, the radiopacity of iron tablets diminishes
■ Toxic serum iron concentrations >500 mcg/dL as the tablets disintegrate, and chewable and liquid formulations
typically are not radiopaque.104
■ Altered arterial blood gases and serum electrolytes associated
Iron poisoning causes vomiting and diarrhea, but these symp-
with a high anion gap metabolic acidosis within 3 to 24 hours
toms are poor indicators of later serious toxicity. The presence of a
■ Elevated BUN, serum creatinine, AST, ALT, and INR within 1 combination of findings such as coma, radiopacities, leukocytosis,
to 2 days and increased anion gap, however, is associated with dangerously
Other Diagnostic Tests high serum concentrations >500 mcg/dL. The presence of single
■ Guaiac test of stools for the presence of blood signs and symptoms, such as vomiting, leukocytosis, or hyperglyce-
mia, is not a reliable indicator of the severity of iron poisoning in
■ Abdominal radiograph to detect solid iron tablets in gas-
adults or children.105,106
trointestinal tract
Once iron is absorbed, it is eliminated only as the result of blood
loss or sloughing of the intestinal and epidermal cells. Thus, iron
Mechanism of Toxicity kinetics essentially represent a closed system with multiple compart-
The toxicity of acute iron poisoning includes local effects on the ments. The serum iron concentration represents a small fraction of
gastrointestinal mucosa and systemic effects induced by excessive the total-body content of iron and is at its greatest concentration in
 84

Ingestion of Gastric and intestinal

SECTION 1

Excess iron absorption

excess iron irritation and necrosis

Fluid, electrolyte, blood loss Increased capillary permeability Hepatic injury Cellular biochemical changes
Foundation Issues

Release of vasodepressant
Hypovolemia substances

Hypoperfusion Loss of vascular tone

Acidosis

Renal dysfunction Shock Myocardial dysfunction

FIGURE 10-6. Pathophysiology of acute iron poisoning.

the postabsorptive and distributive phases, typically 2 to 10 hours complexes in equilibrium with transferrin. The resulting iron–
after ingestion.107 Serum iron concentrations >500 mcg/dL have deferoxamine complex, ferrioxamine, is then excreted in the urine.
been associated with severe toxicity, whereas concentrations <350 Its action on intracellular iron is unclear, but it may have a
mcg/dL typically are not associated with severe toxicity; however, protective intracellular effect or may chelate extramitochondrial
exceptions have been reported for both thresholds.107 Serious toxicity iron.100 The parenteral administration of deferoxamine produces an
is best determined by assessing the development of gross gastrointes- orange–red-colored urine within 3 to 6 hours because of the
tinal bleeding, metabolic acidosis, shock, and coma regardless of the presence of ferrioxamine in the urine.98 For mild-to-moderate cases
serum iron concentration.100 The serum iron concentration serves of iron poisoning, where its use is unclear, the presence of discol-
as a guide for further assessment and treatment options. The ratio ored urine indicates the persistent presence of chelatable iron and
of the serum iron concentration to the total iron-binding capacity the need to continue deferoxamine. The reliance on discolored
previously has been advocated to assess acute iron poisoning, but it urine as a therapeutic end point has been challenged because it is
is no longer used. This procedure is unreliable, insensitive, and has not sensitive and is difficult to detect.108
little relationship to toxicity.106 An initial intravenous infusion of 15 mg/kg/h generally is
indicated, although some have used up to 30 mg/kg/h for life-
Management of Toxicity threatening cases. In these situations, the dose must be titrated
carefully to minimize deferoxamine-induced hypotension.98,100,109
Many patients vomit spontaneously, and ipecac syrup should be
The rapid intravenous infusion of deferoxamine (>15 mg/kg/h)
avoided.103 At the emergency department, gastric lavage with nor-
has been associated with tachycardia, hypotension, shock, general-
mal saline can be considered. Lavage with normal saline may
ized erythema, and urticaria.98,110 Anaphylaxis has been reported
remove iron tablet fragments and dissolved iron, but because the
rarely. The use of deferoxamine for more than 24 hours at doses
lumen of the tube is often smaller than some whole tablets, effective
used for treatment of acute poisoning has been associated with
removal is unlikely.98 Activated charcoal administration is not
exacerbation or development of ARDS.110–112 Although the manu-
warranted routinely because it adsorbs iron poorly. If abdominal
facturer states that the total dose in 24 hours should not exceed
radiographs reveal a large number of iron tablets, whole-bowel
6 g, the basis for this recommendation is unclear, and daily doses
irrigation with polyethylene glycol electrolyte solution typically is
as high as 37.1 g have been administered without incident.109,111
necessary.34 Although removal by gastrostomy has been used in a
Good hydration and urine output may moderate some of the
few cases,100 early and aggressive decontamination and evacuation
secondary physiologic effects of iron toxicity and ensure urinary
of the gastrointestinal tract usually will be adequate to minimize
elimination of ferrioxamine. In the patient who develops renal
iron absorption and thereby reduce the risk of systemic toxicity.
failure, hemodialysis or hemofiltration does not remove excess
Patients with systemic symptoms (e.g., shock, coma, or gross
iron but will remove ferrioxamine.98
gastrointestinal bleeding or metabolic acidosis) should receive
deferoxamine as soon as possible. If the serum iron concentration is
>500 mcg/dL, deferoxamine is also indicated because serious sys-
temic toxicity is likely.98,100 Its use is less clear in patients with serum CLINICAL CONTROVERSY
iron concentrations in the range from 350 to 500 mcg/dL because
There is little evidence on how much deferoxamine should be
many of these patients do not develop systemic symptoms.107
given for iron poisoning or for how long it should be adminis-
Deferoxamine is a highly selective chelator of iron that theoreti-
tered. The dosage regimen should balance the benefits of
cally binds ferric (Fe3+) iron in a 1:1 molar ratio (100 mg deferox-
increased iron removal in patients with exceedingly high serum
amine to 8.5 mg ferric iron) that is more stable than the binding of
iron concentrations versus the risk of developing ARDS when
iron to transferrin. Deferoxamine removes excess iron from the
therapy lasts for more than 1 to 3 days.
circulation and some iron from transferrin by chelating ferric
 85
The desired end point for deferoxamine therapy is not clear. ■ Mild hypertension early will change to severe hypotension
Some have suggested that deferoxamine therapy should cease when

CHAPTER 10
and shock within 1 to 6 hours
the serum iron concentration falls below 150 mcg/dL.100 The decline
of serum iron concentrations, however, may not account for the ■ Unresponsiveness and depressed reflexes within 1 to 3 hours
potential cellular action of deferoxamine irrespective of its effect on ■ Depressed respiratory rate and depth depending on the degree
iron elimination. The cessation of orange–red urine production that of coma
is indicative of ferrioxamine excretion is not reliable because many ■ Common arrhythmias, such as prolonged QRS and QT inter-
individuals cannot distinguish its presence in the urine.108 Consid- vals to ventricular dysrhythmias, within 1 to 6 hours
ering these shortcomings, deferoxamine therapy should be contin-
Laboratory Tests
ued for 12 hours after the patient is asymptomatic and the urine
■ Altered arterial blood gases associated with metabolic acidosis

Clinical Toxicology
returns to normal color or until the serum iron concentration falls
below 350 mcg/dL and approaches 150 mcg/dL. from hypoxia and seizures
■ Altered serum electrolytes, BUN, and serum creatinine in
Other Therapies response to seizures and shock within 3 to 12 hours
Lavage solutions of phosphate or deferoxamine have been pro- Other Diagnostic Tests
posed previously as a means to render iron insoluble, but they ■ ECG with continuous monitoring and pulse oximetry to
were found ineffective and dangerous.95 Oral iron chelating monitor for toxicity and shock
agents, such as deferiprone and deferasirox, are available for the ■ Monitor for complications of pulmonary aspiration, such as
management of chronic iron overload states such as sickle cell hypoxia and pneumonia, by physical findings and chest
anemia, but their role in the treatment of acute iron poisoning radiograph
remains to be determined.113,114

Monitoring and Prevention Prolongation of the QRS complex on ECG indicating nonspecific
intraventricular conduction delay or bundle-branch block is the
Once a poisoning has occurred, acid–base balance (anion gap and most distinctive feature of tricyclic antidepressant overdose.116
arterial blood gases), fluid and electrolyte balance, and perfusion Sinus tachycardia with rates typically <160 beats/min is common
should be monitored. Other indicators of organ toxicity, such as and does not cause serious hemodynamic changes in most patients.
ALT, AST, bilirubin, prothrombin time, serum glucose and creati- Ventricular tachycardia is a common ventricular arrhythmia, but it
nine concentrations, as well as markers of physiologic stress or may be difficult to distinguish from sinus tachycardia in the pres-
infection such as leukocytosis, also should be monitored. ence of QRS complex prolongation and the apparent absence of P
Iron poisoning often is not recognized as a potentially serious waves. It often occurs in patients with marked QRS complex
problem by parents or victims until symptoms develop; thus, prolongation or hypotension and may be precipitated by sei-
valuable time to institute treatment is lost. Parents should be made zures.116,117 High rates of mortality are associated with ventricular
aware of the potential risks and asked to observe basic poison tachycardia; ventricular fibrillation is the terminal rhythm. Torsade
prevention measures. Some hard-coated iron tablets resemble de pointes is observed infrequently with tricyclic antidepressant
candy-coated chocolates and are confused easily by children. Based poisoning. With massive tricyclic antidepressant overdose, slow
on these considerations and the frequency of this poisoning, iron ventricular rhythms may be observed. Hypotension is a significant
tablets are packaged in child-resistant containers. factor in most cases of tricyclic antidepressant poisoning. Refractory
hypotension leading to death is due to vasodilation and impaired
TRICYCLIC ANTIDEPRESSANTS cardiac contractility.116 Other factors, such as extreme heart rates,
intravascular volume depletion, hypoxia, hyperthermia, seizures,
Clinical Presentation and acidosis, may contribute to refractory hypotension.
 Patients may deteriorate rapidly and progress from no symptoms Coma usually is present in patients with tricyclic antidepressant
to life-threatening cardiotoxicity or seizures within 1 hour.115,116 poisoning and may or may not be associated with QRS complex
Major symptoms of tricyclic antidepressant overdose typically are prolongation. In severe cases, coma is sufficient to depress respira-
manifest within 6 hours of ingestion.115 The principal effects of tions. Delirium, manifest as agitation or disorientation, may occur
tricyclic antidepressant poisoning involve the cardiovascular system early in the course of severe poisoning or with poisoning of moderate
and the central nervous system and can result in arrhythmias, severity. Seizures often occur within 2 hours of ingestion and usually
hypotension, coma, and seizures (see presentation box below). are generalized, single, and brief. Seizures may result in acidosis,
hyperthermia, or rhabdomyolysis, and 10% to 20% of patients may
CLINICAL PRESENTATION OF abruptly develop cardiovascular deterioration.116 Myoclonus also
TRICYCLIC ANTIDEPRESSANT POISONING may be observed with tricyclic antidepressant overdose.
Hyperthermia often results from seizure and myoclonic activity
General
in the presence of decreased sweating and is associated with a high
■ Sedating and cardiovascular effects observed within 1 hour of incidence of neurologic sequelae and mortality. Anticholinergic
ingestion, quickly leading to life-threatening symptoms; death symptoms, such as urinary retention, ileus, and dry mucous mem-
is possible within 1 to 2 hours branes, often are observed with tricyclic antidepressant over-
Symptoms dose.115,116 Pupil size is variable. Tricyclic antidepressant overdose
■ Lethargy, coma, and seizures occur within 1 to 6 hours can be staged based on the patient’s symptoms and recovery time.
In stage 1, patients are responsive to pain, have sinus tachycardia,
■ Dry mouth, mydriasis, urinary retention, and hypoactive and recover within 24 hours. In stage 2, seizures, coma, and cardiac
bowel sounds, develop within 1 to 6 hours conduction problems are evident; respiratory support typically is
Signs needed. Patients recover within 24 to 48 hours of ingestion. Stage 3
■ Tachycardia within 1 to 3 hours is characterized by the features of stage 2 with the addition of
respiratory arrest, hypotension, ventricular dysrhythmias, and asys-
 86
tole, which may occur within 1 to 24 hours of ingestion. Typically Incidence
symptoms appear within 2 hours, and more serious effects usually Tricyclic antidepressant poisoning is a common cause of death from
SECTION 1

are not seen until 6 hours postingestion; rarely rapid clinical drug overdose.116,117 The 2005 AAPCC-NPDS report documented
deterioration is observed within 1 to 2 hours.118 11,198 patients with exposures to tricyclic antidepressants; 63% of
Amoxapine, bupropion, and maprotiline are atypical antidepres- these cases were considered to be intentional overdoses. A total of
sants associated with a higher incidence of seizures on overdose; 1,256 people experienced a major effect, and 101 people died.6 The
amoxapine produces minimal cardiotoxicity,116,119 but venlafaxine SSRIs accounted for 48,161 nonfatal exposures and 118 deaths.
has been associated with greater mortality.120 The selective seroto-
nin reuptake inhibitors (SSRIs) generally produce a common toxic-
Risk Assessment
ity profile on overdose despite their structural and pharmacologic
Referral to an emergency department is warranted for ingestions >5
Foundation Issues

distinctions.121 The SSRIs inhibit presynaptic neuronal uptake of

serotonin, resulting in increased synaptic serotonin levels. When mg/kg of amitriptyline, clomipramine, doxepin, and imipramine;
ingested in excess, SSRIs rarely cause death and typically produce >2.5 mg/kg of desipramine, nortriptyline, and trimipramine; and
nausea, vomiting, diarrhea, tremor, and decreased level of con- >1 mg/kg of protriptyline.118 Patients who exhibit weakness, drows-
sciousness.121 Tachycardia and seizures are infrequent.116,119,122 iness, dizziness, tremulousness, and palpitations after an ingestion
Serotonin syndrome is a condition in which associated drugs of a tricyclic antidepressant and patients suspected of a suicide
(e.g., meperidine, nonselective monoamine oxidase inhibitors, dex- gesture or those who are suspected victims of malicious poisoning
tromethorphan, linezolid, tricyclic antidepressants, SSRIs) acutely should be promptly referred to an emergency department.118 A QRS
increase serotonin levels and develops within minutes to hours complex >160 milliseconds or progressive prolongation of the QRS
(typically within 6 hours) after starting a medication, increasing the complex is an indicator of toxicity such as seizures or ventricular
dose of a medication, or overdosing. It is characterized by a arrhythmias and often precedes the onset of serious symp-
collection of neurobehavioral (e.g., confusion, agitation, coma, toms.115,117,125 The QRS complex duration should not be used as the
seizures), autonomic (e.g., hyperthermia, diaphoresis, tachycardia, sole indicator of risk for tricyclic antidepressant poisoning.125
hypertension), and neuromuscular (e.g., myoclonus, rigidity, tremor, Although urine drug analyses routinely screen for tricyclic antide-
ataxia, shivering, nystagmus) signs and symptoms.123 Most cases are pressants, the qualitative result can only suggest or confirm a
mild and resolve spontaneously within 24 to 72 hours. Cardiac potential risk for the development of toxicity.
arrest, coma, and multiorgan system failure have been reported as Patients with coexisting cardiovascular and pulmonary condi-
consequences of serotonin syndrome.123 Recognition of the syn- tions (e.g., ARDS, pulmonary infection, pulmonary aspiration) may
drome is based on a high index of suspicion and identification of be more susceptible to the toxic effects or complications of tricyclic
risk factors. antidepressant poisoning.118 Tricyclic antidepressants interact with
other central nervous system depressant drugs, which together may
lead to increased central nervous system and respiratory depression.
Mechanism of Toxicity
Consult a poison control center for current recommendations for
Many of the toxic effects of tricyclic antidepressants are associated doses of SSRIs that would warrant referral to an emergency depart-
with an exaggeration of their pharmacologic action. The tricyclic ment.126 The risk of serotonin syndrome may be increased shortly
antidepressants, such as type Ia antiarrhythmic drugs, inhibit the after dosage increases of SSRIs or when drug interactions increase
fast sodium channel so that phase 0 depolarization of the myocar- serotonin activity.123 Concomitant or proximal use of SSRIs, tricyc-
dium is slowed.116 This action leads to QRS complex prolongation, lic antidepressants, or nonselective monoamine oxidase inhibitors
atrioventricular block, ventricular tachycardia, and decreased myo- may cause serotonin syndrome. Furthermore, the addition of cer-
cardial contractility. Tricyclic antidepressants also block vascular tain drugs, such as tryptophan, dextromethorphan, cocaine, or
α-adrenergic receptors, resulting in vasodilation, which contrib- sympathomimetics, to SSRI therapy may increase the risk of devel-
utes to hypotension. Sinus tachycardia is related to the inhibition oping serotonin syndrome.123
of norepinephrine reuptake and anticholinergic effects. Other
anticholinergic effects include urinary retention, ileus, dry mucous Management of Toxicity
membranes, and impaired sweating. Inhibition of norepinephrine
Once the ingestion of an overdose of tricyclic antidepressant is
reuptake also may account for the early, transient, and self-limiting
suspected or for any intentional ingestions, medical evaluation and
elevation of blood pressure observed in some patients. The central
treatment should be sought promptly. If the patient is symptomatic,
nervous system toxicity of tricyclic antidepressants is not well
it may be prudent to call for an ambulance because of the rapid
understood.
progression of some cases. At the emergency department, the
patient should be monitored carefully, have vital signs assessed
Causative Agents regularly, and have an intravenous line started. Supportive and
Tricyclic antidepressants and SSRIs are used to treat a variety of symptomatic care includes oxygen, intravenous fluids, and other
behavioral conditions (see Chaps. 71–73). The tricyclic antidepres- treatments as indicated. Prompt administration of activated char-
sants include drugs such as amitriptyline, desipramine, doxepin, coal may decrease the absorption of any remaining tricyclic antide-
imipramine, and nortriptyline. Atypical agents include amoxapine, pressant. It also may be useful beyond the first hour of ingestion
bupropion, maprotiline, nefazodone, trazodone, and venlafaxine. because of decreased gastrointestinal motility from the anticholin-
The SSRIs include fluoxetine, paroxetine, and sertraline. The tricyc- ergic action of tricyclic antidepressants. Gastric lavage may be
lic antidepressants are generally highly protein bound, exhibit a considered if the time of the ingestion is unknown or if ingestion
large volume of distribution, and possess elimination half-lives of 8 occurred within the past 1 to 2 hours. Some practitioners avoid
to 24 hours or more. Virtually none of the drug is eliminated gastric lavage altogether.116 Ipecac syrup should be avoided in
unchanged in the urine. Metabolism of the parent drug produces patients who ingest tricyclic antidepressants because the rapid onset
active metabolites in most cases (e.g., amitriptyline to nortriptyline) of toxicity limits its usefulness. Multiple-dose activated charcoal has
that may contribute to toxicity after the first 12 to 24 hours.116 been shown to increase the elimination of some tricyclic antidepres-
Genetic polymorphism at CYP2D6 may lead to slower recovery in sants in human volunteers42 and has been used in poisoned
patients who are slow hydroxylators.124 patients.115,116 It may be most useful during the first 12 hours of
 87
ingestion while the drug is distributing to tissue compartments. TABLE 10-13 Treatment Options for Acute Tricyclic
Because the tricyclic antidepressants possess a large volume of

CHAPTER 10
Antidepressant Toxicity
distribution, little of the drug is present in the bloodstream; thus
Toxicity Treatment
hemodialysis is not useful for the extracorporeal removal of tricyclic
antidepressants. Cardiovascular
Intravenous sodium bicarbonate is part of the first-line treatment QRS prolongation, if progressive or Intravenous sodium bicarbonate to a blood
of QRS complex prolongation, ventricular arrhythmias, and hypoten- > 0.16 s pH of 7.5 even in the absence of acidosis;
generally avoid other antiarrhythmic drugs
sion caused by tricyclic antidepressant overdose.52,116,127 Typically 1 to
Hypotension Intravascular fluids; intravenous sodium
2 mEq/kg sodium bicarbonate (1 mEq/mL) is administered as a bolus bicarbonate; consider norepinephrine or
infusion (usually a 50-mEq ampule in an adult) and repeated as dopamine

Clinical Toxicology
necessary to achieve an arterial blood pH of 7.50 to 7.55 or abatement Ventricular tachycardia Intravenous sodium bicarbonate; lidocaine,
of toxicity.115,116 A therapeutic effect usually is observed within min- overdrive pacing
utes. Excessive use of sodium bicarbonate may produce dangerous Ventricular bradycardia Epinephrine drip; cardiac pacemaker
alkalemia, which by itself is associated with ventricular arrhyth- Atrioventricular block type II, sec- Cardiac pacemaker
mias.116 The mechanism of action of sodium bicarbonate is unclear. ond or third degree
Although some practitioners have proposed that sodium bicarbonate Cardiac arrest Advanced cardiac life support, prolonged
increases protein binding of tricyclic antidepressants, this theory has resuscitation may be needed
Neurologic
been discounted. Sodium may play an important role by stabilizing
Seizures, agitation Benzodiazepines; neuromuscular blockade
tricyclic antidepressant–induced changes to the sodium gradient of may be needed if hyperthermia or acido-
the myocardium.116,128 Regardless of its action, it is effective and sis is present
generally safe. Hyperventilation to produce a mild state of respiratory Coma Endotracheal intubation; mechanical ventila-
alkalosis has been used to treat some dysrhythmias, but it is used less tion if needed
widely than sodium bicarbonate.115,116 Homeostatic
Hyperthermia Treat seizures and agitation; consider cool-
ing blanket, ice water lavage, and cool
CLINICAL CONTROVERSY water mist of body
Acidosis Intravenous sodium bicarbonate
Because intravenous sodium bicarbonate is used as therapy for
certain arrhythmias and hypotension caused by tricyclic antide-
pressant poisoning, some practitioners have advocated its pro- cardiotoxicity, arterial blood gases should be determined. Patients
phylactic use. Little evidence indicates which patients would who show no signs of toxicity during 6 hours of observation and
benefit from prophylactic use. The risks of potentially producing have received activated charcoal promptly require no further medi-
alkalosis in a patient who is not seriously toxic should be cal monitoring. Psychiatric evaluation is indicated for adolescents
considered. and adults. When signs of tricyclic antidepressant toxicity are
present in a patient, cardiac monitoring generally is recommended
Treatment of the complications of tricyclic antidepressant poi- for at least 24 hours after the patient is without findings.116
soning is outlined in Table 10–13 and includes pharmacologic and Prevention of tricyclic antidepressant poisoning poses unique
nonpharmacologic approaches.115,116 Several agents generally challenges. Many of the dosage forms are small in size, and adults
should be avoided in the treatment of tricyclic antidepressant and children can consume large numbers easily. In the course of
poisoning. Other drugs that inhibit the fast sodium channel, such as treating depression, several antidepressant agents may be tried to
procainamide and quinidine, are contraindicated. Phenytoin has achieve results. By not discarding unused medicines, a storehouse of
limited usefulness in treating tricyclic antidepressant seizures and potentially deadly drugs may be available for children to discover or
has questionable efficacy in managing cardiotoxicity.115 Physostig- for the despondent patient to use to attempt suicide. Although
mine was used in the past as a treatment of tricyclic antidepressant patients take tricyclic antidepressants for therapeutic relief of
cardiotoxicity and seizures because it antagonizes anticholinergic depression, they are also a group likely to contemplate suicide with
actions. However, physostigmine has been associated with brady- tricyclic antidepressants. Strategies that would limit the amount of
cardia and asystole116,129 and has been avoided in the contemporary tricyclic antidepressant prescribed at one time also potentially
treatment of tricyclic antidepressant cardiovascular or central ner- would impair adherence to a dosage regimen and thereby compro-
vous system toxicity. Flumazenil is used to antagonize the effects of mise the therapeutic potential of these agents.116,127 Patients with a
benzodiazepines, but its use in the presence of a tricyclic antidepres- history of suicidal gestures may be candidates for the atypical
sant has been associated with the development of seizures and antidepressants or SSRIs, which possess less cardiotoxicity. General
should be avoided.130 poison prevention measures may limit childhood poisonings, and
Treatment of an overdose of the atypical antidepressants and monitoring depressed patients for suicidal ideation may identify
SSRIs is directed primarily toward decontamination of the gas- patients at risk.131
trointestinal tract with activated charcoal, symptomatic treatment,
and general supportive care. Management of the serotonin syn- ABBREVIATIONS
drome involves discontinuation of the serotoninergic agent and
supportive therapy. Benzodiazepines, propranolol, and cyprohepta- AAPCC-NPDS: American Association of Poison Control Centers’
dine, a serotonin antagonist, have been used successfully.123 National Poison Data System
ALT: alanine aminotransferase
Monitoring and Prevention
ARDS: adult respiratory distress syndrome
Measurement of vital signs, electrolytes, and BUN and a urinalysis
AST: aspartate aminotransferase
are indicated for initial assessment. Patients should be monitored
continuously by ECG, and a 12-lead ECG should be obtained if QRS BUN: blood urea nitrogen
complex prolongation is noted. If patients start to show signs of ECG: electrocardiogram
 88
INR: international normalized ratio 24. Taylor JR, Streetman DS, Castle SS. Medication bezoars: A literature
review and report of a case. Ann Pharmacother 1998;32:940–946.
NAPQI: N-acetyl-p-benzoquinoneimine
SECTION 1

25. Bosse GM, Matyunas NJ. Delayed toxidromes. J Emerg Med 1999;17:679–
PPPA: Poison Prevention Packaging Act (of 1970) 690.
26. Vance MV, Selden BS, Clark RF. Optimal patient position for trans-
port and initial management of toxic ingestions. Ann Emerg Med
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116. Pentel PR, Keyler DE, Haddad LM. Tricyclic antidepressants and depressant ingestions. J Emerg Med 2003;25:185–191.
selective serotonin reuptake inhibitors. In: Haddad LM, Shannon MW, 130. Weinbroum AA, Flaishon R, Sorkine P. A risk-benefit assessment of
Winchester JI, eds. Clinical Management of Poisoning and Drug flumazenil in the management of benzodiazepine overdose. Drug Saf
Overdose, 3rd ed. Philadelphia: WB Saunders, 1998:437–451. 1997;17:181–196.
117. James LP, Kearns GL. Cyclic antidepressant toxicity in children and 131. Friedman RA, Leon AC. Expanding the Black Box—depression, antide-
adolescents. J Clin Pharmacol 1995;35:343–350. pressants, and the risk of suicide. N Engl Med 2007;356:2343–2346.
 91

C HAP T E R

11 Emergency Preparedness:
Identification and Management
of Biological Exposures
COLLEEN M. TERRIFF, JASON E. BROUILLARD, LISA T. COSTANIGRO, AND
JESSICA S. GRUBER

associated with natural disasters. Isolated reports during the past decade
KEY CONCEPTS have heightened concern about a global outbreak of severe acute
respiratory syndrome (SARS) or avian influenza and as a result many
 Bioterrorism agents are organisms or toxins that can cause dis- levels of the community, including schools, businesses, health systems,
ease and death in humans, animals, or plants and elicit terror. first responders, and governments, have begun to address the need for
 Category A bioterrorism agents include anthrax (Bacillus an- planning for public health emergencies. Stockpiling of antibiotics for
thracis), tularemia (Francisella tularensis), smallpox (variola bioterrorism attacks and antivirals for pandemic influenza is
major), plague (Yersinia pestis), botulinum toxin (Clostridium becoming a crucial public health issue. Healthcare providers need to
botulinum), and viral hemorrhagic fevers. play an active role in awareness and preparedness for biological
threats released by terrorists or nature, and the decision-making
 Many bioterrorism agents cause symptoms similar to other process regarding postexposure prophylaxis (PEP), mass vaccina-
more common infectious diseases, like seasonal influenza, and tion, and treatment of biologic exposures to help protect the public.
may be difficult to differentiate without confirmatory laboratory  Bioterrorism agents—organisms or toxins that can cause dis-
testing. ease and death in humans, animals or plants for the purpose of
 Anthrax is a highly virulent, lethal infection; human-to-human eliciting terror—have been used against civilians and military per-
transmission, however, has not been documented. sonnel for centuries. Thousands of years ago crude, but effective
methods were used for bioterrorism. Filth, human cadavers, and
 Individuals with signs and symptoms of botulism should be ad- animal carcasses were flung over city walls, poisons were dropped in
ministered a test dose prior to receiving equine antitoxin therapy. drinking wells, and contaminated clothing and blankets were offered
 Prompt initiation of appropriate empiric therapy, after cultures as gifts to cause disease and, ultimately, death to enemies. More
are obtained, is vital to decreasing the mortality rate associated recently, sophisticated methods have been utilized, such as aero-
with plague. solized technology for spraying plague and an umbrella-looking
device used to shoot ricin toxin pellets for a targeted assassination.2,3
 Emergency preparedness for those at risk and response efforts for Over the past 80 years a variety of methods to weaponize biologic
those exposed to smallpox involves mass vaccination campaigns. agents—enhance the shelf-life or dissemination properties (i.e.,
aerosolize) and/or fill munitions—have been researched.3 Approxi-
Viral hemorrhagic fever, caused by one of a variety of viruses, mately 12 countries throughout the world are believed to have active
can manifest as a febrile illness with a large range of sequela, biological weapons programs, ranging from conducting research on
including bleeding complications. the virulence of selected agents to actually weaponizing them.4
This chapter describes the natural history, symptomatology, diag-
nostic procedures, pharmacologic and nonpharmacologic treatment
The fall of 2001 forever changed how many people through out the of biological agents of highest concern that could be used in a
world felt about flying, airport security, and even opening their mail. bioterrorism attack, such as anthrax, botulinum toxin, plague, small-
Terrorism, especially bioterrorism, became a common term used by the pox, tularemia, viral hemorrhagic fevers and select Category B and C
media, military analysts, both governments and public health officials, agents. The potential consequences of infectious disease outbreaks
and the public at large. Anxiety caused by the 2001 intentional anthrax surrounding natural disasters, which rival bioterrorist events in their
release through the United States mail system, and the ensuing expo- devastating potential, are also discussed. An evidence-based approach
sures and deaths, was further escalated by numerous false alarms evaluating the various treatment options, including those for special
surrounding the delivery of parcels containing unidentified white pow- populations, is presented, when the relevant data is available. Finally,
der.1 Recent devastating natural disasters, such as tsunamis and hurri- information about the roles of healthcare providers in emergency
canes, have reawakened our appreciation of the power and destruction preparedness and response is shared.

The complete chapter,

learning objectives, and other
resources can be found at
www.pharmacotherapyonline.com.

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This page intentionally left blank
 93

12
Emergency Preparedness:
C HAP T E R Identification and Management
of Chemical and
Radiological Exposures
GREENE SHEPHERD AND RICHARD B. SCHWARTZ

cides. Larger and more concentrated quantities are found at industrial

KEY CONCEPTS sites and in their waste byproducts. Injuries from hazardous materials
are relatively common as evidenced by the tens of thousands of
 In mass casualty events with chemical or radiologic exposure, hazardous material incidents recorded by the U.S. Environmental
the majority of victims can be managed with decontamination, Protection Agency during the last decade. The majority of these
observation and supportive care. Antidotal therapies should be incidents occur during transport rather than at the site of manufacture
reserved for more critically injured victims. or use and represent a complex and significant danger for emergency
 Nerve agent poisoning is similar to organophosphate insecti- healthcare workers.1 At the other extreme, a hazardous material
cide poisoning with atropine and pralidoxime being the primary exposure may be the result of an intentional and catastrophic act of
antidotes. terrorism. Historically, acts of chemical or radiologic terrorism have
been rare but have had very high visibility and marked psychological
 Cyanide gas exposure can be rapidly fatal but most victims that
impact. Terrorism represents a profound threat to many countries
are conscious upon arrival to the hospital will not require anti-
around the world. Terrorists, whether representing foreign govern-
dote therapy.
ments, organized religious sects, or individuals, have the capacity to
 Respiratory problems caused by pulmonary agents with low endanger our communities with hazardous materials. Even a single
water solubility may take several hours to develop thus requir- patient contaminated with a hazardous material has the potential to
ing extended observation. overwhelm an unprepared healthcare facility.
 A common thread in all disasters is that community healthcare
 Vesicant chemical weapons are less lethal than other chemical
systems are severely strained by limited communication, lack of
weapons but cause significant morbidity leaving many survi-
personnel with disaster training or experience, lack of plans for
vors that need extensive care.
facility surge capacity and limited availability of medical supplies. If
 Therapeutic agents are available that can block the uptake or chemical or radiologic contamination occurs the system is strained
enhance the elimination of radioactive contamination. even further because of a lack of decontamination training and
 Clinicians, especially pharmacists need to be prepared to take an equipment at hospitals. Preplanning and early detection systems
active role in the design and operationalization of disaster plans need to be in place to facilitate early recognition of the event and the
for their workplace and community. Pharmacists may participate substances involved if the community has any likelihood of being
on established disaster response teams that may be deployed able to mount an effective response to a chemical or radiologic
to assist in the care of individuals outside of their local area. disaster. In all disasters, the normal flow of care is disrupted and the
influx of victims becomes the major focus of the healthcare commu-
nity. Preplanning for acute care needs for large numbers of patients,
Life-threatening hazardous material exposures may happen anywhere may include devising a method for expanding bed and surgical
and at any time. The exposure may be due to an unintentional release capacity as well as preparing specialized antidotes. Even if only
or at the other extreme be the result of an intentional and catastrophic minor injuries result from the event a significant portion of the
act of terrorism.1–6 A hazardous material is defined as any substance affected population will need access to critical every day medica-
that poses a substantial risk to the health or safety of individuals, or the tions, such as insulin and personal needs, such as food and shelter.
environment when improperly handled, stored, transported, or dis- This chapter discusses the major groups of hazardous materials
posed.1 The specific risks are dependent on the quantity and concen- that have been used as weapons. Chemical and radiologic events that
tration of the substance exposure and the physical, chemical, or have occurred in recent years are reviewed to provide an understand-
infectious characteristics of the material. Many of these substances ing of the scope, size, and complexity of such events. The clinical
have the potential to be used as weapons. Small quantities of hazard- presentation, mechanisms of toxicity, and relevant diagnostic
ous materials are used in many commercial products, such as pesti- approaches are discussed for each type of agent. The community and
individual preventative measures that can be taken to minimize the
risks associated with the major types of chemical and radiologic
threats are reviewed and the nonpharmacologic and pharmacologic
The complete chapter, treatment options are critically evaluated. Because controlled clinical
learning objectives, and other trial data is lacking in this area the majority of treatment recommen-
resources can be found at dations in this chapter are based on animal studies, anecdotal experi-
ence, and expert opinion. Finally, the ways in which clinicians can
www.pharmacotherapyonline.com.
actively participate in disaster planning and response at the local, state
and national level are presented.

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This page intentionally left blank
 95

SECTION 2
CARDIOVASCULAR DISORDERS

13
C HAP T E R

Cardiovascular Testing

ROBERT CHILTON AND ROBERT L. TALBERT

Every 36 seconds 1 person dies from cardiovascular disease and each

KEY CONCEPTS day about 2,500 people die in the United States. Cardiovascular
disease exceeds the next four leading causes of death combined
 A careful patient history and physical examination are extreme-
(cancer, lung disease, accidents, and diabetes).1 Another important
ly important in diagnosing cardiovascular disease and should
factor in cardiovascular disease is that greater than 60% of unex-
be done prior to any test.
pected cardiac deaths occur without prior history of heart disease
 Heart sounds and heart murmurs are important in identifying and 70% of patients having a myocardial infarction have coronary
heart valve abnormalities and other structural cardiac defects. artery blockages of about 40% to 60% (Fig. 13–1).
Cardiovascular disease affects 71,300,000 Americans, with one-
 Elevated jugular venous pressure is an important sign of heart
third being older than age 65 years based on the National Health and
failure and may be used to assess severity and response to
Nutrition Examination Survey.2 The current increase in patients older
therapy.
than age 65 years with cardiovascular disease will undoubtedly gener-
 Electrocardiography is useful for determining rhythm distur- ate a large financial burden on the economy and families. Adding to
bances (tachy- or bradyarrhythmias) and changes in ventricular the increasing burden of cardiovascular disease is information from
and atrial size. Centers for Disease Control and Prevention revealing a marked
increase in the number of patients with obesity; additionally, the
 Exercise stress testing provides important information concern- projected 2050 growth rate in both obesity and diabetes is staggering.
ing the likelihood and severity of coronary artery disease; In 1997, the percentage of patient with obesity was approximately
changes in the electrocardiogram, blood pressure, and heart 19.5% of the U.S. population, and in 2004 it was found to have
rate are used to assess the response to exercise. increased by 25% (24.3%). Along with this increase in obesity there
 Cardiac catheterization and angiography are used to assess was a 30% increase in diabetes from 5.3% to 6.9% over this same
coronary anatomy and ventricular performance. period of time.3 The rise of obesity and diabetes will undoubtedly lead
to increases in heart disease prevalence.
 Echocardiography is used to assess valve structure and func- Another area of concern in cardiovascular disease is illustrated by the
tion as well as ventricular wall motion; transesophogeal echo- Framingham Heart Study, which has followed patients for more than
cardiography is more sensitive for detecting thrombus and 40 years and found that the average annual rate of first major cardiovas-
vegetations than transthoracic echocardiography. cular events increase significantly with age. Patients ages 35 to 44 years
Radionuclides such as technetium-99m and thallium-201 are were found to have 7 major cardiovascular events per 1,000 men and to
used to assess wall motion and myocardial viability in patients increase to 68 per 1,000 men by age 85 years, a 9-fold increase.4
with coronary artery disease and heart failure. In summary, one of the most important pieces of information
that patients need to know is that lifestyle changes, that is, healthy-

Pharmacologic stress testing is used when patients cannot per- smart eating with reasonable caloric intake and frequent exercise,
form physical exercise to assess the likelihood of coronary ar- are major keys to a productive healthy life. The importance of
tery disease. lifestyle in saving lives is well illustrated from a recent study by
Chiuve et al., which studied 42,847 men in the Health Professionals
Follow-up Study (cohort) who were 40 to 75 years of age and free of
disease in 1986.5 The healthy lifestyle was defined as no smoking,
body mass index <25 kg/m2, moderate to vigorous activity >30 min/
Learning objectives, review questions, day, moderate alcohol consumption (5 to 30 g/day), and a healthy
and other resources can be found at diet score. Tracking nonfatal myocardial infarctions and fatal coro-
www.pharmacotherapyonline.com. nary heart disease using a multivariate-adjusted Cox proportional
hazards model, men complying with these five lifestyle factors had a

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
SECTION 2 96
Cardiovascular Disorders

FIGURE 13-1. Intravascular ultrasound

(IVUS) of a coronary artery. A. High-
grade obstruction which on angiogram
was thought to be only approximately
50% stenotic. B. Another coronary
artery segment with 50% stenosis but
more prone to rupture.

lower risk of coronary heart disease (relative risk: 0.13; 95% confi- tant. The clinical syndrome of angina is frequently described by
dence interval [CI]: 0.09 to 0.19) compared with men who were at patients as a discomfort from chest ache, pain, or pressure, to dull pain
low risk with no lifestyle factors. Using population-attributable risk in the jaw, back, shoulder, or either arm. Many research studies have
calculations (proportion of cases within the population that could found that family/work stress or exertion brings on increased symp-
have been avoided had all the men adhered to the low-risk lifestyle) toms of angina and rest or nitroglycerin frequently relieves it.6 Another
adherence to five lifestyle changes could prevent 62% of men from important consideration when one considers angina is that in addition
having a coronary event. If patients were taking medication for to epicardial large-vessel coronary artery disease (CAD), angina can
hypertension or hypercholesterolemia they still would have a 57% develop in patients with valvular heart disease, obstructive cardiomy-
reduction ([95% confidence interval (CI) 0.07 to 0.43]). opathies, and hypertension. Symptoms of angina can occur in patients
with noncardiac conditions such as gastrointestinal (esophageal), chest
wall, or pulmonary disease (see Chap. 17). Angina does not necessarily
THE HISTORY relate to the severity or extent of CAD obstruction. Angina that is
increasing in severity, longer in duration or occurring at rest is
A comprehensive history is the cornerstone of a cardiovascular consistent with unstable angina and should be evaluated immediately.7
workup. The value of the history depends on the clinician’s ability to Initial evaluation of chest pain requires a good history and physical
elicit relevant information. Family history is very important because examination.8,9 The quality of chest pain, its location and duration,
of the genetic links involved in many cardiovascular diseases from and factors that provoke or relieve the chest pain are important
early myocardial infarction, strokes, diabetes, valvular heart disease, elements. Rarely do patients with ischemic heart disease describe their
hypertension and familial hypercholesterolemia. The elements of a pain as sharp or stabbing. Commonly, patients state they do not have
comprehensive history include the chief complaint, present prob- chest pain but a heaviness or pressure in the chest. Ischemic chest pain
lems, past medical history, review of systems, and social history. typically lasts only a few minutes and is generally brought on by
The chief complaint needs to be narrowed down and focused if exertion or emotional stress, and is commonly relieved by rest or
possible. Usually the chief complaint/main concern is a short brief nitroglycerin. Based on the history, classify the patient’s symptoms.
statement as to the reason why the patient seeks medical care (get to the Three characteristics to consider are (a) whether the substernal chest
point). The duration of the chief complaint is important, along with discomfort has a classic quality and duration that is (b) provoked by
any prior history of the same problem, the severity of the problem, and exertion or emotional stress and (c) relieved by rest or nitroglycerin.
whether there are any limitations on the patient’s daily activities. Other If all three of these conditions are met, then the patient has classical
areas that need to be addressed are character, any types of motion or angina; if only two of these conditions exist, the pain is considered to
other things that increase or decrease the discomfort, any association be atypical or probably angina; and if none are met, it is considered to
with additional signs or symptoms, and whether the discomfort is be noncardiac chest pain. It is equally important that the patient
increasing in frequency or duration. All these and many other matters inform the healthcare professional that the discomfort the patient is
need to be considered as the clinician does the intake interview with a experiencing, which could be atypical, is the patient’s “angina equiv-
new patient. alent.” Important information when taking a history of patients with
angina is being aware of the grading of angina pectoris by the
CARDIOVASCULAR HISTORY Canadian Cardiovascular Society (see Chap. 17).
It is important in an ischemic chest to differentiate angina from
 Ischemic heart disease is the most common cardiovascular disease acute coronary syndrome. Acute coronary syndrome is more fre-
seen in clinical practice. A focus on chest pain history is very impor- quent, dramatic, and severe (see Chap. 18).
 97

CHAPTER 13
Cardiovascular Testing
FIGURE 13-2. Correlation of the elec-
trocardiogram (ECG) with an aortic
pressure tracing and heart sounds. Nor-
mal heart sounds are S1 and S2; S3 and
S4 are abnormal, as is an opening snap
(OS), which is heard with mitral steno-
sis. S1 may be split in some conditions
(M1, mitral; T1, tricuspid.)

PHYSICAL EXAMINATION HEART SOUNDS

 Auscultation with a stethoscope is used to characterize heart
The cardiovascular physical examination is divided into four categories:
sounds. Auscultation is conducted in a systematic manner to ensure
1. Global examination of the patient for signs of cardiovascular that all sites where normal and abnormal sounds are heard are
disease (CVD) and a review of all body systems. reviewed. Respiratory pattern, various maneuvers such as handgrip
and the Valsalva maneuver, sitting versus standing, and pharmaco-
2. Observation and assessment of physical findings (e.g., jugular logic agents (e.g., amyl nitrate) also may be used in the evaluation of
venous pressure). heart sounds to accentuate or diminish the intensity of these
3. Measurement of parameters of CVD function (pulse, blood sounds. Auscultation is an acquired art and requires considerable
pressure). practice to become competent.
4. Auscultation, percussion, and palpation of the chest and The normal heart sounds include S1 (first heart sound—closure
related cardiac structures. of the mitral and tricuspid valves) and S2 (second heart sound—
aortic and pulmonic valves). Normally the second heart sound
The initial part of the physical examination consists of inspection of becomes split during inspiration because of delayed closure of the
the precordium for normal patterns of rise and fall and any abnormal pulmonic valve (prolongation of right ventricle systole secondary to
markings or shape. The chest is then palpated for normal pulses, thrills an increase in venous return) or because of an inspiratory decrease
(humming vibrations like the throat of a purring cat), and heaves in impedance of the pulmonary bed.
(lifting of the chest wall). Thrills may indicate murmurs, and heaves Other sounds, such as S3 (third heart sound) and S4 (fourth heart
may indicate enlargement of one of the heart chambers or an abnormal sound) and murmurs, are not considered normal but provide
vessel such as an aneurysm. The apical pulse (also known as the point important diagnostic information. Initially, the patient is examined
of maximum impulse) is helpful to estimate heart size and rotation. This lying partially on the left side to accentuate left-sided S3 and S4 and
is usually located in the fifth intercostal space in the midsternal line and mitral murmurs, with the bell on the point of maximum impulse.
radiates in an arc of 1 to 2 cm. Heightened intensity and/or displace- To identify S1 and S2, the patient can be examined lying or sitting.
ment laterally suggests left or right ventricle enlargement, and reduced The other areas that are auscultated are the apex or base of the heart
intensity may be a sign of fluid overload or pericardial effusion. Factors (mitral sounds), the lower left sternal border (tricuspid sounds), the
such as obesity, large breasts, muscularity, and pulmonary disease can second left interspace (pulmonic sounds), and the second right
interfere with determination of the apical pulse. The carotid pulse is interspace (aortic sounds). At each of these locations, S1 and S2
examined for its intensity and, concurrently with the apical pulse, for should be heard (Fig. 13–4).
concordance within the cardiac cycle. Decreased carotid pulsations Heart sounds are characterized by location, pitch, intensity,
may be a result of reduced stroke volume or atherosclerotic narrowing duration, and timing within the cardiac cycle. High-pitched sounds
of the carotid artery. such as S1 and S2, murmurs of aortic and mitral regurgitation, and
Important physical correlations need to be carefully noted, as pericardial friction rubs are best heard with the diaphragm. The bell
shown in Figs. 13–2 and 13–3. These critical associations are basic is preferred for low-pitched sounds such as S3 and S4. S1 is heard as
facts needed to understanding the physical examination of the a click at the end of diastole and usually is synchronous with the
human heart. apical pulse. The intensity of S1 can be increased if systole begins
SECTION 2 98
Cardiovascular Disorders

FIGURE 13-3. Correlation of the electrocardiogram (ECG)

with a carotid pulse pressure tracing and heart sounds.
A split S2 is heard in some conditions (A2, aortic; P2,
pulmonic).

prior to the mitral valve closing, which may occur in high-output ventricular failure. Increased intensity of P2 is seen in pulmonary
states (e.g., exercise, tachycardia, anemia, or hyperthyroidism) and hypertension and dilated pulmonary arteries and with atrial septal
mitral valve stenosis. S1 intensity is decreased in first-degree heart defects. Decreased or absent P2 occurs with aging and in pulmonic
block, mitral regurgitation, states of reduced myocardial contractil- stenosis. Extra heart sounds in systole include early systolic ejection
ity (such as heart failure or coronary artery disease), obesity (diffi- sounds and clicks and midsystolic clicks. Early ejection sounds such
cult to hear), and systemic or pulmonary hypertension. S2 is heard as aortic or pulmonic ejection sounds often are associated with
at the end of systole and is best heard at the tricuspid and mitral valvular disease. Midsystolic to late systolic clicks usually are a result
areas. Most of the sound arises from aortic valve closure. Heart of mitral valve prolapse. Mitral valve prolapse is best heard at or
sounds may be “spilt” if the two valves do not close synchronously. medial to the apex, but also may be heard at the left lower sternal
Physiologic splitting of S1 or S2 is accentuated by inspiration and border.
may disappear with expiration. Splitting of S2 creates a pulmonic The S3 heart sound, or ventricular gallop, is an abnormal low-
(P2) and aortic (A2) sound. S2 frequently is heard as a split sound pitched sound usually heard at the apex of the heart. It is thought to
and is most predominant at the height of inspiration. Although S1 be caused by rapid filling and stretching of the left ventricle when
also may be split, this is often difficult to hear. the left ventricle is somewhat noncompliant. This heart sound is
Pathologic splitting of S2 during expiration is described as wide characteristic of volume overloading, such as in congestive heart
splitting, fixed splitting, and paradoxical splitting and may be indicative failure (especially left-sided heart failure), tricuspid or mitral valve
of both stenosis and regurgitation. With right-sided heart failure, insufficiency, and atrial and/or ventricular septal defects. A physio-
right bundle-branch block, pulmonic stenosis, or atrial septal defects, logic S3 is heard commonly in children and may persist into young
S2 may be split owing to delayed closure of the pulmonic valve. Fixed adulthood. Localization of S3 is helpful for determining heart
splitting of S2 is associated with large atrial septal defects and right rotation within the chest cavity.
The S4 diastolic sound is a dull, low-pitched postsystolic atrial
gallop (rapid blood flow) usually caused by reduced ventricular
compliance. It is best heard at the apex in the left lateral position.
Like S3, it occurs with reduced ventricular compliance and is present
in conditions such as aortic stenosis, hypertension, hypertrophic
Aortic area (base) Pulmonic area cardiomyopathies, and coronary artery disease. It is less specific for
Third left interspace
congestive heart failure than S3.
The frequency range of S3 and S4 is below 100 Hz and requires the
bell of the stethoscope to be used most of the time. This should be
Tricuspid area lightly touched to the skin to obtain the best results.
Mitral area (apex)

HEART MURMURS
Murmurs are auditory vibrations heard on auscultation, and they
occur because of turbulent blood flow within the heart chambers or
through the valves.10 They are classified by timing and duration
FIGURE 13-4. Schematic illustrations of topographic areas on the precor-
within the cardiac cycle (systolic, diastolic, and continuous), loca-
dium for cardiac auscultation. Auscultatory areas do not correspond to tion, intensity, shape (configuration or pattern), pitch (frequency),
anatomic locations of the valves but to the sites at which particular valves are quality, and radiation (Table 13–1). It is important to first note
heard best. (Redrawn from Kinney MR, Packa DR, eds. Andreoli’s Compre- where it is heard best and where it radiates for example from apex to
hensive Cardiac Care, 8th ed. St. Louis: Mosby, 1996, with permission.) left axilla. Using S1 and S2 as a marker for timing, ask yourself this
 99

TABLE 13-1 Characteristics of Heart Sounds

CHAPTER 13
Type of Murmur Examples Location Pitch Radiation Quality
Midsystolic Aortic stenosis 2nd RICS Medium Neck, left sternal border Harsh
Pulmonic stenosis 2nd and 3rd LICS Medium Left shoulder and neck Harsh
Hypertrophic cardiomyopathy 3rd and 4th LICS Medium Left sternal border to apex Harsh
Pansystolic Mitral regurgitation Apex Medium to high Left axilla Blowing
Tricuspid regurgitation Lower left sternal border Medium Right sternum, xiphoid Blowing
Ventricular septal defect 3rd, 4th, and 5th LICS High Often harsh
Diastolic Aortic regurgitation 2nd to 4th LICS High Apex Blowing
Mitral stenosis Apex Low Little or none

Cardiovascular Testing
LICS, left intercostal space; RICS, right intercostal space.

question: Does the murmur occur in systole or diastole? Next • IV — Medium intensity with a palpable thrill
carefully listen to see if the murmur completely fills that phase of the • V — Loud intensity with a palpable thrill; audible even with
systolic cycle (i.e., holosystolic), or if it has discrete start and end the stethoscope placed on the chest with the edge of the
points. Murmurs that occur after second heart sound are considered diaphragm
diastolic murmurs and most commonly relate to mitral stenosis or
• VI — Loudest intensity with a palpable thrill; audible even
aortic insufficiency; however there are many other possibilities.
with the stethoscope raised above the chest
Regurgitant murmurs for example, mitral valve insufficiency, usually
fill the entire phase, while ejection murmurs, like aortic stenosis, Multiple factors determine the grade, which includes the amount
usually have discrete beginning and end points within systole of blood ejected across a valve, severity of the lesion, and chest
(between S1 and S2). Next the shape and quality of the murmur anatomy.
should be described along with descriptive terms about the murmur, Systolic murmurs begin with or after S1 and end at or before S2,
that is, blowing, harsh, rumbling, machinery, musical, and others. depending on the origin of the murmur. They are classified based on
Some murmurs are considered innocent or physiologic and result time of onset and termination within systole: midsystolic, holosystolic
from rapid, turbulent flow of blood into the left ventricle during (pansystolic), early, or late. Some examples of pathologic midsystolic
atrial systole and through the aorta during ventricular systole. Fever, murmurs are pulmonic stenosis, aortic stenosis, and hypertrophic
anxiety, anemia, hyperthyroidism, and pregnancy exacerbate phys- cardiomyopathy. Midsystolic murmurs may include obstruction to
iologic murmurs, and these murmurs need to be distinguished from ventricular outflow (a common example is aortic stenosis; Fig. 13–5),
those suggestive of valvular abnormalities. Another important con- dilation of the aortic root or pulmonary trunk, an increased flow in
sideration is the grading of heart murmurs. The intensity or loud- the great arteries, anatomic changes in the semilunar valves, and some
ness of a murmur is graded using a scale of I to VI. Below are the forms of regurgitation. Holosystolic murmurs occur when blood
different grades. flows from a chamber of higher pressure to one of lower pressure,
such as with mitral or tricuspid regurgitation and ventricular septal
• I — Lowest intensity; difficult to hear even by expert listeners
defects. Early systolic murmurs can be decrescendo and may be
• II — Low intensity, but usually audible by all listeners associated with ventricular septal defects, mitral regurgitation, or
• III — Medium intensity; easy to hear even by inexperienced tricuspid regurgitation. A late systolic murmur preceded by one or
listeners but without a palpable thrill more midsystolic to late systolic clicks is the hallmark of mitral valve

FIGURE 13-5. Aortic valve anatomy. A near-

normal aortic valve is shown on the left and
critical stenosis is shown on the right. The
relationship of the aortic valve to coronary
artery anatomy is shown below.
 100
prolapse, which classically moves during changes in ventricular vol- PERIPHERAL CIRCULATION AND
ume. Atherosclerotic obstruction of the carotid, subclavicular, or ARTERIAL PULSES
SECTION 2

iliofemoral artery can give rise to a crescendo–decrescendo extracar-

diac systolic arterial murmur. In recent years the recognition of peripheral arterial disease (PAD) has
Early diastolic murmurs that are heard more commonly are mitral become very important because of the marked number of patients with
stenosis and aortic regurgitation. Aortic regurgitation begins with A2 asymptomatic disease. PAD affects about 8 million Americans and is
and generally is decrescendo, reflecting the progressive decline in associated with significant morbidity and mortality.11,12 PAD affects
volume and rate of regurgitant flow during diastole. Aortic regurgi- 12% to 20% of Americans age 65 years and older. Despite its preva-
tation is best heard by having the patient lean forward while holding lence and cardiovascular risk implications, only 25% of PAD patients
his or her breath and listening with the diaphragm along the mid left are undergoing treatment.13 Approximately 40% do not complain of
Cardiovascular Disorders

sternal border. Pulmonary hypertension (Graham Steell murmur: an leg pain and only approximately 10% of persons with PAD have the
early diastolic murmur caused by pulmonary insufficiency secondary classic symptoms of intermittent claudication (see Chap. 24).
to pulmonary hypertension) also may cause an early diastolic mur- It includes a variety of arterial syndromes (noncoronary artery)
mur. Middiastolic murmurs occur across the atrioventricular valves that are caused by pathobiologic changes of the arteries that supply
(mitral or tricuspid) during rapid filling and are consistent with the brain, visceral organs, and the limbs. Terminology is also impor-
mitral stenosis or mitral stenosis along with a ventricular septal tant in discussing this area of arterial disease. Peripheral arterial
defect or tricuspid regurgitation with an atrial septal defect. The disease includes an assorted group of disorders that lead to progres-
Austin Flint murmur is a consequence of blood jets from the aortic sive stenosis or occlusion, or aneurysmal dilation, of the aorta and its
regurgitation hitting the anterior leaflet of the mitral valve, leading to noncoronary branch arteries, including the carotid, upper extremity,
a middiastolic, low-pitched rumbling best heard at the cardiac apex visceral, and lower extremity arterial branches. PAD is the preferred
that results in early mitral valve closure because of simultaneous clinical term that should be used to denote stenotic, occlusive, and
rapid left ventricular filling (volume overload) from aortic regurgita- aneurysmal diseases of the aorta and its branch arteries, exclusive of
tion. Continuous murmurs begin in systole and continue without the coronary arteries. Peripheral vascular disease includes pathophys-
interruption into all or part of diastole. Such murmurs are mainly a iologic syndromes that affect the arterial, venous, and lymphatic
result of aortopulmonary connections (e.g., patent ductus arterio- circulations.
sus), arteriovenous connections (e.g., arteriovenous fistula, coronary Current American College of Cardiologists/American Heart Asso-
artery fistula), and disturbances of flow patterns in arteries or veins. ciation (ACC/AHA) guidelines11 for the management of peripheral
Anatomic correlation of murmurs may require cardiac catheteriza- artery disease recommend a vascular history and physical examina-
tion or echocardiography with Doppler, where direct visualization of tion (class I) for patients who are at risk for lower extremity PAD, age
the blood flow abnormality and calculation of flow and chamber less than 50 years with diabetes and one other atherosclerosis risk
pressures can be obtained. In special cases the use of positron factor (smoking, dyslipidemia, hypertension, or hyperhomocys-
emission tomography (PET) and magnetic resonance imaging (MRI) teinemia), age 50 to 69 years and a history of smoking or diabetes,
are also possible options to evaluate flow patterns and gradients of age 70 years and older, ischemic leg symptoms with exertion (inter-
murmurs across heart valves. mittent claudication) or ischemic rest pain, abnormal lower extrem-
ity pulse examination, or known atherosclerotic coronary, carotid, or
JUGULAR VENOUS PRESSURE renal artery disease. They also recommend that patients older than
50 years of age should be asked if they have a family history of a first-
 The jugular venous pressure (JVP) is used as an indirect measure degree relative with an abdominal aortic aneurysm.
of right atrial pressure.10 The JVP is measured in centimeters from One of the most important tests that can be easily done in patients
the sternal angle and is best visualized with the patient’s head rotated suspected of PAD is to do an ankle–brachial index. An ankle–brachial
to the left. The JVP is described for its quality and character, effects of index of <0.90 is 90% sensitive and 95% specific for PAD. Severe PAD
respiration, and patient position-induced changes. When reporting a causing rest pain or ulceration generally occurs with ankle–brachial
JVP, both the extent of elevation and the patient position must be indices of <0.40. This is easily calculated by measuring the systolic
reported. The JVP can be reported as centimeters above the manu- blood pressure in the ankle and dividing it by the systolic blood
brium, or this value plus 5 to 7 cm to indicate the rise of the JVP pressure in the arm (brachial). Normally the lower extremity blood
above the right ventricle. For persons in whom the central venous pressure is higher than the arm. To appreciate the significance of
pressure is normal, JVP is observed in the right internal jugular vein PAD, one only needs to recognize that over a 5-year period in patients
with the patient supine at 30° or less. In the presence of an elevated with PAD the mortality is 30%.14
central venous pressure, the JVP is measured at 60 to 90°. In patients Arterial pulses are evaluated and characterized bilaterally by
with poor myocardial function, the accuracy of the JVP as a measure observation, palpation, and auscultation for presence, character,
of central venous pressure is reduced, and central venous pressure is pattern, and rhythm. Various arterial pulse patterns are described:
best measured directly by means of a Swan-Ganz catheter. pulsus alternans (variation in amplitude beat to beat), bisferiens
The normal JVP is a v wave 1 to 2 cm above the sternal ridge. pulse (increased arterial pulse with a double systolic peak), bigemi-
Elevation in JVP more than halfway to the jaw angle are elevated. Both nal pulse (reduced amplitude associated with premature ventricular
the degree of elevation of the JVP and its wave flow in conjunction beats), and paradoxical pulse (decrease in amplitude with inspira-
with the heartbeat are noted. The first wave, or a wave, represents atrial tion). Although each may be associated with certain disorders (e.g.,
contraction and occurs just prior to S1, giving rise to increased bigeminal pulse in premature ventricular contractions), none is
pressure. It is seen as an undulating pulsation in the internal jugular sensitive or specific enough to be diagnostic. The status of the
vein. The second and much larger wave, the v wave, represents the patient’s overall peripheral circulation is recorded, especially the
increased venous pressure that occurs during venous filling. To inter- presence and degree of edema or skin changes suggestive of venous
pret the JVP accurately, the carotid pulse is palpated concurrently. The or arterial insufficiency. Color, condition, and integrity of the skin
a wave occurs just before the pulse and the v wave just after. Jugular are also recorded, including signs of thrombophlebitis, tenderness,
venous pressure is often elevated in heart failure, and the degree of or swelling. Capillary refill (normal less than 2 seconds) is assessed
elevation can be used to assess the severity of heart failure, and by depressing the nail bed until it blanches and then releasing
diminution of JVP can be used to assess therapy. pressure and watching for the return of color, indicating blood flow.
 101

HEART RATE heart and chambers and surrounding anatomy. The standard chest
radiographs for evaluation of lungs and heart are standing postero-

CHAPTER 13
Heart rate is described by both rate and rhythm. The arterial pulse anterior and lateral views taken at maximal inspiration. Portable
usually is taken at the radius, but carotid or other arterial pulses may chest radiographs usually are less satisfactory because of penetration
be used. In healthy individuals, the heart rate is usually assessed by difficulties, patient rotation, and poor inspiratory effort.
counting the pulse for 15 seconds and multiplying by 4. In patients Initial assessment of the chest radiograph evaluates the quality of
with irregular rhythms, the pulse should be taken over an extended the film for patient rotation, inspiratory effort, and penetration.
period, approximately 1 to 2 minutes, to try to determine the Rotation is assessed by evaluating symmetry of the clavicles and
patient’s average pulse and rhythm. central placement of the carina. Inspiratory effect is considered
Arterial pulses are an accurate measure of the ventricular rate in adequate if the diaphragms are pulled below the ninth rib. Lack of

Cardiovascular Testing
healthy persons with good ventricular function. In patients with a inspiratory effort and obesity lead to a poor-quality chest radio-
rapid ventricular rate—because of supraventricular tachyarrhythmias graph, which makes it more difficult to assess the presence of pleural
such as atrial flutter or fibrillation or rapid ventricular rates (e.g., effusions and fluid in the costophrenic angles. Where possible,
ventricular tachycardia or premature ventricular beats)—extremity comparison with previous or baseline films is done to determine the
pulses (e.g., radial pulse) may be considerably slower than the true quality of film and comparison of structures.
ventricular rate. A more accurate ventricular rate is determined by The posteroanterior view chest radiograph outlines the superior vena
listening to the ventricles with the stethoscope (usually at the apex) or cava, right atrium on the right and left sides, aortic knob, main
counting from an electrocardiogram (ECG). In patients with atrial pulmonary artery, left atrial appendage (especially if enlarged), and left
fibrillation and a fast ventricular rate, a pulse deficit (measure of the ventricle. In the lateral view, the chest radiograph visualizes the right
difference in true ventricular rate and peripheral pulse rate) may exist. ventricle, inferior vena cava, and left ventricle. These structures are
This may be as much as 10 to 20 beats per minute. Consequently, the visualized as shadows of differing density rather than discrete structures.
location of the pulse (radial or apical) should be recorded. The pulse The chest radiograph is approached from two perspectives: (a) obser-
deficit will be reduced as the ventricular rate is controlled with drug vation and (b) clinical correlation. Observation notes gross anatomic
therapy or normal sinus rhythm is restored. features such as size and placement of the cardiac silhouette, defini-
tion of the cardiac border, chamber enlargement, pulmonary vascu-
lature, air–fluid levels, and diaphragm. Cardiac enlargement is
PRACTICE GUIDELINES FOR DIAGNOSTIC determined by the cardiothoracic ratio, which is the maximal trans-
AND PROGNOSTIC TESTING IN verse diameter of the heart divided by the maximal transverse diame-
CARDIOVASCULAR DISEASE TESTING ter of the thorax of a posteroanterior view. Normal averages 0.45, but
it may be up to 0.55 in subjects with large stroke volumes (e.g., highly
The American Heart Association (AHA) and American College of trained athletes). Heart conditions, such as heart failure and hyper-
Cardiology (ACC) task force on practice guidelines publishes guide- tension, may enlarge the heart and so the cardiothoracic ratio.
lines as to the recommended uses for many diagnostic testing Individual chamber enlargement can be seen on the chest radiograph.
methods. Such guidelines were first developed in the 1980s and are Right ventricle enlargement is best seen on the lateral film, where the
updated as more information is available. These are evidence-based heart appears to occupy the retrosternal space. Left atrial enlargement
recommendations that rank the indications and uses of tests into is suspected if there is elevation of the left bronchus or an increase in
three primary classes. Class I indications are those where there is the atrial appendage bulge. Left ventricular enlargement is the most
evidence or agreement that the specific procedure is useful and common feature identified on chest radiograph and is seen as an
effective. Class II indications are those situations where there is elongation and downward displacement of the apex of the heart.
divergence of opinion as to the usefulness of the method. Class III Sometimes a characteristic “boot” or “water bottle” outline is seen
indications are those where there is evidence or agreement that a with left ventricular enlargement, as in heart failure.
diagnostic test is not useful. Each class (usually class II) may be The pulmonary vessels are examined for plumpness and definition
broken down into two or three subcategories. Class IIa indications of vessel walls. Decreased pulmonary flow (e.g., tetralogy of Fallot)
are those where there is evidence or opinion in favor of the test, causes central and peripheral vessels to be decreased in size. Increased
whereas class IIb indications are those where there is less evidence pulmonary flow is associated with high-output states such as hyperthy-
favoring the test. With each class of recommendation for a specific roidism and atrial septal defects. This may lead to enlargement and
clinical scenario, the guidelines indicate the level of evidence for the tortuosity of the central and peripheral vessels. Pulmonary arterial
recommendation. Level A evidence is given if the recommendation hypertension (increased pulmonary resistance) is identified by enlarge-
is based on the availability of multiple randomized clinical trials. ment of the central vessels and diminished peripheral vessels. Pulmo-
Level B evidence is given if only a single randomized trial or nary venous hypertension usually is caused by mitral stenosis or left
multiple nonrandomized trials exist. Level C evidence is given if the ventricular failure. This is characterized by larger-than-normal vessels
recommendation is afforded based on expert opinion only. in the upper lung zones owing to recruitment of upper vessels from
Each guideline provides a preamble to indicate how it was con- blood diverted from the lower constricted vessels (cephalization of
structed and the peer review process. These documents provide the flow).
clinician with an extensive database on the testing methodologies and Heart failure causes Kerley B lines (edema of interlobular septa),
are endorsed by both organizations as acceptable standards of practice. which appear as thin, horizontal reticular lines in the costophrenic
angles. At higher pressures, alveolar edema and pleural effusions appear
TESTING MODALITIES in the pleural space or as blunting of the costophrenic angles. Pericar-
dial effusions also may appear as a large heart, but because it usually
CHEST RADIOGRAPHY occurs rapidly, there is no evidence of pulmonary venous congestion.

The chest radiograph provides supplemental information to the ELECTROCARDIOGRAM

physical examination and is usually the first diagnostic test in a
cardiac workup. It does not provide details of internal cardiac  Measurement of electrical activity in the heart, now known as the
structures but gives global information about position and size of the ECG, was introduced about 75 years ago by Willem Einthoven. The
 102

TABLE 13-2 Drugs That May Affect the Electrocardiogram aVL

SECTION 2

Digoxin Pentamidine aVR

Antiarrhythmics—classes I–IV Lithium
Tricyclic antidepressants Catecholamines (e.g., dopamine, albuterol)
H1 antagonists Diuretics (electrolyte abnormalities)
Methylxanthines
Doxorubicin
I

ECG is simple to perform and is the most frequently used, least

Cardiovascular Disorders

invasive, and cheapest cardiovascular test.15,16 It remains the proce-

dure of first choice for evaluation of chest pain, dizziness, or
syncope. In its simplest interpretation, the ECG characterizes aVF
rhythms and conduction abnormalities. However, the ECG also
provides, by inference, information about the anatomy and struc-
tures of the heart, pathophysiologic changes, and hemodynamics of
the CVD system.17 ECG abnormalities are often the earliest sign of III II
adverse drug effects, ischemia, and electrolyte abnormalities.
Although few ECG recordings are highly specific or sensitive to a
disease state, correlation of findings with clinical and pathologic
states affords the ECG significant diagnostic and prognostic capabil-
ities. Sensitivity and specificity of ECG changes depend primarily on
the clinical setting, recording technique, and skill of interpreters.
Sensitivity and specificity of findings are increased by interpretation FIGURE 13-6. The torso with the six limb leads in a single frontal plane.
in conjunction with patient information such as age, gender, medical
history, and medications. Additionally, prior and/or serial ECGs
should be obtained for comparison prior to identifying new findings to 0.12 second, and it has an amplitude of 0.25 mV (i.e., 2.5 small
on a current ECG as diagnostic. This is particularly important in boxes). The PR segment is created by passage of the impulse through
patients with significant cardiac disease or on medications that alter the atrioventricular node and the bundle of His and its branches,
the ECG (Table 13–2). The ECG is sensitive in detecting rhythm and it has a duration of 0.12 to 0.21 second. The QRS complex
abnormalities, but it does not record the actual activity of the primarily traces the electrical depolarization of the ventricles. Ini-
conduction tissue.18,19 tially, there is a negative deflection, the Q wave, followed by a
The ECG can be used to evaluate ischemia following angioplasty positive deflection, the R wave, and finally a negative deflection, the
or other surgical interventions and to monitor responses to antiar- S wave. Q-wave duration is normally 0.4 second or less, and the
rhythmic agents or in patients receiving drugs with potential cardiac amplitude is 25% or less of the overall height of the QRS complex.
effects. Normal duration of the QRS complex is 0.12 second. The QRS
Electrocardiography is based on the measurement of change in complex is positive in left-sided leads and negative in right-sided
summated three-dimensional electrical vectors or forces that result leads because the left ventricle is much thicker than the right, and
from depolarization and repolarization of cells in the conduction the forces going left during depolarization dominate.
system and heart muscle. The standard external 12-lead ECG uses Following the QRS complex is a plateau phase called the ST
two sets of leads: limb and chest (Fig. 13–6). The six limb leads look segment, which extends from the end of the QRS complex (called the
at the heart in a single frontal plane. Limb lead nomenclature is as J point) to the beginning of the T wave. The ST segment is evaluated
follows: lead I, right arm/left arm; lead II, right arm/left leg; lead III, from its position relevant to the baseline, configuration, and leads
left arm/left leg. Altering resistances create the augmented limb where changes occur. The ST segment is normally on or slightly
leads, which are called aVR, aVL, and aVF. Unipolar chest leads are above the baseline. Configuration changes, convexity upward or
positioned across the chest and labeled V1 to V6. V1 is positioned downward, identify the presence of myocardial ischemia. Lead
slightly to the right of the midline, and V6 is positioned in the left localization of ST-segment changes indicates the area of ischemia.
midaxillary line (Fig. 13–7). Leads aVR and V1 are considered right- The QT interval is measured from the start of the QRS complex to
sided leads, so they appear inverted, and leads aVL, I, II, V5 and V6 the end of the T wave. This varies with heart rate and is corrected
are left-sided leads, so they appear upright on the ECG. Leads II, III, (QTc) for heart rates greater than 60 beats per minute. The normal
and aVF are inferior leads. Leads V1 to V4 are anterior wall leads. QTc is less than 0.42 second in men and 0.43 second in women.
Single-lead ECGs or ECG monitors frequently use lead II. Repolarization of the ventricle leads to the T wave. The T wave
Recording of the ECG has several standard features. The paper is usually goes in the same direction as the QRS complex. The normal
divided into squares of 1 mm; each 10 mm (10 small boxes) is axis of the ECG is 30° (above the horizontal) to +110° (away from
equivalent to 1 mV. Paper speed is 25 mm per second. Each small the horizontal) (see Fig. 13–7). The six frontal plane (A) and the six
box on the tracing paper equals 0.04 second (40 milliseconds), and horizontal plane (B) leads provide a three-dimensional representa-
each big box is 0.2 second. If there is one QRS complex per six big tion of cardiac electrical activity.
boxes (6 × 0.20 second), the patient has a heart rate of 50 beats per The ECG is evaluated in a systematic manner to avoid omission
minute, whereas one QRS per big box indicates a heart rate of 300 of important characteristics. All ECGs are interpreted for the fol-
beats per minute. lowing elements: rate, general rhythm, intervals, voltage, axis, wave-
The ECG pattern is named alphabetically and is read from left to forms, abnormal features (e.g., Q waves), and technical aspects such
right, beginning with the P wave. Electrical activation (depolariza- as adequacy of lead placement and calibration.20 The number of P
tion) of the right and then the left atrium as a result of discharge waves and QRS complexes (RR interval) is also used to determine
from the sinoatrial nodes causes an upward or positive deflection in rate. QRS complexes may be more useful if heart block exists. The
lead II called the P wave. The normal duration of the P wave is up rhythm from the ECG is identified by the following features:
 103

A B

CHAPTER 13
Posterior

Right Left

+V
6

MCL

Cardiovascular Testing
+V
5

+V
+V +V +V 4
1 2 3

Anterior

V1 V2
V3
V4 V5 V6

FIGURE 13-7. A. Electrode positions of the precordial leads. (MCL, midclavicular line; V1, fourth intercostal space at the
right sternal border; V2, fourth intercostal space at the left sternal border; V3, halfway between V2 and V4; V4, fifth intercostal
space at the midclavicular line; V5, anterior axillary line directly lateral to V4; V6, anterior axillary space directly lateral V5.)
B. The precordial reference figure. Leads V1 and V2 are called right-sided precordial leads; leads V3 and V4, midprecordial
leads; and leads V5 and V6, left-sided precordial leads. (Redrawn from Kinney MR, Packa DR, eds. Andreoli’s
Comprehensive Cardiac Care, 8th ed. St. Louis: Mosby, 1996, with permission.)

1. The rate of the QRS (>100/min is tachycardia and <60/min is cardiac cycle. Gating is either prospective, where a certain portion
bradycardia). of the cardiac cycle is predetermined as the time during which the
2. The regularity of the QRS. (The presence or absence of the images are obtained, or retrospective, where the ECG and image are
QRS complex with each P wave helps to identify if the rhythm recorded simultaneously but independently and later matched for
is atrial or ventricular in origin and if each atrial beat [P wave] concurrent events. This allows multiple cardiac cycles to be over-
is being conducted to the ventricles. The regularity of the QRS laid, thus increasing the sensitivity to detect abnormalities.
identifies conditions such as atrial fibrillation and extra beats.) Anomalies on the ECG include abnormal intervals, altered wave-
form configurations, and rate variability. Other findings give evidence
3. Configuration of the QRS—wide or narrow—indicating if it is
for various forms of heart block, ischemia, infarction, atrial and
generated from electrical activity that arose in the atria or
ventricular enlargement and hypertrophy, atrial and ventricular
ventricles.
rhythm disorders, pericarditis, metabolic abnormalities, drug-induced
Always reported are the RR, PR, QRS, and QT intervals and the changes, and pacemaker-related changes. ECG patterns found on
duration, magnitude, and configuration of the P waves, QRS com- consecutive leads can help to identify where a particular conduction
plexes, ST segments, T waves, and U waves.21 Computer interpreta- defect or impulse generation is occurring or anatomic problem is
tion of the ECG provides a standardized reading and records and located. For example, ST-segment elevation in V2 to V6 is indicative of
calculates basic rhythm patterns, heart rate, and intervals but does not anterior wall myocardial infarction from occlusion of the left anterior
interpret arrhythmias. Independent review of the ECG is necessary descending coronary artery. Single-lead abnormalities most frequently
for accurate translation of findings. In epidemiologic studies, the ECG are attributed to poor lead placement, position of the patient, or
is used to assess physical fitness, document the prevalence of ischemic recording artifacts.22
heart disease (IHD), and identify subclinical heart disease. The sensi- Examples of some common findings will be discussed briefly. Short
tivity and specificity of ECG changes are highly dependent on the PR intervals are associated with the Wolff-Parkinson-White and
pretest probability of heart disease. As the pretest probability of heart Lown-Ganong-Levine syndromes and reflect the presence of acces-
disease increases, the sensitivity and specificity of ECG findings sory pathways. Long PR intervals are measures of heart block. The
increase. The use and value of the ECG as a screening tool are presence of a Q wave is a marker for loss of electrically functioning
controversial. It is only used where the diagnosis of heart disease myocardium and suggests a prior myocardial infarction. It also may
would preclude active employment, such as in airline pilots. The ECG be present in congenital heart disorders, hypertrophic cardiomyopa-
frequently is used in conjunction with other diagnostic tests to thy, left ventricular hypertrophy, conduction defects such as Wolff-
provide additional data, to monitor the patient, and to identify if Parkinson-White syndrome, and intraventricular conduction defects.
abnormalities detected during tests correlate with ECG changes.20–22 U waves are relatively nonspecific, the most common cause being
Gating, or linkage of and simultaneous recording of an ECG and hypertension. Bundle-branch blocks are frequent findings and indi-
other diagnostic tests, such as echocardiography and computed cate conduction defects in one of the bundles of His. Their presence
tomography (CT) scans, allow for correlation of images with the confounds the interpretation of important ECG findings such as
 104
ischemia. Right bundle-branch block is associated with an R wave and making voltage criteria a less useful tool to identify hypertrophy.
the following abnormalities: QRS complex greater than or equal to 12 LVH also may be assessed using echocardiography.
SECTION 2

milliseconds, delayed right ventricular forces resulting in terminal R Electrolyte abnormalities have characteristic signs on the ECG and
waves in the right-sided leads and S wave in the left-sided lead, and can be used as monitoring parameters. Hypokalemia may increase
right-sided ST-segment depression and T-wave inversion. Left bundle- ventricular ectopic beats and causes ST-segment depression, T-wave
branch block is characterized by the following: QRS complex greater flattening, and the appearance of a U wave (usually when the serum
than or equal to 12 milliseconds, delayed left ventricular activation, potassium concentration is less than 3.0 mEq/L). Hyperkalemia results
loss of the normal “septal Q wave” in the left-sided leads, and left- in very characteristic changes in the ECG. Potassium concentrations
sided ST-segment depression and T-wave inversion. Intraventricular above 6.0 mEq/L produce tall, peaked T waves. As the concentration
conduction delay usually causes a wide QRS complex, and generally rises further, intraventricular conduction becomes blocked, with wid-
Cardiovascular Disorders

there are ST-segment–T-wave abnormalities. ening of the QRS complex, and ultimately, a sine wave develops.
Myocardial ischemia, ranging from injury to necrosis, results in T- Hypercalcemia causes a short QT interval and, occasionally, ST-
wave changes, ST-segment abnormalities, and changes in the QRS segment depression, sinus arrest, and atrioventricular conduction
complex. Myocardial infarction results in a typical pattern of ECG blocks. Hypocalcemia causes a long QT interval and some broadening
changes that begins with tall, peaked T waves persisting up to several of the T wave. A number of drugs cause characteristic changes in the
hours, followed by ST-segment elevation with a coved (convexity ECG that may mask interpretation of other findings. Table 13–2 lists
upward) configuration, and inverted T waves. Development of a new commonly used drugs that may alter the ECG. Pericardial effusion,
Q wave has a high specificity but low sensitivity for acute myocardial obesity, and large breasts limit the amount of voltage that is measured
ischemia. Q waves that are 4 milliseconds or longer in duration and on the skin surface and reduce the QRS voltage. In the presence of
25% or greater of the overall QRS height are considered diagnostic large pericardial effusions, rapid changes in the positive to negative
and occur within minutes to hours of occlusion. Although Q waves deflection of the QRS complex or electrical alternans may occur
usually evolve within hours of infarction, they may not become because the heart is swinging on a beat-to-beat basis.
evident for several days. The finding of new and significant Q waves Signal-averaged ECG may be used to help elucidate the presence
on an ECG is indicative of a previous infarction. Q waves persist of low-amplitude bioelectrical potentials.23 Derangements of ven-
indefinitely in 80% to 90% of myocardial infarctions. The location of tricular activation and late potentials can be detected on the ECG
Q waves identifies the region of myocardium affected and the after the QRS and ST segments and are thought to be associated
coronary artery blocked (e.g., inferior infarction will result in Q with increased risk of ventricular arrhythmias. Traditional ECGs are
waves in II, III, and aVF associated with blockage in the right unable to detect these potentials because they are “lost” in the noise
coronary artery). Non–Q-wave (subendocardial) myocardial infarc- of the ECG recording. Signal-averaged ECG improves the signal-to-
tion implies that the Q wave does not meet the diagnostic criteria for noise ratio, enabling the low-amplitude potentials to be interpreted.
Q-wave infarction. ST-segment depression may be present. Signal-averaged ECG can be used to identify patients at risk for
ST-segment changes are very common and always should be developing sustained ventricular tachycardia after myocardial
compared with a previous ECG. ST-segment elevation may be seen infarction. Patients with IHD and unexplained syncope who are at
in persons with no known coronary disease but is usually indicative risk for sustained ventricular tachycardia also may be candidates for
of hyperacute ischemia. ST-segment depression is never considered signal-averaged ECG. Other potential uses of signal-averaged ECG
a normal finding. ST-segment scooping (convexity downward) may include patients with nonischemic cardiomyopathy with sustained
be normal, but coving (convexity upward) is abnormal. Depression ventricular tachycardia, detection of acute rejection of heart trans-
of the ST segment that does not return quickly to normal and plant, and assessment of the proarrhythmia potential of antiar-
changes in multiple leads suggests clinically significant heart disease. rhythmic drug therapy.
Diffuse ST-segment elevation in all leads except V1 and aVR
suggests the diagnosis of pericarditis. Exertion in normal individu- AMBULATORY ELECTROCARDIOGRAM
als may cause J-point depression with a rapid rise of the ST segment, MONITORING
and this may be confused with ST-segment depression because of
the configuration. Poor R-wave progression (usually increase in size Ambulatory ECG monitoring (AECG), or Holter monitoring,
moving from V1 to V6) suggests anterior myocardial infarction, but named for its inventor, is an aid to detect, document, characterize,
smaller R waves also can occur in diseases such as chronic obstruc- and evaluate arrhythmias and other ECG abnormalities over
tive pulmonary disease. T-wave changes are the most frequent and extended periods of time.24,25 AECG provides information regarding
most sensitive abnormality on the ECG but are also the least specific random abnormal cardiac electrical activity during daily activity and
and frequently are found in persons with no heart disease. helps relate altered electrical activity to precipitating factors and
Left atrial enlargement is characterized by a P wave that is ≥12 mV patient symptomatology. algorithms. AECG also helps in the discov-
in lead II, or the negative component of the biphasic P wave is 4 mV ery and investigation of arrhythmias and ST-segment deviation
in duration and 0.1 mV in depth in lead V1. In right atrial enlarge- along with more sophisticated analyses of R-R intervals, QRS-T
ment, the P wave in lead II can exceed 0.25 mV and usually has a morphology including late potentials, Q-T dispersion, and T-wave
vertical axis. Ventricular hypertrophy results in increased deflection alternans. Additionally, some findings on AECG have been used to
of the QRS complex because of the increased muscle mass. Left determine prognostic implications. Different types of recording
ventricular hypertrophy (LVH) is diagnosed from the ECG using systems are discussed later in this chapter in the Echocardiogram
several different sets of criteria; none are considered highly sensitive section: one version is noninvasive, which can be patient activated
or specific. LVH often is indicative of hypertension and resulting and varies in duration of recording from hours to days, and the other
ventricular enlargement and strain. Commonly used voltage criteria version is invasive, which can be implanted like a pacemaker and
indicating LVH are summation of the S wave in V1 and the R wave removed later and can record for years. Most of the current new
in V5 or the S wave in V2 and the R wave in V6 that exceeds 3.5 mV recording systems are digital (recommended guidelines by AHA/
(35 small boxes) or the R wave in lead aVL that exceeds 1.1 mV (11 ACC) and have a diagnostic frequency response range for more
small boxes). Right ventricular hypertrophy is characterized by an R accurate investigation of ST-segment deviations.
wave in V1 that is equal to or greater than the S wave in that lead. In Although controversial, AECG is used as a diagnostic and screen-
persons who are obese, increased voltage may not be apparent, ing tool for asymptomatic ischemia. It is difficult to interpret
 105
changes in the ST segment recorded during AECG owing to ampli- TABLE 13-4 Indications for Ambulatory Electrocardiogram
tude, and definitions of significant changes recorded with AECG are

CHAPTER 13
Arrhythmia Detection to Assess Risk for Future
still in evolution. As a prognostic tool, it is used primarily to evaluate Cardiac Events in Patients without Symptoms
patients with known CVD who have symptoms that may be associ- from Arrhythmia
ated with an arrhythmia. It is also used in clinical trials to evaluate
Class I
the efficacy of drug therapy.26
None
Guidelines as to the recommended uses of AECG are available Class IIb
from AHA/ACC. The major class I indications for AECG include 1. Post-myocardial infarction patients with left ventricular dysfunction (ejection
diagnosis in patients with symptoms suggestive of arrhythmias, fraction <40%)
prognostic delineation in patients with cardiac disease considered at 2. Patients with congestive heart failure

Cardiovascular Testing
risk for arrhythmia-related events, and measurement of efficacy of 3. Patients with idiopathic hypertrophic cardiomyopathy
interventions in patients with known and characterized arrhyth- Class III
mias. Examples of indications and clinical rhythm disturbances are 1. Patients who have sustained myocardial contusion
listed in Tables 13–3, 13–4, and 13–5. 2. Systemic hypertensive patients with left ventricular hypertrophy
A major limitation of AECG is the amount of data collected with 3. Post-myocardial infarction patients with normal left ventricular function
4. Preoperative arrhythmia evaluation of patients for noncardiac surgery
ECG abnormalities that are of unknown clinical significance. High
5. Patients with sleep apnea
day-to-day variability of frequency and type of arrhythmias means 6. Patients with valvular heart disease
that repeat AECG may demonstrate as much as a 90% difference in
the number of premature ventricular contractions. Little correlation Adapted from AHA/ACC guidelines.
of arrhythmia suppression and clinical outcomes is available. No
AECG study has shown a mortality advantage when used in conjunc- intermittent recorders, which continuously monitor the ECG but
tion with antiarrhythmic drugs or devices. Following an intervention only record preprogrammed abnormal ECG events or are patient-
(drugs or device), at least a 63% to 95% reduction in arrhythmia activated based on occurrence of symptoms, and (c) real-time analyt-
frequency is required for AECG to be considered a valuable arrhyth- ical recorders, which record throughout the monitoring period and
mia detection and evaluation tool. Compared with electrophysiology analyze each beat as it occurs. Monitors digitize, encode, and store
testing in the Electrophysiologic Study Versus Electrocardiographic the information in a solid-state memory or on magnetic tape. Event
Monitoring (ESVEM) study, AECG was equivalent but not superior monitors are preprogrammed to record parameters such as the
to electrophysiology testing in the ability to select initial drug number of premature ventricular contractions and heart rate. During
therapy.22 The Asymptomatic Cardiac Ischemia Pilot (ACIP) study monitoring, the patient maintains a diary, in which the occurrence,
found that 75% of patients with asymptomatic evidence of ischemia duration, and severity of symptoms (e.g., light-headedness, chest
on AECG had multivessel coronary artery disease on angiography.26 pain) are recorded, plus any specific activities undertaken, develop-
During AECG, the patient wears a portable ECG recorder that ment of symptoms with the activity, and any interventions such as
weighs about 8 to 16 oz. The recorder uses two to four chest leads the taking of medication. A clocking device in the recorder allows
(V5 and V3 most commonly). Additional leads do not improve the later correlation of the patient’s diary with the recorded ECG.
sensitivity of AECG significantly. If ST-segment changes are known Evaluation and analysis of the ECG record are complex. Com-
to occur in certain leads, these can be used during AECG. Most puter-assisted interpretation is used to scan the ECG and identify
AECG recordings are for 24 to 48 hours, but they can extend to irregular rhythms, rates, and specific preprogrammed changes. The
weeks or months where the frequency of events related to ECG main advantage of computer analysis is to reduce interpretation of
abnormalities is low. Implantable devices are used when long artifact recordings. Each beat recorded during AECG is evaluated
periods of monitoring are necessary. Currently used equipment is for its arrhythmia potential and classified as normal or abnormal.
able to detect and analyze arrhythmias, ST-segment deviations, QRS The morphology of each QRS-T section is examined for ischemia
complexes, RR intervals, and late potentials. potential, although, as indicated previously, baseline ST-segment
Three types of monitors are available: (a) continuous monitors, abnormalities and adjustments in amplitude of the recording may
which record an ECG strip over the duration of the test, (b) event or preclude interpretation of these segments. The ACC/AHA guide-
lines provide detail as to the suitability of using ST segments for
analysis of ischemia.27 Various drugs, such as digoxin and the
TABLE 13-3 Indications for Ambulatory Electrocardiogram tricyclic antidepressants that cause baseline ECG abnormalities,
Monitoring to Assess Symptoms Possibly Related to may preclude patients from being evaluated with AECG.
Rhythm Disturbances Sections identified by the computer as abnormal or those corre-
Class I lating with patient symptoms are then evaluated and characterized
Patients with unexplained syncope, near syncope, or episodic dizziness in whom
the cause is not obvious
TABLE 13-5 Indication for Ambulatory Electrocardiogram
Patients with unexplained recurrent palpitation
Class IIb
Monitoring for Ischemia
Patients with episodic shortness of breath, chest pain, or fatigue that is not Class I
otherwise explained None
Patients with neurologic events when transient atrial fibrillation or flutter is Class IIa
suspected 1. Patients with suspected variant angina
Patients with symptoms such as syncope, near syncope, episodic dizziness, or Class IIb
palpitation in whom a probable cause other than an arrhythmia has been 1. Evaluation of patients with chest pain who cannot exercise
identified but in whom symptoms persist despite treatment of this other cause 2. Preoperative evaluation for vascular surgery of patients who cannot exercise
Class III 3. Patients with known coronary artery disease and atypical chest pain syndrome
Patients with symptoms such as syncope, near syncope, episodic dizziness, or Class III
palpitation in whom other causes have been identified by history, physical 1. Initial evaluation of patients with chest pain who are able to exercise
examination, or laboratory tests 2. Routine screening of asymptomatic subjects
Patients with cerebrovascular accidents, without other evidence of arrhythmia
Adapted from AHA/ACC guidelines.
 106

TABLE 13-6 Confounding Factors in Ambulatory capacity can be obtained by directly measuring the oxygen con-
Electrocardiogram Monitoring sumption but this is not routinely available because of complexity
SECTION 2

and cost of equipment. If one uses functional capacity to exercise

Patient Factors Equipment Factors
capacity, prediction of cardiovascular risk can be assessed.30 It is also
Electrolyte abnormalities Battery failure essential to evaluate the inability of the heart rate to increase
Hyperventilation Loose lead appropriately during exercise (chronotropic incompetence) testing.
Lead interference by patient Mechanical failure of recorder Peak heart rate, age related predicted maximum heart rate have
Medications Motor failure
important prognostic importance. Heart rate during exercise is an
Physiologic variations in waveforms Overrecording
Medications Computer inability to detect arrhythmia
expression of decreased parasympathetic tone and increased sympa-
Patient activities (e.g., sudden exercise) thetic tone. In disease states affecting electrical conduction or
Cardiovascular Disorders

Presence of atrial fibrillation possibly heart failure this becomes important. The second impor-
tant area is heart rate recovery after exercise testing. Normal
further (e.g., potentially pathologic rhythms) by technical personnel individuals and especially athletes have a rapid fall in heart rate
and physicians. Confounding factors when using AECG can arise during the first 30 seconds after exercise vs a patient with heart
from the patient and the device (Table 13–6). AECG is evolving disease who has slow fall in heart rate. This heart rate response is
rapidly, primarily related to improved technology with respect to markedly influenced by parasympathetic tone.
data interpretation, signal quality, and improved understanding of The ETT provides diagnostic information in patients with known
the implications of ECG changes. or suspected IHD and prognostic information in patients after
myocardial infarction or revascularization. However, there are no
data that support its use as a screening tool for CAD or for detection
EXERCISE STRESS TESTING of early CAD in asymptomatic subjects.
 Exercise stress (tolerance) testing (ETT) is a noninvasive test used The principle behind ETT is to increase myocardial oxygen
to evaluate clinical and cardiovascular responses to exercise.27–29 ETT demand above myocardial oxygen supply and coronary reserve,
is used frequently as an initial test, in conjunction with physical thereby provoking ischemia (inadequate myocardial perfusion),
examination and patient symptoms, to aid in the selection of addi- using exercise as a stressor. Ischemia is detected by patient symp-
tional testing modalities. It is a simple test that can be conducted in a toms, ECG changes, and/or hemodynamic changes. The type of
physician’s office and is about 20 times less expensive than an ECG changes, leads affected, and patient performance are used as an
angiogram and almost three times less expensive than stress echocar- index of severity and location of disease. ETT is a very practical test
diography. Almost two-thirds of ETTs billed to Medicare in 1996 in that it can assess patients’ functional capacity.30
were conducted in physicians’ offices, and one-third was conducted Some examples of classes I, II, and III indications from the ACC/
by noncardiologists.27 AHA guidelines for ETT are presented here.31 The major class I
Central facts to remember about ETT is that its value to diagnose indications are evaluation of males older than age 40 years who have
CAD is largely dependent on the risk of the population studied. For symptoms suggestive of CAD and risk factors for CAD or atypical
example, it is not very helpful in identifying CAD if one does ETT symptoms suggestive of CAD. Another class I indication is to help
on patients who are young and without risk factors because their assess prognosis and functional capacity in patients with confirmed
risk is extremely low; but if one tests a population of people that has CAD.32 Frequently, the ETT is performed following an acute myo-
multiple risk factors and is older, it is more useful (Table 13–7). cardial infarction for this purpose (Table 13–8). Class II indications
Even though one uses these considerations, randomized trial data
on the clinical value of screening exercise testing are absent and it is
not known whether a strategy of routine screening exercise testing TABLE 13-8 Exercise Stress Testing after Myocardial Infarction
in selected subjects reduces the risk for premature mortality or Class I
major cardiac morbidity. A recent report from the U.S. Preventive 1. Before discharge for prognostic assessment, activity prescription, evaluation of
Services Task Force26 recommended against the use of exercise medical therapy (submaximal at about 4 to 76 days).
testing as a screening tool, in a large part because most studies were 2. Early after discharge for prognostic assessment, activity prescription, evalua-
completed in asymptomatic patients, and because of the well- tion of medical therapy, and cardiac rehabilitation if the predischarge exercise
test was not done (symptom limited; about 14–21 days).
established Bayesian argument.
3. Late after discharge for prognostic assessment, activity prescription, evaluation
One of most important parts of exercising testing is functional
of medical therapy, and cardiac rehabilitation if the early exercise test was
capacity, even though it is rarely measured directly. Functional submaximal (symptom limited; about 3 to 6 weeks).
Class IIa
After discharge for activity counseling and/or exercise training as part of cardiac
TABLE 13-7 Comparing Pretest Likelihoods of Coronary Artery rehabilitation in patients who have undergone coronary revascularization.
Disease in Low-Risk Symptomatic Patients with Class IIb
High-Risk Symptomatic Patients—Duke Database Periodic monitoring in patients who continue to participate in exercise training or
cardiac rehabilitation.
Nonanginal Class III
Chest Pain Atypical Angina Typical Angina 1. Severe comorbidity likely to limit life expectancy and/or candidacy for
Age
(Years) Men Women Men Women Men Women revascularization.
2. At any time to evaluate patients with acute myocardial infarction who have
35 3–35 1–19 8–59 2–39 30–88 10–78
uncompensated congestive heart failure, cardiac arrhythmia, or noncardiac
45 9–47 2–22 21–70 5–43 51–92 20–79
conditions that severely limit their ability to exercise. (Level of Evidence: C )
55 23–59 4–25 45–79 10–47 80–95 38–82
3. Before discharge to evaluate patients who have already been selected for, or
65 49–69 9–29 71–86 20–51 93–97 56–84
have undergone, cardiac catheterization. Although a stress test may be useful
Each value represents the percent with significant coronary artery disease (CAD). The first is the before or after catheterization to evaluate or identify ischemia in the
percentage for a low-risk, mid-decade patient without diabetes, smoking, or hyperlipidemia. The distribution of a coronary lesion of borderline severity, stress imaging tests are
second is that of the same age patient with diabetes, smoking, and hyperlipidemia. Both high- and recommended. (Level of Evidence: C )
low-risk patients have normal resting electrocardiograms. If ST-T–wave changes or Q waves had been
present, the likelihood of CAD would be higher in each entry of the table. Adapted from AHA/ACC guidelines.
 107

TABLE 13-9 2002 Exercise Testing Guideline Recommendations recordings are obtained, with definitive readings 2 minutes into
each stage. Patients are questioned 2 to 3 minutes into each stage of

CHAPTER 13
Class I
the test about symptoms such as headache, dizziness, and chest
1. Patients undergoing initial evaluation with suspected or known CAD, including
pain. Clinical symptoms assessed include color of skin, level of
those with complete right bundle-branch block or less than 1 mm of resting
ST depression. perspiration, and evidence of peripheral cyanosis and light-headed-
2. Patients with suspected or known CAD, previously evaluated, now presenting ness. Patients are encouraged to exercise as vigorously as they can to
with significant change in clinical status. ensure an optimal test result. Onset, nature, and duration of all
3. Low-risk unstable angina patients 8 to 12 hours after presentation who have changes in symptoms, hemodynamics, and ECG are noted. Follow-
been free of active ischemic or heart failure symptoms. ing the test there is a cool-down period during which the patient is
4. Intermediate-risk unstable angina patients 2 to 3 days after presentation who seated or lying and is observed for changes as described earlier.
have been free of active ischemic or heart failure symptoms.

Cardiovascular Testing
ETT requires considerable effort, with many patients requiring
Class IIa encouragement to perform to the best of their ability. Some patients
1. Intermediate-risk unstable angina patients who have initial cardiac markers
use the test as a personal challenge and perform better on repeated
that are normal, a repeat ECG without significant change, and cardiac markers
attempts. This is referred to as a training effect and may be a
6 to 12 hours after the onset of symptoms that are normal and no other
evidence of ischemia during observation. (Level of Evidence: B) confounding factor in using ETT to assess the effect of drug therapy
Class IIb or after interventions for IHD in clinical trials.
1. Patients with the following resting ECG abnormalities: Interpretation of the test requires correlation of clinical, ECG, and
Preexcitation (Wolff-Parkinson-White) syndrome. other parameters measured during the test with the patient’s history
Electronically paced ventricular rhythm. (e.g., age, gender, concurrent risk factors, and medical history) and
1 mm or more of resting ST depression. concomitant therapy. Results of ETT can be used as a guide to future
Complete left bundle-branch block or any interventricular conduction defect patient management, including suitability for interventional cardiol-
with a QRS duration greater than 120 ms. ogy and selection of pharmacotherapy. A positive test is defined as 1
2. Patients with a stable clinical course who undergo periodic monitoring to
mm of horizontal or downsloping depression or elevation of the ST
guide treatment.
segment for 60 to 80 milliseconds after the QRS complex. For
Class III
1. Patients with severe comorbidity likely to limit life expectancy and/or patients with baseline ST-segment depression, combinations of
candidacy for revascularization. abnormal responses (e.g., 2 mm of ST-segment depression with
2. High-risk unstable angina patients. hemodynamic abnormalities) would be necessary to call a test posi-
tive. ST-segment depression of 2 mm or more, especially in conjunc-
CAD, coronary artery disease; ECG, electrocardiogram.
Adapted from AHA/ACC guidelines.
tion with heart rates of less than 120 beats per minute, low levels of
stress, or depression persisting for up to 6 minutes after the cessation
of the test, is associated with a poor prognosis. Depression of the ST
are patients with variant angina or women with a history of typical segment in multiple leads is also significant. Other ECG changes
or atypical chest pain (Table 13–9). Examples of class III indications include development of U waves and increased complexity and/or
are patients with simple premature ventricular contractions on a frequency of premature ventricular contractions or beats, especially if
resting ECG with no other signs or symptoms of CAD. Additionally, associated with bigeminy or periods of ventricular tachycardia.
ETT is used to assess symptoms such as chest pain or breathlessness. Although ECG changes and heart rate responses are used as
ETT should be used only if the results are able to alter patient objective end points of ETT, patient and clinical end points are
management or to assess patient function. actually preferred. The use of the 85% to 90% maximally predicted
Guidelines for conducting and interpreting the tests and details of heart rate is highly variable among patients and often is not
testing equipment and environment are outlined in the 2002 ACC/ achieved because of concomitant drug therapy and different levels
AHA guidelines on ETT standards.33 ETT is conducted on a tread- of fitness. Symptom-limited or patient-directed tests are continued
mill or bicycle ergometer or by means of a handgrip. These dynamic to the predetermined end point(s) unless the patient tires or certain
methods are used to assess exercise tolerance because they induce characteristics are noted. Clinical symptoms, exhaustion, chest pain,
both a volume and pressure load on the heart. Both modalities also and changes in blood pressure, heart rate, and the ECG (rhythm,
allow the degree of stress to be delivered in a graded and calibrated configuration, and rate) are used as end points for such open-ended
manner. Treadmill walking is preferred over the ergometer because tests. Also, patient performance, measured as exercise duration, time
it involves more muscle mass and the maximal oxygen consump- until symptoms, stress at which symptoms occur, and hemody-
tion (VO2max) achieved with cycle ergometer is 10% to 15% lower namic parameters, is a better indicator of an adequate test than is
than with the treadmill. heart rate response. Close-ended testing is the use of fixed end points
Many protocols have been designed and validated for use with such as time on the treadmill or maximal heart rate.
ETT, but the two used most commonly are the Bruce and Naughton The product of blood pressure and heart rate (double product) is
protocols. Protocols help to decrease inter- and intrapatient vari- a measure of myocardial oxygen demand. In patients with stable
ability and allow for standardization in the interpretation of the angina, the double product is reproducible on repeat ETTs; conse-
tests. Protocols may be customized for individual patients to ensure quently, it is used as an objective parameter to follow an individual
an exercise time of 6 to 12 minutes and a heart rate of 85% to 90% patient’s disease. Inappropriate or inadequate responses in blood
of maximum predicted (adjusted for age and gender). Protocols pressure and/or heart rate to exercise suggest heart disease. A
detail gradient, speed, and rates of change of these parameters reduction in heart rate or a flat response (failure to increase heart
during the test. rate above 120 beats per minute) with increasing levels of stress has
In preparation for ETT, patients fast prior to the test for a a poor prognosis. Likewise, failure to increase the systolic blood
minimum of 3 hours, may not exercise 12 hours prior to the test, pressure or the finding of a sustained decrease of more than 10 mm
and must dress suitably for exercise. Baseline evaluation consists of Hg is also associated with a worse prognosis. Such responses
history and physical examination, blood pressure, heart rate, and indicate that the heart has an inadequate reserve to respond to
ECG. The test begins with a 1-minute warmup period to orient the stress. Patients who are unable to progress beyond stage II of the
patient to the equipment. Each stage of the test is maintained for at Bruce protocol have a poor prognosis and more severe IHD. Other
least 3 minutes. Continuous blood pressure, heart rate, and ECG rating scales (e.g., Borg, which measures perceived exertion) may be
 108

TABLE 13-10 MET Relationship to Activity and Function TABLE 13-12 Contraindications to Exercise Testing
SECTION 2

METS Level of Activity ET Result Absolute

Acute myocardial infarction (within 2 days)
1 Resting <6 METS
High-risk unstable angina
2 Level walking at 2 miles/h Symptom-limited lifestyle
Uncontrolled cardiac arrhythmias causing symptoms or hemodynamic compromise
4 Level walking at 4 miles/h Sedentary lifestyle tolerated
Symptomatic severe aortic stenosis
13 Cycling 9–10 miles/h Little or no activity-limited lifestyle
Uncontrolled symptomatic heart failure
20 Shoveling heavy snow No limitations on lifestyle
Acute pulmonary embolus or pulmonary infarction
ET, exercise testing; METS, metabolic equivalents of task. Acute myocarditis or pericarditis
Acute aortic dissection
used in conjunction with the objective results from the ETT to Relative
Cardiovascular Disorders

classify patients into high- and low-risk groups. Silent ischemia may Left main coronary stenosis
confound the interpretation of ETT because blood pressure and Moderate stenotic valvular heart disease
ECG changes may occur in the absence of symptoms. Electrolyte abnormalities
Severe arterial hypertension
To provide standardized comparability between tests and
Tachyarrhythmias or bradyarrhythmias
patients, metabolic equivalents (METS) are used as a measure of
Hypertrophic cardiomyopathy and other forms of outflow tract obstruction
VO2max. A MET is a measure of resting oxygen uptake. Activity Mental or physical impairment leading to inability to exercise adequately
energy demands then can be calculated in terms of METS. For High-degree atrioventricular block
example, 4 METS is equivalent to walking at 4 miles per hour. The
Adapted from AHA/ACC guidelines.
number of METS a patient can undertake without symptoms of
ischemia correlates with prognosis and helps to guide appropriate
ETT is relatively safe, with an estimated risk of acute myocardial
management strategies. Table 13–10 has examples of METS and
infarction or death of 10 per 10,000 tests overall. Most adverse effects
activity correlations. Exercise capacities of less than 5 METS are
are cardiac in nature, including arrhythmias (primarily bradyar-
associated with a poor prognosis; those greater than 13 METS have
rhythmias), sudden death, hypotension, and myocardial infarction.
a good prognosis despite the presence of disease.
Patients in whom ETT is contraindicated are those who are unable
Meta-analysis of more than 24,000 patients in 147 studies showed
or who should not exercise because of physiologic or psychological
a mean sensitivity of 68% and specificity of 77% for ETT as a
limitations and indications for termination (Tables 13–11, 13–12,
diagnostic test. The specificity of ETT to detect the presence of
and 13–13). Unstable angina is usually a contraindication to ETT
CAD, compared with angiography, is 84%. Sensitivity ranges from
because of the instability of the patient’s disease state and because
40% to 90%, depending on the number of vessels affected, with a
patients cannot exercise to a satisfactory level for the test to be
mean of 66%.
considered adequate. However, once such a patient is stable, ETT is
As a prognostic test, ETT is very popular after myocardial infarc-
excellent for prognostic evaluation. In patients with untreated life-
tion and can be conducted within 3 days of an acute event. It can be
threatening arrhythmias or congestive heart failure, ETT is also
used to determine functional capacity, assess the degree of rehabilita-
contraindicated. Patients with comorbid diseases such as chronic
tion, and identify patients at risk for further cardiovascular events.
obstructive pulmonary disease or peripheral vascular disease may be
Immediately after myocardial infarction, a modified protocol is used;
limited in their exercise capacity, whereas lower-limb amputees are
the test is terminated when a heart rate of 70% to 75% of age- and
unable to perform the standard treadmill test. For patients with
gender-predicted maximum is reached (e.g., 140 beats per minute for
disabilities or other medical conditions that limit their exercise
those younger than age 40 years and 130 beats per minute for those
capacity independent of heart disease, pharmacologic stress testing
older than age 40 years) or a METS level of 5 for patients older than
with dipyridamole, adenosine, or dobutamine is an alternative (see
age 40 years or of 7 for those younger than age 40 years. Tests usually
Pharmacologic Stress Testing below).
are done prior to discharge or within 6 weeks of infarction. In the
Drug therapy rarely is discontinued for the test primarily because
periinfarction period, mortality and reinfarction rates caused by ETT
few data exist to support better test results off drug therapy. Patients
are 0.02% and 0.09%, respectively. Patients may be stratified into
on β-blockers or calcium channel blockers may not achieve maximal
low-, intermediate-, and high-risk categories, depending on the evi-
heart rates, but ETT helps to demonstrate patients’ exercise capacity
dence for ischemia and the level of exercise tolerance.33
on drug therapy. Nitrates do not alter exercise capacity directly and
theoretically may improve patient response because they relieve or
TABLE 13-11 Exercise Testing before and after Revascularization
prevent symptoms of ischemia. Digoxin interferes with interpreta-
Class I tion of ST-segment changes, and patients rarely achieve ST-segment
1. Demonstration of ischemia before revascularization. changes greater than 1 mm even in the face of significant ischemia.
2. Evaluation of patients with recurrent symptoms that suggest ischemia after
revascularization.
TABLE 13-13 Indications for Terminating Exercise Testing
Class IIa
After discharge for activity counseling and/or exercise training as part of cardiac Absolute indications
rehabilitation in patients who have undergone coronary revascularization. Drop in systolic blood pressure of >10 mm Hg from baseline blood pressure
Class IIb despite an increase in workload, when accompanied by other evidence of
1. Detection of restenosis in selected, high-risk asymptomatic patients within the ischemia
first 12 months after percutaneous coronary intervention. Moderate to severe angina
2. Periodic monitoring of selected, high-risk asymptomatic patients for restenosis, Increasing nervous system symptoms (e.g., ataxia, dizziness, or near syncope)
graft occlusion, incomplete coronary revascularization, or disease progression. Signs of poor perfusion (cyanosis or pallor)
Class III Technical difficulties in monitoring electrocardiogram or systolic blood pressure
1. Localization of ischemia for determining the site of intervention. Subject’s desire to stop
2. Routine, periodic monitoring of asymptomatic patients after percutaneous Sustained ventricular tachycardia
coronary intervention or coronary artery bypass grafting without specific ST elevation (>1.0 mm) in leads without diagnostic Q-waves (other than V1 or
indications. aVR)
Adapted from AHA/ACC guidelines. Adapted from AHA/ACC guidelines.
 109
Because of its long half-life, digoxin does not need to be discontinued
prior to the test (see Table 13–2).

CHAPTER 13
ECHOCARDIOGRAM
T
 The echocardiogram (ECHO) is the use of ultrasound to visualize Chest wall
anatomic structures, such as the valves, within the heart and to ARV
describe wall motion.34,35 Clinically, the ECHO is the most fre-
quently used noninvasive cardiovascular test, aside from the ECG. It RV
competes well with invasive techniques, such as cardiac catheteriza-
IVS Ao

Cardiovascular Testing
tion with angiography, for the evaluation of ischemia and valvular
abnormalities. ECHO is relatively cheap to perform and can be done
at the bedside, in the operating room, or in the physician’s office. LV
The major disadvantages of the ECHO relate to technical limitations
AMV LA
of operator-dependent images and competition from other noninva-
PPM PMV
sive technologies such as MRI and CT scanning that provide similar
information with superior tissue-type resolution. The ECHO is often PLV
used as an initial evaluative tool following auscultation detection of
an abnormality, thus providing a baseline visual characterization.
Apex Base
Serial determinations in a given patient, especially following a change
in clinical condition or a procedure, allow evaluation of progression FIGURE 13-8. Schematic of two-dimensional echocardiography to illus-
of disease over time. trate location of cardiac structures as “seen” by the transducer. The
The ECHO remains the procedure of choice in the diagnosis and transducer is swept in an arc so that several pictures of the heart are
evaluation of a number of conditions such as valvular dysfunction obtained to generate the final electrocardiogram. (Ao, aorta; AMV, anterior
(aortic and mitral stenosis and regurgitation and endocarditis), wall mitral valve; ARV, anterior right ventricle; IVS, interventricular septum; LA,
left atrium; LV, left ventricle; PLV, posterior left ventricle; PMV, posterior
motion abnormalities associated with ischemia, and congenital abnor-
mitral valve; PPM, posterior papillary muscle; RV, right ventricle.) (Redrawn
malities, such as ventricular or atrial septal defects. Images obtained
from Coryu BC, et al. Application of electrocardiography in acute
from ECHO are used to estimate chamber wall thickness and left myocardial infarction. Cardiovasc Clin 1995;2:113, with permission.)
ventricle ejection fraction, assess ventricular function, and detect
abnormalities of the pericardium such as effusions or thickening.
Echocardiography is based on the principle of differential acous- be visualized, including the valves and left atrium. Images are
tic impedance (or tissue density) and the laws of reflection and displayed as “windows.”
refraction. Sound waves directed across tissues from a transducer Two-dimensional echocardiography employs multiple windows of
will reflect back sound waves of different frequencies. The ability of the heart, and each view provides a wedge-shaped image. Windows
the ultrasonic beam to penetrate chest wall structures is inversely most commonly used include parasternal long- and short-axis and
proportional to the frequency of the signal. With transthoracic apical two- and four-chamber views (Fig. 13–8). These views are
echocardiography, frequencies of 2.0 to 5.0 MHz are commonly processed onto a videotape to produce a motion picture of the heart.
used in adults, and frequencies of 3.5 to 10.0 MHz are used in Two-dimensional echocardiography renders increased accuracy in
children. Serial determinations in a given patient using the same calculating ventricular volumes, wall thickness, and degree of valvular
conditions and ECHO images (windows) provide the best form of stenosis compared with M-mode echocardiography. Patient-specific
internal control to allow comparisons of test results. In clinical calculated parameters such as ejection fraction and wall thickness are
trials, echocardiograms are read and interpreted independently by compared with standardized values (population-based) or with pre-
two or three clinicians to provide a means of control. viously obtained values from the patient. Although ejection fraction is
Two primary approaches to ECHO are used in clinical practice. still commonly obtained with echocardiography, it is a derived num-
Transthoracic echocardiography (TTE) is conducted with the trans- ber, so it is considered subjective. Other tests to determine ejection
ducer on the chest wall, whereas transesophageal echocardiography fraction provide different numbers and highlight the difficulty of
(TEE) is conducted with the transducer in the esophagus. In TTE, comparing results between tests. Ejection fraction from echocardiog-
several modes of operation are possible, the most common being raphy is also limited by the diminished views of total ventricular
M-mode (motion) and two-dimensional (2D) imaging. Both M- volume able to be visualized, especially in persons with distorted
mode and 2D echocardiography provide visualization of heart ventricles. Despite these limitations, echocardiography remains the
structures and can indicate numerous structural abnormalities such most common modality for ejection fraction determination.
as aneurysms, wall thickness abnormalities, chamber collapse (e.g., The ECHO can be used for diagnosis and prognosis and as a serial
tamponade), and valvular stenosis. TEE is used primarily for assess- evaluation tool to assess acute and chronic ischemic heart disease
ment of valvular anatomy and function or to image intracardiac and regional left ventricular function. Areas of ischemic myocar-
masses such as tumors or thrombi and valvular vegetations.36 dium are seen on the ECHO as aberrations in wall motion. Wall
In M-mode echocardiography, the transducer is placed at a single motion abnormalities are seen as altered thicknesses of various
site on the chest (usually along the sternal border), and the ultra- segments of the heart. Wall motion abnormalities are graded using
sound is directed posteriorly. M-mode echocardiography records descriptive terms such as akinetic, hypokinetic, dyskinetic, and hyper-
only static objects in one plane, producing a single picture of a small kinetic. It is possible to visualize the complete ventricle (in seg-
region of the heart, or an “ice pick view.” Results depend on the ments), allowing both global and regional left ventricular function
exact placement of the transducer with respect to the underlying to be assessed. Studies show that the locations of segmental ventric-
structures. Conventional M-mode echocardiography provides visu- ular wall motion abnormalities correspond with areas of CAD.
alization of the right ventricle, left ventricle, and posterior left Echocardiography can be linked with the various stress tests (ETT,
ventricular wall and pericardium. If the transducer is swept in an arc dipyridamole or dobutamine) to assess stress-induced structural or
from the apex to the base of the heart, virtually the whole heart can functional abnormalities (e.g., changes in wall motion). As a serial
 110
monitoring test, echocardiography is comparable with angiography blood flow patterns. It allows measurement of transvalvular pressure
as a prognostic tool and can be used as a treatment planning tool. gradients, valve area, and pressure changes on either side of the valve.
SECTION 2

After myocardial infarction, echocardiography is a useful noninva- Doppler echocardiography is either continuous or pulsed; the former
sive diagnostic tool for detection of ventricular aneurysms, thrombi, is used to assess pressure changes, whereas the latter is used to localize
and pericardial effusions and can be used serially for diagnostic and points of origin and creation of turbulent and high blood flow. Color
prognostic information. Doppler is used to visualize blood flow (e.g., regurgitation). Turbu-
In TEE, the transducer is advanced into the esophagus and rests just lence associated with valvular and wall motion abnormalities can be
behind the heart.37 The transducer also can be passed into the fundus visualized and quantified clearly. In aortic regurgitation, Doppler
of the stomach to obtain better images of the ventricles. Images are echocardiography is one of the best noninvasive technique to assess
obtained in either the horizontal or vertical plane.38 This is a low-risk the pressure and severity of regurgitation. Color-flow mapping allows
Cardiovascular Disorders

invasive procedure and does not require routine antibiotic prophylaxis tracing of the jet direction and an indication of its volume, point of
for patients at risk of developing endocarditis. Complications such as wall contact, and width. Because Doppler echocardiography distin-
esophageal tears or perforation, esophageal burns, transient ventricu- guishes different types of turbulence, it can simultaneously identify
lar tachycardia, minor throat irritation, and transient vocal cord more than one type of valvular abnormality (e.g., aortic regurgitation
paralysis have been reported rarely. In one series of 10,218 studies, and mitral stenosis) and the source of concomitant heart murmur.
only 1 death (0.0098%) was reported, comparable with that with The ACC/AHA 2003 task force has published clinical guidelines for
esophageal gastroduodenoscopy (0.004%). TEE is contraindicated in application of echocardiography. In recent years, the use of intraop-
patients with esophageal abnormalities, in whom passage of the trans- erative TEE has significantly increased and standard for valvular heart
ducer might be limited (e.g., esophageal strictures or varices). surgery and other types of cardiovascular surgery (Table 13–14).
TEE yields higher resolution and improved visualization of struc-
tures, especially pulmonary veins and valves, compared with TTE. NUCLEAR CARDIOLOGY39,40
Interference of ribs, lungs, and subcutaneous tissues is reduced,
enabling TEE to be more useful in patients in whom TTE is limited Nuclear cardiology continues to be a major advance as a noninvasive
because of pulmonary disease, mechanical ventilation, or obesity. A testing method. Radionuclides with short half-lives, which can be
high-frequency transducer (5 MHz for adults) is used, thus producing
better image resolution. TEE is used for the same indications as TTE.
Visualization of the heart valves—in particular, the mitral valve—is TABLE 13-14 Recommendations for
superior, allowing more accurate evaluation of both native and pros- Intraoperative Echocardiography
thetic valves. Clinical studies show that it is possible to visualize Class I
valvular vegetations as small as 5 mm with TEE. The ACC/AHA 1. Evaluation of acute, persistent, and life-threatening hemodynamic distur-
guidelines recommend TEE if the TTE is equivocal and the patient has bances in which ventricular function and its determinants are uncertain and
staphylococcal bacteremia. In a study comparing vegetation visualiza- have not responded to treatment.
tion, TEE detected vegetations in 90% of patients, compared to TTE 2. Surgical repair of valvular lesions, hypertrophic obstructive cardiomyopathy,
detecting vegetations in 58%. It also can help to define complications and aortic dissection with possible aortic valve involvement.
of endocarditis such as thrombosis or valve leakage. In aortic dissec- 3. Evaluation of complex valve replacements requiring homografts or coronary
reimplantation, such as the Ross prodecure.
tion, TEE is able to identify the initial flap and origin of dissection and
4. Surgical repair of most congenital heart lesions that require cardiopulmonary
has an overall sensitivity and specificity of 97% and 100%, respectively.
bypass.
CT remains the diagnostic method of choice for aortic dissection, but 5. Surgical intervention for endocarditis when preoperative testing was inade-
TEE offers a sensitive and fast test that can be conducted in the quate or extension to perivalvular tissue is suspected.
emergency room. 6. Placement of intracardiac devices and monitoring of their position during port-
Other uses of TEE include identification of cardiac thrombus, access and other cardiac surgical interventions.
especially thrombi in the left atrium, and assessment of atrial 7. Evaluation of pericardial window procedures in patients with posterior or
dilation. After transient ischemic attacks or cerebrovascular acci- loculated pericardial effusions.
dents, TEE may enable identification of the site of cardiac emboli by Class IIa
providing excellent images of likely sources, namely, ventricular or 1. Surgical procedures in patients at increased risk of myocardial ischemia,
myocardial infarction, or hemodynamic disturbances.
atrial thrombus, valvular vegetation, cardiac shunts, cardiac tumors,
2. Evaluation of valve replacement, aortic atheromatous disease, the Maze
or atrial and ventricular septal defects. In a study of almost 1,500
procedure, cardiac aneurysm repair, removal of cardiac tumors, intracardiac
patients with cerebral ischemia or nonvalvular atrial fibrillation, thrombectomy, and pulmonary embolectomy.
atrial thrombi were seen in 183 patients when evaluated by TEE 3. Detection of air emboli during cardiotomy, heart transplant operations, and
versus only in 2 patients when evaluated by TTE. TEE can be used for upright neurosurgical procedures.
intraoperative cardiac imaging to ascertain development of ischemia. Class IIb
Another advance with echocardiography has been the addition of 1. Evaluation of suspected cardiac trauma, repair of acute thoracic aortic
Doppler and color-flow Doppler technology. The Doppler principle dissection without valvular involvement, and anastomotic sites during heart
involves reflecting sound off a moving object—in the case of echo- and/or lung transplantation.
cardiography, the red blood cell. As the red cell moves in relation to 2. Evaluation of regional myocardial function during and after off-pump coronary
artery bypass graft procedures.
the transducer, a frequency shift occurs in the reflected wave.
3. Evaluation of pericardiectomy, pericardial effusions, and pericardial surgery.
Assessment with Doppler echocardiography combines structural
4. Evaluation of myocardial perfusion, coronary anatomy, or graft patency.
images and hemodynamic monitoring. Thus it is possible to evaluate 5. Dobutamine stress testing to detect inducible demand ischemia or to predict
the impact of structural disease on cardiac function and quantify the functional changes after myocardial revascularization.
associated hemodynamics. Color enhancement allows flow direction 6. Assessment of residual duct flow after interruption of patent ductus arteriosus.
to be visualized; different colors are used for antegrade and retro- Class III
grade flow. These improve resolution of structures, identify patterns 1. Surgical repair of uncomplicated secundum atrial septal defect.
of blood flow, and allow calculation of flow gradients. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ASE 2003 guideline update for the
Doppler echocardiography is used primarily in conjunction with clinical application of echocardiography—summary article. J Am Coll Cardiol 2003;42(5):954-970.
traditional echocardiography for analysis of valvular function or Full text at http://content.onlinejacc.org/.41
 111
used either alone or combined with other substances to form agents patency after coronary artery bypass. Certain characteristics of the
with particular properties, such as technetium-99m pyrophosphate, images obtained have been linked with various prognostic values but

CHAPTER 13
have expanded the role for nuclear imaging in cardiology. await confirmation in comparative and long-term prognostic trials.
Nuclear imaging techniques have demonstrated equal sensitivity Other technetium-labeled agents used include technetium-t-butyl
and specificity to many of the invasive “gold standard” testing isonitrile (99mTc-TIBI); technetium-carboxy isopropyl isonitrile
modalities. The major limitations of nuclear cardiology are the (99mTc-CPI); technetium-sestamibi, also known as methoxy-isobu-
availability of suitable radionuclides and correlation of nuclear tyl isonitrile (Tc-MIBI); and technetium-teboroxime. Technetium-
images with cardiovascular function. sestamibi has a similar myocardial uptake pattern to thallium and
Despite the availability of new radionuclides, technetium-99m produces similar results but with improved image quality because it
(99mTc) and thallium-201 (201Tl) remain the two most commonly generates a much higher photon yield. This is now popular as an

Cardiovascular Testing
used radionuclides. 99mTc is ideal for clinical imaging because it has alternative perfusion imaging agent to thallium. Technetium-
a half-life of about 6 hours, a single 140-keV photon peak suitable teboroxime is still primarily an investigational agent. The main
for available imaging systems, primarily gamma ray emission, and advantage of the newer technetium compounds is the lack of
the ability to be combined with multiple pharmaceuticals. It is redistribution perfusion, allowing for delayed imaging. This is
generated in-house by a benchtop generator that reduces transpor- particularly useful in acute clinical settings; the radiopharmaceutical
tation costs and provides immediate availability. The short half-life can be injected during the acute event and imaging undertaken
means high doses and repeat injections can be given to evaluate when the patient is more stable.
efficacy of interventional therapy over a relatively short period of
time. 201Tl has a much longer half-life of 73 hours, which prevents Thallium Scanning
the use of multiple doses close together but does mean that delayed
Thallium is a potassium analog taken up into normal myocardium
imaging is possible following administration of the agent. Uptake
by passive diffusion and possibly by active transport via the Na+-K+-
into cells depends on blood flow. The energy from 201Tl is x-ray,
adenosine triphosphatase (ATPase) pump. Uptake depends on
with an energy level of 69 to 83 keV. Production of 201Tl requires a
regional blood flow and in a linear fashion up to very high blood flow
cyclotron. Images are obtained with a conventional gamma camera.
rates. It is used primarily for the analysis of coronary and myocardial
perfusion. High thallium uptake occurs in perfused myocardium; in
Technetium Scanning ischemic myocardium, uptake is reduced significantly. Scans taken
Technetium scanning is used for the evaluation of blood pool and during acute ischemia or following infarction show areas of poor or
myocardial perfusion and as an infarct-avid agent to identify dam- nil distribution of thallium corresponding to the site of ischemia. A
aged myocardium. Analysis of the blood pool, as in multigated scan repeated 4 to 6 hours after the initial scan may show a
angiography, uses technetium either alone or as a red blood cell redistribution of the thallium into areas that previously had little to
complex. The former obtains images following a bolus of techne- no thallium uptake. These defects are referred to as partial defects,
tium and traces its passage from the venous system through the demonstrating areas hypoperfused during “stress” but viable myo-
heart to the aorta and is known as first-pass angiography. Equilib- cardium at rest. Redistribution occurs because there is delayed
rium tests where technetium is bound to red blood cells provide an washout of thallium from poorly perfused myocardium, resulting in
imaging time of several hours, which allows serial images to be less contrast between the density of thallium in different areas of the
obtained. These tests are used to determine right and left ventricular heart. This gives the appearance of “redistribution” of the radionu-
ejection fractions, detect cardiac shunts, estimate ventricular vol- clide into the previously ischemic area. To enhance evaluation of
umes, and view wall motion.42 potential partial defects, a second injection of thallium can be used.
Infarct-avid radionuclides such as technetium-pyrophosphate Areas of nil distribution are called cold spots or fixed defects and
(99mTc-PYP) are used to describe the presence and extent of dam- reflect infarcted myocardium.
aged myocardium after myocardial infarction, in suspected myocar- Thallium scanning with the aid of computer analysis segregates the
dial contusion, and following chest wall injuries. Imaging with images into anatomic regions and specifically localizes areas of dead
99m
Tc-PYP is applicable when myocardial infarction is suspected or necrotic myocardial tissue. In conjunction with echocardiography
clinically, but patient history, ECG changes, and laboratory evidence or single-photon emission computed tomography (SPECT), thallium
are not definitive. Uptake of 99mTc-PYP into infarcted tissue depends scans can correlate areas of abnormal wall motion with areas of poor
on regional blood flow, myocardial calcium concentration, the perfusion. Sensitivity and specificity of thallium scanning to detect
degree of irreversible myocardial injury, and time after infarction. IHD disease are comparable with those of ETT (75% and 80%,
99m
Tc-PYP attaches to calcium deposited in the infarcted area, so the respectively). When used in conjunction with exercise ECG, sensitiv-
approach is known as hot-spot scanning. False hot spots may occur ity increases to approximately 80%. Thallium scanning also can be
where there is necrotic myocardial tissue, as in myocarditis, myocar- used in conjunction with ETT to allow detection of lower levels of
dial abscesses, old infarctions, and myocardial trauma. Additionally, ischemia than may be determined from ECG abnormalities or patient
uptake has been seen during unstable angina and ventricular dyski- symptoms. Thallium is injected at the peak of the ETT, and exercise
nesia and at sites of ventricular aneurysms, suggesting that these are continues for another 30 to 60 seconds, when the initial images are
associated with transient low blood flow. In infarcted tissue, 99mTc- taken. Repeat images are taken at 3 to 4 hours.
PYP levels can be as high as 18 to 20 times that of normal myocar- Thallium scanning is useful in patients with atypical chest pain
dium, which gives rise to very distinct borders between the infarcted and ambiguous or false-positive ETT to determine if IHD is the
and normal myocardium. Uptake of 99mTc-PYP into necrotic myo- cause of symptoms and the ETT abnormalities. Thallium scanning
cardium is delayed and not measurable until after about 4 hours of is also used for postoperative evaluation of revascularization or
coronary occlusion. Scans prior to this time are usually negative and angioplasty procedures and for preoperative evaluation for prog-
become positive about 12 hours after occlusion. Peak intensity of nostic stratification for persons with IHD. A normal thallium scan
99m
Tc-PYP is reached at 48 hours. Washout occurs over 5 to 7 days, heralds a benign outcome, even in patients who have angiographi-
so 99mTc-PYP is a useful late marker of infarction, especially in cally evident CAD. The finding of redistribution is a marker of
patients who present late or with a silent infarction. Images are jeopardized but viable myocardium that has important prognostic
viewed by comparing sternum and rib uptake with that seen in the value. Major cardiac events such as myocardial infarction in
myocardium. This type of imaging also can be used to assess graft patients with normal 201Tl studies average less than 1% per year. The
 112
best predictor of coronary events, which correlates thallium scans lar, cardiac, and noncardiac surgery. Pharmacologic stress testing
with clinical significance, is the number of myocardial segments evaluates wall motion abnormalities and perfusion defects under
SECTION 2

with transient (redistribution) defects. stress and has been shown in numerous studies to have comparable
A number of other radiopharmaceuticals have found some use in sensitivity and specificity with the traditional ETT. Using planar
cardiovascular testing, such as labeled antimyosin antibodies. The- scanning and dipyridamole, sensitivity to detect IHD ranges from
oretically, these antibodies should be more specific markers of 67% to 95% with a 67% to 100% specificity. A summary of 13 studies
myocyte necrosis. The currently used antibodies are a murine Fab in almost 900 patients gave a pooled sensitivity of 85% and specificity
fragment. Phase I, II, and III trials suggest that these are highly of 87%. SPECT scanning has at least comparable sensitivity and
specific for irreversibly injured myocytes, but they have limitations slightly lower specificity to planar imaging but produces higher-
in terms of pharmacokinetic properties. Uptake into myocardial quality imaging, which may enhance quantitative interpretation.
Cardiovascular Disorders

tissues is very slow, with a prolonged blood pool activity seen for at Dipyridamole testing is safe and effective in the elderly and in
least 24 hours. In clinical use, the antibody is given within 24 hours those with unstable angina immediately after myocardial infarction
of the infarction, and planar or SPECT imaging is undertaken 24 to (within days). It also may be used to assess the status of revascular-
48 hours later. Despite the supposed specificity of the antibody to ization procedures.43 As a prognostic test, dipyridamole testing is
myosin, localization is more dependent on blood flow than on very useful. In several studies, abnormal scans have shown about a
myosin concentration, so measurement of infarction size is not as 10-fold increase in event rates over 1 to 2 years of followup.
accurate as expected. Another investigational agent, [123I]phenyl- Abnormal scans also have been shown to be an independent risk
pentadecanoic acid, is able to assess both myocardial perfusion and factor for myocardial infarction and death with a relative risk ratio
metabolism by virtue of its affinity for fatty acid metabolism. of 3.1. Reversible defects correlate best with events, with one study
demonstrating a 4.41 relative risk ratio for cardiac events.
Adverse effects with dipyridamole thallium testing are minimal,
Pharmacologic Stress Testing the main adverse effects being chest pain (with or without ischemic

Pharmacologic stress testing is an alternative to ETT and ETT changes on the ECG), headache, dizziness, and nausea. Adverse
with thallium in patients who are unable or unwilling to undergo effects are related to the increased adenosine activity and can be
ETT.43,44 Additionally, pharmacologic stress testing is now used ameliorated by xanthine compounds because they are direct com-
more than 50% of the time to assess coronary perfusion. The petitive antagonists of adenosine. Caffeine products must be
pharmacologic agent produces stress by a hyperemic (vasodilator) avoided for about 24 hours prior to the test. Adenosine is associated
response or by increasing myocardial oxygen demand (heart rate with a higher incidence of adverse effects (80% versus 50%), but
and myocardial contractility). Agents currently used include dipy- these are very transient, and some studies have shown that patients
ridamole and adenosine (hyperemic stress) and dobutamine (myo- prefer it over dipyridamole. Both agents are relatively contraindica-
cardial stress). Pharmacologic stress tests can be linked to various ted in patients with a history of bronchospasm.
imaging techniques such as thallium planar scanning, SPECT, MRI, Dobutamine, a synthetic catecholamine, raises heart rate and car-
and echocardiography. Dobutamine is linked most frequently to diac output, which increases myocardial oxygen demand. Ischemia
echocardiography, allowing quantification of wall motion abnor- develops in areas where stenosis prevents the increase in oxygen
malities, which correlate well with areas of ischemia. demand from being met with increased blood flow. Ischemia is
The principle of dipyridamole and adenosine thallium imaging is detected by the ECHO as regional wall motion abnormalities or with
related to their coronary arteriolar vasodilator properties. Dipy- thallium scanning.
ridamole inhibits adenosine cellular reuptake, resulting in increased Dobutamine, when used as a stress test, is given in doses of 10 to
concentrations of adenosine in the blood and tissues. Adenosine is 40 mcg/kg per minute.44 The dose is titrated at 3-minute intervals in
a potent coronary artery vasodilator and can increase perfusion four increments of 10 mcg/kg per minute. If thallium is used, it is given
to five times over baseline. Areas distal to a coronary artery obstruc- 2 to 3 minutes before the end of infusion. Atropine 0.5 to 1 mg may
tion will show a relative hypoperfusion compared with normal be given to augment the heart rate response to 85% of the patient’s
coronary arteries because there is reduced perfusion pressure as a calculated maximum. ECG and blood pressure are recorded contin-
consequence of preferential perfusion of normal segments over uously throughout the test, and ECHO recordings are made during
stenotic segments. Acutely, these areas will appear as cold spots, but the last minute of each dose level and during recovery.
on the redistribution scans, the defects will fill, indicating viable but β-Blocker and calcium channel blocker therapy may interfere
jeopardized myocardium. with the heart rate response to dobutamine stress tests and is
Dipyridamole is given intravenously in a dose of 0.142 mg/kg per recommended to be discontinued prior to the test. Dobutamine
minute over 4 minutes. This dose has been shown to increase stress testing is relatively well tolerated. Reasons to discontinue the
baseline coronary blood flow in the normal tissues up to four to five test include development of severe chest pain, extensive new wall
times over control. Some studies have used doses up to 0.84 mg/kg motion abnormalities, ST-segment elevation and depression sug-
to enhance the vasodilator response. At the higher dose, acute gestive of significant ischemia, tachyarrhythmias, and symptomatic
adverse effects such as chest pain are more common. Adenosine for reductions in blood pressure.45 β-Blockers can be used to reverse
stress testing is an unlabeled use of this drug. Adenosine is given most adverse effects if they persist. Dobutamine stress tests are
over 6 minutes at a dose of 0.140 mcg/kg per minute. At the end of contraindicated in patients with aortic stenosis, uncontrolled hyper-
infusion (dipyridamole) or after 3 minutes (adenosine), a 2.5- to 4- tension, and severe ventricular arrhythmias. Ventricular fibrillation
mCi dose of thallium is given. The maximum effect of dipyridamole and myocardial infarction occur at a rate of approximately 0.05%.
occurs at 5 to 7 minutes and adenosine at approximately 30 seconds Dobutamine stress testing has been studied as a diagnostic, prog-
after the end of infusion. Imaging follows immediately and can be nostic, and therapy assessment tool after myocardial infarction and
repeated at 24 hours (thallium scanning) to heighten the redistribu- for unstable and chronic angina. One study compared dobutamine,
tion defects from fixed or partial defects. dipyridamole, and ETT with coronary angiography for diagnostic
Like exercise thallium scanning, dipyridamole and adenosine accuracy in patients with IHD and showed an overall accuracy of
scanning or echocardiography is used to detect IHD, evaluate the 87% for ETT, 82% for dobutamine, and 77% for dipyridamole. A
prognosis of patients with known disease, assess patients after myo- recent review of 14 studies of 942 patients for the detection of IHD
cardial infarction, and as a risk-stratification method prior to vascu- with dobutamine stress testing calculated the sensitivity to be
 113
approximately 80% (70% to 100%) with a 75% (64% to 100%) TABLE 13-15 ACCF/AHA 2007 Clinical Expert Consensus
specificity. Sensitivity is highest for detection of three-vessel disease

CHAPTER 13
Document on Coronary Artery Calcium Scoring By
(92%). Dobutamine-sestamibi stress testing seems to be less sensitive Computed Tomography—Conclusions
than thallium even for multivessel disease. Comparative studies with
1. What is the role of coronary calcium measurement by coronary CT scanning in
ETT and dipyridamole echocardiography show dobutamine to be
asymptomatic patients with intermediate CHD risk (between 10% and 20% 10-
more sensitive. After myocardial infarction, dobutamine stress test- year risk of estimated coronary events)?
ing identifies patients at high risk of subsequent cardiac events. For The Committee judged that it may be reasonable to consider use of CAC
patients with suspected or known IHD, a positive dobutamine stress measurement in such patients based on available evidence that demonstrates
test is an independent predictor of cardiac events, and a negative test incremental risk prediction information in this selected (intermediate-risk) patient
affords protection from cardiac death.46 group. This conclusion is based on the possibility that such patients might be

Cardiovascular Testing
The current 2006 guidelines on the use of these tests in clinical reclassified to a higher risk status based on high CAC score, and subsequent
practice are rather brief, only to say that cardiac imaging is currently patient management may be modified.
undergoing rapid evolution. The use of these types of test in 2. What is the role of coronary calcium measurement by CT scan in patients with
intermediate to high risk patients are markedly increasing. The low CHD risk (below 10% 10-year risk of estimated CHD events)?
The Committee does not recommend use of CAC measurement in this selected
identification of asymptomatic intermediate-risk patients (10% to
patient group. This patient group is similar to the “population screening”
20% risk of cardiovascular death/myocardial infarction in 10 years) scenario, and the Committee does not recommend screening of the general
is still undergoing considerable debate. The clinical treatment of population using CAC measurement.
these patients with atherosclerosis must include appropriate risk 3. What is the role of coronary calcium measurement by fast CT scan in asymptomatic
factor treatment according to existing AHA guidelines. Patients patients with high CHD risk (greater than 20% estimated 10-year risk of estimated
with high-risk findings of cardiovascular disease may require more CHD events, or established coronary disease, or other high-risk diagnoses)?
invasive testing but global risk reduction will still be required before The Committee does not advise CAC measurement in this selected patient stratum
and after there testing or invasive treatment if essential.47 as they are already judged to be candidates for intensive risk-reducing therapies
based on current NCEP guidelines.
4. Is the evidence strong enough to reduce the treatment intensity in patients with
COMPUTED TOMOGRAPHY calcium score = 0 in patients who are considered intermediate risk before
coronary calcium score?
CT scanning is becoming more popular as a primary screening No evidence is available that allows the Committee to make a consensus judgment
procedure in the evaluation of CVD and function because it provides on this question. Accordingly, the Committee felt that current standard recommen-
similar information as other diagnostic procedures (e.g., catheteriza- dations for treatment of intermediate risk patients should apply in this setting.
tion, echocardiography) and is less expensive and less invasive than a 5. Is there evidence that coronary calcium measurement is better than other
routine heart catheterization. In recent years, advancement in tech- potentially competing tests in intermediate risk patients for modifying cardiovas-
nology has considerably enhanced definition and spatial resolution of cular disease risk estimate?
all cardiac structures that are useful in evaluation of many specific In general, CAC measurement has not been compared to alternative approaches
areas, such as coronary arteries, aortic and pericardial disease, and to risk assessment in head-to-head studies. The question cannot be adequately
answered from available data.
paracardiac and cardiac masses. Very accurate determination of
6. Should there be additional cardiac testing when a patient is found to have high
chamber volume and size and mass calculations of myocardial wall coronary calcium score (e.g., CAC is greater than 400)?
thickness can be obtained from CT scanning than with other methods Current clinical practice guidelines indicate that patients classified as high risk based
such as echocardiography or angiography. Additionally, CT scanning on high-risk factor burden or existence of known high-risk disease states (e.g.,
acquires three-dimensional images.48 New techniques such as diabetes) are regarded as candidates for intensive preventive therapies (medical
ultrafast CT (cine-CT) scanning have significantly improved prob- treatments). There is no clear evidence that additional noninvasive testing in this
lems with cardiac motion that distorted conventional CT images. In clear patient population will result in more appropriate selection of treatments.
cine-CT scanning, complete tomograms are assembled within one 7. Is there a role for CAC testing in patients with atypical cardiac symptoms?
cardiac cycle (50 msec), thus providing real-time images. For ultrafast Evidence indicates that patients considered to be at low risk of coronary disease by
CT scanners, a set event within the cardiac cycle (determined by virtue of atypical cardiac symptoms may benefit from CAC testing to help in
ruling out the presence of obstructive coronary disease. Other competing
ECG) usually is used as initiator for imaging to ensure standardiza-
approaches are available, and most of these competing modalities have not
tion. Conventional CT scanning requires that images be correlated been compared head-to-head with CAC.
with the cardiac cycle by gating the CT to the ECG. Cine-CT scans 8. Can coronary calcium data collected to date be generalized to specific patient
examine the heart at 10 to 14 tomographic levels in <10-mm slices. populations (women, African American men)?
The resolution has improved considerably in the last few years as a CAC data are strongest for Caucasian, non-Hispanic men. The Committee
result of advances in many areas of computer science and now 64- recommends caution in extrapolating CAC data derived from studies in white
section multidetector CT scans are significantly better. men to women and to ethnic minorities.
Although still in its infancy, cine-CT scanning has matured signifi- 9. What is the appropriate followup when an incidental finding in the lungs or other
cantly and is now being used as a screening tool for evaluating the risk noncardiac tissues is found on a fast coronary CT study?
of significant obstructive CAD and as a diagnostic tool for CAD in Current radiology guidelines should be considered when determining need for
followup of incidental findings on a fast CT study, such as that which was recently
limited centers. Recent AHA/ACC guidelines address the current state
published to guide followup of small pulmonary nodules.
of practice with this methodology. The CT scan will show localized
areas of infarction and abnormal perfusion and allows quantification CAC, coronary artery calcium; CHD, coronary heart disease; CT, computed tomography; NCEP,
of the extent and density of coronary artery calcification.49 Cine-CT National Cholesterol Education Program.
Greenland, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on
scanning is more sensitive and specific than fluoroscopy in identifying coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment
the extent and density of coronary artery calcification. The calcium and in evaluation of patients with chest pain. J AM Coll Cardiol 2007;49:378–402.
score (calcium density and volume of calcium) in patients older than
30 to 70 years with known CAD is significantly higher than in subjects than TTE but in many expert centers, TEE maybe as good.
with no CAD and appears to correlate well with the degree of coronary Currently 3D echocardiography can add other important infor-
artery occlusion (Table 13–15).50 mation to a critical patient’s case, for example, valvular leaks and
New CT scanning may be more definitive and accurate in the wall motion changes. Diagnostic accuracy of aortic dissections
diagnosis of aortic dissection and evaluation of the pericardium with CT scanning is >90%. CT scanning affords definition of the
 114
edges of the intimal flap of the dissection, and true and false TABLE 13-16 Criteria for Cardiac Computed Tomography (CCT)
channels can be seen. It also demarcates the components of the and Cardiac Magnetic Resonance (CMR)
SECTION 2

myocardial wall from the inner endocardial wall through to the ACCF/ACR/SCCT/SCMR/ASNC/NASCI/SCAI/SIR
epicardial surface and pericardium, allowing visualization of 2006 Appropriateness
abnormalities, such as aneurysms and thrombin. Detection of the
Appropriate test for specific indication (Score 7–9)
presence of a thrombus on a CT scan is comparable in accuracy
Detection of CAD: Symptomatic
with 2D echocardiography. The pericardium appears as a distinct Intermediate pretest probability of CAD
entity and can be evaluated for thickening and calcification. CT ECG uninterpretable or unable to exercise
scanning is the most sensitive technique to differentiate types of Evaluation of Intracardiac Structures (Use of CT Angiogram)
pericarditis and estimate pericardial fluid volume. Compared with Evaluation of suspected coronary anomalies
Cardiovascular Disorders

echocardiography, CT scanning is equivocal to define loculated Acute Chest Pain (Use of CT Angiogram)
and hemorrhagic effusions. Important advances in 3D echocardi- Intermediate pretest probability of CAD
ography is currently making significant advancement as we have No ECG changes and serial enzymes negative
seen with new CT scanners. Morphology (Use of CT Angiogram)
In the evaluation of cardiac masses, CT scanning shows the mass Assessment of complex congenital heart disease including anomalies of
coronary circulation, great vessels, and cardiac chambers and valves
as a distinct space-occupying entity. Tissue density differentiation as
Evaluation of coronary arteries in patients with new onset heart failure to
seen on a CT scan allows characterization of density, aiding in assess etiology.
determination of the nature of masses. Masses as small as 0.5 to 1 Evaluation of Intra- and Extracardiac Structures (Use of Cardiac CT)
cm can be identified on CT scans. Evaluation of cardiac mass (suspected tumor or thrombus)
Like radionuclide assessment, contrast angiography, and echocar- Patients with technically limited images from echocardiogram, MRI, or TEE
diography, CT scanning can be used to calculate ejection fraction, left Evaluation of pericardial conditions (pericardial mass, constrictive pericarditis,
ventricular volume, and stroke volume. The blood pool is defined or complications of cardiac surgery)
with intravenous iodinated contrast material. Ventricular volumes, Patients with technically limited images from echocardiogram, MRI, or TEE
ejection fraction, and stroke volume are determined directly from the Evaluation of pulmonary vein anatomy prior to invasive radiofrequency
blood pool on each image. Values obtained with CT scanning are ablation for atrial fibrillation
Noninvasive coronary vein mapping prior to placement of biventricular
more accurate and reproducible than those obtained on angiography
pacemaker
and ECHO. The three-dimensional image of a CT scan also allows Noninvasive coronary arterial mapping, including internal mammary artery
determination of the extent and distribution of LVH in patients with prior to repeat cardiac surgical revascularization
hypertrophic or congestive cardiomyopathy. Evaluation of Aortic and Pulmonary Disease (Use of CT Angiograma)
CT scanning has proven to be an effective noninvasive method to Evaluation of suspected aortic dissection or thoracic aortic aneurysm
visualize congenital heart disease, but its role is challenged by the Evaluation of suspected pulmonary embolism
higher-resolution capacity of MRI.50 For measuring parameters in Uncertain for specific indication (Score 4–6)
some congenital disorders, such as evaluation of ventricular func- Inappropriate test for that indication (Score 1-3)
tion and estimation of the volume of cardiac shunts, CT scanning CAD, coronary artery disease; ECG, electrocardiogram; MRI, magnetic resonance imaging; TEE,
still remains an important choice. As patients have more procedures transesophageal echocardiography.
a
related to implanted metallic devices, CT scanning is a very impor- Nongated, CT angiogram which has a sufficiently large field of view for these specific indications.
Hendel (Guidelines). JACC 2007;48:1475. Summary of Table 11–20.
tant option and newer CT scanners are making major strides in
many areas of congenital heart disease.
A few practical considerations when one considers CT for evalu- the high resolution and spatial capabilities mean that CT scanning
ating the coronary arteries. Diagnostic quality imaging may require offers unique properties. It is important to remember that CT
in most cases the patient to have normal sinus rhythm, and a scanning radiation dosage on average is three times more than a
targeted heart rate of less than 65 beats per minute during image routine heart catheterization. Current coronary angiography has a
acquisition. The patient’s heart rate should be measured during a mean effective radiation dosage of approximately 5 mSv (mil-
breath-holding test to determine whether the administration of a β- lisievert) and cardiac CT varies between 6.9 and 20 mSv depending
blocker is necessary. If the heart rate drops after inspiration breath on the configuration.54,55
holding by 10 beats per minute, the study should be of good quality.
However, sometimes short-acting β-blockers are needed to reduce POSITRON EMISSION TOMOGRAPHY
heart rates to below 65 beats per minute.51
Recently published guidelines from the AHA52 on the assessment PET is a relatively new modality for diagnostic imaging in CVD
of coronary artery disease by cardiac computed tomography have an medicine.56,57 PET has found a niche to characterize myocardial physi-
excellent review of the topic with a wonderful reference section. ologic and metabolic activity, perfusion, and viability. PET can measure
Table 13–16 is an overview of current considerations for scanning. regional myocardial uptake of exogenous glucose and fatty acids,
Most expert panels generally agree that patients with a prior quantitate free fatty acid metabolism, define perfused myocardium
probability of a coronary event in the intermediate range (>6% in energy source(s), and evaluate myocardial chemoreceptor sites.61
10 years but <20% in 10 years), a calcium score of >100 would yield Although many other techniques can be used similarly to evaluate
a posttest probability >2% per year in the majority of patients. This myocardial function, PET images are superior in definition. The pri-
would place the patient in the range of a coronary heart disease risk mary advantages of PET are its noninvasive nature, the ability to do
equivalent population and within a level requiring secondary pre- repeat scans within a short period of time, such as before and after
vention strategies. Table 13–17 describes the American College of percutaneous transluminal coronary angioplasty (PTCA), and the
Cardiology Foundation (ACCF) results of appropriate use of car- reproducibility of images over time. PET is very expensive because of
diac computed tomography in cardiovascular disease from the the need for onsite cyclotrons for many of the radiotracers, and there is
Appropriateness Criteria Working Group.53 limited availability of sites that offer the technique. Cheaper forms of
In summary, CT scanning, especially cine-CT scanning, is a PET-like scanning are in development, but image resolution is lower.
rapidly evolving technique for evaluation of CVD. It remains an PET uses positron-emitting isotopes such as oxygen-15, nitrogen-
expensive alternative to other methodologies in many instances, but 13, carbon-11, and fluoride-18. These are incorporated into sub-
 115
11
TABLE 13-17 Interpretation and Recommendations for CT Heart lism, and [ C]acetate is an indirect marker for myocardial oxygen
consumption, allowing assessment of ventricular performance.

CHAPTER 13
Scanning and CACP Scoring
[11C]Palmitate is a useful marker for normal myocardial oxygen
Negative test result
consumption because baseline energy needs of the myocardium are
A negative test (score = 0) makes the presence of atherosclerotic plaque,
including unstable or vulnerable plaque, highly unlikely.
met through fatty acid oxidation. Clearance of [11C]palmitate is
A negative test (score = 0) makes the presence of significant luminal obstructive biexponential, and studies in animals and in healthy men show
disease highly unlikely (negative predictive power by EBCT on the order of clearance to be proportional to cardiac workload and myocardial
95% to 99%). oxygen consumption. In acute ischemia, the first component of
A negative test is consistent with a low risk (0.1% per year) of a cardiovascular clearance is reduced and the second is increased. The use of [11C]palm-
event in the next 2 to 5 years. itate to assess myocardial metabolism in ischemic tissue is limited
Positive test result

Cardiovascular Testing
because there is altered transport and storage of the compound and
A positive test (CAC 0) confirms the presence of a coronary atherosclerotic significant back diffusion of the agent into the vascular space.
plaque. FDG accumulates in the heart proportional to glucose use by the
The greater the amount of coronary calcium, the greater the atherosclerotic
myocardial cell and so is a marker of cell viability. FDG studies help
burden in men and women, irrespective of age.
The total amount of coronary calcium correlates best with the total amount of
to identify the affected vascular bed and allow evaluation as to
atherosclerotic plaque, although the true atherosclerotic burden is underestimated. whether angioplasty or surgery might be used. Detection of hiber-
High score nating myocardium is possible because it predominantly uses glu-
A high calcium score (an Agatston score >100) is consistent with a high risk of a cose and can be seen readily on PET scans. Patients with a
cardiac event within the next 2 to 5 years (2% annual risk). significant degree of jeopardized or hibernating myocardium iden-
Risk prediction tified on PET scanning then could be candidates for revasculariza-
Coronary artery calcium measurement can improve risk prediction in conventional tion procedures. In contrast, a perfusion study would not show as
intermediate-risk patients, and CACP scanning should be considered in individu- good differentiation of infarcted versus hibernating tissue, and
als at intermediate risk for a coronary event (1.0% per year to 2.0% per year) for revascularization may not be considered. In studies of recovery of
clinical decision making with regard to refinement of risk assessment.
left ventricular function following revascularization, PET has a
Decisions for further testing (such as stress testing or cardiac catheterization)
beyond assistance in risk stratification in patients with a positive CACP score
positive predictive value of 72% and a negative predictive value of
cannot be made on the basis of coronary calcium scores alone, as calcium score 83%. PET with FDG has been used in the assessment of cardiomy-
correlates poorly with stenosis severity in a given individual and should be based opathies. In ischemic cardiomyopathy, discrete regional ischemia is
upon clinical history and other conventional clinical criteria. seen as a patchy, nonhomogeneous uptake of the tracers; dilated
cardiomyopathies show global decreased uptake of tracers.
CACP, coronary artery calcified plaque; CAC, coronary artery calcium; CT, computed tomography;
EBCT, electron-beam computed tomography. In CAD, PET is used to assess and follow the physiologic signifi-
cance of stenotic lesions. After infarction, PET myocardial substrate
stances such as water, glucose analogs, or fatty acids, the metabolic metabolism studies are used to evaluate the amount and activity of
substrates for myocardial tissue. For myocardial perfusion studies, viable tissue around the infarcted area and the site and extent of
rubidium-82 (82Rb), nitrogen-13 ammonia ([13N]H3), and 15O2- infarction. Myocardial perfusion studies with PET identify more
labeled water are used. For myocardial substrate metabolism accurately the viable and nonviable myocardium compared with
studies, [11C]palmitate, [11C]acetate, and [18F]2-deoxyglucose technetium and thallium. PET also quantifies regional myocardial
(FDG) are used. All these substances have very short half-lives (<10 perfusion more accurately than other modalities. When linked with
minutes). In the fasting state, perfused myocardium primarily uses physiologic or pharmacologic stress tests, PET enables evaluation of
fatty acids as energy source. Postprandially, glucose is the preferred the myocardium under stress conditions. Studies in patients with
substrate. Ischemic myocardium primarily metabolizes glucose more than 50% stenosis on angiography suggest that dipyridamole
because mitochondrial fatty acid oxidation is impaired. Hence, with stress SPECT and [13N]ammonia PET are comparable tests to assess
PET using either a fatty acid or glucose substrate, ischemic versus coronary artery perfusion, with respective sensitivities of 98% and
nonischemic areas can be defined. Frequently, PET is used in 96% and specificities of 88% and 81%. SPECT analysis using FDG
conjunction with pharmacologic stress testing to provoke ischemia, compared with PET with FDG shows comparable accuracy for the
with images obtained before and after stress application. detection of CAD. Comparative studies with SPECT thallium in
Uptake of 82Rb occurs via the Na+-K+-ATPase pump and occurs conjunction with bicycle ergometer or dipyridamole versus PET
preferentially in viable tissue. Net uptake into tissue resolving from an perfusion scanning showed comparative sensitivities (76% to 79%)
ischemic insult and infarcted tissue is reduced. With a half-life of 1.26 but improved specificity (90% versus 82%, p <0.005).58
minutes, serial images of myocardial perfusion can be taken as fre- The future of PET appears promising. Improved tomographic
quently as every 5 minutes, and a dobutamine stress test is completed scanners, development of new radiopharmaceuticals, and improved
within 45 minutes. Comparative studies with ETT, SPECT, and stress understanding of substrate metabolism and its relationship to
echocardiography show PET to be more accurate in the detection of myocardial tissue viability will provide new dimensions to assess
IHD. The substrate [13N]H3 rapidly crosses capillary membranes and and evaluate myocardial function. Research enterprises are develop-
is trapped in the myocardium by glutamate–glutamine reactions. This ing agents to label receptors as a tool to determine cardiovascular
product produces high-contrast images with a sensitivity of 88% to physiology and how altered receptor function, biochemical abnor-
97% and a specificity of 90% to 100% to detect IHD. 15O2-labeled malities, substrate metabolism, or other as yet unrecognized abnor-
water has a high extraction ratio into myocardial tissue, which appears malities impair cardiac function. It continues to be used mostly to
to be independent of blood flow or the metabolic state of the myocar- answer research questions than in clinical practice settings. A few
dium. 15O2-labeled water studies are done in conjunction with specialized, large centers do offer PET scanning.
[15O]carbon monoxide (labels red blood cells in the vascular space)
studies to help eliminate some of the background activity that occurs CARDIAC CATHETERIZATION
as a result of the high extraction ratio.58 AND ANGIOGRAPHY 59
Tracers used for assessment of myocardial metabolism are selected
based on the type of metabolism of interest: FDG traces glucose  Development of the cardiac catheterization technique was a
metabolism, [11C]palmitate traces mitochondrial fatty acid metabo- major milestone in the diagnosis and management of CVD because
 116
it provided a physiologic and anatomic approach to assess patency of TABLE 13-18 Recommendations for Coronary Angiography in
coronary vessels and hemodynamic parameters of cardiac function. Patients with Known or Suspected Coronary Artery
SECTION 2

Cardiac catheterization is the technique used to gain vascular access Disease Who Are Currently Asymptomatic or Have
to the coronary arteries by intravascular catheters and heart cham- Stable Angina
bers. Once cardiac catheterization is complete, other diagnostic and
Class I
therapeutic procedures, such as angiography, ventriculography, and
1. Canadian Cardiovascular Society (CCS) class III and class IV angina on medical
PTCA, and drug administration (e.g., thrombolytics) may be under- treatment. (Level of Evidence: B)
taken. Following interventional procedures such as PTCA, catheter- 2. High-risk criteria on noninvasive testing regardless of anginal severity. (Level
ization with angiography can be used to evaluate efficacy of the of Evidence: A)
intervention. In recurrent clinical syndromes, following a procedure, 3. Patients who have been successfully resuscitated from sudden cardiac death or
Cardiovascular Disorders

catheterization is used to help delineate a new management strategy. have sustained (>30 seconds) monomorphic ventricular tachycardia or nonsus-
Catheterization is also now used commonly with PTCA and/or drug tained (<30 seconds) polymorphic ventricular tachycardia. (Level of Evidence: B)
therapy in the management of acute coronary syndromes. Class IIa
Additionally, catheterization allows assessment of valvular func- 1. CCS class III or IV angina, which improves to class I or II with medical therapy.
tion and computation of various cardiac performance parameters (Level of Evidence: C )
2. Serial noninvasive testing with identical testing protocols, at the same level of
such as cardiac output, stroke volume, systemic vascular resistance,
medical therapy, showing progressively worsening abnormalities. (Level of
cardiac chamber pressures, and blood flow. It also allows for Evidence: C )
placement of cardiac pacemakers. Drug administration during car- 3. Patients with angina and suspected coronary disease who, because of
diac catheterization is used primarily for assessment of end points disability, illness, or physical challenge, cannot be adequately risk stratified by
in clinical trials (e.g., thrombolytics to assess coronary artery pat- other means. (Level of Evidence: C )
ency), for management of events (e.g., chest pain) during catheter- 4. CCS class I or II angina with intolerance to adequate medical therapy or with
ization, or for diagnostic purposes (e.g., ergonovine to evaluate failure to respond, or patients who have recurrence of symptoms during
coronary spasm). Further applications of cardiac catheterization adequate medical therapy as defined above. (Level of Evidence: C )
include aortic root angiography, pulmonary angiography, retrieval 5. Individuals whose occupation involves the safety of others (e.g., pilots, bus
of foreign bodies, and atherectomy.60 drivers, etc.) who have abnormal but not high-risk stress test results or multiple
clinical features that suggest high risk. (Level of Evidence: C )
More than 1 million cardiac catheterizations are performed in the
Class III
United States each year, making it the second most frequent in- 1. Angina in patients who prefer to avoid revascularization even though it might
hospital procedure. Images obtained during catheterization are be appropriate. (Level of Evidence: C )
stored on 35-mm cineradiographic film or are digitized, allowing 2. Angina in patients who are not candidates for coronary revascularization or in
comparison of studies at a later date. The ACC/AHA guidelines on whom revascularization is not likely to improve quality or duration of life.
angiography and PTCA describe the classes I, II, and III indications (Level of Evidence: C )
for each of these procedures; examples are given in Tables 13–18 3. As a screening test for coronary artery disease in asymptomatic patients. (Level
and 13–19.63 The guidelines for angiography, PTCA, and catheter- of Evidence: C )
ization also include recommendations regarding technique, proce- 4. After coronary artery bypass grafting or angioplasty when there is no evidence
dures, facilities, personnel, and training. of ischemia on noninvasive testing, unless there is informed consent for
research purposes. (Level of Evidence: C )
The cardiac catheterization procedure requires vascular access,
5. Coronary calcification on fluoroscopy, electron-beam computed tomography,
usually obtained percutaneously at brachial or femoral arteries or or other screening tests without criteria listed above. (Level of Evidence: C )
veins. Left-sided catheterization provides access to the aorta, left
ventricle, and left atrium. Right-sided catheterization enables the Scanlon PJ, Faxon DP, Audet A-M, et al. ACC/AHA Guidelines for Coronary Angiography: Executive
Summary and Recommendations. Circulation 1999;99:2345–2357. ©American Heart Association, Inc.
right side of the heart, coronary sinus, pulmonary arteries, and
pulmonary wedge position to be reached. Left-sided catheterization
is used for coronary angiography and ventriculography, whereas short-acting benzodiazepines, frequently are given to ensure patient
right-sided catheterization is used for determination of cardiac comfort and safety, but the patient is awake and aware of the
performance parameters. procedure. Patient cooperation is necessary to obtain the angiogra-
Prior to an elective procedure, the patient is given nothing by phic views and assess symptoms. The patient is required to remain
mouth (after midnight) except for oral medications. It is not still for about 6 to 8 hours to reduce the risk of bleeding from the
necessary to stop any medications except warfarin prior to catheter- catheter entry site(s). Depending on the procedure, patients may be
ization. Patients receiving warfarin may be transitioned to low- discharged the same day or within 24 hours, if stable.
molecular-weight or unfractionated heparin or anticoagulation may Heparin products are used during procedures such as angiog-
be discontinued depending on the clinical scenario about 3 days raphy, left-sided heart catheterization, and PTCA to prevent throm-
prior to the procedure. Heparin products are stopped about 6 hours botic complications. Depending on the procedure undertaken,
before the procedure to allow normalization of coagulation. There
are no data to support low-molecular-weight heparin during cathe- TABLE 13-19 Recommendations for Coronary Angiography in
terization procedures because its longer half-life may increase the Patients with Nonspecific Chest Pain
risk of intra- and postprocedural bleeding. Patients who require
Class I
anticoagulation prior to angiography (e.g., those with acute coro-
High-risk findings on noninvasive testing. (Level of Evidence: B)
nary syndromes) usually are treated with unfractionated heparin or Class IIa
low-molecular-weight heparin. None.
Patients frequently develop chest pain and/or vasospasm during Class IIb
introduction and manipulation of catheters and injection of angiog- Patients with recurrent hospitalizations for chest pain who have abnormal (but not
raphic dyes. Nitroglycerin/nitroprusside and/or morphine may be high-risk) or equivocal findings on noninvasive testing. (Level of Evidence: B)
given for chest pain. Nitroglycerin also is used to prevent vasospasm Class III
and is given sublingually or by intravenous infusion. The use of All other patients with nonspecific chest pain. (Level of Evidence: C )
nitroprusside has increased in recent years because it is a direct Scanlon PJ, Faxon DP, Audet A-M, et al. ACC/AHA Guidelines for Coronary Angiography: Executive
smooth muscle vasodilator. Sedatives, such as midazolam and other Summary and Recommendations. Circulation 1999;99:2345–2357. ©American Heart Association, Inc.
 117
heparin is either discontinued almost immediately following the such as a vagal reflex with hypotension, bradycardia, and nausea, can
procedure or continued for 12 to 24 hours. Heparin administration occur. These occur most frequently in conjunction with patient

CHAPTER 13
during the procedure is measured with the activated clotting time, anxiety and can be prevented or treated with atropine. An increased
not the partial thromboplastin time. For patients undergoing percu- predisposition to myocardial infarction during and after the proce-
taneous coronary intervention, aspirin, and clopidogrel are used dure is seen in patients with unstable angina, recent subendocardial
prior to and following the procedure. Despite the invasive nature of infarction, and type 1 diabetes mellitus. After catheterization,
the procedure, there are no data to support the need for prophylac- patients may have elevated creatine phosphokinase and troponins as
tic antibiotics in patients at risk for bacterial endocarditis because of a consequence of tissue damage during the procedure. There is some
valvular prostheses or a prior history of rheumatic fever. At present, controversy as to how to interpret these values with respect to what
the infectious risk of this procedure is extremely low. With the they indicate regarding myocardial damage. Acute closure of a

Cardiovascular Testing
advent of classes IIb/IIIa receptor antagonists such as tirofiban, coronary vessel or myocardial ischemia is managed by return to the
eptifibatide, and abciximab, which improve short- and long-term catheterization laboratory or cardiac surgery. All facilities should be
coronary artery patency rates with high-risk percutaneous coronary in close liaison with a cardiothoracic surgery unit.
intervention, patients who receive a stent also will receive one of Angiography, which accompanies most cardiac catheterization
these agents prior to, during, and/or after the procedure. Abciximab procedures, is defined as the “radiographic visualization of coronary
is usually preferred. vessels after injection of radiopaque contrast medium.” Despite the
During the procedure, hemodynamic parameters, blood pressure, expanding role of cardiac catheterization, angiography is used most
and heart rate are monitored continuously. ECG monitoring and frequently to describe the presence and extent of CAD and to allow
intermittent 12-lead ECGs are also maintained. Measurements taken planning for medical or surgical intervention. Cardiac catheteriza-
during catheterization are obtained only after hemodynamic stabili- tion with angiography is the “gold standard” in the diagnosis and
zation: at baseline, following catheter movement, or during pharma- assessment of CAD, against which all new invasive and noninvasive
cologic intervention. Information obtained during catheterization is tests are measured. Unlike most other procedures, angiography
in real time and is assumed to reflect the ongoing status of the determines the morphology of a stenotic lesion and the degree of
coronary circulation. Procedurally related vasospasm may be mis- luminal obstruction. However, this does not relate well to physio-
leading because the catheter itself is a powerful stimulus for spasm. logic or functional significance of the lesion.59 For example, a 50%
Complications associated with cardiac catheterization procedures luminal occlusion not considered significant by radiologic stan-
and attending angiographic or interventional activities are related to dards may still be the lesion producing symptomatic chest pain, and
the expertise and experience of the operator, with case load being a a diabetic patient with significant microvascular CAD may appear
good indicator of the latter. The incidence of significant complica- to have unaffected larger arteries at angiography and yet still be at
tions related to catheterization with angiography is reported to be risk of a cardiac event. Angiography also assesses the presence of
less than 2%, with mortality approximately 0.11%. Patient factors collateral circulation and dynamic abnormalities such as vasospasm.
such as hemodynamic stability and renal function increase risk. The extent of disease by angiography is defined as the number of
There are no absolute contraindications to coronary angiography, vessels, and the vessels affected are named. Angiography is able to
and the relative contraindications are not well substantiated (Table detect lesions that occlude the vessel by as little as 20%. Occlusions
13–20). In essence, clinical stability of the patient and potential of 75% or more are almost always seen on angiography. Significant
benefit of the procedure in terms of future patient management narrowing is usually assumed to be 50% or more, although some
predicate the importance of relative contraindications. Complication studies use 70% narrowing as the cutoff point. The lesion can be
rates, especially those of a thrombotic nature, increase with the dwell measured in several ways. Considerable controversy exists as to the
time of the catheters, duration of catheterization, catheter type, and best methodology. During angiography, the lesion is compared
operator technique. Bleeding complications can be reduced by visually with surrounding vessels. Inherent difficulties include indi-
ensuring that patients have normal coagulation studies prior to the vidual evaluator variability and also the assumption that surround-
procedure and remain at bedrest for several hours after the proce- ing vessels are normal. Calipers can be used to document physical
dure, and that the nursing staff undertakes good care of the catheter size, but generally, the degree of stenosis is reported as a percentage
entry and exit sites. In the event of bleeding complications, direct of narrowing. Various grading scales, such as the coronary artery
pressure is required with sandbags, followed by emergency surgery if score and myocardial jeopardy scores, are used, and these scores
there is no resolution, to prevent further complications. Heart predict long-term outcomes. Coronary artery lesions most prone to
perforation is an uncommon but potentially lethal complication rupture and thrombosis are those with 40% to 60% narrowing, so
requiring emergency surgical intervention. Other complications, lesions with less than 50% narrowing are not benign.
Multiple views are required to obtain a good image of the vessel;
the right anterior oblique planes are used most commonly (two
TABLE 13-20 Contraindications of Cardiac Catheterization and views at 90° to each other). Lesions may be described as concentric
Other Proceduresa and smooth (simple lesions) or eccentric and broad with a rough
Recent stroke Patient noncomplianceb surface (complicated lesions). The number of lesions is also consid-
Advanced physiologic age Digoxin intoxication ered of importance to the severity and prognosis of IHD, although
Severe anemia Anaphylaxis to radiographic dyes there is considerable variation in the accuracy of such predictions
Severe hypertension Active infection because angiographic and pathologic correlation of lesions is imper-
Active gastrointestinal bleed Severe electrolyte imbalances fect. The occurrence of spasm, variants in anatomy, and collateral
Fever Unstable condition filling also complicate interpretation of the angiogram.
Other comorbid illnesses, e.g., COPDc,d Angiographic films are used to plan interventions, in particular
COPD, chronic obstructive pulmonary disease; PTCA, percutaneous transluminal coronary angio- coronary artery bypass grafting and percutaneous coronary inter-
plasty. vention. They are also used during both surgery and percutaneous
a
Primarily contraindications to procedures such as arteriography and PTCA. coronary intervention to guide the procedure. Ventriculographic
b
Patient not willing to undergo further treatment (e.g., surgery based on results of catheterization).
c
Disease states that may prohibit or increase risk of other interventions (e.g., surgery).
studies may be performed during cardiac catheterization to obtain
d
Patients in whom emergency cardiac surgery would pose a high risk (e.g., during acute asthma or information about the contours of the heart and to assess global and
acute exacerbation of COPD). segmental function. Regional wall motion, filling defects, and the
 118
SECTION 2
Cardiovascular Disorders

FIGURE 13-9. Intravascular ultrasound

(IVUS) imaging demonstrating mild to
severe atherosclerosis. Optical coherence
tomography demonstrating a lipid pool
inside of a plaque.

presence of mural thrombi also may be visualized. During this coronary arteries) can be visualized, but they require a more
procedure, radiopaque dye is injected into the heart chambers, and complex system for image reconstruction and show more artifacts
serial films are taken to follow the dye passage. Left ventricular in imaging. Recently, new software packages have allowed detailed
ventriculography is a routine part of left-sided catheterization images identifying calcium, fibrofatty, and lipid plaques. This could
unless ventricular function information is already available from be a major advance in IVUS clinical use (Fig. 13–9).
other noninvasive studies or there are specific contraindications to In contrast to angiography, IVUS provides quantitative informa-
the procedure. tion from within the vessel on diameter, circumference, luminal
Cardiac performance is also best assessed during catheterization diameter, plaque volume, and percent stenosis. Qualitative infor-
procedures as direct visualization of performance along with calcu- mation regarding the amount of plaque stenosis, plaque composi-
lated parameters that can be obtained simultaneously and represent tion (e.g., calcific, fibrous, or fatty plaque), and the presence of
real-time values. Measured and observed parameters obtained dur- plaque versus thrombus, thrombus versus tumor, and aneurysm
ing catheterization are used to determine cardiac performance. and hematoma can be provided by IVUS. IVUS is also used as a
Contractility, as judged by wall motion and ejection fraction, can be therapeutic adjunct with PTCA, atherectomy, stent or graft place-
used to assess global cardiac performance and to plan and evaluate ment, and fibrinolysis, although routine use may not be justified.
or assess therapy. These combination procedures may be monitored in real time as the
Invasive cardiology is growing rapidly not only in terms of the procedure (e.g., atherectomy) is being performed. In current trials,
numbers of patients undergoing such procedures but also in terms IVUS has been very helpful in evaluation of disease progression or
of the diversity of procedures. The development of electrophysio- regression. Many current trials are underway to test medication for
logic studies for the assessment and treatment of arrhythmias was atherosclerosis regression, plaque morphology changes and other.66
made possible because of catheterization. The diversity of tech- Another new development in imaging the inner wall of the
niques is “limited only by the imagination of the physician and coronary is the recently developed, intravascular optical coherence
inventiveness of the microtechnologist.” tomography providing high-resolution, cross-sectional images of
tissue with an axial resolution of 10 microns and a lateral resolution
of 20 microns.63 Optical coherence tomography images of human
INTRAVASCULAR ULTRASOUND coronary atherosclerotic plaques are much more structurally
Intravascular ultrasound (IVUS) is a procedure that uses a very detailed than IVUS.63 Clinically, the detection of thin fibrous caps
small ultrasound transducer on the tip of a coronary catheter to (vulnerable atheromas) (<65 microns) is below the resolution of the
construct detailed images of the inner wall of a coronary artery. It current 40-MHz IVUS (100 to 200 microns).60 A summary of tests
combines braided polyethylene catheter technology with miniatur- used in cardiovascular medicine is provided in Appendices 13–1
ized ultrasound transducers that can be inserted into a variety of and 13–2.
vascular beds within the body, including the coronary artery vascu-
lature.60–63 Catheter configurations vary and may include over-the-
wire, monorail, and fixed-guidewire tip configurations, resulting in
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myocardial infarction. N Engl J Med 2003;348:933–940. esophageal compared with transthoracic echocardiography in infective
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18. Zimetbaum PJ, Josephson ME. Use of the electrocardiogram in acute 40. Sabharwal NK, Lahiri A. Role of myocardial perfusion imaging for risk
myocardial infarction. N Engl J Med 2003;348:933–940. stratification in suspected or known coronary artery disease. Heart
19. Fisch C. Evolution of the clinical electrocardiogram. J Am Coll Cardiol 2003;89:1291–1297.
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Study Versus Electrocardiographic Monitoring (ESVEM) trial. Am J 44. Beleslin BD, Ostojic M, Stepanovic J, et al. Stress echocardiography in
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24. Kadish AH, Buxton AE, Kennedy HL, et al. ACC/AHA clinical compe- 45. Greco CA, Salustri A, Seccareccia F, et al. Prognostic value of dobuta-
tence statement on electrocardiography and ambulatory electrocardi- mine echocardiography early after uncomplicated acute myocardial
ography: A report of the American College of Cardiology/American infarction: A comparison with exercise electrocardiography. J Am Coll
Heart Association/American College of Physicians-American Society Cardiol 1997;29:261–267.
of Internal Medicine Task Force on Clinical Competence (ACC/AHA 46. Sabharwal NK, Lahiri A. Role of myocardial perfusion imaging for risk
Committee to Develop a Clinical Competence Statement on Electro- stratification in suspected or known coronary artery disease. Heart
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2001;104:3169–3178. 47. Gibbons RJ, Eckel RH. The Utilization of Cardiac Imaging 2006. 2006,
25. Linzer M, Yang EH, Estes M, et al. Diagnosing syncope: 1. Value of http://www.americanheart.org/presenter.jhtml?identifier=3004557.
history, physical examination and electrocardiography. Ann Intern 48. Thompson BH, Stanford W. Evaluation of cardiac function with ultrafast
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49. Lazem F, Barbir M, Banner N, et al. Coronary calcification detected by 55. Globits S, Higgins CB. Assessment of valvular heart disease by mag-
ultrafast computed tomography is a predictor of cardiac events in netic resonance imaging. Am Heart J 1995;129:369–381.
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heart transplant recipients. Transplant Proc 1997;29:572–575. 56. Schwaiger M, Muzik O. Assessment of myocardial perfusion by perfu-
50. Ganz W, Serafini A, Lerner D, et al. Cardiovascular magnetic reso- sion emission tomography. Am J Cardiol 1991;67:35D–43D.
nance imaging goes beyond anatomy. Crit Rev Diagn Imaging 57. Schelbert HR. Metabolic imaging to assess myocardial viability. J Nucl
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51. Shim SS, Kim Y, Lim SM. Improvement of image quality with beta- 58. Schwaiger M, Hutchins G. Quantification of regional myocardial perfu-
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53. Hendel RC, Douglas PS, Peterson ED, et al. ACCF/ACR/SCCT/SCMR/ Bishop lecture. J Am Coll Cardiol 1994;23:525–532.
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puted tomography and cardiac magnetic resonance imaging: a report of intravascular ultrasound radiofrequency data analysis. Circulation
the American College of Cardiology Foundation Quality Strategic Direc- 2002;106:2200–2206.
tions Committee Appropriateness Criteria Working Group, American 62. Nicholls SJ, Tuzcu EM, Sipahi I, Schoenhagen P, Nissen SE. Intravas-
College of Radiology, Society of Cardiovascular Computed Tomogra- cular ultrasound in cardiovascular medicine. Circulation 2006;114:55–
phy, Society for Cardiovascular Magnetic Resonance, American Society 59.
of Nuclear Cardiology, North American Society for Cardiac Imaging, 63. Elliott MR, Thrush AJ. Measurement of resolution in intravascular
Society for Cardiovascular Angiography and Interventions, and Society ultrasound images. Physiol. Meas 1996;17, 259–265.
of Interventional Radiology. J. Am Coll. Cardiol 2006;48;1475–1497. 64. Kawasaki M, Bouma BE, Bressner J, et al. Diagnostic accuracy of
54. Udo Hoffmann,, Antonio J. Pena, Ricardo C. Cury. Cardiac CT in optical coherence tomography and integrated backscatter intravascu-
emergency department patients with acute chest pain. Radiographics lar ultrasound images for tissue characterization of human coronary
2006;26:963–979. plaques. J Am Coll Cardiol 2006;48:81–88.
 121

Appendix 13-1

CHAPTER 13
Types of Tests Used to Evaluate the Cardiovascular System
Cardiac Functiona
Myocardial Perfusion Pump Electrical Rhythm Anatomy
Type of test Stress tests Angiography ECG Echocardiography
Nuclear imaging MUGA Electrophysiologic studies Angiography

Types of Tests Used to Evaluate the Cardiovascular System

Angiography Echocardiography Holter monitoring Intravascular ultrasound
Echocardiography Angioscopy
Parameters evaluated Coronary anatomy and blood flow Cardiac output Rhythm Chamber size
Myocardial perfusion Ejection fraction Rate Wall motion
Valvular function Conduction pathways Valve function
Shunts Valve structure
Pericardium
Coronary anatomy
ECG, electrocardiogram; MUGA, multigated acquisition.
a
Not all tests for any one cardiac function are used to evaluate all parameters listed.

Appendix 13-2
Types of Tests for Various Cardiac Diseases or Features
Feature/Disorder CXR Echo Angiography Nuclear Scan CT MRI ET ECG PET
a
Ischemic — +++ ++++ +++ ++/++ ++ ++ ++ +++
Valvular + ++++ +++ + +++ +++ ++ + +
Congenital ++ ++++ +++ + +++ ++++ + + +
Anatomy + +++ ++ + +++ ++++ — + +
Cardiomyopathy + ++++ +++ ++ +++ +++ — — ++
Pericardial + ++++ ++ — ++++ ++++ — ± —
Endocarditis — ++++b + — ++ +++ — ± —
Masses — ++++ + — +++ +++ — — +
Metabolism — — — + — — — — ++++
Graft patency — ± +++ ++ + ++ ++ + +++
CA anatomy — — ++++ ++ + ++ ++ + +
Ventricular function — ++++ +++ ++ +++ +++ + — ++
CA, coronary artery; CT, computed tomography; CXR, chest radiograph; ECG, electrocardiogram; echo, echocardiography; ET, exercise testing; PET, positron emission tomography.
a
Ultrafast or cine-CT may be very useful in detecting ischemia based on calcium disposition.
b
Transesophageal echocardiography is superior to transthoracic echocardiography.
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C HAP T E R

14 Cardiopulmonary Arrest

JEFFREY F. BARLETTA AND JEFFREY L. WILT

EPIDEMIOLOGY
KEY CONCEPTS
 High-quality cardiopulmonary resuscitation (CPR) with minimal In an adult patient, cardiopulmonary arrest usually results from the
interruptions in chest compressions should be emphasized in development of an arrhythmia.11 Most cardiac arrests take place
all patients following cardiac arrest. outside the hospital, and most patients have underlying acute or
chronic heart disease.6 In more than two-thirds of patients, cardiac
 Chest compressions before a defibrillation attempt might be arrest occurs as the first manifested clinical event with no preceding
warranted especially with cardiac arrests that are not witnessed. symptoms or warning.6,12 Although the most common arrhythmia is
 The purpose of using vasopressors following cardiac arrest is to either VF or PVT, the number of patients with out-of-hospital
increase both coronary and cerebral perfusion pressures. cardiac arrests presenting with VF as the initial rhythm has changed
dramatically.4,13 In one study, the number of patients with VF was
 Either epinephrine or vasopressin is an appropriate drug of first 61% in 1980 compared with only 41% in 2000, a reduction of
choice in patients with ventricular fibrillation (VF)/pulseless greater than 30%.13 A similar trend was noted with in-hospital
ventricular tachycardia (PVT). cardiac arrest as one study reported the number of patients present-
 Amiodarone is preferred over lidocaine as the antiarrhythmic ing with VF or PVT as the initial rhythm to be only 23%.14 Hospital
drug of choice in patients with VF/PVT. survival for in-hospital cardiac arrest related to VF or PVT is
approximately 36% with 75% having a good neurologic outcome.14
 Therapy for pulseless electrical activity (PEA) or asystole is Survival for out-of-hospital cardiac arrest caused by VF or PVT is
aimed at identifying the precipitating cause of the arrest. 25% to 40%, with higher survival rates being observed in communi-
ties that have a rapid response system.6,15,16
 Intraosseous administration is the preferred alternative for drug
In contrast to adult patients, only 15% of pediatric patients
delivery if intravenous access cannot be obtained.
present with VF or PVT as the initial rhythm.2 This is probably
because most pediatric arrests are respiratory-related as opposed to
the primary cardiac etiology seen in adult patients. Unfortunately,
INTRODUCTION survival following pediatric out-of-hospital cardiopulmonary arrest
ranges only from 2% to 10%, with most survivors having a poor
Cardiopulmonary arrest is the abrupt cessation of spontaneous and
neurologic status.2
effective ventilation and circulation following a cardiac or respira-
tory event.1 CPR provides artificial ventilation and circulation until
it is possible to provide advanced cardiac life support (ACLS) and ETIOLOGY
reestablish spontaneous circulation. In the United States, there are
more than 460,000 victims of sudden cardiac arrest each year with The most common cause of cardiopulmonary arrest in adult
most occurring outside the hospital.2–4 The annual incidence of patients is an acute myocardial infarction (MI) or pulmonary
sudden cardiac arrest has been estimated to be approximately 0.55 embolism (PE) representing more than 70% of victims.17 In pediat-
per 1,000 population and in the United States, sudden cardiac death ric patients, conversely, cardiopulmonary arrest is often the termi-
represents up to 15% of total mortality.5–7 nal event of progressive shock or respiratory failure.2 The cause of
Early attempts at resuscitation date back to the biblical era.8 cardiac arrest varies with age, the underlying health of the child, and
Modern-day resuscitation began in the late 1950s when it was the location of the event. Out-of-hospital arrests frequently are
discovered that expired air delivered via a mouth-to-mouth tech- associated with events such as trauma, sudden infant death syn-
nique can maintain adequate oxygenation of blood.9 Later, in 1960, drome, drowning, poisoning, choking, severe asthma, and pneumo-
Kouwenhoven and colleagues described “closed chest cardiac mas- nia.3 In-hospital pediatric arrests are associated with sepsis,
sage,” and together with mouth-to-mouth ventilation, modern-day respiratory failure, drug toxicity, metabolic disorders, and arrhyth-
CPR was born.10 mias. Pediatric out-of-hospital arrest generally presents with
hypoxia and hypercarbia progressing to respiratory arrest and
bradycardia and finally to asystolic cardiac arrest.

Learning objectives, review questions,

PATHOPHYSIOLOGY OF CPR
and other resources can be found at
www.pharmacotherapyonline.com. There are two proposed theories describing the mechanism of blood
flow during CPR.1,18,19 The first theory, known as the cardiac pump

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 124
theory, states that the active compression of the heart between the a 3% decrease in survival was noted for each 1-year increment in
sternum and vertebrae creates an “artificial systole” in which intra- age.22 Other proposed risk factors include concomitant diseases,
SECTION 2

ventricular pressure increases, the atrioventricular valves close, the initial pH, duration of resuscitation, and end-tidal carbon dioxide.11
aortic valve opens, and blood is forced out of the ventricles. When
ventricular compression ends, the decline in intraventricular pres- ■ GENERAL APPROACH TO TREATMENT
sure causes the mitral and tricuspid valves to open, and ventricular
filling begins. The second, more recent theory is the thoracic pump National conferences and organized committees have played a major
theory. The basis for this theory is the belief that blood flow results role in encouraging widespread competency in CPR technique. The
from intrathoracic pressure alterations induced by chest compres- first national conference took place in 1966 and recommended the
sions. During compression or systole, a pressure gradient develops training of healthcare professionals in the techniques of CPR.8 Since
then, the American Heart Association (AHA) has organized seven
Cardiovascular Disorders

between the intrathoracic arteries and the extrathoracic veins,

causing forward blood flow from the lungs into the systemic additional national conferences to update philosophies for providing
circulation. The heart merely acts as a passive conduit for flow. After CPR and emergency cardiovascular care (ECC) to the general popu-
compression ends, or diastole, intrathoracic pressure declines, and lation. The most recent conference was held in 2005, which provides
blood flow returns to the lungs. the latest set of recommendations for CPR and ECC.2
The concept of cough CPR supports the importance of changes in The Guidelines 2005 Conference recommendations were built on
intrathoracic pressure as a means of generating forward blood the same edifice that led to the ECC 2000 guidelines in that they are
flow.18,19 During vigorous coughing, intrathoracic pressures increase internationally developed as well as evidence-based. The classifica-
tion system used was consistent with that used by the AHA/
secondary to contractions of the diaphragm, abdominal muscles,
American College of Cardiology for evidence-based guidelines [i.e.,
and intracostal muscles. These pressure changes occur without direct
class I through class III or indeterminate (Table 14–1)]. These
chest compression and are sufficient to maintain consciousness. The
guidelines differ from previous years although, as they have been
observation that cough alone can maintain consciousness led many
streamlined to simplify the treatment algorithms, to reduce the
investigators to question the cardiac pump theory and accept the
amount of information clinicians need to learn, and to clarify the
thoracic pump theory. In reality, it is likely that both models apply to
most important issues. Additionally, a new process for disclosure
the mechanism of blood flow during CPR.19
and conflicts of interest was implemented.
The AHA continues to use the “chain of survival” to highlight the
CLINICAL PRESENTATION
treatment approach and illustrate the importance of a timely
Symptoms response.2 Based on the concept that “a chain is only as strong as its
■ Anxiety, change in mental status or unconscious weakest link,” each element in the chain is essential for a successful
resuscitation outcome. The four links of the chain of survival are as
■ Cold, clammy extremities
follows:
■ Dyspnea, shortness of breath or no respiration
1. Early recognition of the emergency and activation of emergen-
■ Chest pain
cy medical services (EMS)
■ Diaphoresis
2. Early bystander basic life support (BLS) and CPR
■ Nausea and vomiting
3. Early delivery of a shock with a defibrillator
Signs
4. Early ACLS followed by postresuscitation care delivered by
■ Hypotension healthcare professionals
■ Tachycardia, bradycardia, irregular or no pulse
Although all four links of the chain of survival are important, the
■ Cyanosis most crucial may be the first three, particularly early CPR.2 Cardio-
■ Hypothermia pulmonary resuscitation provides critical blood flow to the heart
and brain, prolongs the time VF is present (prior to the deteriora-
■ Distant or absent heart and lung sounds
tion to asystole), and increases the likelihood that a shock will
terminate VF resulting in a rhythm compatible with life.2 In one
TREATMENT study of out-of-hospital cardiac arrest, early recognition of cardiac
arrest (odds ratio [OR] 4.4, 95% confidence interval [CI] 3.1–6.4),
Cardiopulmonary Resuscitation early CPR (OR 3.7, 95% CI 2.5–5.4), and defibrillation within 8
minutes (OR 3.4, 95% CI 1.4–8.4) were associated with an increase
■ DESIRED OUTCOME in survival to hospital discharge.20 Advanced cardiac life support,
conversely, did not improve survival (OR 1.1, 95% CI 0.8–1.5). 
The goal of CPR is the return of spontaneous circulation (ROSC),
Henceforth, the guidelines for CPR and ECC emphasize the provi-
with effective perfusion (and similarly, ventilation) as quickly as
sion of high-quality CPR with minimal interruptions in chest
possible to minimize hypoxic damage to vital organs. It is not
compressions.2 The use of drug therapy as part of ACLS, however,
sufficient to restore spontaneous circulation if the patient is left
has evolved to a minimal role because survival to hospital discharge
neurologically devastated or incurs severe morbidity in the process.
does not appear to be impacted.
Factors proven to enhance survival to hospital discharge include the
occurrence of a witnessed arrest, rapid implementation of bystander
CPR, presence of VF as the initial rhythm, and early defibrillation
therapy for VF.4,20 In one report, the rate of survival to hospital
GENERAL MANAGEMENT OF
discharge was 74% when defibrillation was performed within 3 CARDIAC ARREST
minutes of a witnessed cardiac arrest compared with 49% when
defibrillation was performed after 3 minutes (P = 0.02).21
■ BASIC LIFE SUPPORT
Several patient-specific factors exist that can affect resuscitation The general management of cardiac arrest is based on algorithms
survival, but few have been evaluated in clinical trials. In one study, developed by the AHA, and are published for widespread dissemi-
 125

TABLE 14-1 Evidence-Based Treatment Recommendations Subsequent to this, the rescuer should determine if there is an
effective pulse. If there is an effective pulse, then rescue breathing

CHAPTER 14
Recommendation
with frequent assessments of effective circulation should be contin-
Recommendations (Grades)
ued until help arrives. If there is no pulse, then chest compressions
Immediate bystander CPR Class I need to be immediately instituted. The recommended rate is 100
High-quality CPR should be performed with minimal beats/min, with cycles of 30 compressions followed by 2 rescue
interruption in chest compressions and defibrillation
breaths. The 2005 guidelines for CPR and ECC stress that there
as soon as it can be accomplished.
should be minimal interruptions in chest compressions. If there is
Epinephrine Class IIb
1 mg IV/IO should be administered every 3 to 5 no AED available, then cycles of compressions/breaths should
minutes in patients with VF, PVT, PEA, or asystole continue, with pulse checks every 2 minutes (5 cycles) until help

Cardiopulmonary Arrest
Vasopressin Class indeterminate arrives or the patient regains spontaneous circulation. If there is an
40 units IV/IO can replace either the first or second AED available, then the rhythm should be checked to determine if
dose of epinephrine in patients with VF, PVT, or defibrillation is advised. If so, then one shock should be delivered
asystole. There is insufficient evidence to recommend with the immediate resumption of chest compressions/rescue
either for or against its use in PEA. breaths. After five cycles, the rhythm should be reevaluated to
Amiodarone Class IIb determine the need for defibrillation. This algorithm should be
300 mg IV/IO can be followed by 150 mg IV/IO in
repeated until help arrives, or the rhythm is no longer “shockable.”
patients with VF/PVT unresponsive to CPR, shock, and
If the rhythm is not shockable, then chest compressions/rescue
a vasopressor.
Lidocaine Class indeterminate breath cycles should be continued until help arrives, or the victim
Lidocaine can be considered an alternative to amio- recovers spontaneous circulation (Fig. 14–1).
darone in patients with VF/PVT. The initial dose is 1
to 1.5 mg/kg IV. Additional doses of 0.5 to 0.75 mg/ ■ ADVANCED CARDIAC LIFE SUPPORT
kg can be administered at 5 to 10 minute intervals to
a maximum dose of 3 mg/kg if VF/PVT persists. Once ACLS providers arrive, then further definitive therapy is
Magnesium Class IIa given. If the rhythm is not shockable, then it is likely to be either
Magnesium is recommended for VF/PVT that is caused asystole or pulseless electrical activity (PEA) (Fig. 14–2). The gen-
by torsade de pointes. 1 to 2 g diluted in 10 mL D5W eral management of these rhythms is CPR and pharmacologic
should be administered IV/IO push over 5 to 20 therapy as listed below. For PEA, the rescuer must consider revers-
minutes. Clinical studies have not demonstrated a ible causes (Table 14–2). If the person is in VF or PVT, then one
benefit when magnesium was routinely administered shock should be delivered (appropriate to the available electrical
during CPR when torsade de pointes was not present. device), with the immediate resumption of 30 compressions and 2
Fibrinolysis Class IIa
breaths for 5 cycles prior to rechecking the rhythm or pulse. If there
Thrombolytics should be considered on a case-by-case
basis when pulmonary embolism is suspected.
is still a shockable rhythm, then one shock should be delivered and
Hypothermia Class IIa at this time pharmacologic intervention can be considered. After the
Hypothermia should be implemented in unconscious first unsuccessful shock, vasopressors are the initially recommended
adult patients with ROSC after out-of-hospital cardiac pharmacologic intervention (before or after the second shock), and
arrest when the initial rhythm was VF. These patients after the second unsuccessful shock, antiarrhythmics can be consid-
should be cooled to 32°C (89.6°F) to 34°C (93.2°F) ered (before or after the third shock). Five cycles of chest compres-
for 12 to 24 hours. sions/breaths should be performed in between attempts at
Hypothermia may be beneficial for patients with non- Class IIb defibrillation. This algorithm will repeat until either a pulse is
VF arrest out-of-hospital or for in-hospital cardiac obtained with effective circulation, the rhythm changes, or the
arrest.
patient expires. For completeness, please refer to the guidelines
Atropine Class indeterminate
Atropine 1 mg IV/IO every 3 to 5 minutes (maximum
published by the AHA.2
total of 3 doses or 3 mg) can be considered for
patients with asystole or PEA.
CPR, cardiopulmonary resuscitation; D5W, 5% dextrose in water; IO, intraosseous; IV, intravenous; VENTRICULAR FIBRILLATION/
PEA, pulseless electrical activity; PVT, pulseless ventricular tachycardia; ROSC, return of spontaneous VENTRICULAR TACHYCARDIA
circulation; VF, ventricular fibrillation.
Key for evidence-based classifications2:
Class I: High-level prospective studies support the action or therapy and the benefit substantially
■ NONPHARMACOLOGIC THERAPY
outweighs the potential for harm. The treatment should be administered. Electrical defibrillation is the only effective method of restoring a
Class IIa: The weight of evidence supports the action or therapy, and the therapy is considered
perfusing cardiac rhythm, therefore it is a crucial link in the “chain
acceptable and useful. It is reasonable to administer the treatment.
Class IIb: The evidence documented only short-term benefits, or positive results were documented of survival” especially for a witnessed arrest.2 The probability of
with lower levels of evidence. Class IIb recommendations can be considered either optional or successful defibrillation is directly related to the time interval
recommended by experts despite the absence of high-level supporting evidence. between the onset of VF and the delivery of the first shock.2
Class III: The risk outweighs the benefit for a particular treatment. The treatment should not be Generally, with each passing minute, the rate of survival decreases by
administered and can be harmful.
Class indeterminate: This is either a continuing area of research or an area where research is just
8% to 10% when CPR is not provided.23 In one study, a 23% relative
beginning. No recommendation (either for or against) can be made. improvement in survival was observed with each 1-minute reduction
in the time to defibrillation (OR 0.77, 95% CI 0.73–0.81).24
nation.2 The initial algorithm is BLS, and the first action is to  Although early defibrillation is crucial for survival following
determine responsiveness of the patient. If there is no response, the cardiac arrest, several studies have suggested that CPR prior to
rescuer should immediately activate the emergency medical defibrillation can lead to more successful outcomes.23 One study
response team, and obtain an automated external defibrillator (published after the 2005 guidelines) cites the concept of “cardioce-
(AED) if one is available. Next, the victim’s airway should be rebral” resuscitation, based on applying appropriate cardiac resusci-
opened, with an assessment of effective breathing. If the victim is tation principles to the three phases of cardiac arrest: First, the
not breathing, then two rescue breaths should be administered. “electrical” phase (0–4 minutes) when defibrillation is most likely to
 126

Non-Responsive Victim
SECTION 2

Activate EMS; Get AED

Open Airway; Check Breathing IF BREATHING

If not breathing, give two rescue breaths Assist as needed
Cardiovascular Disorders

IF PULSE PRESENT
Rescue Breathing
Assess for pulse
Check pulse every 2 minutes

NO PULSE
Cycles of compressions and rescue breaths (30:2)
Continue until ACLS provider or AED arrives
Check for pulse every 5 cycles

IF NON-SHOCKABLE
AED arrives RHYTHM
Check rhythm Resume CPR with rhythm checks
every 5 cycles

SHOCKABLE
RHYTHM
One shock
FIGURE 14-1. Treatment algorithm for adult Resume CPR for 5 cycles
cardiopulmonary arrest. (BLS, basic life Reassess rhythm
support.)

be effective; second, the “circulatory” phase (4–10 minutes or could lead to asystole. It can be more important to first provide
longer) where adequate coronary or cerebral perfusion prior to some blood flow and cardiac perfusion via CPR to “flush out” the
defibrillation is likely to be helpful; and, third, the “metabolic” deleterious metabolic factors that have accumulated during
phase (greater than 10 minutes) in which survival is very low, and ischemia.23 Because of this, the recent guidelines offer that EMS
hypothermia is likely to be the most beneficial approach.23,25 Using personnel can give 2 minutes of chest compressions prior to
a protocol where each defibrillation, including the first, was pre- attempting defibrillation. Recommendations are similar for victims
ceded by 200 uninterrupted chest compressions, an increase in total in the metabolic phase recognizing the likelihood of achieving
survival (57% [19/33] vs. 20% [18/92], P = 0.001) and neurologi- ROSC, however, is drastically lower. Further trials are needed to
cally normal survival (48% [16/33] vs. 15% [14/92], P = 0.001) was evaluate this resuscitation technique.25
noted compared to standard CPR practices.25 As opposed to the previous guidelines, where “stacked,” multiple
Other clinical trials have evaluated the impact of delaying defibril- shocks were initially given, persons in VF or PVT should receive
lation to allow for CPR in patients with out-of-hospital VF.26,27 In electrical defibrillation with one shock.2 The defibrillation attempt
one trial, the provision of roughly 90 seconds of CPR prior to should be with 360 joules (monophasic defibrillator) or 150 to 200
defibrillation was associated with an increased rate of hospital joules (biphasic defibrillator). Automatic external defibrillators are
survival (compared with a historical control group) when response reliable, computerized defibrillators that can be useful for both
intervals were 4 minutes or longer (27% vs. 17%; P <0.007).26 In a healthcare providers and lay personnel. These devices are effective,
second trial, hospital survival rates were higher in patients with easy to use, and have led to the development of public access
response intervals greater than 5 minutes when 3 minutes of CPR defibrillation programs in many communities.15,28 When an arrest
was administered prior to defibrillation (22% vs. 4%; P = 0.006).27 is witnessed, and AED is immediately available, it should be used as
Collectively, these trials support the theory of a three-phase time- soon as possible. However, CPR should be started immediately
sensitive model for resuscitation after cardiac arrest mentioned (after EMS activation), as the AED is being prepared. If early CPR is
above. Successful defibrillation most likely will occur when cardiac provided to a witnessed VF arrest, and defibrillation is able to be
arrest victims are in the electrical phase because there is enough provided within 3 to 5 minutes, survival rates have been reported to
tissue oxygenation still present to support metabolic demands. be has high as 41% to 74%.2,15,21,29–31
Conversely, when cardiac arrest victims are in the circulatory phase, After defibrillation is attempted, CPR should be immediately
global ischemia has already occurred, and immediate defibrillation restarted and continued for 2 minutes without checking a pulse.
 127

CHAPTER 14
Pulseless Arrest Victim
Assess Rhythm

Asystole or PEA
VF/PVT

Cardiopulmonary Arrest
One shock Resume CPR (5 cycles)
Resume CPR (5 cycles) Vasopressor
Recheck rhythm Consider atropine
Evaluate for reversible cause

PERSISTENT VF/PVT
One shock
Recheck rhythm
Vasopressor before or
Go to appropriate algorithm
after shock
Resume CPR (5 cycles)
Recheck rhythm

PERSISTENT VF/PVT
One shock
Consider antiarrhythmic
before or after shock If patient develops return
Resume CPR (5 cycles) of circulation, begin
post-resuscitation care

Recheck rhythm FIGURE 14-2. Treatment algorithm for adult

Go to appropriate algorithm cardiopulmonary arrest. (ACLS, advanced cardiac
life support.)

TABLE 14-2 Potentially Reversible Causes of PEA and Asystole (Think: 6 H’s; 6 T’s)
Condition Clues Treatment
Hypovolemia History, flat neck veins Intravenous fluids
Hypoxia Cyanosis, blood gases, airway problems Ventilation, oxygen
Hydrogen ion (acidosis) History of bicarbonate-responsive preexisting acidosis Sodium bicarbonate, hyperventilation
Hyper (Hypo) kalemia History of renal failure, diabetes, recent dialysis, dialysis fistulas, medications Calcium chloride, insulin, glucose, sodium bicarbonate, sodium
polystyrene sulfonate, dialysis
Hypothermia History of exposure to cold, central body temperature Rewarming, oxygen, intravenous fluids
Hypoglycemia History of diabetes Glucose infusion
Toxin (Drug overdose) Bradycardia, history of ingestion, empty bottles at the scene, pupils, neurologic Drug screens, intubation, lavage, activated charcoal
exam
Tamponade (Cardiac) History (trauma, renal failure, thoracic malignancy), no pulse with CPR, vein Pericardiocentesis
distension, impending tamponade-tachycardia, hypotension, low pulse pres-
sure changing to sudden bradycardia as terminal event
Tension pneumothorax History (asthma, ventilator, chronic obstructive pulmonary disease, trauma), Needle decompression
no pulse with CPR, neck vein distension, tracheal deviation
Thrombosis, coronary History, ECG, enzymes Thrombolytics, oxygen, nitroglycerin, heparin, aspirin, morphine
Thrombosis, pulmonary History, no pulse with CPR, distended neck veins Pulmonary arteriogram, surgical embolectomy, thrombolytics
Trauma History, examination Volume infusion, intracranial pressure monitoring, bleeding con-
trol, surgical intervention
CPR, cardiopulmonary resuscitation; ECG, electrocardiogram; PEA, pulseless electrical activity.
Data from American Heart Association 2 and Ornato and Peberdy.4
 128
The omission of the pulse check after defibrillation is a paradigm is rarely above 40 mm Hg.2,33  Although this amount of pressure
shift in the algorithm, and is related to myocardial stunning with is often enough to provide vital perfusion and oxygenation, sym-
SECTION 2

resultant poor perfusion and diminished cardiac output immedi- pathomimetic therapy is indicated to augment both the coronary
ately after electrical therapy.2 After 2 minutes of chest compressions, and cerebral perfusion pressures seen during this low-flow state.
the rhythm and pulse should be rechecked. If there is still evidence Epinephrine continues to be a drug of first choice for the treat-
of VF or PVT, then pharmacologic therapy with repeat attempts at ment of VF, PVT, asystole, and PEA despite a paucity of evidence
single-discharge defibrillation should be attempted. demonstrating improved survival in humans2 (Table 14–3). Epi-
Endotracheal intubation and intravenous (IV) access should be nephrine is both an α- and β-receptor agonist, although its effective-
obtained when feasible, but not at the expense of stopping chest ness is primarily through its α effects. The β effects can in fact be
compressions. The 2005 guidelines for CPR and ECC strongly stress harmful as β-stimulation increases myocardial oxygen demand and
Cardiovascular Disorders

the need for uninterrupted CPR.2 Once an airway is achieved, can increase the severity of postresuscitation myocardial dysfunc-
patients should be ventilated with 100% oxygen. The recent guide- tion.34 This has led some investigators to evaluate simultaneous β-
lines suggest that lower tidal volumes and rates can be beneficial.2 blocker administration in conjunction with sympathomimetic ther-
There are several airway adjuncts that are potentially available, such apy using an animal model.32,35,36 Unfortunately, these studies have
as laryngeal mask airways and esophageal-tracheal combination produced mixed results.
tubes. However, the definitive airway is an endotracheal tube placed Several studies have compared the effects of pure α1-agonists,
with direct laryngoscopy. such as phenylephrine and methoxamine, with epinephrine as these
agents lack any β-activity.37,38 These studies have shown the use of
■ PHARMACOLOGIC THERAPY α1-agonists to have no long-term survival advantage over epineph-
rine. One reason that selective α1-agonists are not superior to
Sympathomimetics epinephrine is related to the α2 effects. Agents that have potent α2
The use of sympathomimetics is a major part of drug therapy in effects (e.g., epinephrine and norepinephrine) can be more effective
CPR. Animal studies have demonstrated that coronary perfusion because the α2-adrenergic receptors lie extrajunctionally in the
pressures above 30 mm Hg are associated with adequate forward intima of the blood vessels, making them more accessible to circu-
blood flow and improved survival.32 In humans, even with properly lating catecholamines—even in low-flow states that occur during
performed chest compressions, coronary perfusion pressures are CPR.38 Furthermore, during ischemia, the number of postsynaptic
only 10 to 15 mm Hg, the systolic arterial pressure is rarely above 80 α1-receptors decreases, which suggests a greater role for α2-agonist
mm Hg, the diastolic pressure is low, and the carotid mean pressure activity during CPR.39

TABLE 14-3 Summary of Adult High-Dose Epinephrine Studies

Epinephrine Dosing Initial Resuscitation Hospital Discharge Discharge Neurologic Status
Author Design SDE vs. HDE N SDE vs. HDE SDE vs. HDE SDE vs. HDE
a
Gueugniaud et P, MC, 1 mg vs. 5 mg, 3327 601/1650 678/1677 46/1650 38/1677 26/46 (56.5%) 26/38 (68.4%)
al., 1998 R, DB up to 15 (36.4%) (40.4%) (2.8%) (2.3%) Discharged without neuro-
doses logic impairment
Sherman et al., P, MC, 0.01 mg /kg vs. 140 7/62 (11%) 15/78 (19%) Not addressed Not addressed
1997 R, DB 0.1 mg /kg, up
to 4 doses
Choux et al., P, R, DB 1 mg vs. 5 mg, 536 85/265 (32%) 96/271 20/54 (37%) 23/63b GCS ≥9 (at day 3):
1995 up to 15 (35.5%) (35.4%) 4/20 3/23
doses EEG normal (at day 3):
1/20 3/23
Lipman et al., P, R, DB 1 mg vs. 10 mg, 35 11/16 (69%) 15/19 (79%) 1/16 (6.3%) 0/19 (0%) Not addressed
1993 up to 3 doses
Stiell et al.,1992 P, R, DB 1 mg vs. 7 mg, 650 76/333 (23%) 56/317 (18%) 16/333 (5%) 10/317 (3%) 94% 90%
up to 5 doses Remained in their best CPC
on discharge
Brown et al., P, MC, 0.02 mg /kg vs. 1280 190/632 (30%) 217/648 (33%) 26/632 (4%) 31/648 (5%) 92% 94%
1992 R, DB 0.2 mg /kg for Conscious at discharge (CPC = 1–3)
the first dose
Callaham et al., P, R, DB 1 mg vs. 15 mg, 556 22/270 (8%) 37/286a (13%) 3/270 (1.2%) 5/286 (1.7%) 2.3% 3.2
1992 up to 3 doses Mean CPC score
Lindner et al., P, R, DB 1 mg vs. 5 mg 68 6/40 (15%) 16/28a (57%) 2/40 (5%) 4/28 (14%) Not addressed
1991 for the first
dose
Callaham et al., Ret HDE: ≥ 50 mcg / 68 Not addressed 11/35 (31%) 6/33 (18.2%) Intact: 8/11 vs. 4/6
1991 kg or total Impaired: 2/11 vs. 2/6
dose >2.8 Vegetative: 1/11 vs. 0/6
mcg /kg /min
CPC, cerebral performance category; DB, double-blind; EEG, electroencephalogram; GCS, Glasgow Coma Scale; HDE, high-dose epinephrine; MC, multicenter; P, prospective; R, randomized; Ret, retrospective;
SDE, standard dose epinephrine.
a
P < 0.05.
b
Number of patients admitted to the hospital alive on day 3.
Data from Brown et al.,49 Calaham et al.,50 Choux et al.,51 Gueugniaud et al.,52 Lipman et al.,53 Sherman et al.,54 and Stiell et al.55
 129
Several investigators have compared norepinephrine with epineph- temic vascular resistance. Although it acts on various receptors
rine in both human and animal models.33,40–43 Norepinephrine is a throughout the body, its vasoconstrictive properties are caused

CHAPTER 14
potent α-agonist (both α1 and α2) but also has β1-agonist effects. In primarily by its effects on the V1 receptor.57 Measurement of
the only large-scale randomized, double-blind, prospective trial that vasopressin levels in patients undergoing CPR has shown a high
compared norepinephrine with epinephrine in the prehospital car- correlation between the levels of endogenous vasopressin released
diac arrest setting, there were no significant differences in ROSC and the potential for ROSC.58 In fact, in one study, plasma vaso-
(norepinephrine, 13% [35:260] vs. epinephrine, 8% [22:270]; P = pressin concentrations were approximately three times as high in
0.19), hospital admission (norepinephrine, 13% [36:260] vs. epineph- survivors compared with nonsurvivors, suggesting that vasopressin
rine, 10% [27:270]; P = 0.37), or discharge (norepinephrine, 2.6% is released as an adjunct vasopressor to epinephrine in life-threaten-
[7:260] vs. epinephrine, 1.2% [3:270]; P = 0.37).41 A second, smaller ing events such as cardiac arrest.59

Cardiopulmonary Arrest
study demonstrated higher resuscitation rates with norepinephrine Vasopressin may have several advantages over epinephrine. First,
compared to epinephrine (64% [16:25] vs. 32% [8:25]) but no the metabolic acidosis that frequently accompanies cardiopulmo-
significant difference in hospital discharge.42 Consequently, epineph- nary arrest can blunt the vasoconstrictive effect of adrenergic agents
rine remains the first-line sympathomimetic for CPR. such as epinephrine. This effect does not occur with vasopressin.
The recommended dose for epinephrine is 1 mg administered by Second, the stimulation of β-receptors caused by epinephrine can
intravenous (IV) or by intraosseous (IO) injection every 3 to 5 increase myocardial oxygen demand and complicate the postresusci-
minutes.2 This epinephrine dose was derived from animal studies (0.1 tative phase of CPR. Because vasopressin does not act on β-recep-
mg/kg in a 10-kg dog) and equates to approximately 0.015 mg/kg for tors, this effect does not occur with its use. Vasopressin also can have
a 70-kg human.44 Both animal and human studies have demonstrated a beneficial effect on renal blood flow by stimulating V2 receptors in
a positive dose-response relationship with epinephrine suggesting that the kidney, causing vasodilation and increased water reabsorption.
higher doses might be necessary to improve hemodynamics and With regard to splanchnic blood flow, however, vasopressin has a
achieve successful resuscitation.45–48 These results, however, have not detrimental effect when compared to epinephrine.60
been replicated in human studies41,49–56 (see Table 14–3). Collectively, Clinical experience with vasopressin in humans is limited, and
these studies have shown that high-dose epinephrine can increase the comparative trials evaluating vasopressin and epinephrine have
initial resuscitation success rate, but that overall survival is not signifi- produced mixed results57 (Table 14–4). Potential reasons include
cantly different. The discrepancy between animal and human studies the setting in which cardiac arrest was evaluated (in-hospital versus
can be caused by the fact that most victims of cardiac arrest have out-of-hospital), variability in the quality of CPR performed, the
coronary artery disease, a condition not present in an animal model. average time from collapse to study drug administration, and the
In a human model, however, atherosclerotic plaques can aggravate the number of patients presenting with VF as the initial rhythm.
balance between myocardial oxygen supply and demand. Moreover, In the largest comparative trial with vasopressin and epinephrine
the interval from arrest to treatment in animal studies is shorter than for out-of-hospital cardiac arrest conducted to date, no significant
the interval frequently reported in human studies. Because time to differences were noted in ROSC, hospital admission rate, or dis-
CPR and defibrillation are crucial variables for success, prolonging this charge rate.61 Furthermore, when patients were stratified according
time period can lower resuscitation rates. to their initial presenting rhythm, no significant differences were
noted for patients with VF or PEA. Interestingly, patients with
asystole had a significantly higher rate of hospital admission (29%
Vasopressin vs. 20%; P = 0.02) and discharge (4.7% vs. 1.5%; P = 0.04) when
Vasopressin, also known as antidiuretic hormone, is a potent, non- vasopressin was administered compared with epinephrine. In addi-
adrenergic vasoconstrictor that increases blood pressure and sys- tion, a subgroup analysis of 732 patients who required additional

TABLE 14-4 Summary of Adult Vasopressin Comparative Trials

Initial Resuscitation Hospital Discharge
Initial
Author Design Setting Rhythm Interventiona N Vasopressin Epinephrine Vasopressin Epinephrine
Lindner, et P, R, DB Out-of- VF: 100% Vasopressin 40 units vs. 40 16/20 (80%) 11/20 (55%) 8/20 (40%) 3/20 (15%)
al., 1997 hospital Epinephrine 1 mg for
initial drug treatment
Stiell, et al., P, R, TB, MC In-hospital VF/PVT: 21% Vasopressin 40 units vs. 200 62/104 (60%) 57/96 (59%) 12/104 13/96 (14%)
2001 PEA: 48% Epinephrine 1 mg for (12%)
Asystole: 31% initial drug treatment
Wenzel, et P, R, DB, MC Out-of- VF/PVT: 40% Vasopressin 40 units vs. 1186 145/589 (25%) 167/597 57/578 58/588
al., 2004 hospital PEA: 16% Epinephrine 1 mg for 2 (28%) (10%) (10%)
Asystole: 45% doses as initial drug
treatment
Guyette, et Ret Out-of- VF/PVT: 27% Epinephrine vs. Epineph- 298 16/37b (43%) 58/231b NR NR
al., 2004 hospital PEA: 17% rine + vasopressin (25%)
Asystole: 51%
Grmec, et P, O with Ret Out-of- VF/PVT: 100% Epinephrine 1 mg vs. 109 Initial therapy: 23/51 Initial therapy: 10/51 (20%)
al., 2006 control hospital Vasopressin 40 units 17/27 (63%)b (45%)b 7/27 (26%)
initially vs. Vasopressin Delayed ther- Delayed ther-
40 units after 3 doses of apy: 19/31 apy: 8/31
epinephrine 1 mg (61%)b (26%)
DB, double-blind; MC, multicenter; O, observational; P, prospective; PEA, pulseless electrical activity; PVT, pulseless ventricular tachycardia; R, randomized; Ret, retrospective; TB, triple-blind; VF, ventricular fibrillation.
a
All study groups received epinephrine following the initial study drug.
b
P <0.05.
Data from Wenzel et al.,61 Guyette, et al.,109 Lindner et al.,110 Stiell et al.,111 and Grmec, et al.112
 130
epinephrine therapy despite the two doses of study drug revealed strate the benefit of an antiarrhythmic agent over placebo in
significant benefits in ROSC (37% vs. 26%; P = 0.002), hospital patients with out-of-hospital cardiac arrest.
SECTION 2

admission rate (26% vs. 16%; P = 0.002), and discharge rate (6.2% A subsequent trial compared amiodarone 5 mg/kg with lidocaine
vs. 1.7%; P = 0.002) with vasopressin. There was a trend, however, 1.5 mg/kg in patients with out-of-hospital cardiac arrest caused by
toward a poorer neurologic state or coma among the patients who VF.68 In this trial, amiodarone was associated with a relative improve-
survived to discharge and received vasopressin. ment of 90% in survival to hospital admission compared with
The effectiveness of vasopressin for cardiac arrest has also been lidocaine (22.8% vs. 12%; OR 2.17, 95% CI 1.21–3.83; P = 0.009).
evaluated in a systematic review/meta-analysis.62 No significant dif- Similar to the previous trial, there was no difference in survival to
ferences were noted between vasopressin and epinephrine in failure hospital discharge (amiodarone, 5% vs. lidocaine, 3%; P = 0.34).
of ROSC (relative risk [RR] 0.81, 95% CI 0.58–1.12), death before Amiodarone and lidocaine have also been compared following in-
Cardiovascular Disorders

hospital admission (RR 0.72, 95% CI 0.38–1.39), death within 24 hospital cardiac arrest secondary to VF or PVT. In a multicentered,
hours (RR 0.74, 95% CI 0.38–1.43) or death before hospital dis- retrospective review, 194 patients who received amiodarone (n = 74),
charge (RR 0.96, 95% CI 0.87–1.05). Similarly, no differences were lidocaine (n = 79), or both (n = 41) were evaluated.69 The rate of
noted in death before hospital discharge when patients were strati- survival at 24 hours was 55%, 63%, and 50% for patients receiving
fied according to their initial rhythm (VF/PVT, RR 0.97, 95% CI amiodarone, lidocaine, or both, respectively (P = 0.39). There was no
0.79–1.19; PEA, RR 1.02, 95% CI 0.95–1.10; asystole, RR 0.97, 95% difference in survival to hospital discharge (39% for amiodarone,
CI 0.94–1.00). 45% for lidocaine, and 42% for patients receiving both agents; P =
 Overall, these studies suggest that vasopressin is effective as 0.72). After adjusting for multiple covariates, Cox regression analysis
part of ACLS following cardiac arrest, but its superiority to epineph- revealed higher mortality for those patients who received amiodarone
rine remains questionable. Vasopressin can be more beneficial when (as opposed to lidocaine) (survival to 24 hours: hazard ratio 3.15,
used for out-of-hospital cardiac arrests, arrests secondary to asys- 95% CI 1.68–5.92, P < 0.001; survival to hospital discharge: hazard
tole, or situations when the effect of catecholamines may be dimin- ratio 3.25, 95% CI 1.22–8.65, P = 0.02) and in those patients with VF/
ished because of profound acidosis than when it is used for in- PVT as the initial rhythm (as opposed to bradycardia followed by VF/
hospital cardiac arrest secondary to VF or PVT. Further research is PVT) (survival to 24 hours: hazard ratio 3.36, 95% CI 1.98–5.71,
needed to define the role of vasopressin in cardiac arrest. P < 0.001; survival to hospital discharge: hazard ratio 3.6, 95% CI 1.2–
10.6, P = 0.021). The mean initial dose of amiodarone, however, was
Antiarrhythmics 190 mg, and only 25% of patients received the recommended dose of
300 mg. Additionally, the time to first dose of antiarrhythmic was
The purpose of antiarrhythmic drug therapy following unsuccessful
significantly longer in the amiodarone group than in the lidocaine
defibrillation and vasopressor administration is to prevent the
group (14 minutes vs. 6 minutes, P < 0.001) Although these differ-
development or recurrence of VF and PVT by raising the fibrillation
ences could have biased the results in favor of lidocaine, they provide
threshold. Clinical evidence demonstrating improved survival to
a “real-world” experience with the use of amiodarone. Further large-
hospital discharge, however, is lacking. As the role of antiarrhyth-
scale trials are needed to determine the preferred antiarrhythmic for
mics during CPR remains limited, only two individual agents are
both in-hospital and out-of-hospital cardiac arrest.  In the mean-
currently recommended in the 2005 guidelines for CPR and ECC:
time, amiodarone remains the preferred antiarrhythmic during car-
amiodarone and lidocaine.
diac arrest according to the 2005 guidelines for CPR and ECC with
The use of lidocaine has been beneficial in animal studies and in
lidocaine considered as an alternative.2
patients with arrhythmias following an acute myocardial infarction,
but its benefit in cardiac arrest remains questionable. In the only
published case-control trial where patients were classified according Thrombolytics
to whether they received lidocaine, no significant difference was Because most cardiac arrests are related to either MI or PE, several
noted in ROSC, admission to the hospital, or survival to hospital investigators have evaluated the role of thrombolytics during CPR.
discharge between groups.63 Similarly, a prospective study compar- Several studies have demonstrated successful use of thrombolytics,
ing the effectiveness of lidocaine with that of standard-dose epi- but few have shown improvements to hospital discharge70–76 (Table
nephrine showed not only a lack of benefit with lidocaine but also a 14–5). Of note, an increase in bleeding, which is especially concern-
higher tendency to promote asystole.64 In contrast, a retrospective ing in the setting of traumatic or prolonged CPR, has not been noted.
analysis in patients with VF indicated that lidocaine was associated Thrombolytics, therefore, should be considered on a case-by-case
with a higher rate of ROSC and hospitalization (P < 0.01) but not an basis when PE is suspected.2 A large, international, multicentered,
increase in the hospital discharge rate.65 randomized controlled trial is currently underway to better address
Amiodarone is classified as a class III antiarrhythmic but possesses the efficacy and safety of thrombolytic therapy during CPR.17
electrophysiologic characteristics of all four Vaughan Williams clas-
sifications. The most frequent adverse effect is hypotension, which Magnesium
has occurred in approximately 20% of clinical trials. This hypoten-
Although severe hypomagnesemia has been associated with VF/
sion appears to be related to the diluent used for the amiodarone
PVT, clinical trials have not demonstrated any benefit with the
solution (i.e., polysorbate 80) and the rate of IV administration. An
routine administration of magnesium during a cardiac arrest. Two
aqueous formulation is available, which has not been associated with
observation trials, however, have shown an improvement in ROSC
these deleterious effects.66
in patients with arrests associated with torsade de pointes.2 There-
In a large, randomized, double-blind trial in out-of-hospital
fore, magnesium administration should be limited to these patients.
cardiac arrest secondary to VF or PVT, patients were randomized to
receive either amiodarone 300 mg or placebo.67 Recipients of
amiodarone were more likely to be resuscitated and survive to ■ POSTRESUSCITATIVE CARE
hospital admission than were recipients of placebo (44% and 34%,
respectively; P = 0.03) for a relative improvement of 29%. There was Therapeutic Hypothermia
no difference in survival to hospital discharge for those patients who Restoration of blood flow following cardiac arrest can lead to several
received amiodarone compared to placebo (13.4% vs. 13.2%, chemical cascades and destructive enzymatic reactions that can result
respectively; P = not significant). This was the first trial to demon- in cerebral injury. These reactions include free-radical production,
 131

TABLE 14-5 Summary of Adult Thrombolytic Comparative Trials

CHAPTER 14
Initial Resuscitation Hospital Discharge Major Bleeding
Drug No No No
Author Design Studied N Thrombolytic Thrombolytic Thrombolytic Thrombolytic Thrombolytic Thrombolytic
Kurkciyan, et Ret t-PA 100 mg 42 17/21a (81%) 9/21a (43%) 2/21 (10%) 1/21 (5%) 5/21 (24%) NA
al., 2000
Bottiger, et al., P, NR, PC t-PA 50 mg, up to 90 27/40a (68%) 22/50a (44%) 6/40 (15%) 4/50 (8%) 2/40 (5%) 0/50 (0%)
2001 2 doses
Ruiz-Bailen, et Ret SK (3%) 303 22/67a (33%) 144/236a 12/67a (18%) 109/236a 5/67 (7%) 2/236 (1%)
al., 2001 t-PA (94%) (61%) (46%)

Cardiopulmonary Arrest
Other (3%)
Lederer, et al., Ret t-PA 324 76/108a (70%) 110/214a 27/108a (25%) 33/214a (15%) 6/45 (13%) 7/46 (15%)
2001 (51%)
Abu-Laban, et P, R, MC, t-PA 100 mg 233 25/117 (21%) 27/116 (23%) 1/117 (1%) 0/116 (0%) 2/117 (2%) 0/116 (0%)
al., 2002 PC
Janata et al., Ret t-PA 0.6–1 mg/kg 66 24/36 (67%) 13/30 (43%) 7/36 (19%) 2/30 (7%) 9/36 (25%) 3/30 (10%)
2003 (100 mg max)
Fatovich, et al., P, R, DB, Tenecteplase 50 35 8/19a (42%) 1/16a (6%) 1/19 (5%) 1/16 (6%) 0 0
2004 PC mg
Stadlbauer, et Ret Tenecteplase or 1186 44/99a (46%) 355/1087a 14/99 (14%) 101/1067 0 NA
al., 2006 reteplase (33%) (10%)
DB, double-blind; MC, multicentered; NA, not available; NR, non-randomized; P, prospective; PC, placebo controlled; R, randomized; Ret, retrospective; SK, streptokinase; t-PA, tissue plasminogen activator.
a
P <0.05
Data from Abu-Laban et al.,70 Bottiger et al.,71 Fatovich et al.,72 Janata et al.,73 Kurkciyan et al.,74 Lederer et al.,75 Ruiz-Bailen et al.,76 and Stadlbauer et al.113

excitatory amino acid release, and calcium shifts, leading to mito- In light of these trials, unconscious adult patients with spontaneous
chondrial damage and apoptosis (programmed cell death).77 Hypo- circulation after out-of-hospital cardiac arrest should be cooled to
thermia can protect from cerebral injury by suppressing these 32°C (89.6°F) to 34°C (93.2°F) for 12 to 24 hours when the initial
chemical reactions, thereby reducing the production of free radicals. rhythm is VF.2,77 Such cooling also can be of benefit for other rhythms
Various animal models have demonstrated improved functional or in-hospital cardiac arrests. There is insufficient evidence to make a
recovery and reduced cerebral deficits with the induction of mild recommendation on the use of therapeutic hypothermia in children,
therapeutic hypothermia.77 Clinical trials in humans have shown however, an evaluation in neonates with asphyxiation suggested that
similar results.78,79 hypothermia in this select population may be beneficial.80
One trial was conducted in nine centers in five European coun- Hypothermia must be used with caution, however, as there are
tries.78 In this study, patients who had been resuscitated after cardiac several complications that can develop. Coagulopathy, dysrhythmias,
arrest caused by VF but remained comatose were assigned randomly hyperglycemia, increased incidence of pneumonia, as well as sepsis
to undergo therapeutic hypothermia, targeting a temperature of have been described.79,81 Further research is needed in this area.
32°C (89.6°F) to 34°C (93.2°F), for 24 hours. The primary end point
was neurologic outcome within 6 months of cardiac arrest. Second- Glucose Control
ary end points were mortality (within 6 months) and complication
Electrolyte abnormalities are frequent after cardiac arrest, and can
rate within 7 days. A favorable neurologic outcome was achieved in
be very deleterious to outcome. Although no controlled evidence
55% of patients in the hypothermia group as opposed to 39% in the
exists regarding glucose control post–cardiac arrest, there is growing
normothermia group (P = 0.009). Additionally, mortality rates were
consensus among critical care practitioners that tight glucose con-
improved significantly in the hypothermia group (41% vs. 55%; P =
trol improves outcome among critically ill patients. Studies have
0.02). Based on this difference, seven patients would need to be
documented increased survival, as well as less infectious complica-
treated with hypothermia to prevent one death. The rate of compli-
tions using insulin drips to obtain tight glucose control (i.e., 80 to
cations (e.g., bleeding, pneumonia, sepsis, and renal failure) did not
110 mg/dL).82 Because hyperglycemia is common after cardiac
differ between the two groups (73% for the hypothermia group and
arrest, it would seem reasonable for post-arrest providers to main-
70% for the normothermia group; P = 0.70).
tain normoglycemia, albeit further study is warranted to determine
A second trial was conducted in four hospitals in Melbourne,
the role of tight glycemic control in these patients.
Australia.79 Entry criteria were similar to the previous trial, but the
target temperature for hypothermia was 33°C (91.4°F), which was
maintained for 12 hours. The primary outcome measure was Cardiovascular Perfusion
survival to hospital discharge with good neurologic function. Forty- The patient who has achieved ROSC often has myocardial stunning/
nine percent of patients in the hypothermia group had good dysfunction, either caused by reperfusion injury or the direct
neurologic function on discharge (to either home or a rehabilitation effects of defibrillation.2 Postresuscitation support involves ade-
facility) compared with 26% of patients in the normothermia group quate fluid and vasopressor support in order to maintain sufficient
(P = 0.046). Mortality rates were similar between the two groups cardiac output with acceptable organ perfusion. Evaluation should
(51% for the hypothermia group and 68% for the normothermia thus include electrocardiographic and echocardiographic analysis.
group; P = 0.145). Hypothermia was associated with a lower cardiac Patients often develop a delayed vasodilatation that is responsive to
index, higher systemic vascular resistance, and hyperglycemia. It is fluids and vasoactive support. Invasive monitoring can be required;
important to note that only 8% of patients with cardiac arrest were however the optimal target numbers for either mean arterial pres-
selected for therapeutic hypothermia in these two studies. Thus, sure or hemodynamic indices have not been ascertained. It is also
further research needs to focus on the subset of arrest patients who unclear whether antiarrhythmics are beneficial in the post-arrest
are most likely to benefit from this strategy. timeframe, despite the fact that many arrests are precipitated by
 132
dysrhythmias. Relative adrenal insufficiency has also been shown to its use in PEA. Epinephrine should be administered similarly to its
develop in the post-arrest period, but adrenal replacement has not use in VF/PVT; that is, 1 mg every 3 to 5 minutes.
SECTION 2

been shown to date to be efficacious. However, again borrowing on Atropine is an antimuscarinic agent that blocks the depressant
critical care literature in sepsis, adrenal replacement in the correct effect of acetylcholine on both the sinus and atrioventricular nodes,
situation has been shown to be beneficial.83 Whether or not this is thus decreasing parasympathetic tone. During asystole, parasympa-
true in post–cardiac arrest requires further study. thetic tone may increase because of the vagal stimulation that occurs
secondary to intubation, the effects of hypoxia and acidosis, or
alterations in the balance of parasympathetic and sympathetic
NON-VF/PVT RHYTHMS: control.85 Unfortunately, there are no prospective controlled trials
PEA AND ASYSTOLE showing benefit from atropine for the treatment of asystole or PEA.
Cardiovascular Disorders

Earlier small observational reports found some response to atro-

■ NONPHARMACOLOGIC THERAPY pine in asystole or pulseless idioventricular rhythm but little evi-
dence to suggest that long-term outcomes were altered.86 In one
Pulseless electrical activity is defined as the absence of a detectable
retrospective case-control study, a success rate of 14% (6:43) was
pulse and the presence of some type of electrical activity other than VF
noted with atropine compared with to a 0% (0:41) rate with a
or PVT. Several studies have documented that patients with PEA
control but no patients survived to hospital discharge.86 In a second
actually have mechanical cardiac contractions, but they are too weak
retrospective study, asystole was terminated in only 4 of 22 patients
to produce a palpable pulse or blood pressure. Asystole is defined as
(18%) when atropine was administered.87 Once again, none sur-
the presence of a flat line on the electrocardiogram (ECG) monitor.
vived to hospital discharge. Finally, a third retrospective review
Although PEA is still classified as a “rhythm of survival,” the success
evaluated 101 patients who received atropine for asystole.88 Twenty-
rate of treatment is much lower than the rates seen with VF/PVT.14
four patients (24%) survived 24 hours after resuscitation. It is
PEA is often caused by treatable conditions, and the resuscitation team
unclear how many survived to hospital discharge. These results
needs to identify and correct these conditions emergently if the
show that although atropine can achieve ROSC in some instances,
resuscitation is to be successful. The rate of survival among patients
asystolic arrest is almost always fatal. Given the relative safety of
with out-of-hospital cardiac arrest secondary to asystole is 1% to 2%
atropine, the ease of administration, low cost, and theoretical
but can be up to 10% in patients with in-hospital arrest.13,14,20 Success-
advantages, atropine should be considered for asystole or PEA.2 The
ful treatment of both PEA and asystole depends almost entirely on
beneficial effects, however, are limited.
diagnosis of the underlying cause (see Table 14–2).  The algorithm
for treatment of PEA is the same as the treatment of asystole. Both
conditions require CPR, airway control, and IV access. Asystole should ■ ACID/BASE MANAGEMENT
be reconfirmed by checking a second lead on the cardiac monitor. Acidosis seen during cardiac arrest is the result of decreased blood
Defibrillation should be avoided in patients with asystole because the flow and inadequate ventilation. Chest compressions generate
parasympathetic discharge that occurs with defibrillation can reduce approximately 20% to 30% of normal cardiac output, leading to
the chance of ROSC and worsen the chance of survival. The emphasis inadequate organ perfusion, tissue hypoxia, and metabolic acidosis.
in resuscitation is good quality CPR without interruption and to try to In addition, the lack of ventilation causes retention of carbon
identify a correctable cause. If available, transcutaneous pacing can be dioxide, leading to respiratory acidosis. This combined acidosis
attempted. Asystole often represents confirmation of death rather than produces not only reduced myocardial contractility and negative
a rhythm to be treated; therefore, withdrawal of efforts must be inotropic effect, but also the appearance of arrhythmias because of
strongly considered if there is not a rapid ROSC.2 a lower fibrillation threshold. In early cardiac arrest, adequate
Much like VF/PVT, there is an interest in hypothermia in these alveolar ventilation is the mainstay of control to limit the accumu-
post-arrest patients. Metabolic parameters (e.g., lactate and oxygen lation of carbon dioxide and control the acid–base imbalance.2 With
[O2] extraction) have been shown to be improved when post-arrest arrests of long duration, buffer therapy is often considered, how-
comatose adults survived their arrest and were treated with hypo- ever, few data supports its use during cardiac arrest.
thermia.84 Further studies are warranted in this area. Although sodium bicarbonate was once given routinely to reduce
the detrimental effects associated with acidosis (e.g., reduced myo-
■ PHARMACOLOGIC THERAPY cardial contractility), enhance the effect of epinephrine, and
improve the rate of defibrillation, there are few clinical data sup-
The primary pharmacologic agents used in the treatment of asystole
porting its use.89 In fact, sodium bicarbonate can have some
are vasopressors (i.e., epinephrine and vasopressin) and atropine.
detrimental effects.89,90 The effect of sodium bicarbonate can be
Studies comparing epinephrine and vasopressin in patients with PEA
described by the following reaction:
and asystole have not demonstrated an advantage with one agent
over the other. In one large trial of patients with out-of-hospital [HCO3–] + [H+] ↔ [H2CO3] ↔ [H2O] + [CO2]
cardiac arrest, a post hoc, subgroup analysis was conducted for those
patients with asystole.61 In these patients, ROSC was 16% with When sodium bicarbonate is added to an acidic environment, this
vasopressin and 17% with epinephrine (OR 1.00, 95% CI 0.7–1.6; reaction will shift to the right, thereby increasing tissue and venous
P = 0.87), survival to hospital admission was 29% with vasopressin hypercarbia. The carbon dioxide generated by this reaction will
and 20% with epinephrine (OR 0.6, 95% CI 0.4–0.9, P = 0.02) and diffuse into the cell and decrease intracellular pH. The accumula-
survival to hospital discharge was 4.7% with vasopressin and 1.5% tion of intracellular carbon dioxide, specifically within the myocar-
with epinephrine (OR 0.3, 95% CI 0.1–1.0, P = 0.04). An increase in dium, is inversely correlated with coronary perfusion pressure
intact neurologic survival, however, was not noted. In contrast, 40% produced by CPR. Intracellular acidosis also will decrease myocar-
(8/20) of patients who received vasopressin and subsequently dial contractility, further complicating the low-flow state associated
required additional treatment with epinephrine were discharged in a with CPR.89 Furthermore, treatment with sodium bicarbonate often
coma or vegetative state compared to 0% (0/5) of patients who overcorrects extracellular pH because sodium bicarbonate has a
received epinephrine only (P = 0.14). Nevertheless, vasopressin can greater effect when the pH is closer to normal.90 The induced
be substituted for the first or second dose of epinephrine in patients alkalosis, causes an increase in the affinity of oxygen to hemoglobin
with asystole.2 There is insufficient data to recommend for or against (“left shift”), thus interfering with oxygen release into the tissues.
 133
Sodium bicarbonate can be used in special circumstances (i.e., ume challenges during the rewarming process. The use of steroids,
underlying metabolic acidosis, hyperkalemia, salicylate overdose, or antibiotics, and barbiturates has been proposed, but none of these

CHAPTER 14
tricyclic antidepressant overdose), however, the dosage should be agents have ever been shown to increase survival rates.2
guided by laboratory analysis if possible. There has been clinical It is debatable when to stop resuscitative efforts in the hypother-
interest in other buffering agents (an equimolar mixture of sodium mic patient. Many authors have proposed that a patient should not
bicarbonate and sodium carbonate [Carbicarb]; tris(hydroxymethyl be pronounced until the core temperature has been restored to near
aminomethane [THAM]; a mixture of THAM, acetate, sodium normal.2 Once the patient is in the hospital, it is still the judgment
bicarbonate, and phosphate [Tribonat]) as they have shown less of the treating physician when efforts should be terminated.
potential for the adverse effects seen with sodium bicarbonate.2
However, there is a dearth of clinical experience with these agents, ■ PREGNANCY

Cardiopulmonary Arrest
and outcome studies are not available.
Pregnancy is a unique situation in that survival of both the fetus and
the mother depend on CPR. The best hope for survival of the fetus
is maternal survival. Because of the gravid uterus, resuscitation
MODIFICATIONS FOR SPECIAL SITUATIONS needs to be modified. Because the vena cava and aorta can be
obstructed by a uterus of approximately 20 weeks of gestation or
■ DROWNING later, it is appropriate to position the patient approximately 15 to 30
Drowning is a process resulting in primary respiratory impairment degrees back from the left lateral decubitus position, or to pull the
from immersion in a liquid. It is a common, preventable cause of uterus to the side.93
morbidity and mortality. The most important inciting event is the Airway control is important in the pregnant patient. The airway
hypoxia induced by submersion. Thus, early care of the drowning may be smaller because of the hormonal changes and edema that
patient includes immediate rescue breathing, even before he or she is accompany pregnancy. Similarly, because of increased intraabdom-
removed from the water. This is performed much in the same way as inal pressure exerted by the uterus, as well as hormonal changes that
for other victims of cardiac arrest. Prompt initiation of this therapy change the resting state of the gastroesophageal sphincter, clinicians
increases chance of survival.91 Once victims are removed from the need to be acutely aware of the increased risk of aspiration. Because
water, immediate chest compressions should be started if they are of this, cricoid pressure needs to be maintained continuously during
pulseless. Drowning victims can present with any of the pulseless airway manipulation. The rescuer may need to give smaller tidal
rhythms; standard guidelines need to be followed for therapy of these volumes than normal because of the diaphragm elevation that
rhythms. accompanies the later stages of pregnancy. Similarly, circulatory
support also has to be adjusted. In particular, chest compressions
■ HYPOTHERMIA need to be administered slightly above the center of the sternum to
adjust for the anatomic changes of the pregnant uterus.2
Unintentional hypothermia (as opposed to the therapeutic hypo-
In an arrest situation during pregnancy the ACLS provider needs
thermia used post-arrest, described above) is defined by a body
to follow the standard guidelines, including the same use of defibril-
temperature <30°C (86°F), and is associated with marked derange-
lation and medications. Although it is true that vasoactive agents,
ments in body function. Because it can depress virtually every body
such as epinephrine, can diminish uterine blood flow, safer alterna-
system, including pulse and respiration, the patient may appear to
tives do not exist.2
be dead on the initial evaluation. Hypothermia can lead to benefit
Although etiologies of arrest in pregnancy are often the same as in
on brain recovery after cardiac arrest (discussed earlier), thus
the nonpregnant patient, there are several unique situations that
aggressive intervention is clearly indicated when there is a hypother-
need to be considered in the differential diagnosis of a pregnancy
mic arrest victim.
arrest. These include: excess magnesium sulfate institution (i.e.,
If the patient still has a perfusing rhythm, therapy is mainly based
iatrogenic from treating eclampsia) in which case the therapeutic
on rewarming techniques. For mild hypothermia (i.e., >34°C
administration of calcium gluconate can be lifesaving; amniotic
[>93.2°F]), passive rewarming is recommended. For moderate
embolism, which is associated with complete cardiovascular collapse
hypothermia (i.e., 30°C to 34°C [86°F to 93.2°F]), active external
during labor and delivery (cardiopulmonary bypass has been report-
rewarming is recommended, and for severe hypothermia (i.e.,
edly successful in salvaging this condition); preeclampsia/eclampsia
<30°C [<86°F]) active internal rewarming is recommended. These
developing after 20 weeks of gestation producing hypertension and
patients need to be manipulated very gently as VF is sometimes
multiple organ dysfunction; as well as vascular events including
precipitated by movement.92
acute coronary syndromes and acute pulmonary embolism.94,95
If the patient is in cardiac arrest, then the standard BLS algorithm
It is paramount to remember that unless circulation is restored to
should be followed. However, there are some modifications that the
the mother, both the mother and the fetus will succumb especially
rescuer needs to consider. The rescuer should evaluate for respira-
if standard therapy is not used correctly and promptly. Because of
tion and pulse for a longer time frame, as these can be slow or very
this the resuscitation leader should consider the need for emergent
difficult to realize. If there is no breathing, then rescue breaths
hysterotomy (i.e., Cesarean delivery) and delivery as soon as the
should ensue. If there is any doubt about the presence of a pulse,
arrest happens. The best survival reported for infants >24 weeks of
then chest compressions should be started immediately. If the
gestation happens when delivery occurs no more than 5 minutes
patient is in VF or PVT then electrical therapy should be given in a
after the arrest of the mother.2,96
standard manner. However, the hypothermic heart may be less
responsive to medications or defibrillation, and thus there have been
worries about the optimal temperature at which to start defibrilla- ■ TRAUMA
tion attempts.2 There are no published consensus guidelines regard- Cardiac resuscitation of the trauma arrest patient is basically per-
ing this. Immediately after defibrillation, CPR should resume as in formed with the same guidelines as any other arrest. There are some
the standard manner. During CPR, continued attempts at rewarm- specific etiologies to rapidly consider however, as the survival of an
ing are of paramount importance. Included in this concept is out-of-hospital cardiac arrest caused by trauma is rare.2 The rescuer
preventing further heat loss (i.e., removal of wet clothing, protection needs to consider airway obstruction, pneumothorax, tracheobron-
from the environment, etc.). Patients often require significant vol- chial injury, cardiac or large arterial injury, cardiac tamponade,
 134
severe head injury with secondary cardiac collapse, and other the availability of access and their apparent efficacy in introducing
injuries specific to the particular trauma.2 The best survival seems to the drug into the central circulation. When selecting a route for
SECTION 2

be in young patients with treatable penetrating injuries. drug administration, it is of utmost importance to minimize any
Trauma patients often suffer head or cervical injuries; thus interruptions in chest compressions during CPR.
cervical spine precautions should be used in these patients. A jaw Central venous access will result in a faster and higher peak drug
thrust maneuver is the preferred way to open the airway, with in- concentration than peripheral access, but central line access is not
line stabilization during attempts at advanced airway placement.2 needed in most resuscitation attempts. If a central line is already
The rescuer must be vigilant for the development of tension pneu- present, however, it should be the access site of choice. Central lines
mothorax during ventilation. Inadequate ventilation of one side is located above the diaphragm are preferable to those located below
usually caused by tube malposition, tension pneumothorax, or the diaphragm because of poor blood flow during CPR.102 If IV
Cardiovascular Disorders

hemothorax. These conditions are usually treated by medical per- access (either central or peripheral) has not been established a large
sonnel at the hospital after transport. peripheral venous catheter should be inserted. Peripheral drug
Chest compressions should be performed in a standard manner. administration yields a peak concentration in the major systemic
Any visible hemorrhage should be controlled with direct pressure. arteries in roughly 1.5 to 3 minutes but circulation time can be
Fluid resuscitation is done with a goal of adequate blood pressure shortened by up to 40% if the drug is followed by a 20-mL fluid
and organ perfusion. The specific details of fluid resuscitation are bolus with elevation of the extremity.102
highly controversial however, and the optimal volume infusion for  The 2005 guidelines for CPR and ECC now recommend IO
trauma resuscitation is a subject of ongoing debate. administration as the preferred alternative if IV administration
Open thoracotomy for trauma-induced arrest has been per- cannot be achieved.2 Drug administration using the IO route is as
formed in many instances. For penetrating chest trauma patients quick and effective as drug administration via central access and
who arrest immediately before arrival or in the emergency depart- superior to that achieved with peripheral access. Several studies have
ment, open thoracotomy can allow relief of tamponade, control of documented the effectiveness and safety of this administration route
major vessel hemorrhage, or direct repair of cardiac insult.97 In the in both adults and children.2 Potential anatomic sites for insertion
case of blunt trauma however, open thoracotomy does not improve for an IO needle are the distal tibia, the proximal tibia, and the distal
outcome. femur.103 Intraosseous infusion devices are available that allow for
For definitive post-arrest care, trauma patients should be rapidly rapid insertion (i.e., within 90 seconds) and are easy to use.104
transferred to a facility with expertise in the provision of trauma In the event that neither IV nor IO access can be established, then
care. a few drugs can be administered endotracheally. These drugs are
atropine, lidocaine, epinephrine, naloxone, and vasopressin.2 Med-
■ ELECTRICAL SHOCK ications administered through the endotracheal route, however, will
have both a lower and delayed peak concentration than when they
There are many etiologies of electrical shock injuries, from lightning are administered by the IV or IO routes.2 Furthermore, clinical trials
strike (mortality estimated to be 30%, with 70% of survivors have failed to demonstrate any benefit with using the endotracheal
sustaining significant morbidity) to high-tension current, to house- route.105,106 In fact, one clinical trial noted lower rates of ROSC
hold current.98,99 The severity of injury depends on the site, type of
(15% [15:101] vs. 27% [134:495], P ≤ 0.01), hospital admission (9%
current, duration of contact, pathway, and the magnitude of deliv- [9:101] vs. 20% [97:495], P ≤ 0.02), and hospital discharge (0%
ered electricity. [0:101] vs. 5% [27:495], P ≤ 0.02) with endotracheal drug adminis-
Cardiac arrest is common in electrical injury caused by current tration compared to IV.106 Currently, the recommended endotra-
passing through the heart during the “vulnerable period” of the
cheal dose is 2 to 2.5 times larger than the IV/IO dose.2 Given the
cardiac cycle. In large-current events, such as lightning strike, the
unpredictable absorption and the lack of clinical effectiveness,
heart undergoes massive depolarization simultaneously.100 Some-
however, either the IV or IO routes are preferred.
times the intrinsic pacemaker can restore an organized cardiac
electrical cycle, but because of injury to other muscles, specifically
the thoracic musculature, the patient cannot retain or sustain viable ETHICAL AND ECONOMIC CONSIDERATIONS
circulation because of the lack of ventilation and oxygenation.101
When approaching a victim of electrocution, the rescuer must The primary objective of CPR is to obtain neurologic survival. Because
first be certain of his or her own safety. Thereafter, standard BLS, this is often unobtainable, many healthcare professionals are attempt-
prompt CPR, and ACLS when available is indicated. Electric shock ing to identify patients unlikely to benefit from cardiac resuscitation.
is often associated with multiple trauma, including spinal injury, One difficulty in accomplishing this task is defining medical futility.
multiple injuries to the skeletal muscles, as well as fractures. These The two major determinants of medical futility are length of life and
factors need to be evaluated by the resuscitation team. quality of life.2 An intervention that cannot increase length or quality
Airway control can be difficult because of the edema that often of life is considered futile. Key factors in CPR are the disease underly-
accompanies such injuries; thus an advanced airway early in the ing the cardiac arrest and the expected state of health after resuscita-
treatment process is recommended.2 With soft tissue swelling, there tion. One important question that is debated often is how low should
is often a need for aggressive fluid resuscitation in these patients. the chance of survival be before medical therapy is considered futile?
The underlying tissue, or visceral organ damage, is often worse than Is the chance of 1 or 2 months of life for a patient an acceptable goal?
the external appearance. It is usually recommended that these These are important questions that must be addressed when deter-
patients be transferred to centers with expertise in dealing with mining resuscitation status. Ethically, healthcare providers are obli-
these types of injuries. gated to respect patient autonomy, which is easiest in the arrest
situation if the patient has an advance directive. If the patient loses the
ability to make informed decisions regarding medical care, then a
GUIDELINES FOR DRUG ADMINISTRATION spouse or a designated healthcare advocate must act as a surrogate
decision maker, invoking what has been termed substituted judgment:
The routes of administration that are available for drug delivery following the predetermined wishes of the patient.
during CPR include IV (both central and peripheral access), IO, and Unfortunately, there is no scientific evidence or scoring system
endotracheal. The chosen route represents a compromise between that can predict the outcome following CPR. Therefore, all patients
 135
in cardiac arrest should receive resuscitation unless the patient has require advanced care. Neurologic function should be assessed by
a “do not attempt resuscitation” (DNAR) order, signs of irreversible means of the Cerebral Performance Category and the Glasgow

CHAPTER 14
death, or vital organ function deterioration that makes it impossible Coma Scale.107,108 Nonresponse to an array of suitable interventions
to expect any benefit from CPR—despite maximum therapy.2 can indicate that resuscitation is impossible.
Withholding CPR attempts in these futile cases not only would
decrease the number of patients left in a vegetative state with poor
neurologic status but also would improve the cost-effectiveness of ABBREVIATIONS
CPR programs. CPR is of minimal economic benefit if the only
outcome following ROSC is a prolonged, expensive hospital stay. ACLS: advanced cardiac life support
The decision to terminate resuscitative efforts usually rests with AHA: American Heart Association

Cardiopulmonary Arrest
the treating medical team in the hospital. This is often based on BLS: basic life support
many factors, including time to CPR, time of CPR, time to ROSC,
CPP: coronary perfusion pressure
premorbid conditions, and so forth. None of these is clearly predic-
tive of outcome however. In a prehospital arrest, it is the duty of the CPR: cardiopulmonary resuscitation
treating team to provide BLS and ACLS unless there is clear ECC: emergency cardiovascular care
evidence of death (i.e., signs of rigor mortis), the provision of CPR EMS: emergency medical services
would place the rescuer at personal risk, or there is clear evidence of
IO: intraosseous
a DNAR order.
IV: intravenous
MI: myocardial infarction
CLINICAL CONTROVERSIES PEA: pulseless electrical activity
Some clinicians feel that vasopressin should be the vasopressor PE: pulmonary embolism
of first choice in patients with VF/PVT although others prefer
ROSC: return of spontaneous circulation
epinephrine.
PVT: pulseless ventricular tachycardia
Although amiodarone is considered the preferred antiarrhyth-
mic in patients with VF/PVT, there is conflicting data regarding VF: ventricular fibrillation
its effect on outcome when compared to lidocaine.
Some clinicians feel that CPR should be performed before REFERENCES
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 136
16. Stiell IG, Wells GA, Field BJ, et al. Improved out-of-hospital cardiac 41. Callaham M, Madsen CD, Barton CW, et al. A randomized clinical trial
arrest survival through the inexpensive optimization of an existing of high-dose epinephrine and norepinephrine vs standard-dose epi-
SECTION 2

defibrillation program: OPALS study phase II. Ontario Prehospital nephrine in prehospital cardiac arrest. JAMA 1992;268(19):2667–2672.
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protocol to assess the efficacy and safety of tenecteplase during cardio- 43. Lindner KH, Ahnefeld FW, Schuermann W, Bowdler IM. Epinephrine
pulmonary resuscitation in patients with out-of-hospital cardiac and norepinephrine in cardiopulmonary resuscitation. Effects on myo-
arrest: The Thrombolysis in Cardiac Arrest (TROICA) Study. Eur J cardial oxygen delivery and consumption. Chest 1990;97(6):1458–1462.
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1993;22(2 pt 2):281–288. 45. Brown CG, Werman HA, Davis EA, et al. Comparative effect of graded
Cardiovascular Disorders

19. Tucker KJ, Savitt MA, Idris A, Redberg RF. Cardiopulmonary resusci- doses of epinephrine on regional brain blood flow during CPR in a
tation. Historical perspectives, physiology, and future directions. Arch swine model. Ann Emerg Med 1986;15(10):1138–1144.
Intern Med 1994;154(19):2141–2150. 46. Brunette DD, Jameson SJ. Comparison of standard versus high-dose
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of-hospital cardiac arrest. N Engl J Med 2004;351(7):647–656. Med 1990;19(1):8–11.
21. Valenzuela TD, Roe DJ, Nichol G, et al. Outcomes of rapid defibrilla- 47. Gonzalez ER, Ornato JP, Garnett AR, et al. Dose-dependent vasopres-
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22. Rea TD, Eisenberg MS, Becker LJ, et al. Temporal trends in sudden 48. Kosnik JW, Jackson RE, Keats S, et al. Dose-related response of centrally
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23. Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: A 3-phase 49. Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose
time-sensitive model. JAMA 2002;288(23):3035–3038. and high-dose epinephrine in cardiac arrest outside the hospital. The
24. De Maio VJ, Stiell IG, Wells GA, Spaite DW. Optimal defibrillation Multicenter High-Dose Epinephrine Study Group. N Engl J Med
response intervals for maximum out-of-hospital cardiac arrest survival 1992;327(15):1051–1055.
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25. Kellum MJ, Kennedy KW, Ewy GA. Cardiocerebral resuscitation dose epinephrine therapy in patients resuscitated from cardiac arrest.
improves survival of patients with out-of-hospital cardiac arrest. Am J JAMA 1991;265(9):1117–1122.
Med 2006;119(4):335–340. 51. Choux C, Gueugniaud PY, Barbieux A, et al. Standard doses versus
26. Cobb LA, Fahrenbruch CE, Walsh TR, et al. Influence of cardiopulmo- repeated high doses of epinephrine in cardiac arrest outside the
nary resuscitation prior to defibrillation in patients with out-of- hospital. Resuscitation 1995;29(1):3–9.
hospital ventricular fibrillation. JAMA 1999;281(13):1182–1188. 52. Gueugniaud PY, Mols P, Goldstein P, et al. A comparison of repeated
27. Wik L, Hansen TB, Fylling F, et al. Delaying defibrillation to give basic high doses and repeated standard doses of epinephrine for cardiac
cardiopulmonary resuscitation to patients with out-of-hospital ventric- arrest outside the hospital. European Epinephrine Study Group. N
ular fibrillation: A randomized trial. JAMA 2003;289(11):1389–1395. Engl J Med 1998;339(22):1595–1601.
28. Davis EA, Mosesso VN, Jr. Performance of police first responders in 53. Lipman J, Wilson W, Kobilski S, et al. High-dose adrenaline in adult
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29. Caffrey SL, Willoughby PJ, Pepe PE, Becker LB. Public use of auto- 54. Sherman BW, Munger MA, Foulke GE, et al. High-dose versus
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sonnel and paramedics as responders. Resuscitation 2005;65(3):279–283. adult cardiac arrest. N Engl J Med 1992;327(15):1045–1050.
31. White RD, Russell JK. Refibrillation, resuscitation and survival in out- 56. Lindner KH, Ahnefeld FW, Prengel AW. Comparison of standard and
of-hospital sudden cardiac arrest victims treated with biphasic auto- high-dose adrenaline in the resuscitation of asystole and electrome-
mated external defibrillators. Resuscitation 2002;55(1):17–23. chanical dissociation. Acta Anaesthesiol Scand 1991;35(3):253–256.
32. Hilwig RW, Kern KB, Berg RA, et al. Catecholamines in cardiac arrest: 57. Miano TA, Crouch MA. Evolving role of vasopressin in the treatment
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versus epinephrine on myocardial hemodynamics during CPR. Ann 59. Lindner KH, Strohmenger HU, Ensinger H, et al. Stress hormone
Emerg Med 1989;18(4):336–340. response during and after cardiopulmonary resuscitation. Anesthesiol-
34. Zhong JQ, Dorian P. Epinephrine and vasopressin during cardiopul- ogy 1992;77(4):662–668.
monary resuscitation. Resuscitation 2005;66(3):263–269. 60. Voelckel WG, Lindner KH, Wenzel V, et al. Effects of vasopressin and
35. Cammarata G, Weil MH, Sun S, et al. Beta1-adrenergic blockade epinephrine on splanchnic blood flow and renal function during and after
during cardiopulmonary resuscitation improves survival. Crit Care cardiopulmonary resuscitation in pigs. Crit Care Med 2000;28(4):1083–
Med 2004;32(9 suppl):S440–443. 1088.
36. Ditchey RV, Lindenfeld J. Failure of epinephrine to improve the 61. Wenzel V, Krismer AC, Arntz HR, et al. A comparison of vasopressin
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closed-chest resuscitation in dogs. Circulation 1988;78(2):382–389. Engl J Med 2004;350(2):105–113.
37. Holmes HR, Babbs CF, Voorhees WD, et al. Influence of adrenergic drugs 62. Aung K, Htay T. Vasopressin for cardiac arrest: A systematic review
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38. Ornato JP. Use of adrenergic agonists during CPR in adults. Ann 63. Harrison EE. Lidocaine in prehospital countershock refractory ven-
Emerg Med 1993;22(2 pt 2):411–S416. tricular fibrillation. Ann Emerg Med 1981;10(8):420–423.
39. Brown C, Wiklund L, Bar-Joseph G, et al. Future directions for 64. Weaver WD, Fahrenbruch CE, Johnson DD, et al. Effect of epineph-
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cology. Resuscitation, 1996;33(2):163–177. ventricular fibrillation. Circulation 1990;82(6):2027–2034.
40. Brown CG, Robinson LA, Jenkins J, et al. The effect of norepinephrine 65. Herlitz J, Ekstrom L, Wennerblom B, et al. Lidocaine in out-of-
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 137
66. Gallik DM, Singer I, Meissner MD, et al. Hemodynamic and surface 89. Levy MM. An evidence-based evaluation of the use of sodium bicarbonate
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67. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscita- 90. Bjerneroth G. Tribonat—A comprehensive summary of its properties.
tion after out-of-hospital cardiac arrest due to ventricular fibrillation. Crit Care Med 1999;27(5):1009–1013.
N Engl J Med 1999;341(12):871–878. 91. Kyriacou DN, Arcinue EL, Peek C, Kraus JF. Effect of immediate
68. Dorian P, Cass D, Schwartz B, et al. Amiodarone as compared with resuscitation on children with submersion injury. Pediatrics 1994;94(2
lidocaine for shock-resistant ventricular fibrillation. N Engl J Med pt 1):137–142.
2002;346(12):884–890. 92. Schneider SM. Hypothermia: From recognition to rewarming. Emerg
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ventricular arrhythmias. Crit Care Med 2006;34(6):1617–1623. aortocaval compression during resuscitation in late pregnancy. Anaes-
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activator in cardiac arrest with pulseless electrical activity. N Engl J Med 94. Munro PT. Management of eclampsia in the accident and emergency
2002;346(20):1522–1528. department. J Accid Emerg Med 2000;17(1):7–11.
71. Bottiger BW, Bode C, Kern S, et al. Efficacy and safety of thrombolytic 95. Stanten RD, Iverson LI, Daugharty TM, et al. Amniotic fluid embolism
therapy after initially unsuccessful cardiopulmonary resuscitation: A causing catastrophic pulmonary vasoconstriction: Diagnosis by trans-
prospective clinical trial. Lancet 2001;357(9268):1583–1585. esophageal echocardiogram and treatment by cardiopulmonary
72. Fatovich DM, Dobb GJ, Clugston RA. A pilot randomised trial of bypass. Obstet Gynecol 2003;102(3):496–498.
thrombolysis in cardiac arrest (The TICA trial). Resuscitation 96. Boyd R, Teece S. Towards evidence based emergency medicine: Best
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in cardiac arrest due to massive pulmonary embolism. Resuscitation College of Surgeons-Committee on Trauma. Practice management
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 139

C HAP T E R

15 Hypertension

JOSEPH J. SASEEN AND ERIC J. MACLAUGHLIN

An angiotensin-converting enzyme (ACE) inhibitor, angiotensin

KEY CONCEPTS II receptor blocker (ARB), or calcium channel blocker (CCB)
may be used as first-line agents in patients without compelling
 The risk of cardiovascular (CV) morbidity and mortality is direct- indications. Clinical trials have demonstrated that these agents
ly correlated with blood pressure (BP). Even patients with pre- reduce the risk of CV events when used to treat hypertension.
hypertension have an increased risk of CV disease.

β-Blockers do not reduce CV events to the extent that thiazide-
 Outcome trials have shown that antihypertensive drug therapy type diuretics, ACE inhibitors, ARBs, or CCBs do when used as
substantially reduces the risks of CV events and death in pa- the primary antihypertensive agent in patients with hyperten-
tients with hypertension. sion but without a compelling indication for β-blocker therapy.
 Essential hypertension is usually an asymptomatic condition. A  Compelling indications are comorbid conditions where specific
diagnosis cannot be made based on one elevated BP measure- drug therapies have been shown in outcome trials to provide
ment. Elevated values from the average of two or more mea- unique long-term benefits (reducing the risk of CV events).
surements on two or more clinical encounters are needed to
diagnose hypertension.  Patients with diabetes are at very high risk for CV events. All pa-
tients with diabetes and hypertension should be managed with
 The overall goal of treating hypertension is to reduce hypertension- either an ACE inhibitor or an ARB. These are typically in combi-
associated morbidity and mortality from CV events. The selection nation with one or more other antihypertensive agents because
of specific drug therapy is based on evidence that demonstrates multiple agents frequently are needed to lower BP to less than
CV risk reduction. 130/80 mm Hg.
 A goal BP of less than 140/90 mm Hg is appropriate for general Older patients with isolated systolic hypertension are often at
prevention of CV events or CV disease. However, achieving BP of risk for orthostatic hypotension when antihypertensive drug
less than 130/80 mm Hg goal is recommended in patients with therapy is started, particularly with diuretics, ACE inhibitors, and
diabetes, significant chronic kidney disease, known coronary artery ARBs. Although overall treatment should be the same, low ini-
disease (myocardial infarction, stable angina, unstable angina), tial doses should be used and dosage titrations should be grad-
noncoronary atherosclerotic vascular disease (ischemic stroke, ual to minimize risk of orthostatic hypotension.
transient ischemic attack, peripheral arterial disease, abdominal
aortic aneurism), or a 10% or greater 10-year risk of fatal coronary  Alternative antihypertensive agents have not been proven to
heart disease or nonfatal myocardial infarction based on Framing- reduce the risk of CV events compared with first-line antihyper-
ham risk scoring. Patients with left ventricular dysfunction (systolic tensive agents. They should be used primarily in combination
heart failure) have a BP goal of less than 120/80 mm Hg. with first-line agents to provide additional BP lowering.
 Lifestyle modifications should be prescribed in all patients with  Hypertensive urgency is ideally managed by adjusting mainte-
hypertension and prehypertension. However, they should never nance therapy (adding a new antihypertensive and/or increas-
be used as a replacement for antihypertensive drug therapy in ing the dose of a present medication). This provides a gradual
patients with hypertension, especially patients with additional reduction in BP, which is a safer treatment approach than very
CV risk factors. rapid reductions in BP.
 Thiazide-type diuretics have traditionally been classified as  Most patients require combination therapy to achieve goal BP
first-line agents for treating most patients with hypertension. values. Combination regimens should include a diuretic, pref-
This recommendation is supported by clinical trials showing erably a thiazide-type. If a diuretic was not the first drug used,
reduced CV morbidity and mortality with thiazide diuretic ther- it should be the second drug add-on therapy for most patients.
apy. Comparative data from the landmark Antihypertensive
 Patients have resistant hypertension when they fail to attain
and Lipid-Lowering Treatment to Prevent Heart Attack Trial
goal BP values while adherent with an appropriate three drug-
(ALLHAT) confirm the first-line role of thiazide-type diuretics.
regimen. This three-drug regimen must include full doses and
include a diuretic.

Learning objectives, review questions,

and other resources can be found at Hypertension is a common disease that is simply defined as persis-
www.pharmacotherapyonline.com. tently elevated arterial blood pressure (BP). Although elevated BP
was perceived to be “essential” for adequate perfusion of essential

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 140
organs during the early and middle 1900s, it is now identified as one steroids, and angiotensinogen are also documented.5 In the future,
of the most significant risk factors for cardiovascular (CV) disease. identifying individuals with these genetic traits could lead to alter-
SECTION 2

Increasing awareness and diagnosis of hypertension, and improving native approaches to preventing or treating hypertension; however,
control of BP with appropriate treatment, are considered critical this is not currently recommended.
public health initiatives to reduce CV morbidity and mortality.
The Seventh Report of the Joint National Committee on the SECONDARY HYPERTENSION
Detection, Evaluation, and Treatment of High Blood Pressure
(JNC7) is the most prominent evidence-based clinical guideline in Fewer than 10% of patients have secondary hypertension where
the United States for the management of hypertension,1 supple- either a comorbid disease or drug is responsible for elevating BP
mented by the 2007 American Heart Association (AHA) Scientific (Table 15–1).1,6 In most of these cases, renal dysfunction resulting
Cardiovascular Disorders

Statement on the treatment of hypertension.2 This chapter reviews from severe chronic kidney disease or renovascular disease is the
relevant components of these guidelines and additional evidence most common secondary cause. Certain drugs, either directly or
from clinical trials, with a focus on the pharmacotherapy of hyper- indirectly, can cause hypertension or exacerbate hypertension by
tension. Data from the National Health and Nutrition Examination increasing BP. Table 15–1 lists the most common agents. Some of
Survey from 1999 to 2000 indicate that of the population of Ameri- these agents are herbal products. Although these are not technically
cans with hypertension, 68.9% are aware that they have hyperten- drugs, they have been identified as secondary causes. When a
sion, only 58.4% are on some form of antihypertensive treatment, secondary cause is identified, removing the offending agent (when
and only 34% of all patients have controlled BP.3 Therefore, there are feasible) or treating/correcting the underlying comorbid condition
ample opportunities for clinicians to improve the care of patients should be the first step in management.
with hypertension.
PATHOPHYSIOLOGY 5,7
EPIDEMIOLOGY
Multiple factors that control BP are potential contributing compo-
Approximately 31% of the population (72 million Americans) have nents in the development of essential hypertension. These include
high BP (≥140/90 mm Hg).4 The percentage of men with high BP is malfunctions in either humoral (i.e., the renin–angiotensin–aldos-
higher than that of women before the age of 45 years, but between terone system [RAAS]) or vasodepressor mechanisms, abnormal
the ages of 45 and 54 years the percentage is slightly higher with
women.4 After age 55 years, a much higher percentage of women TABLE 15-1 Secondary Causes of Hypertension
have high BP than men.4 Prevalence rates are highest in non-
Hispanic blacks (33.5%) followed by non-Hispanic whites (28.9%) Diseases Drugs Associated with Hypertension in Humans a
and Mexican Americans (20.7%).3 Chronic kidney disease Prescription drugs
BP values increase with age, and hypertension (persistently ele- Cushing’s syndrome • Adrenal steroids (e.g., prednisone, fludrocortisone,
vated BP values) is very common in the elderly. The lifetime risk of Coarctation of the aorta triamcinolone)
developing hypertension among those 55 years of age and older who Obstructive sleep apnea • Amphetamines/anorexiants (e.g., phendimetrazine,
Parathyroid disease phentermine, sibutramine)
are normotensive is 90%.1 Most patients have prehypertension
Pheochromocytoma • Antivascular endothelin growth factor agents (bevaci-
before they are diagnosed with hypertension, with most diagnoses
Primary aldosteronism zumab, sorafenib, sunitinib), estrogens (usually oral
occurring between the third and fifth decades of life. In the popula- Renovascular disease contraceptives)
tion age ≥60 years, the prevalence of hypertension in 2000 was Thyroid disease • Calcineurin inhibitors (cyclosporine and tracolimus)
estimated at 65.4%, which is significantly higher than the 57.9% • Decongestants (phenylpropanolamine and analogs)
prevalence estimated in 1988.3 • Erythropoiesis stimulating agents (erythropoietin and
darbepoietin)
• Nonsteroidal antiinflammatory drugs,
ETIOLOGY cyclooxygenase-2 inhibitors
• Others: venlafaxine, bromocriptine, bupropion, bus-
In most patients, hypertension results from an unknown patho- pirone, carbamazepine, clozapine, desulfrane, ket-
physiologic etiology (essential or primary hypertension). This form of amine, metoclopramide
hypertension cannot be cured, but it can be controlled. A small Situations: β-blocker or centrally acting α-agonists
percentage of patients have a specific cause of their hypertension (when abruptly discontinued); β-blocker without α-
(secondary hypertension). There are many potential secondary blocker first when treating pheochromocytoma
causes that are either concurrent medical conditions or are endoge- Street drugs and other natural products
nously induced. If the cause can be identified, hypertension in these Cocaine and cocaine withdrawal
patients has the potential to be cured. Ephedra alkaloids (e.g., Ma-huang), “herbal ecstasy,”
other phenylpropanolamine analogsa
Nicotine withdrawal, anabolic steroids, narcotic
ESSENTIAL HYPERTENSION withdrawal, methylphenidate, phencyclidine,
ketamine, ergotamine and other ergot-containing
More than 90% of individuals with hypertension have essential
herbal products, St. John’s wort
hypertension.1 Numerous mechanisms have been identified that
Food substances
may contribute to the pathogenesis of this form of hypertension, so
Sodium
identifying the exact underlying abnormality is not possible.
Ethanol
Genetic factors may play an important role in the development of Licorice
essential hypertension. There are monogenic and polygenic forms Tyramine-containing foods if taking a monoamine oxi-
of BP dysregulation that may be responsible for essential hyperten- dase inhibitor
sion.5 Many of these genetic traits feature genes that affect sodium a
Agents of most clinical importance.
balance, but genetic mutations altering urinary kallikrein excretion, Data from Kaplan NM, Kaplan’s Clinical Hypertension. 8th ed. Philadelphia, PA: Lippincott Williams
nitric oxide release, and excretion of aldosterone, other adrenal & Wilkins, 2002:1–550.
 141
neuronal mechanisms, defects in peripheral autoregulation, and TABLE 15-3 Classification of Blood Pressure in Adults
disturbances in sodium, calcium, and natriuretic hormones. Many (Age ≥18 Years)a

CHAPTER 15
of these factors are cumulatively affected by the multifaceted RAAS,
Systolic Blood Diastolic Blood
which ultimately regulates arterial BP. It is probable that none of
Classification Pressure (mm Hg) Pressure (mm Hg)
these factors is solely responsible for essential hypertension; how-
ever, most antihypertensives specifically target these mechanisms Normal <120 and <80
and components of the RAAS. Prehypertensionb 120–139 or 80–89
Stage 1 hypertension 140–159 or 90–99
Stage 2 hypertension ≥160 or ≥100
ARTERIAL BLOOD PRESSURE a
Classification determined based on the average of two or more properly measured seated blood
pressure measurements from two or more clinical encounters. If systolic and diastolic blood pressure

Hypertension
Arterial BP is the pressure in the arterial wall measured in millime-
values yield different classifications, the highest category is used for the purpose of determining a
ters of mercury (mm Hg). The two typical arterial BP values are
classification.
systolic BP (SBP) and diastolic BP (DBP). SBP is achieved during b
For patients with diabetes mellitus, significant chronic kidney disease, known coronary artery disease
cardiac contraction and represents the peak value. DBP is achieved (myocardial infarction, stable angina, unstable angina), noncoronary atherosclerotic vascular disease
after contraction when the cardiac chambers are filling, and repre- (ischemic stroke, transient ischemic attack, peripheral arterial disease, abdominial aortic aneurism), or a
sents the nadir value. The difference between SBP and DBP is called Framingham risk score of 10% or greater, values ≥130/80 mm Hg are considered above goal; patients
with left ventricular dysfuction have a blood pressure goal of less than 120/80 mm Hg.
the pulse pressure and is a measure of arterial wall tension. Mean
arterial pressure is the average pressure throughout the cardiac cycle
decreases to its lowest daily values during sleep. This is followed by
of contraction. It is sometimes used clinically to represent overall
arterial BP, especially in hypertensive emergency. During a cardiac a sharp rise starting a few hours prior to awakening with the highest
values occurring midmorning. BP is also increased acutely during
cycle, two-thirds of the time is spent in diastole and one-third in
systole. Consequently, the mean arterial pressure can be estimated physical activity or emotional stress.
by using the following equation:
Classification
mean arterial pressure = (SBP × 1/3) + (DBP × 2/3)
The JNC7 classification of BP in adults (age ≥18 years) is based on
Arterial BP is hemodynamically generated by the interplay the average of two or more properly measured BP readings from
between blood flow and the resistance to blood flow. It is mathe- two or more clinical encounters (Table 15–3).1 It includes four
matically defined as the product of cardiac output and total periph- categories: normal, prehypertension, stage 1 hypertension, and stage
eral resistance according to the following equation: 2 hypertension. Prehypertension is not considered a disease cate-
BP = cardiac output × total peripheral resistance gory, but identifies patients whose BP is likely to increase into the
classification of hypertension in the future.
Cardiac output is the major determinant of SBP, whereas total Hypertensive crises are clinical situations where BP values are very
peripheral resistance largely determines DBP. In turn, cardiac out- elevated, typically greater than 180/120 mm Hg.7 They are catego-
put is a function of stroke volume, heart rate, and venous capaci- rized as either a hypertensive emergency or hypertensive urgency.
tance. Table 15–2 lists physiologic causes of increased cardiac Hypertensive emergencies are extreme elevations in BP that are
output and total peripheral resistance and correlates them to poten- accompanied by acute or progressing target-organ damage. Hyper-
tial mechanisms of pathogenesis. tensive urgencies are high elevations in BP without acute or pro-
Under normal physiologic conditions, arterial BP fluctuates gressing target-organ injury. Recommendations for managing
throughout the day. It typically follows a circadian rhythm, where it hypertensive crises are described later in this chapter.

 Cardiovascular Risk and Blood Pressure

TABLE 15-2 Potential Mechanisms of Pathogenesis
Epidemiologic data clearly indicate a strong correlation between BP
Blood pressure is the mathematical product of cardiac output and peripheral and CV morbidity and mortality.8 Risk of stroke, myocardial infarc-
resistance. Elevated blood pressure can result from increased cardiac output and/ tion, angina, heart failure, kidney failure, or early death from a CV
or increased total peripheral resistance.
cause are directly correlated with BP. Starting at a BP of 115/75 mm
Increased cardiac output Increased cardiac preload:
Hg, risk of CV disease doubles with every 20/10 mm Hg increase.1 Even
• Increased fluid volume from excess
sodium intake or renal sodium retention
patients with prehypertension have an increased risk of CV disease.
(from reduced number of nephrons or  Treating patients with hypertension with antihypertensive
decreased glomerular filtration) drug therapy provides significant benefits. Large-scale, placebo-
Venous constriction:
controlled, outcome trials show that the increased risks of CV
• Excess stimulation of the RAAS events and death associated with elevated BP are reduced substan-
• Sympathetic nervous system overactivity tially by antihypertensive drug therapy.9–12
Increased peripheral resistance Functional vascular constriction: SBP is a stronger predictor of CV disease than DBP in adults ≥50
• Excess stimulation of the RAAS years of age and is the most important clinical BP parameter for most
• Sympathetic nervous system overactivity patients.1 Patients with DBP values less than 90 mm Hg and SBP
• Genetic alterations of cell membranes values ≥140 mm Hg have isolated systolic hypertension. Isolated sys-
• Endothelial-derived factors tolic hypertension is believed to result from pathophysiologic changes
Structural vascular hypertrophy: in the arterial vasculature consistent with aging. These changes
• Excess stimulation of the RAAS decrease the compliance of the arterial wall and portend an increased
• Sympathetic nervous system overactivity risk of CV morbidity and mortality. Pulse pressure is the difference
• Genetic alterations of cell membranes between the SBP and the DBP. It is believed to reflect extent of
• Endothelial-derived factors atherosclerotic disease in the elderly and is a measure of increased
• Hyperinsulinemia resulting from obesity arterial stiffness. Higher pulse pressure values are correlated with an
or the metabolic syndrome
increased risk of CV mortality, especially in those with isolated
RAAS, renin–angiotensin–aldosterone system. systolic hypertension.
 142

HUMORAL MECHANISMS and chloride delivered to the distal tubule stimulates renin release.
Catecholamines increase renin release probably by directly stimulat-
SECTION 2

Several humoral abnormalities may be involved in the development ing sympathetic nerves on the afferent arterioles that in turn activate
of essential hypertension. These abnormalities may involve the the juxtaglomerular cells. Decreased serum potassium and/or intra-
RAAS, natriuretic hormones, and hyperinsulinemia. cellular calcium are detected by the juxtaglomerular cells resulting
in renin secretion.
Renin catalyzes the conversion of angiotensinogen to angiotensin
The Renin–Angiotensin–Aldosterone System I in the blood. Angiotensin I is then converted to angiotensin II by
The RAAS is a complex endogenous system that is involved with angiotensin-converting enzyme (ACE). After binding to specific
most regulatory components of arterial BP. Activation and regula- receptors (classified as either AT1 or AT2 subtypes), angiotensin II
Cardiovascular Disorders

tion are primarily governed by the kidney (Fig. 15–1). The RAAS exerts biologic effects in several tissues. The AT1 receptor is located
regulates sodium, potassium, and fluid balance. Consequently, this in brain, kidney, myocardium, peripheral vasculature, and the
system significantly influences vascular tone and sympathetic ner- adrenal glands. These receptors mediate most responses that are
vous system activity and is the most influential contributor to the critical to CV and kidney function. The AT2 receptor is located in
homeostatic regulation of BP. adrenal medullary tissue, uterus, and brain. Stimulation of the AT2
Renin is an enzyme that is stored in the juxtaglomerular cells, receptor does not influence BP regulation.
which are located in the afferent arterioles of the kidney. The release Circulating angiotensin II can elevate BP through pressor and
of renin is modulated by several factors: intrarenal factors (e.g., volume effects. Pressor effects include direct vasoconstriction, stim-
renal perfusion pressure, catecholamines, angiotensin II), and ulation of catecholamine release from the adrenal medulla, and
extrarenal factors (e.g., sodium, chloride, and potassium). centrally mediated increases in sympathetic nervous system activity.
Juxtaglomerular cells function as a baroreceptor-sensing device. Angiotensin II also stimulates aldosterone synthesis from the adrenal
Decreased renal artery pressure and kidney blood flow are sensed by cortex. This leads to sodium and water reabsorption that increases
these cells and stimulate secretion of renin. The juxtaglomerular plasma volume, total peripheral resistance, and ultimately BP. Aldos-
apparatus also includes a group of specialized distal tubule cells terone also has a deleterious role in the pathophysiology of other CV
referred to collectively as the macula densa. A decrease in sodium diseases (heart failure, myocardial infarction [MI] and kidney dis-

Afferent
Sympathetic 3 Arteriole Juxtaglomerular ANGIOTENSINOGEN
Nerves Cells
Re
n in
S e cr Macula densa signal
e tio Renal artery pressure/blood flow
Nephron

n Sympathetic stimulation Renin 7

Macula
Densa
ANGIOTENSIN I
Glomerulus

Converting Enzyme 1

Efferent
Arteriole
ANGIOTENSIN II
2

Adrenal Kidney Intestine CNS Peripheral Nervous System Vascular Smooth Heart
Cortex Muscle
Sympathetic Discharge
3 4
Aldosterone Vasopressin 4 Contractility
synthesis 6 Vasoconstriction

Sodium/Water Blood Total Peripheral Cardiac

Reabsorption 5 Resistance 5 Output
Volume

Blood Pressure

FIGURE 15-1. Diagram representing the renin–angiotensin–aldosterone system. The interrelationship between the kidney, angiotensin II, and
regulation of blood pressure are depicted. There are three major regulators of renin secretion from the juxtaglomerular cells in this system. The primary
sites of action for major antihypertensive agents are included. (, angiotensin-converting enzyme inhibitors; , angiotensin II receptor blockers; , β-
blockers; , calcium channel blockers; , diuretics; , aldosterone antagonists; , direct renin inhibitor; CNS, central nervous system.)
 143
ease) by promoting tissue remodeling leading to myocardial fibrosis Both are present in all tissue innervated by the sympathetic nervous
and vascular dysfunction. Clearly, any disturbance in the body that system. However, in some tissues β1-receptors predominate and in

CHAPTER 15
leads to activation of the RAAS could explain chronic hypertension. other tissues β2-receptors predominate. Stimulation of β1-receptors
The heart and brain contain a local RAAS. In the heart, angiotensin in the heart results in an increase in heart rate and contractility,
II is also generated by a second enzyme, angiotensin I convertase whereas stimulation of β2-receptors in the arterioles and venules
(human chymase). This enzyme is not blocked by ACE inhibition. causes vasodilation.
Activation of the myocardial RAAS increases cardiac contractility and The baroreceptor reflex system is the major negative-feedback
stimulates cardiac hypertrophy. In the brain, angiotensin II modulates mechanism that controls sympathetic activity. Baroreceptors are nerve
the production and release of hypothalamic and pituitary hormones, endings lying in the walls of large arteries, especially in the carotid
and enhances sympathetic outflow from the medulla oblongata. arteries and aortic arch. Changes in arterial pressure rapidly activate

Hypertension
Peripheral tissues can locally generate biologically active angio- baroreceptors that then transmit impulses to the brainstem through
tensin peptides, which may explain the increased vascular resistance the ninth cranial nerve and vagus nerves. In this reflex system, a
seen in hypertension. Some evidence suggests that angiotensin decrease in arterial BP stimulates baroreceptors, causing reflex vaso-
produced by local tissue may interact with other humoral regulators constriction and increased heart rate and force of cardiac contraction.
and endothelium-derived growth factors to stimulate vascular These baroreceptor reflex mechanisms may be blunted (less respon-
smooth muscle growth and metabolism. These angiotensin peptides sive to changes in BP) in the elderly and those with diabetes.
may, in fact, instigate increased vascular resistance in low plasma Stimulation of certain areas within the central nervous system
renin forms of hypertension. Components of the tissue RAAS may (nucleus tractus solitarius, vagal nuclei, vasomotor center, and the
also be responsible for the long-term hypertrophic abnormalities area postrema) can either increase or decrease BP. For example, α2-
seen with hypertension (left ventricular hypertrophy, vascular adrenergic stimulation within the central nervous system decreases
smooth muscle hypertrophy, and glomerular hypertrophy). BP through an inhibitory effect on the vasomotor center. However,
angiotensin II increases sympathetic outflow from the vasomotor
Natriuretic Hormone center, which increases BP.
The purpose of these neuronal mechanisms is to regulate BP and
Natriuretic hormone inhibits sodium and potassium-adenosine
maintain homeostasis. Pathologic disturbances in any of the four
triphosphatase and thus interferes with sodium transport across cell
major components (autonomic nerve fibers, adrenergic receptors,
membranes. Inherited defects in the kidney’s ability to eliminate
baroreceptors, or central nervous system) could conceivably lead to
sodium can cause an increased blood volume. A compensatory
chronically elevated BP. These systems are physiologically interre-
increase in the concentration of circulating natriuretic hormone
lated. A defect in one component may alter normal function in
theoretically could increase urinary excretion of sodium and water.
another, and such cumulative abnormalities may then explain the
However, this same hormone is also thought to block the active
development of essential hypertension.
transport of sodium out of arteriolar smooth muscle cells. The
increased intracellular sodium concentration ultimately would
increase vascular tone and BP. PERIPHERAL AUTOREGULATORY
COMPONENTS
Insulin Resistance and Hyperinsulinemia Abnormalities in renal or tissue autoregulatory systems could cause
The development of hypertension and associated metabolic abnor- hypertension. It is possible that a renal defect in sodium excretion may
malities is referred to as the metabolic syndrome.13 Hypothetically, first develop, which can then cause resetting of tissue autoregulatory
increased insulin concentrations may lead to hypertension because processes resulting in a higher arterial BP. The kidney usually maintains
of increased renal sodium retention and enhanced sympathetic normal BP through a volume-pressure adaptive mechanism. When BP
nervous system activity. Moreover, insulin has growth hormone- drops, the kidneys respond by increasing retention of sodium and
like actions that can induce hypertrophy of vascular smooth muscle water. These changes lead to plasma volume expansion that increases
cells. Insulin also may elevate BP by increasing intracellular calcium, BP. Conversely, when BP rises above normal, renal sodium and water
which leads to increased vascular resistance. The exact mechanism excretion are increased to reduce plasma volume and cardiac output.
by which insulin resistance and hyperinsulinemia occur in hyper- This ultimately will maintain homeostatic BP conditions.
tension is unknown. However, this association is strong because Local autoregulatory processes maintain adequate tissue oxygen-
many of the criteria used to define this population (elevated BP, ation. When tissue oxygen demand is normal to low, the local
abdominal obesity, dyslipidemia, and elevated fasting glucose) are arteriolar bed remains relatively vasoconstricted. However, increases
often present in patients with hypertension.13 in metabolic demand trigger arteriolar vasodilation that lowers
peripheral vascular resistance and increases blood flow and oxygen
NEURONAL REGULATION delivery through autoregulation.
Intrinsic defects in these renal adaptive mechanisms could lead to
Central and autonomic nervous systems are intricately involved in plasma volume expansion and increased blood flow to peripheral
the regulation of arterial BP. A number of receptors that either tissues, even when BP is normal. Local tissue autoregulatory pro-
enhance or inhibit norepinephrine release are located on the pre- cesses that vasoconstrict would then be activated to offset the
synaptic surface of sympathetic terminals. The α and β presynaptic increased blood flow. This effect would result in increased periph-
receptors play a role in negative and positive feedback to the eral vascular resistance, and if sustained, would also result in
norepinephrine-containing vesicles located near the neuronal end- thickening of the arteriolar walls. This pathophysiologic component
ing. Stimulation of presynaptic α-receptors (α2) exerts a negative is plausible because increased total peripheral resistance is a com-
inhibition on norepinephrine release. Stimulation of presynaptic β- mon underlying finding in patients with essential hypertension.
receptors facilitates norepinephrine release.
Sympathetic neuronal fibers located on the surface of effector VASCULAR ENDOTHELIAL MECHANISMS
cells innervate the α- and β-receptors. Stimulation of postsynaptic
α-receptors (α1) on arterioles and venules results in vasoconstric- Vascular endothelium and smooth muscle play important roles in
tion. There are two types of postsynaptic β-receptors, β1 and β2. regulating blood vessel tone and BP. These regulating functions are
 144
mediated through vasoactive substances that are synthesized by Laboratory Tests
endothelial cells. It has been postulated that a deficiency in the local
■ Blood urea nitrogen/serum creatinine, fasting lipid panel,
SECTION 2

synthesis of vasodilating substances (prostacyclin and bradykinin)

or excess vasoconstricting substances (angiotensin II and endo- fasting blood glucose, serum electrolytes, spot urine albumin-
thelin I) contribute to essential hypertension, atherosclerosis, and to-creatinine ratio. The patient may have normal values and
other CV diseases. still have hypertension. However, some may have abnormal
Nitric oxide is produced in the endothelium, relaxes the vascular values consistent with either additional CV risk factors or
epithelium, and is a very potent vasodilator. The nitric oxide system hypertension-related damage.
is an important regulator of arterial BP. Patients with hypertension Other Diagnostic Tests
may have an intrinsic deficiency in nitric oxide, resulting in inade- ■ 12-lead electrocardiogram (to detect left ventricular hypertro-
Cardiovascular Disorders

quate vasodilation. phy), estimated glomerular filtration rate (using Modification

of Diet in Renal Disease equation).
ELECTROLYTES AND OTHER CHEMICALS ■ 10-year risk of fatal coronary heart disease or non-fatal
myocardial infarction, based on Framingham scoring.
Epidemiologic and clinical data have associated excess sodium intake
with hypertension. Population-based studies indicate that high salt Target-Organ Damage
diets are associated with a high prevalence of stroke and hypertension. ■ The patient may have a previous medical history or diagnostic
Conversely, low salt diets are associated with a low prevalence of findings that indicate the presence of hypertension-related
hypertension. Clinical studies consistently show that dietary sodium target-organ damage:
restriction lowers BP in many (but not all) patients with elevated BP. ■ Brain (stroke, transient ischemic attack)
The exact mechanisms by which excess sodium leads to hypertension
are unknown. However, they may be linked to increased circulating ■ Eyes (retinopathy)
natriuretic hormones, which would inhibit intracellular sodium ■ Heart (left ventricular hypertrophy, angina or prior MI, prior
transport causing increased vascular reactivity and increased BP. coronary revascularization, heart failure)
Altered calcium homeostasis also may play an important role in ■ Kidney (chronic kidney disease)
the pathogenesis of hypertension. A lack of dietary calcium hypothet-
■ Peripheral vasculature (peripheral arterial disease)
ically can disturb the balance between intracellular and extracellular
calcium, resulting in an increased intracellular calcium concentra-
 DIAGNOSTIC CONSIDERATIONS
tion. This imbalance can alter vascular smooth muscle function by
increasing peripheral vascular resistance. Some studies show that Hypertension is termed the “silent killer” because most patients do
dietary calcium supplementation results in a modest BP reduction in not have symptoms. The primary physical finding is elevated BP.
patients with hypertension. The diagnosis of hypertension cannot be made based on one
The role of potassium fluctuations is also inadequately under- elevated BP measurement. The average of two or more measure-
stood. Potassium depletion may increase peripheral vascular resis- ments taken during two or more clinical encounters should be used
tance, but the clinical significance of small serum potassium to diagnose hypertension.1 Thereafter, this BP average can be used
concentration changes is unclear. Furthermore, data demonstrating to establish a diagnosis, and then classify the stage of hypertension
reduced CV risk with dietary potassium supplementation is very present using Table 15–3.
limited.
Measuring Blood Pressure
CLINICAL PRESENTATION Indirect measurement of BP using a sphygmomanometer is a
common routine medical screening tool that should be conducted
CLINICAL PRESENTATION OF HYPERTENSION at every healthcare encounter.1
General Sphygmomanometry—American Heart Association Proce-
■ The patient may appear very healthy, or may have the pres- dure14 The appropriate procedure to measure BP has been
ence of additional CV risk factors: described by the AHA.14 It is imperative that the measurement
• Age (≥55 years for men and 65 years for women) equipment (inflation cuff, stethoscope, manometer) meet certain
national standards to ensure maximum quality and precision with
• Diabetes mellitus the ascultatory measurement of BP.
• Dyslipidemia (elevated low-density lipoprotein-choles- The AHA stepwise technique is recommended:
terol, total cholesterol, and/or triglycerides; low high-
• Patients should refrain from nicotine or caffeine ingestion for 30
density lipoprotein-cholesterol)
minutes and be seated with the lower back supported in a chair
• Microalbuminuria and with their bare arm supported and resting near heart level.
• Family history of premature CV disease Feet should be flat on the floor (with legs not crossed). Measur-
• Obesity (body mass index ≥30 kg/m2) ing BP in the supine or standing position may be required under
special circumstances (suspected orthostatic hypotension, vol-
• Physical inactivity
ume depletion, or dehydration). The measurement environ-
• Tobacco use ment should be relatively quiet and provide privacy.
Symptoms • Measurement should begin only after a 5-minute period of rest.
■ Most patients are asymptomatic. • A properly sized cuff (pediatric, small, regular, large, or extra
Signs large) should be used. If the cuff is too small, the measured BP
■ Previous BP values in the prehypertension or hypertension can be overestimated. The inflatable rubber bladder inside the
category. cuff should encircle at least 80% of the arm of the upper arm
in length and 40% in width.
 145
• The palpatory method should be used to estimate the SBP:
CLINICAL CONTROVERSY

CHAPTER 15
• Place the cuff on the upper arm 2 to 3 cm above the
antecubital fossa and attach it to the manometer (either a Aggressive treatment of white coat hypertension is controversial.
mercury or aneroid) However, patients with white coat hypertension may have
• Close the inflation valve with the thumb and index finger, increased CV risk compared with those without such BP changes.15
and inflate the cuff to 70 mm Hg
Several additional factors can result in erroneous BP measure-
• Simultaneously palpate the radial pulse with the index and
ments. Pseudohypertension is a falsely elevated BP measurement. It
middle fingers of the opposite hand
may be seen in the elderly, those with long-standing diabetes, or in
• Inflate in increments of 10 mm Hg by pumping the inflation those with chronic kidney disease caused by rigid, calcified brachial

Hypertension
bulb (as it is resting in the palm of your hand) with the arteries.14 In these patients, the true arterial BP when measured
pinky, ring, and middle fingers (the last three) until the directly with intraarterial measurement (the most accurate measure-
radial pulse disappears ment of BP) is much lower than that measured using the indirect cuff
• Note the pressure at which radial pulse disappears; this is the method. The Osler maneuver can be used to test for pseudohyper-
estimated SBP tension. In this maneuver, the BP cuff is inflated above peak SBP. If
• Release pressure from the cuff by turning the valve counter- the radial artery remains palpable, the patient has a positive Osler
clockwise sign (rigid artery), which may indicate pseudohypertension.
Elderly patients with a wide pulse pressure may have an auscultatory
• The bell (not the diaphragm) of the stethoscope should be gap which can lead to underestimated SBP or overestimated DBP
placed on the skin of the antecubital fossa, directly over where measurements.14 In this situation, as the cuff pressure falls from the
the brachial artery is palpated. The stethoscope earpieces true SBP value, the Korotkoff sound may disappear (indicating a false
should be inserted appropriately. The valve should be closed DBP measurement), reappear (a false SBP measurement), and then
with the cuff then inflated rapidly to about 30 mm Hg above disappear again at the true DBP value. This is often identified by using
the estimated SBP from the palpatory method. The value the palpatory method to estimate SBP and then inflating the cuff an
should be only slightly opened to release pressure at a very slow additional 30 mm Hg above this estimate because the “gap” is usually
rate of 2 to 3 mm Hg per second. less than 30 mm Hg. When an auscultatory gap is present, Korotkoff
• The clinician should listen for Korotkoff sounds with the sounds are usually heard when pressure in the cuff first starts to
stethoscope. The first phase of Korotkoff sounds are the initial decrease after inflation. This may be eliminated by raising the arm
presence of clear tapping sounds. Note the pressure at the first overhead for 30 seconds before bringing it to the proper position and
recognition of these sounds. This is the SBP. As pressure inflating the cuff. This maneuver decreases the intravascular volume
continues to deflate, note the pressure when all sounds disap- and improves inflow thereby allowing Korotkoff sounds to be heard.14
pear (also known as the fifth Korotkoff phase). This is the Patients with irregular ventricular heart rates (e.g., atrial fibrilla-
DBP. tion, atrial flutter) may have misleading BP values when measured
• Measurements should be taken to the nearest 2 mm Hg. indirectly. In this situation, SBP and DBP values may vary from one
heartbeat to the next.
• A second measurement should be obtained after a minimum
of 1 minute, and the average should be documented. If these
values differ by more than 5 mm Hg, additional measurements Ambulatory and Self Blood Pressure Monitoring
should be collected and averaged. Ambulatory BP monitoring using an automated device can docu-
• Neither the patient nor the observer should talk during mea- ment BP at frequent time intervals (e.g., every 15 to 30 minutes)
surement. throughout a 24-hour period.14 Ambulatory BP values are usually
• At the first visit, BP should be measured in both arms. When lower than clinic-measured values. The upper limit for normal
consistent interarm differences exist, the higher number ambulatory BP is 140/90 mm Hg during the day, 125/75 mm Hg at
should be used for diagnostic and treatment purposes. night, and 135/85 mm Hg during 24 hours. Home BP measurements
are collected by patients, preferably in the morning, using home
It is recommended that the stethoscope bell, rather than the monitoring devices. Either of these may be warranted in patients
diaphragm, be used for measurement, although some studies sug- with suspected white coat hypertension (without hypertension-
gest little difference between two.14 Low-frequency Korotkoff related target-organ damage) to differentiate white coat from essen-
sounds, however, may not be heard clearly and accurately with the tial hypertension.1 Moreover, ambulatory BP monitoring may be
diaphragm. This is especially problematic in patients with faint or helpful in patients with apparent drug resistance, hypotensive symp-
“distant” sounds. toms while on antihypertensive therapy, episodic hypertension (e.g.,
Inaccuracies with indirect measurements result from inherent white coat hypertension), autonomic dysfunction, and to identify
biologic variability of BP, inaccuracies related to suboptimal tech- “nondippers” whose BP does not decrease by >10% during sleep and
nique, and the white coat effect.14 Variations in BP occur with which may portend increased risk of BP-related complications.1,14
environmental temperature, the time of day and year, meals, physi- Some data suggest that 24-hour and home BP measurements
cal activity, posture, alcohol, nicotine, and emotions. In the clinic correlate better with CV risk than do conventional office-based BP
setting, standard BP measurement procedures (e.g., appropriate rest measurements.14,16 However, one controlled study found that ambu-
period, poor technique, minimal number of measurements) are latory BP and self BP monitoring are complementary to conventional
often not followed, which results in poor estimation of true BP. clinic-based measurements.17 Limitations of these measurements that
Approximately 15% to 20% of patients have white coat hypertension, may prohibit routine use of such technology include lack of validated
where BP values rise in a clinical setting but return to normal in devices, complexity of use, costs, and lack of prospective outcomes
nonclinical environments using home or ambulatory BP measure- data describing normal ranges for these measurements. Although
ments.14 Interestingly, the rise in BP dissipates gradually over several self-monitoring of BP at home is less complicated and less costly than
hours after leaving the clinical setting. It may or may not be ambulatory monitoring, patients may omit or fabricate readings.
precipitated by other stresses in the patient’s daily life. Thus, devices that have a memory or printouts are recommended.14
 146

CLINICAL EVALUATION Target-Organ Damage

Target-organ damage (see Clinical Presentation of Hypertension
SECTION 2

Frequently, the only sign of essential hypertension is elevated BP.

The rest of the physical examination may be completely normal. above) can develop as a complication of hypertension. The primary
However, a complete medical evaluation (a comprehensive medical organs involved are the eye, brain, heart, kidneys, and peripheral
history, physical examination, and laboratory and/or diagnostic blood vessels. Clinical CV events (e.g., MI, stroke, kidney failure)
tests) is recommended after diagnosis to (a) identify secondary are clinical end points of target-organ damage and are the primary
causes, (b) identify other CV risk factors or comorbid conditions causes of CV morbidity and mortality in patients with hypertension.
that may define prognosis and/or guide therapy, and (c) assess for The probability of CV events and CV morbidity and mortality in
the presence or absence of hypertension-associated target-organ patients with hypertension is directly correlated with the severity of
damage.1 All patients with hypertension should have the following BP elevation and additional CV risk factors.
Cardiovascular Disorders

measured prior to initiating therapy: 12-lead electrocardiogram; spot Hypertension accelerates atherosclerosis and stimulates left ven-
urine albumin-to-creatinine ratio; blood glucose and hematocrit; tricular and vascular hypertrophy. These pathologic changes are
serum potassium, creatinine (with estimated glomerular filtration thought to be secondary to both a chronic pressure overload and a
rate [GFR]), and calcium; and a fasting lipid panel.1,18 For patients variety of nonhemodynamic stimuli. Some of the nonhemodynamic
without a history of coronary artery disease, noncoronary athero- disturbances that have been implicated in these effects include the
sclerotic vascular disease (also referred to as coronary artery disease adrenergic system, RAAS, increased synthesis and secretion of endo-
risk equivalents), left ventricular dysfunction, or diabetes, it is also thelin I, and a decreased production of prostacyclin and nitric oxide.
important to estimate a 10-year risk of fatal coronary heart disease or Accelerated atherogenesis in hypertension is accompanied by prolif-
nonfatal myocardial infarction using Framingham Risk scoring eration of smooth muscle cells, lipid infiltration into the vascular
(http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm).2 endothelium, and an enhancement of vascular calcium accumulation.
Cerebrovascular disease is a consequence of hypertension. A neu-
rologic assessment can detect either gross neurologic deficits or a
Secondary Causes slight hemiparesis with some incoordination and hyperreflexia that
Table 15–1 lists the most common secondary causes of hyperten- are indicative of cerebrovascular disease. Stroke can result from
sion. A complete medical evaluation may provide clues for identify- lacunar infarcts caused by thrombotic occlusion of small vessels or
ing secondary hypertension. intracerebral hemorrhage resulting from ruptured microaneurysms.
Patients with secondary hypertension may complain of symptoms Transient ischemic attacks secondary to atherosclerotic disease in the
suggestive of the underlying disorder, but some are asymptomatic. carotid arteries are possible long-term complications of hypertension.
Patients with pheochromocytoma may have a history of paroxysmal Retinopathies can occur in hypertension and may manifest as a
headaches, sweating, tachycardia, and palpitations. Over half of these variety of different findings. A funduscopic examination can detect
patients suffer from episodes of orthostatic hypotension. In primary hypertensive retinopathy and can be categorized according to the
aldosteronism, symptoms related to hypokalemia usually include Keith-Wagener-Barker retinopathy classification. Retinopathy mani-
muscle cramps and muscle weakness. Patients with Cushing’s syn- fests as arteriolar narrowing, focal arteriolar constrictions, arteriove-
drome may complain of weight gain, polyuria, edema, menstrual nous crossing changes (nicking), retinal hemorrhages and exudates,
irregularities, recurrent acne, or muscular weakness and have several and disk edema. Accelerated arteriosclerosis, a long-term consequence
classic physical features (e.g., moon face, buffalo hump, hirsutism, of essential hypertension, can cause nonspecific changes such as
abdominal striae). Patients with coarctation of the aorta may have increased light reflex, increased tortuosity of vessels, and arteriovenous
diminished or even absent femoral pulses, and patients with renal nicking. Focal arteriolar narrowing, retinal infarcts, and flame-shaped
artery stenosis may have an abdominal systolic–diastolic bruit. hemorrhages usually are suggestive of accelerated or malignant phase of
Routine laboratory tests may also help identify secondary hyper- hypertension. Papilledema is swelling of the optic disk and is caused by
tension. Baseline hypokalemia may suggest mineralocorticoid- a breakdown in autoregulation of capillary blood flow in the presence
induced hypertension. Protein, blood cells, and casts in the urine of high pressure. It is usually only present in hypertensive emergencies.
may indicate renovascular disease. Some laboratory tests are used Heart disease is the best identified form of target-organ damage.
specifically to diagnose secondary hypertension. These include A thorough cardiac and pulmonary examination can identify car-
plasma norepinephrine and urinary metanephrine for pheochro- diopulmonary abnormalities. Clinical manifestations include left
mocytoma, plasma and urinary aldosterone concentrations for ventricular hypertrophy, coronary heart disease (angina, prior MI,
primary aldosteronism, and plasma renin activity, captopril stimu- and prior coronary revascularization), and heart failure. These
lation test, and renal artery angiography for renovascular disease. complications may lead to cardiac arrhythmias, angina, MI, and
Certain medications and herbal products can result in drug- sudden death. Coronary disease (also called coronary heart disease
induced hypertension (see Table 15–1). For some patients, the or coronary artery disease) and associated CV events are the most
addition of these agents can be the cause of hypertension or can common causes of death in patients with hypertension.
exacerbate underlying hypertension. Identifying a temporal rela- The kidney damage caused by hypertension is characterized patho-
tionship between starting the suspected agent and developing ele- logically by hyaline arteriosclerosis, hyperplastic arteriosclerosis, arte-
vated BP is most suggestive of drug-induced BP elevation. riolar hypertrophy, fibrinoid necrosis, and atheroma of the major
renal arteries. Glomerular hyperfiltration and intraglomerular hyper-
NATURAL COURSE OF DISEASE tension are early stages of hypertensive nephropathy. Microalbumin-
uria is followed by a gradual decline in renal function. The primary
Essential hypertension is usually preceded by elevated BP values that are renal complication in hypertension is nephrosclerosis, which is sec-
in the prehypertension category. BP values may fluctuate between ondary to arteriosclerosis. Atheromatous disease of a major renal
elevated and normal levels for an extended period of time. These artery may give rise to renal artery stenosis. Although overt kidney
changes may begin as early as the second decade of life. During this stage, failure is an uncommon complication of essential hypertension, it is an
many patients have a hyperdynamic circulation with increased cardiac important cause of end-stage kidney disease, especially in African
output and normal or even low peripheral vascular resistance. As the Americans, Hispanics, and Native Americans. It is not completely
disease progresses, peripheral vascular resistance increases, and BP eleva- understood why these ethnic groups are more at risk for kidney decline
tion is sustained to the point where essential hypertension is diagnosed. than other ethnic groups.
 147
The peripheral vasculature is a target organ. Physical examination Significant chronic kidney disease is considered to be moderate-to-
of the vascular system can detect evidence of atherosclerosis, which severe chronic kidney disease, defined as estimated GFR <60 mL/

CHAPTER 15
may present as arterial bruits (aortic, abdominal, or peripheral), min/1.73 m2 (correlating to a serum creatinine >1.3 mg/dL in women
distended veins, diminished or absent peripheral arterial pulses, or and >1.5 in men) or albuminuria (>300 mg/day or >200 mg/g
lower-extremity edema. Peripheral arterial disease is a clinical creatinine).
condition that can result from atherosclerosis, which is accelerated Framingham risk score is calculated using the risk calculator avail-
in hypertension. Other CV risk factors (e.g., smoking) can increase able at http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm
the likelihood of peripheral arterial disease as well as all other forms Some clinicians advocate attaining BP goal values that are lower
of target-organ damage. than what is recommended as a modality to further reduce CV risk
following the myth that “lower is better.” Contrary to this, a J-curve

Hypertension
hypothesis, where lowering BP too much might increase the risk of
TREATMENT CV events, has been described.20 However, these data are based off
of observational studies and cannot establish a cause-and-effect
Hypertension relationship because of confounding variables.
Lower goal BP values have been evaluated prospectively in the
■ DESIRED OUTCOMES Hypertension Optimal Treatment (HOT) trial.19 In this study, more
 Overall Goal of Therapy than 18,700 patients were randomized to target DBP values of 90
mm Hg or less, 85 mm Hg or less, or 80 mm Hg or less. Although
The overall goal of treating hypertension is to reduce hypertension- the actual DBP values achieved were 85.2, 83.2, and 81.1 mm Hg,
associated morbidity and mortality.1 This morbidity and mortality is respectively, the risk of major CV events was the lowest with a BP of
related to target-organ damage (e.g., CV events, heart failure, and 139/83 mm Hg, and the lowest risk of stroke was with a BP of 142/
kidney disease). Reducing risk remains the primary purpose of hyper- 80 mm Hg. Risk of events in subjects with either diabetes or
tension therapy and the specific choice of drug therapy is significantly ischemic heart disease were lowest at DBP values of less than 80 mm
influenced by evidence demonstrating such risk reduction. Hg. No J-curve relationship was seen.

 Surrogate Goal of Therapy

Treating patients with hypertension to achieve a desired target BP value CLINICAL CONTROVERSY
is simply a surrogate goal of therapy. Reducing BP to goal does not There is increasing evidence suggesting that ambulatory BP
guarantee that target-organ damage will not occur. However, attaining measurements may be more accurate and better predict target-
goal BP values is associated with lower risk of CV disease and target- organ damage than manual BP measurements using a sphyg-
organ damage.1,19 Targeting a goal BP value is a tool that clinicians can momanometer in a clinic setting (considered the gold stan-
easily use to evaluate response to therapy and is the primary method dard).14 Studies document that large numbers of individuals
used to determine the need for titration and regimen modification. may be misdiagnosed or misclassified based on clinic BP
Most patients have a goal BP of less than 140/90 mm Hg for the measurements as a result of a variety of factors such as poor
general prevention of CV events or CV disease (e.g., coronary artery technique, daily variability of BP, and white coat hyperten-
disease).1,2 However, this goal is lowered to less than 130/80 mm Hg sion. Validated ambulatory BP monitoring may obviate some
for patients with diabetes, significant chronic kidney disease, known of these factors, but their role in the routine management of
coronary artery disease (myocardial infarction, stable angina, unsta- hypertension is unclear.
ble angina), noncoronary atherosclerotic vascular disease (ischemic
stroke, transient ischemic attack, peripheral arterial disease, abdom-
■ AVOIDING CLINICAL INERTIA
inal aortic aneurism), or a 10% or greater 10-year risk of fatal
coronary heart disease or nonfatal myocardial infarction based on Although hypertension is one of the most common medical
Framingham risk scoring (http://www.nhlbi.nih.gov/guidelines/ conditions, BP control rates are poor. Many patients, especially
cholesterol/risk_tbl.htm).2 Moreover, patients with left ventricular older patients, with hypertension are at goal DBP values but
dysfunction (heart failure) have a BP goal of less than 120/80 mm Hg.2 continue to have elevated SBP values. It has been estimated that of
the hypertensive population that is treated, yet not controlled,
76.9% have SBP ≥140 mm Hg with DBP values less than 90 mm
GOAL BLOOD PRESSURE Hg.21 For most patients with hypertension, attaining the SBP goal
VALUES RECOMMENDED BY THE almost always assures achievement of the DBP goal. When cou-
AMERICAN HEART ASSOCIATION IN 20072 pled with the fact that SBP is a better predictor of CV risk than
DBP, SBP must be used as the primary clinical marker of disease
• Most patients for general prevention <140/90 mm Hg
control in hypertension.
• Patients with diabetes (referred to as <130/80 mm Hg Clinical inertia in hypertension has been defined as an office visit
coronary artery disease risk equivalent), at which no therapeutic move was made to lower BP in a patient
significantchronic kidney disease, known with uncontrolled hypertension.22 Clinical inertia is not the entire
coronary artery disease (myocardial infarction, reason why most patients with hypertension do not have at-goal BP
stable angina, unstable angina), noncoronary values. However, it is certainly a major reason that can be simply
atherosclerotic vascular disease (ischemic remedied through more aggressive treatment with drug therapy.
stroke, transient ischemic attack, peripheral This can involve initiating, titrating, or changing drug therapy.
arterial disease, abdominal aortic aneurism
[referred to as coronary artery disease risk ■ GENERAL APPROACH TO TREATMENT
equivalents]), or a Framingham risk score
of 10% or greater After a definitive diagnosis of hypertension is made, most patients
should be placed on both lifestyle modifications and drug therapy
• Patients with left ventricular dysfunction <120/80 mm Hg
concurrently. Lifestyle modification alone is considered appropriate
(heart failure)
therapy for patients with prehypertension. However, lifestyle modi-
 148

Initial Drug Therapy

SECTION 2

Choices

FIGURE 15-2. Algorithm for treatment of hypertension. No Compelling Compelling

Drug therapy recommendations are graded with strength Indications Indications
of recommendation and quality of evidence in brackets. (see Fig.15–3)
Strength of recommendations: A, B, C = good, moderate,
Cardiovascular Disorders

and poor evidence to support recommendation, respec-

Stage 1 Stage 2
tively. Quality of evidence: 1 = Evidence from more than
Hypertension Hypertension
1 properly randomized, controlled trial. 2 = Evidence from
(SBP 140–159 or DBP 90– (SBP >160 or DBP >100
at least one well-designed clinical trial with randomization;
99 mm Hg) mm Hg)
from cohort or case-controlled analytic studies; or dramatic
results from uncontrolled experiments or subgroup analy-
ses. 3 = Evidence from opinions of respected authorities, Thiazide-type diuretics [A-1]; Two-drug combination for most [A-3].
based on clinical experience, descriptive studies, or reports
of expert communities. (ACE, angiotensin-converting ACE inhibitor, ARB, CCB, or Usually a thiazide-type diuretic with
enzyme; ARB, angiotensin receptor blocker; CCB, calcium combination [A-2]. an ACE inhibitor, or ARB, or CCB [A-2].
channel blocker; DBP, diastolic blood pressure; SBP, sys-
tolic blood pressure.) (Adapted from references 1 and 2.)

fications alone are not considered adequate for patients with hyper- 3. As little as 10 pounds of weight loss can decrease BP signifi-
tension and additional CV risk factors, especially patients with BP cantly in overweight patients.
goals of less than 130/80 mm Hg (e.g., diabetes, coronary artery 4. Abdominal obesity is associated with the metabolic syndrome,
disease, chronic kidney disease) or less than 120/80 mm Hg (i.e., left which is a precursor to diabetes, dyslipidemia, and, ultimately,
ventricular dysfunction), who have not attained this goal BP. CV disease.13
The choice of initial drug therapy depends on the degree of BP
5. Diets rich in fruits and vegetables and low in saturated fat
elevation and presence of compelling indications (see Patients with
lower BP in patients with hypertension.
Compelling Indications section). Most patients with stage 1 hyper-
tension should be initially treated with a thiazide-type diuretic, ACE 6. Most people experience some degree of SBP reduction with
inhibitor, ARB, or CCB. For patients with more severe BP elevation sodium restriction.
(stage 2 hypertension), combination drug therapy, with one of the
The Dietary Approaches to Stop Hypertension (DASH) eating
agents being preferably a thiazide type-diuretic, is recommended.
plan is a diet that is rich in fruits, vegetables, and low-fat dairy
Figure 15–2 outlines this general approach. There are six compelling
products with a reduced content of saturated and total fat. It is
indications where specific antihypertensive drug classes have evi-
advocated by the JNC7 as a reasonable and feasible diet that is
dence showing unique benefits in patients with the compelling
proven to lower BP. Intake of sodium should be minimized as much
indication (Fig. 15–3).
as possible, ideally to 1.5 g/day, although an interim goal of less than
2.3 g/day may be reasonable considering the difficulty in achieving
■  NONPHARMACOLOGIC THERAPY these low intakes. Patients should be aware of the multiple sources
All patients with prehypertension and hypertension should be of dietary sodium (e.g., processed foods, soups, table salt) so that
prescribed lifestyle modifications. Table 15–4 lists modifications they may follow these recommendations. Potassium intake should
that lower BP. These approaches are recommended by the JNC7 be encouraged through fruits and vegetables with high content
and the AHA.1,23 They can provide small to moderate reductions in (ideally 4.7 g/day) in those with normal kidney function. Excessive
SBP. Aside from lowering BP in patients with known hypertension, alcohol use can either cause or worsen hypertension. Patients with
lifestyle modification can decrease the progression to hypertension hypertension who drink alcoholic beverages should restrict their
in patients with prehypertension BP values.23 In a portion of daily intake (see Table 15–4). Patients should be counseled that 1
patients with hypertension that have relatively good BP control drink is equivalent to 1.5 oz of 80-proof distilled spirits (e.g.,
while on single antihypertensive drug therapy, sodium reduction whiskey), a 5 oz glass of wine (12%), or 12 oz of beer.23
and weight loss may allow withdrawal of drug therapy.24 Carefully designed programs of physical activity can lower BP.
A sensible dietary program is one that is designed to reduce Regular physical activity for at least 30 minutes most days of the week
weight gradually, for overweight and obese patients, and one that is recommended for all adults, with at least 60 minutes recommended
restricts sodium intake with only moderate alcohol consumption. for adults attempting to lose weight or maintain weight loss.25 Studies
Successful implementation of dietary lifestyle modifications by show that aerobic exercise can reduce BP, even in the absence of weight
clinicians requires aggressive promotion through reasonable patient loss. Patients should consult their physicians before starting an exercise
education, encouragement, and continued reinforcement. Patients program, especially those with CV and/or target-organ disease.
may better understand the rationale for dietary intervention in Cigarette smoking is a major, independent, modifiable risk factor
hypertension if they are provided the following observations and for CV disease. Patients with hypertension who smoke should be
facts23: thoroughly counseled regarding the additional health risks that
result from smoking. Moreover, the potential benefits that cessation
1. Hypertension is two to three times more likely in overweight can provide should be explained to encourage cessation. Several
than in lean persons. smoking-cessation programs, pharmacotherapy options, and aids
2. More than 60% of patients with hypertension are overweight. are available to assist patients.
 149

CHAPTER 15
Compelling
Indication(s)

Chronic Recurrent
Left Ventricular Postmyocardial Coronary Diabetes
Kidney Stroke
Function Infarction Disease Mellitus
Disease Prevention

Hypertension
Diuretic with ȕ-Blocker Diuretic with
ȕ-Blocker ACE inhibitor ACE inhibitor
ACE inhibitor [A-1]; ACE inhibitor
[A-1]; [A-1]; [A-1];
Standard [A-1]; [A-2]
Pharmacotherapy then add then add or or
then add ACE inhibitor OR
ACE inhibitor
ȕ-Blocker [A-1] or [A-1] or ARB ARB [A-2] ARB [A-1]
[A-1] ARB [A-2] ARB [A-2]
[A-2]

ARB [A-2] or
Aldosterone CCB [B-2],
Add-on aldosterone Diuretic
antagonist diuretic
Pharmacotherapy antagonist [B-2]
[A-2] [B-2]
[A-2]

ȕ-Blocker
[B-2],
CCB [B-2]

FIGURE 15-3. Compelling indications for individual drug classes. Compelling indications for specific drugs are evidence-based recommendations
from outcome studies or existing clinical guidelines. The order of drug therapies serves as a general guidance that should be balanced with clinical
judgment and patient response; however, standard pharmacotherapy should be considered first-line recommendations, preferably in the order
depicted. Add-on pharmacotherapy recommendations then are intended to be used to further reduce risk of cardiovascular events and to lower
blood pressure to goal values. Blood pressure control should be managed concurrently with the compelling indication. Drug therapy
recommendations are graded with strength of recommendation and quality of evidence in brackets. Strength of recommendations: A, B, C =
good, moderate, and poor evidence to support recommendation, respectively. Quality of evidence: 1 = Evidence from more than one properly
randomized, controlled trial. 2 = Evidence from at least one well-designed clinical trial with randomization; from cohort or case-controlled analytic
studies or multiple time series; or dramatic results from uncontrolled experiments or subgroup analyses. 3 = Evidence from opinions of respected
authorities, based on clinical experience, descriptive studies, or reports of expert communities. (ACE, angiotensin-converting enzyme; ARB,
angiotensin receptor blocker; CCB, calcium channel blocker.) (Adapted from references 1, 2, 58, and 74.)

■ PHARMACOTHERAPY comes data have demonstrated CV risk reduction benefits with these
classes. Several have subclasses where significant differences in mech-
A diuretic (primarily a thiazide-type), ACE inhibitor, angiotensin II anism of action, clinical use, side effects, or evidence from outcomes
receptor blocker (ARB), or calcium channel blocker (CCB) are studies exist. β-Blockers are effective antihypertensive agents that
considered primary antihypertensive agents that are acceptable first- previously were considered primary agents. They are now preferred
line options (Table 15–5). These agents should be used to treat the either to treat a specific compelling indication, or in combination
majority of patients with hypertension because evidence from out- with one of the aforementioned primary antihypertensive agents for

TABLE 15-4 Lifestyle Modifications to Prevent and Manage Hypertension

Approximate Systolic Blood
Modification Recommendation Pressure Reduction (mm Hg)a
Weight loss Maintain normal body weight (body mass index 18.5–24.9 kg /m2) 5–20 per 10-kg weight loss
DASH-type dietary patterns Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated 8–14
and total fat
Reduced salt intake Reduce daily dietary sodium intake as much as possible, ideally to ≈65 mmol/day (1.5 g /day sodium, 2–8
or 3.8 g /day sodium chloride)
Physical activity Regular aerobic physical activity (at least 30 min/day, most days of the week) 4–9
Moderation of alcohol intake Limit consumption to ≤ 2 drinks/day in men and ≤1 drink/day in women and lighter-weight persons 2–4
DASH, Dietary Approaches to Stop Hypertension.
a
Effects of implementing these modifications are time and dose dependent and could be greater for some patients.
Data from Chobanian et al.,1 and Kostis et al.24
 150

TABLE 15-5 Primary Antihypertensive Agents

SECTION 2

Usual Dose Daily

Class Subclass Drug (Brand Name) Range (mg/day) Frequency Comments
Diuretics Thiazides Chlorthalidone (Hygroton) 12.5–25 1 Dose in the morning to avoid nocturnal diuresis; thiazides are
Hydrochlorothiazide 12.5–25 1 more effective antihypertensives than loop diuretics in most
(Microzide) patients; use usual doses to minimize adverse metabolic
Indapamide (Lozol) 1.25–2.5 1 effects; ideally maintain potassium concentration between
Metolazone (Zaroxolyn) 2.5–5 1 4.0–5.0 mEq/L to minimize metabolic effects; hydrochlo-
rothiazide and chlorthalidone are generally preferred, with
25 mg/day generally considered the maximum effective
Cardiovascular Disorders

dose; chlorthalidone is nearly twice as potent as hydrochlo-

rothiazide; have additional benefits in osteoporosis; may
require additional monitoring in patients with a history of
gout or hyperglycemia
Loops Bumetanide (Bumex) 0.5–4 2 Dose in the morning and afternoon to avoid nocturnal diuresis;
Furosemide (Lasix) 20–80 2 higher doses may be needed for patients with severely
Torsemide (Demadex) 5–10 1 decreased glomerular filtration rate or left ventricular dys-
function
Potassium Amiloride (Midamor) 5–10 1 or 2 Dose in the morning or afternoon to avoid nocturnal
sparing Amiloride/hydrochlorothiaz- 5–10/50–100 1 diuresis; weak diuretics that are generally used in combi-
ide (Moduretic) nation with thiazide-type diuretics to minimize hypokale-
Triamterene (Dyrenium) 50–100 1 or 2 mia; avoid in patients with severe chronic kidney disease
Triamterene/hydrochlorothi- 37.5–75/25–50 1 (estimated glomerular filtration rate <30 mL/min/1.73
azide (Dyazide) m2); may cause hyperkalemia, especially in combination
with an ACE inhibitor, ARB, direct renin inhibitor or
potassium supplements
Aldosterone Eplerenone (Inspra) 50–100 1 or 2 Dose in the morning or afternoon to avoid nocturnal
antagonists Spironolactone (Aldactone) 25–50 1 or 2 diuresis; eplerenone contraindicated in patients with an
Spironolactone/hydrochlo- 25–50/25–50 1 estimated creatinine clearance <50 mL/min, elevated
rothiazide (Aldactazide) serum creatinine (>1.8 mg/dL in women, >2 mg/dL in
men), and type 2 diabetes with microalbuminuria; avoid
spironolactone in patients with chronic kidney disease
(estimated glomerular filtration rate <30 mL/min/1.73 m2);
may cause hyperkalemia, especially in combination with
an ACE inhibitor, ARB, direct renin inhibitor or potassium
supplements
ACE inhibitors Benazepril (Lotensin) 10–40 1 or 2 Starting dose may be reduced 50% in patients who are on a
Captopril (Capoten) 25–150 2 or 3 diuretic, are volume depleted, or are very elderly because of
Enalapril (Vasotec) 5–40 1 or 2 risks of hypotension; may cause hyperkalemia in patients
Fosinopril (Monopril) 10–40 1 with chronic kidney disease or in those receiving potassium-
Lisinopril (Prinivil, Zestril) 10–40 1 sparing diuretics, aldosterone antagonists, ARB, or direct
Moexipril (Univasc) 7.5–30 1 or 2 renin inhibitors; can cause acute kidney failure in patients
Perindopril (Aceon) 4–16 1 with severe bilateral renal artery stenosis or severe stenosis
Quinapril (Accupril) 10–80 1 or 2 in artery to solitary kidney; do not use in pregnancy or in
Ramipril (Altace) 2.5–10 1 or 2 patients with a history of angioedema
Trandolapril (Mavik) 1–4 1
ARBs Candesartan (Atacand) 8–32 1 or 2 Starting dose may be reduced 50% in patients who are on a
Eprosartan (Teveten) 600–800 1 or 2 diuretic, are volume depleted, or are very elderly because
Irbesartan (Avapro) 150–300 1 of risks of hypotension; may cause hyperkalemia in patients
Losartan (Cozaar) 50–100 1 or 2 with chronic kidney disease or in those receiving potas-
Olmesartan (Benicar) 20–40 1 sium-sparing diuretics, aldosterone antagonists, ACE inhib-
Telmisartan (Micardis) 20–80 1 itors, or direct renin inhibitor; can cause acute kidney
Valsartan (Diovan) 80–320 1 failure in patients with severe bilateral renal artery stenosis
or severe stenosis in artery to solitary kidney; do not cause
a dry cough like ACE inhibitors may; do not use in
pregnancy
Calcium chan- Dihydropyridines Amlodipine (Norvasc) 2.5–10 1 Short-acting dihydropyridines should be avoided, especially
nel blockers Felodipine (Plendil) 5–20 1 immediate-release nifedipine and nicardipine; dihydropy-
Isradipine (DynaCirc) 5–10 2 ridines are more potent peripheral vasodilators than nondi-
Isradipine SR (DynaCirc SR) 5–20 1 hydropyridines and may cause more reflex sympathetic
Nicardipine SR (Cardene SR) 60–120 2 discharge (tachycardia), dizziness, headache, flushing, and
Nifedipine long-acting (Adalat peripheral edema; have additional benefits in Raynaud’s
CC, Procardia XL) 30–90 1 syndrome
Nisoldipine (Sular) 10–40 1
(continued)
 151

TABLE 15-5 Primary Antihypertensive Agents (continued)

CHAPTER 15
Usual Dose Daily
Class Subclass Drug (Brand Name) Range (mg/day) Frequency Comments
Nondihydropy- Diltiazem SR (Cardizem SR) 180–360 2 Extended-release and sustained-release products are preferred
ridines for hypertension; these agents block slow channels in the
Diltiazem SR (Cardizem CD, Cartia 120–480 1 heart and reduce heart rate; may produce heart block,
XT, Dilacor XR, Diltia XT, Tiazac, especially in combination with β-blockers; these products are
Taztia XT) not AB rated as interchangeable on a equipotent mg-per-mg
Diltiazem ER (Cardizem LA) 120–540 1 (morning basis because of different release mechanisms and different
or evening) bioavailability parameters; Cardizem LA, Covera HS, and

Hypertension
Verapamil SR (Calan SR, Isoptin 180–480 1 or 2 Verelan PM have delayed drug release for several hours after
SR, Verelan) dosing; when dosed in the evening can provide chronother-
Verapamil ER (Covera HS) 180–420 1 (in the apeutic drug delivery starting shortly before patients awake
evening) from sleep; have additional benefits in patients with atrial
Verapamil oral drug absorp- 100–400 1 (in the tachyarrhythmia
tion system ER (Verelan PM) evening)
β-Blockers Cardioselective Atenolol (Tenormin) 25–100 1 Abrupt discontinuation may cause re-bound hypertension;
Betaxolol (Kerlone) 5–20 1 inhibit β1-receptors at low to moderate dose, higher doses
Bisoprolol (Zebeta) 2.5–10 1 also block β2-receptors; may exacerbate asthma when selec-
Metoprolol tartrate (Lopressor) 100–400 2 tivity is lost; have additional benefits in patients with atrial
Metoprolol succinate (Toprol 50–200 1 tachyarrhythmia or preoperative hypertension
XL)
Nonselective Nadolol (Corgard) 40–120 1 Abrupt discontinuation may cause rebound hypertension;
Propranolol (Inderal) 160–480 2 inhibit β1- and β2-receptors at all doses; can exacerbate
Propranolol long-acting 80–320 1 asthma; have additional benefits in patients with essential
(Inderal LA, InnoPran XL) tremor, migraine headache, thyrotoxicosis
Timolol (Blocadren) 10–40 1
Intrinsic sympatho- Acebutolol (Sectral) 200–800 2 Abrupt discontinuation may cause rebound hypertension; par-
mimetic activity Carteolol (Cartrol) 2.5–10 1 tially stimulate β-receptors while blocking against additional
Penbutolol (Levatol) 10–40 1 stimulation; no clear advantage for these agents; contraindi-
Pindolol (Visken) 10–60 2 cated in patients with coronary disease or post-myocardial
infarction
Mixed α- and β- Carvedilol (Coreg) 12.5–50 2 Abrupt discontinuation may cause rebound hypertension; addi-
blockers Carvedilol phosphate (Coreg CR) 20–80 1 tional α-blockade produces more orthostatic hypotension
Labetalol (Normodyne,
Trandate) 200–800 2
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ER, extended-release; SR, sustained-release.

patients without a compelling indication. Other antihypertensive Landmark placebo-controlled clinical trials—SHEP (Systolic Hyper-
drug classes are considered alternative drug classes that may be used tension in the Elderly Program),9 STOP (Swedish Trial in Old
in select patients after primary agents (Table 15–6). Patients),10 and MRC (Medical Research Council)11—showed signifi-
cant reductions in stroke, MI, all-cause CV disease, and mortality with
thiazide-type diuretic-based therapy versus placebo. These trials
CLINICAL CONTROVERSY allowed for β-blockers as add-on therapy for BP control. Newer agents
(ACE inhibitors, ARBs, and CCBs) were not available at the time of
Prehypertension is a BP classification that identifies patients who
these studies. However, subsequent clinical trials have compared these
do not have hypertension, but are at risk for developing it. The
newer antihypertensive agents to thiazide-type diuretics.27–32 These data
Trial of Preventing Hypertension (TROPHY) showed that treat-
show similar effects, but most trials used a prospective open-label,
ing patients with prehypertension with the ARB candesartan
blinded end point study methodology that is not double-blinded and
decreased progression to stage 1 hypertension.26 However, it is not
limited their ability to prove equivalence of newer drugs to diuretics.
known whether managing prehypertension with antihypertensive
Other prospective trials have compared different primary antihyperten-
drug therapy, in addition to lifestyle modifications, decreases CV
sive agents to each other.29,33,34 Although these studies used head-to-
events or whether this treatment approach is cost-effective.
head comparisons, they did not use a thiazide-type diuretic as their
comparator treatment. Consequently, their results cannot be easily
 Thiazide-Type Diuretics as Traditional used to justify an antihypertensive drug class other than a thiazide-type
First-Line Therapy for Most Patients diuretic as first-line therapy.
JNC7 guidelines recommend thiazide-type diuretics whenever pos- The ALLHAT Study30 The result of the Antihypertensive and
sible, as first-line therapy for most patients, which is consistent with Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
the traditional pharmacotherapy of hypertension.1 However, AHA was the deciding evidence that the JNC7 used to justify thiazide-
guidelines do not recommend thiazide-type diuretics as preferred type diuretics as first-line therapy.30 It was designed to test the
over an ACE inhibitor, ARB, or CCB for first-line therapy. Figure hypothesis that newer antihypertensive agents (an α-blocker, ACE
15–2 displays the algorithm for the treatment of hypertension. This inhibitor, or dihydropyridine CCB) would be superior to thiazide-
recommendation is specifically for patients without compelling type diuretic-based therapy. The primary objective was to compare
indications and is based on best available evidence demonstrating the combined end point of fatal coronary heart disease and nonfatal
reductions in CV morbidity and mortality. MI. Other hypertension-related complications (e.g., heart failure,
 152

TABLE 15-6 Alternative Antihypertensive Agents

SECTION 2

Usual Dose Daily

Class Drug (Brand Name) Range (mg/day) Frequency Comments
α1-Blockers Doxazosin (Cardura) 1–8 1 First dose should be given at bedtime; counsel patients to rise from a
Prazosin (Minipress) 2–20 2 or 3 sitting or laying position slowly to minimize risk of orthostatic hypoten-
Terazosin (Hytrin) 1–20 1 or 2 sion; have additional benefits in men with benign prostatic hyperplasia
Direct renin inhibitor Aliskiren (Tekturna) 150–300 1 May cause hyperkalemia in patients with chronic kidney diease and
diabetes or in those receiving a potassium-sparing diuretic, aldos-
terone antagonist, ACE inhibitor, or ARB; may cause acute kidney
failure in patients with severe bilateral renal artery stenosis or
Cardiovascular Disorders

severe stenosis in artery to solitary kidney; do not use in pregnancy

Central α2-agonists Clonidine (Catapres) 0.1–0.8 2 Abrupt discontinuation may cause rebound hypertension; most effec-
Clonidine patch (Catapres-TTS) 0.1–0.3 1 weekly tive if used with a diuretic to diminish fluid retention; clonidine patch
Methyldopa (Aldomet) 250–1000 2 is replaced once per week; not recommended in very elderly
Peripheral adrenergic Reserpine (generic only) 0.05–0.25 A very useful agent that has been used in many of the major clinical
antagonist trials; should be used with a diuretic to diminish fluid retention
Direct arterial vasodilators Minoxidil (Loniten) 10–40 1 or 2 Should be used with diuretic and β-blocker to diminish fluid retention
Hydralazine (Apresoline) 20–100 2 to 4 and reflex tachycardia
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

stroke) were evaluated as secondary end points. This was the largest ences in the incidences of certain CV events in some comparisons
hypertension trial ever conducted and included 42,418 patients ages (e.g., stroke was lower with diuretic- or CCB-based regiments
55 and older with hypertension and one additional CV risk factor. versus ACE inhibitor-based regimens), there were no differences in
This prospective, double-blind trial randomized patients to chlor- total major CV events when ACE inhibitors, CCBs, or diuretics were
thalidone-, amlodipine-, doxazosin-, or lisinopril-based therapy for compared to each other. In studies evaluating ARB-based therapy to
a mean of 4.9 years. control regimens, the incidence of major CV events was lower with
The doxazosin arm was terminated early when a significantly ARB-based regimens. However, the control regimens used in these
higher risk of heart failure versus chlorthalidone was observed.35 The comparisons included both active antihypertensive drug therapies
other arms were continued as scheduled and no significant differ- and placebo.
ences in the primary end point were seen between the chlorthalidone Data from meta-analyses may not be as influential as data from
and lisinopril or amlodipine treatment groups. However, chlorthali- well-designed, prospective, randomized, controlled trials (e.g., the
done had statistically fewer secondary end points than amlodipine ALLHAT). However, they provide clinically useful data that support
(heart failure) and lisinopril (combined CV disease, heart failure, using ACE inhibitor-, CCB-, or ARB-based treatment for hyperten-
and stroke). The study conclusions were that chlorthalidone-based sion as first-line therapy. Clinicians can use meta-analyses data as
therapy was superior in preventing one or more major forms of CV supporting evidence when selecting an alternative first-line antihy-
disease and was less expensive than amlodipine or lisinopril-based pertensive regimen for hypertension in most patients, in addition to
therapy. the 2007 AHA recommendations.41
ALLHAT was designed as a superiority study with the hypothesis Other major consensus guidelines recommend multiple first-line
that amlodipine, doxazosin, and lisinopril would be better than options for treating hypertension in most patients. The 2007 Euro-
chlorthalidone.36 It did not prove this hypothesis because the primary pean Society of Hypertension–European Society of Cardiology guide-
end point was no different between chlorthalidone, amlodipine, and lines and the 2006 United Kingdom’s National Institute for Health
lisinopril. Many subgroup analyses of specific populations (e.g., black and the Clinical Excellence guidelines list more than one drug therapy
patients, chronic kidney disease, diabetes) from the ALLHAT have option as an acceptable first-line treatment approach.42,43 The Euro-
been conducted to assess response in certain unique patient popula- pean Society of Hypertension–European Society of Cardiology guide-
tions.37–39 Surprisingly, none of these analyses demonstrated superior lines are founded on the principle that CV risk reduction is a function
CV event reductions with lisinopril or amlodipine versus chlorthali- of BP control that is largely independent of specific antihyperten-
done. Overall, thiazide-type diuretics remain unsurpassed in their sives.42 The United Kingdom guidelines stratify patients based on age
ability to reduce CV morbidity and mortality in most patients. and race; they recommend an ACE inhibitor first-line for patients
Most patients require two or more agents to control BP. There- younger than age 55 years, and either a CCB or thiazide-type diuretic
fore, a thiazide-type diuretic should be one of these agents unless first-line for patients age 55 years or older and for black patients.43
contraindicated.

β-Blockers versus Other First-Line Drug Therapies
Clinical trials data cumulatively suggests that β-blockers may not
Other First-Line Treatment Options for reduce CV events to the extent that ACE inhibitors, CCBs, or ARBs
Most Patients do. These data are from three meta-analyses of clinical trials
Clinical trials data cumulatively demonstrate that ACE inhibitor-, evaluating β-blocker–based therapy for hypertension.44–47 Overall,
CCB-, or ARB-based antihypertensive therapy reduces CV events. these analyses demonstrated fewer reductions in CV events with β-
These agents may be used in patients without compelling indica- blocker–based antihypertensive therapy compared mostly with ACE
tions, similarly to thiazide-type diuretics, as first-line therapy. The inhibitor- and CCB-based therapy. Although comparative data with
Blood Pressure Lowering Treatment Trialists’ Collaboration evalu- ARB-based therapy are more limited, a similar trend was observed.
ated the incidence of major CV events and death among different Meta-analyses data evaluating β-blockers and their ability to
antihypertensive drug classes from 29 major randomized trials in reduce CV events have limitations. Most studies that were included
162,341 patients.40 In placebo-controlled trials, the incidences of used atenolol as the β-blocker studied. Thus it is possible that
major CV events were significantly lower with ACE inhibitor- and atenolol is the only β-blocker that does not reduce risk of CV events
CCB-based regimens than with placebo. Although there were differ- as well as the other primary antihypertensive drug classes. However,
 153
it is acceptable to extrapolate these findings to the β-blocker drug carvedilol, and metoprolol succinate are the only β-blockers proven
class in general. Interestingly, the 2006 United Kingdom guidelines to be beneficial in left ventricular dysfunction.48

CHAPTER 15
recommend a β-blocker only after other primary antihypertensive After diuretics, ACE inhibitors, and β-blockers (collectively con-
agents (thiazide-type diuretics, CCBs, ACE inhibitors, or ARBs) sidered standard therapy), other agents may be added to further
have been used. These findings also call in question the validity of reduce CV morbidity and mortality, and reduce BP if needed. Early
results from prominent prospective, controlled clinical trials evalu- data suggested that ARBs may be better than ACE inhibitors in left
ating antihypertensive drug therapy that use β-blocker–based ther- ventricular dysfunction.51 However, when directly compared in a
apy, especially atenolol, as the primary comparator.29,34,47 well-designed prospective trial, ACE inhibitors were found to be
β-Blocker therapy in patients without compelling indications still better.52 ARBs are acceptable as an alternative therapy for patients
has a prominent role in the management of hypertension. It is who cannot tolerate ACE inhibitors, and possibly as add-on therapy
important for clinicians to remember that β-blocker–based antihy-

Hypertension
to those already on a standard three-drug regimen based on data
pertensive therapy does not increase risk of CV events; β-blocker– from the CHARM (Candesartan in Heart Failure: Assessment of
based therapy reduces risk of CV events compared to no antihyper- Reduction in Mortality and Morbidity) studies.53,54
tensive therapy. Using a β-blocker as a primary antihypertensive The addition of aldosterone antagonists can reduce CV morbidity
agent is optimal when a thiazide-type diuretic, ACE inhibitor, ARB, and mortality in left ventricular dysfunction.55,56 Spironolactone has
or CCB cannot be used as the primary agent. Additionally, using a been studied in severe left ventricular dysfunction and has shown
β-blocker in a young patient with hypertension that is thought to benefit in addition to diuretic and ACE inhibitor therapy.55
have high adrenergic drive, as evidenced by an elevated heart rate, Eplerenone has been studied in patients with symptomatic left
may still be clinically reasonable.46 β-Blockers still have an impor- ventricular dysfunction within 3 to 14 days after an acute MI in
tant role as an alternative add-on agent to reduce BP in patients addition to standard therapy.56 An aldosterone antagonist may be
with hypertension but without compelling indications. considered in addition to a diuretic, ACE inhibitor or ARB, and β-
blocker. It is not currently recommended to use both an aldosterone
 Patients with Compelling Indications1 inhibitor and an ARB as add-on therapy to a standard therapy,
because of the potential increase in risk of severe hyperkalemia.48
The JNC7 report identifies six compelling indications. Compelling
indications represent specific comorbid conditions where evidence Post-Myocardial Infarction57 β-Blocker (those without intrin-
from clinical trials supports using specific antihypertensive classes sic sympathomimetic activity [ISA]) and ACE inhibitor therapy are
to treat both the compelling indication and hypertension (see Fig. recommended in the AHA/American College of Cardiology and
15–3). Data from these clinical trials demonstrate a reduction in CV JNC7 guidelines.1,2,57 β-Blockers decrease cardiac adrenergic stim-
morbidity and/or mortality that justifies use in patients with hyper- ulation and reduce the risk of a subsequent MI or sudden cardiac
tension and with such a compelling indication. Some compelling death, as demonstrated in clinical trials. ACE inhibitors improve
indications include recommendations that are provided by other cardiac remodeling, cardiac function, and reduce CV events post-
national treatment guidelines, or from newer clinical trials, which MI. These two drug classes, with β-blockers first, are considered
are complementary to the JNC7 guidelines. the first drugs of choice for patients who have experienced a MI.
One study, the Valsartan in Acute Myocardial Infarction Trial
Left Ventricular Dysfunction: Systolic Heart Failure48 Five
(VALLIANT), demonstrated that ARB therapy is similar to ACE
drug classes are listed as compelling indications for heart failure.
inhibitor therapy in patients post-MI with left ventricular dysfunc-
These recommendations specifically refer to left ventricular dysfunc-
tion.58 However, ARBs are considered alternatives to ACE inhibitors
tion (also known as systolic heart failure), where the primary physio-
in post-MI patients with left ventricular dysfunction. These patients
logic abnormality is decreased cardiac output. ACE inhibitor with
have coronary artery disease, and have a BP goal of less than 130/80
diuretic therapy is recommended as the first-line regimen of choice.
mm Hg. Framingham risk scoring is not needed.
ACE inhibitor therapy is recommended based on numerous outcome
Eplerenone reduces CV morbidity and mortality in patients soon
studies showing reduced CV morbidity and mortality 48; diuretics are
after an acute MI (within 3 to 14 days).56 However, this supporting
also a part of this first-line regimen because they provide sympto-
evidence was in patients with symptoms of acute left ventricular
matic relief of edema by inducing diuresis. Loop diuretics are often
dysfunction. Considering that this drug has the propensity to cause
needed, especially in patients with more advanced disease. Patients
significant hyperkalemia and the patient population studied,
with left ventricular dysfunction have a BP goal of less than 120/80
eplerenone should only be used in selected patients following a MI
mm Hg, so multiple drug therapies are typically needed.
with very diligent monitoring of potassium.
Evidence from clinical trials shows that ACE inhibitors signifi-
cantly modify disease progression by reducing morbidity and mor- Coronary Artery Disease57,59 Chronic stable angina and acute
tality. Although left ventricular dysfunction was the primary disease coronary syndrome (unstable angina and acute MI) are forms of
in these studies, ACE inhibitor therapy will also control BP. ACE coronary disease (also called coronary artery disease or ischemic heart
inhibitors should be started with low-doses in patients with heart disease). This compelling indication is also referred to as high coro-
failure, especially those in acute exacerbation. Heart failure induces nary disease risk and high CV disease risk in the JNC7 report.1 These
a compensatory high renin condition, and starting ACE inhibitors are the most common forms of hypertension-associated target-organ
under these conditions can cause a pronounced first-dose effect and disease. β-Blocker therapy has the most evidence demonstrating
possible orthostatic hypotension. benefits in these patients. β-Blockers (those without ISA) are first-line
β-Blocker therapy is appropriate to further modify disease in left therapy in chronic stable angina and have the ability to reduce BP,
ventricular dysfunction, and is a component of this first-line regi- improve myocardial oxygen consumption and decrease demand.
men (standard therapy) for these patients. In patients on an initial These patients have coronary artery disease, and have a BP goal of less
regimen of diuretics and ACE inhibitors, β blockers reduce CV than 130/80 mm Hg. Framingham risk scoring is not needed.
morbidity and mortality.49,50 It is of paramount importance that β- Long-acting CCBs are either alternatives (the nondihydropyridine
blockers be dosed appropriately because of the risk of inducing an CCBs diltiazem and verapamil) or add-on therapy (dihydropyridine
acute exacerbation of heart failure. They must be started in very low CCBs) to β-blockers in chronic stable angina.59 The International
doses, doses much lower than that used to treat hypertension, and Verapamil-Trandolapril Study (INVEST) demonstrated no difference
titrated slowly to high-doses based on tolerability. Bisoprolol, in CV risk reduction when β-blocker–based therapy was compared to
 154
nondihydropyridine CCB-based therapy in this population.60 None- CCBs are useful add-on agents for BP control in patients with
theless, the preponderance of data are with β-blockers and they remain diabetes. Several studies have compared an ACE inhibitor with either
SECTION 2

therapy of choice.1,2,57,59 a dihydropyridine CCB or a β-blocker. In the studies comparing a

For acute coronary syndromes (ST-elevation MI and unstable dihydropyridine with an ACE inhibitor, the ACE inhibitor group had
angina/non–ST-segment MI), first-line therapy should consist of a significantly lower rates of CV end points, including MIs and all CV
β-blocker and ACE inhibitor.61,62 This regimen will lower BP, events.67 These data do not suggest that CCBs are harmful in diabetic
control acute ischemia, and reduce CV risk. patients, but indicate that they are not as protective as ACE inhibitors.
CCBs (especially nondihydropyridine CCBs) and β-blockers pro- Although data are limited, nondihydropyridine CCBs (diltiazem and
vide antiischemic effects; they lower BP and reduce myocardial verapamil) appear to have more renal protective effects than the
oxygen demand in patients with hypertension and coronary disease. dihydropyridines.65
β-Blockers reduce CV risk in patients with diabetes. These agents
Cardiovascular Disorders

However, cardiac stimulation may occur with dihydropyridine CCBs

or β-blockers with ISA, making these agents less desirable. Conse- should be used when needed as add-on therapy with other standard
quently, β-blockers with ISA should be avoided, nondihydropy- agents, or to treat another compelling indication (e.g., post-MI). β-
ridines CCBs should be alternatives to β-blockers, and Blockers have been shown in at least one study to be as effective as
dihydropyridines should be add-on therapy to β-blockers. ACE inhibitors in protection against morbidity and mortality in
Once ischemic symptoms are controlled with β-blocker and/or patients with diabetes.66
CCB therapy, other antihypertensive drugs can be added to provide β-Blockers (especially nonselective agents) may mask the signs and
additional CV risk reduction. Clinical trials have demonstrated that symptoms of hypoglycemia in patients with tightly controlled diabe-
the addition of an ACE inhibitor, or alternatively an ARB further tes because most of the symptoms of hypoglycemia (i.e., tremor,
reduces risk CV events in patients with chronic stable angina.63 tachycardia, and palpitations) are mediated through the sympathetic
Thiazide-type diuretics can be added thereafter to provide addi- nervous system. Sweating, a cholinergically mediated symptom of
tional BP lowering and to further reduce CV risk. Neither ACE hypoglycemia, should still occur during a hypoglycemic episode
inhibitors, nor thiazide-type diuretics provide anti-ischemic effects. despite β-blocker therapy. Patients may also have a delay in hypogly-
There has been concern that overtreating high BP in patients with cemia recovery time because compensatory recovery mechanisms
coronary artery disease may bring about more harm than good need the catecholamine inputs that are antagonized by β-blocker
(termed the J-curve phenomenon). Coronary blood flow occurs therapy. Finally, unopposed α-receptor stimulation during the acute
during diastole and the rate of flow is directly influenced by the hypoglycemic recovery phase (as a consequence of endogenous epi-
DBP. Therefore, excessively reducing DBP may compromise coro- nephrine release intended to reverse hypoglycemia) may result in
nary perfusion, especially in patients with fixed coronary artery acutely elevated BP because of vasoconstriction. Despite these poten-
stenosis, and lead to myocardial infarction. This concern has been tial problems, β-blockers can be safely used in patients with diabetes.
theoretical based on retrospective analyses, and prospective studies Based on the weight of all evidence, ACE inhibitors or ARBs are
have not found a J-curve until DBPs were very low (<60 mm Hg). preferred first-line agents for treating patients with hypertension
and diabetes. The need for combination therapy should be antici-
Diabetes Mellitus1,64–67 The primary cause of mortality in dia-
pated, and thiazide-type diuretics should be the second agent added.
betes is CV disease, and hypertension management is a very impor-
Based on scientific evidence, β-blockers and CCBs are useful evi-
tant risk-reduction strategy. The BP goal in diabetes is less than 130/
dence-based agents in this population, but are considered add-on
80 mm Hg. Diabetes is considered a coronary artery disease risk
therapies to the aforementioned agents.
equivalent and Framingham risk scoring is not needed. Five antihy-
pertensive agents have evidence supporting their compelling indica- Chronic Kidney Disease68 Patients with hypertension may develop
tions in diabetes (see Fig. 15–3). All of these agents have been shown damage to either the renal tissue (parenchyma) or the renal arteries.
to reduce CV events in patients with diabetes. However, risk reduc- Chronic kidney disease initially presents as microalbuminuria (30 to
tion may not be equal when comparing these agents. 299 mcg/mg albumin-to-creatinine ratio on a spot urine sample or
 All patients with diabetes and hypertension should be treated ≥30 mg albumin in a 24-hour urine collection) that can progress to
with either an ACE inhibitor or an ARB.64 Pharmacologically, both overt kidney failure. The rate of kidney function deterioration is
of these agents should provide nephroprotection as a result of accelerated when both hypertension and diabetes are present. Once
vasodilation in the efferent arteriole of the kidney. Moreover, ACE patients have an estimated GFR of less than 60 mL/min/1.73 m2 or
inhibitors have overwhelming data demonstrating CV risk reduc- albuminuria, they have significant chronic kidney disease and the
tion in patients with established forms of heart disease. Evidence risk of CV disease and progression to severe chronic kidney disease
from outcome studies have demonstrated reductions in both CV increases.1 Strict BP control to a goal of less than 130/80 mm Hg can
risk (mostly with ACE inhibitors) and reduction in risk of progres- slow the decline in kidney function. Although this strict BP goal is
sive kidney dysfunction (mostly with ARBs) in patients with diabe- recommended in significant chronic kidney disease, long-term ben-
tes.64 There is controversy surrounding which agent is better efits of this lower BP goal have mostly been demonstrated in patients
because data support both drug classes. Nonetheless, either drug with both significant chronic kidney disease and diabetes.69 This
class should be used to control BP as one of the drugs in the strict control often requires two or more antihypertensive agents.
antihypertensive regimen for patients with diabetes because multi- In addition to lowering BP, ACE inhibitors and ARBs reduce
ple agents are often needed to attain goal BP values. intraglomerular pressure, which can theoretically provide additional
A thiazide-type diuretic is recommended as the second agent to benefits by further reducing the decline in kidney function. ACE
lower BP and provide additional CV risk-reduction. A subgroup inhibitors and ARBs have been shown to reduce progression of
analysis of patients with diabetes from the ALLHAT trial showed no chronic kidney disease in diabetes64 and in those without diabe-
difference in long term risk of CV events in the chlorthalidone and tes.65,70 It is difficult to differentiate whether the kidney protection
lisinopril treatment groups.38 Therefore, some argue that thiazide- benefits are from RAAS blockade or BP lowering. A recent meta-
type diuretics, used in low-doses, are equally effective in patients with analysis failed to demonstrate any unique long-term kidney-protec-
hypertension and diabetes. Nonetheless, the entire body of evidence tive effects of RAAS-blocking drugs compared with other antihyper-
evaluating pharmacotherapy in patients with hypertension and diabe- tensive drugs.71 Moreover, a subgroup analysis of patients from the
tes, and consensus guidelines, support an ACE inhibitor or ARB first- ALLHAT stratified by different baseline GFR values also did not
line, with a thiazide-type diuretic as add-on therapy.1,64,65 show a difference in long-term outcomes with chlorthalidone versus
 155
37
lisinopril. Nonetheless, consensus guidelines recommend either an tors in some patients. Although these agents are potent, many of them
ACE inhibitor or ARB as first-line therapy to control BP and preserve have a much greater incidence of adverse effects. Moreover, they do

CHAPTER 15
kidney function in chronic kidney disease. not have compelling outcomes data showing reduced morbidity and
Some data indicate that the combination of an ACE inhibitor with mortality in hypertension. They are generally reserved for patients
an ARB may be more effective than either agent alone.72 However, with resistant hypertension, and should only be used as add-on
routine use of this combination in all patients with chronic kidney therapy with other primary antihypertensive agents.
disease is controversial. Because these patients typically require mul-
tiple antihypertensive agents, diuretics and a third antihypertensive Special Populations1
drug class (e.g., β-blocker, CCB) are often needed.
Selection of drug therapy should follow the guidelines provided by
the JNC7, which are summarized in Figures 15–2 and 15–3. These

Hypertension
should be maintained as the guiding principles of drug therapy.
CLINICAL CONTROVERSY
However, there are some patient populations where the approach to
Thiazide-type diuretics traditionally have been viewed as less drug therapy may be slightly different or necessitate tailored dosing
effective than loop diuretics in patients with severe chronic strategies. In some cases this is because other agents have unique
kidney disease. Some clinicians routinely replace thiazide-type properties that benefit a coexisting condition, but may not be based
diuretics with a loop diuretic in patients who have estimated on evidence from outcomes studies in hypertension.
creatinine clearances below 30 mL/min. However, limited data
demonstrate that the antihypertensive effects of hydrochlorothi- Hypertension in Older People Hypertension often presents as
azide are equal to that of furosemide in patients with chronic isolated systolic hypertension in the elderly. Epidemiologic data
renal failure and hypertension.73 indicate that CV morbidity and mortality are more closely related to
SBP than to DBP in patients ages 50 years and older, so this
Patients may rarely experience acute kidney failure when given an population is at high risk for hypertension-related target-organ
ACE inhibitor or ARB. The potential to produce acute kidney damage.1 Although several placebo-controlled trials have specifically
failure is particularly problematic in patients with bilateral renal demonstrated risk reduction in this form of hypertension, many
artery stenosis or a solitary functioning kidney with stenosis. older people with hypertension are either not treated, or treated yet
Patients with renal artery stenosis are usually older, and the condi- not controlled.21
tion is more common in patients with diabetes and in those who The SHEP was a landmark, double-blind, placebo-controlled trial
smoke. Patients with renal artery stenosis do not necessarily have that evaluated chlorthalidone-based treatment (with atenolol or
evidence of kidney disease unless sophisticated tests are performed. reserpine as add-on therapy) for isolated systolic hypertension.9 A
Evaluating kidney function shortly after starting the drug can 36% reduction in total stroke, a 27% reduction in coronary artery
minimize this risk. disease, and 55% reduction in heart failure were demonstrated versus
placebo. The Syst-Eur (Systolic Hypertension in Europe) was another
Recurrent Stroke Prevention Ischemic stroke is considered target-
placebo-controlled trial that evaluated treatment with a long-acting
organ damage caused by hypertension. Attaining goal BP values in
dihydropyridine CCB.12 Treatment resulted in a 42% reduction in
patients who have experienced a stroke, or a transient ischemic attack,
stroke, 26% reduction in coronary artery disease, and 29% reduction
is considered a primary modality to reduce risk of a second stroke. In
in heart failure. These data clearly demonstrate reductions in CV
general, these patients have noncoronary atherosclerotic vascular dis-
morbidity and mortality in older patients with isolated systolic hyper-
ease, are considered a coronary artery disease risk equivalent, and have
tension, especially with thiazide-type diuretics and long-acting dihy-
a BP goal of less than 130/80 mm Hg. However, BP lowering should
dropyridine CCBs.
only be attempted after patients have stabilized following an acute
The very-elderly population (age ≥80 years) has been underrepre-
cerebrovascular event. One clinical trial, PROGRESS (Perindopril
sented in clinical trials, including the SHEP and Syst-Eur studies. This
Protection Against Recurrent Stroke Study), showed that the incidence
population often is not treated to goal either because of a fear of
of recurrent stroke in patients with a history of ischemic stroke can be
lowering BP too much or because of limited data demonstrating
reduced when a thiazide-type diuretic is used in combination with an
benefit. The best available data in the very elderly comes from meta-
ACE inhibitor.31 Reduction in recurrent stroke was seen with this
analyses.76,77 Although these data do not show reductions in mortal-
combination therapy, even in those who had BP values less than 140/
ity, they consistently show fewer strokes with antihypertensive drug
90 mm Hg. Recurrent stroke was not reduced with ACE inhibitor
therapy. However, care should be taken that BP not be excessively
monotherapy in the PROGRESS, it was only reduced when the
lowered in this population, as it this is associated with increased risk
thiazide-type diuretic was added.
of mortality.78 The HYVET (Hypertension in the Very Elderly Trial),
Reductions in risk of recurrent stroke have also been seen with
a prospective controlled clinical trial was recently stopped early due to
ARBs.74 In another clinical trial, the MOSES (Morbidity and Mor-
significant reductions in stroke and total mortality with antihyperten-
tality After Stroke, Eprosartan Compared with Nitrendipine for
sive treatment in the very elderly versus placebo.79
Secondary Prevention), patients with a history of stroke or transient
Thiazide-type diuretics or β-blockers have been compared with
ischemic attack had a lower risk of a recurrent stoke when treated
either ACE inhibitors or CCBs in elderly patients with either systolic
with ARB-based therapy compared to dihydropyridine CCB-based
or diastolic hypertension or both.80 In the Swedish Trial in Old
therapy. Therefore, both an ACE inhibitor with a thiazide-type
Patients with Hypertension-2 (STOP-2) study, no significant differ-
diuretic,1,75 or ARB-based therapy are evidence-based antihyperten-
ences were seen between conventional drugs and either ACE inhib-
sive regimens for patients with a history of cerebrovascular disease,
itors or CCBs. However, there were significantly fewer MIs and
specifically ischemic stroke or transient ischemic attack, to prevent
cases of heart failure in the ACE inhibitor group compared with the
recurrent stroke. These recommendations do not apply to patients
CCB group. These data suggest that overall treatment may be more
with a history of hemorrhagic stroke.
important than specific antihypertensive agents in this population.
Elderly patients are more sensitive to volume depletion and
Alternative Drug Treatments sympathetic inhibition than younger individuals. This may lead to
It is necessary to use other agents such as α-blockers, central α2- orthostatic hypotension (see Patients at Risk for Orthostatic
agonists, a direct renin inhibitor, adrenergic inhibitors, and vasodila- Hypotension below). In the elderly, this can increase the risk of falls
 156
as a consequence of the associated dizziness and risk of fainting. ing complications for both mother and fetus. Eclampsia, the onset of
Centrally acting agents and α-blockers should generally be avoided convulsions in preeclampsia, is a medical emergency. Gestational
SECTION 2

or used with caution in the elderly because they are frequently hypertension is defined as new-onset hypertension arising after
associated with dizziness and postural hypotension. Diuretics and midpregnancy in the absence of proteinuria, and chronic hyperten-
ACE inhibitors provide significant benefits and can safely be used in sion is elevated BP that is noted before the pregnancy began. It is
the elderly, but smaller-than-usual initial doses might be needed. controversial whether treating elevated BP in patients with chronic
The JNC7 and AHA goal BP recommendations are independent hypertension in pregnancy is beneficial. However, women with
of age.1,2 Age-adjusted goals are inappropriate. Moreover, treatment chronic hypertension prior to pregnancy are at increased risk of a
of hypertension in older patients should follow the same principles number of complications, including superimposed preeclampsia,
that are outlined for general care of hypertension. However, initial preterm delivery, fetal growth restriction or demise, placental abrup-
Cardiovascular Disorders

drug doses may be lower, and dosage titrations should occur over a tion, heart failure, and acute kidney failure.82
longer period of time to minimize the risk of hypotension. An Definitive treatment of preeclampsia is delivery. Delivery is indi-
interim goal of a SBP of below 160 mm Hg may be necessary for cated if pending or frank eclampsia is present. Otherwise, manage-
those with very high initial SBP, but the ultimate goal should still be ment consists of restricting activity, bedrest, and close monitoring. Salt
less than 140 mm Hg, less than 130 mm Hg, or less than 120 mm restriction, or any other measures that contract blood volume, should
Hg, depending on CV risk and comorbid conditions of the patient. not be employed. Antihypertensive agents are used prior to induction
of labor if DBP is greater than 105 to 110 mm Hg with a target DBP of
Patients at Risk for Orthostatic Hypotension Orthostatic
95 to 105 mm Hg. Intravenous hydralazine is most commonly used,
hypotension is a significant drop in BP when standing and can be
and intravenous labetalol is also effective. Immediate-release oral
associated with dizziness and/or fainting. It is defined as a SBP
nifedipine has been used, but it is not approved by the Food and
decrease of greater than 20 mm Hg or DBP decrease of greater than
Drug Administration (FDA) for hypertension and untoward fetal
10 mm Hg when changing from supine to standing.1 Older patients
and maternal effects (hypotension with fetal distress) have been
(especially those with isolated systolic hypotension), patients with
reported.
diabetes, severe volume depletion, baroreflex dysfunction, auto-
Many agents can be used to treat chronic hypertension in preg-
nomic insufficiency, and use of venodilators (α-blockers, mixed α/
nancy (Table 15–7). Unfortunately, there is little consensus and few
β-blockers, nitrates, and phosphodiesterase inhibitors) all increase
data regarding the most appropriate therapy in pregnancy. Methyl-
risk of orthostatic hypotension. In patients with these risks, antihy-
dopa is still considered the drug of choice.1 Data indicate that
pertensive agents should be started in low doses, especially diuretics,
uteroplacental blood flow and fetal hemodynamics are stable with
ACE inhibitors, and ARBs.
methyldopa. Moreover, it is viewed as very safe, based on long-term
Hypertension in Children and Adolescents 81 Detecting hyper- followup data (7.5 years) that has not demonstrated adverse effects
tension in children requires special attention to BP measurement, on childhood development. β-Blockers, labetalol and CCBs are also
and is defined as SBP and/or DBP that is greater than 95th percentile reasonable alternatives. ACE inhibitors and ARBs are known terato-
for sex, age, and height on at least three occasions.81 BP between the gens and are absolutely contraindicated.83Aliskiren also should not
90th and 95th percentile, or equal to or greater than 120/80 mm Hg be used in pregnancy.
in adolescents, is considered prehypertension. Hypertensive children
African Americans1,84 Hypertension affects African American
often have a family history of high BP, and many are overweight,
patients at a disproportionately higher rate, and hypertension-
predisposing them to insulin resistance and associated CV disease.
related target-organ damage is more prevalent than in other popu-
Unlike hypertension in adults, secondary hypertension is more
lations. Reasons for these differences are not fully understood, but
common in children and adolescents. An appropriate workup for
may be related to differences in electrolyte homeostasis, GFR,
secondary causes is essential if elevated BP is identified. Kidney
sodium excretion and transport mechanisms, plasma renin activity,
disease (e.g., pyelonephritis, glomerulonephritis) is the most com-
and BP response to plasma volume expansion.
mon cause of secondary hypertension in children. Coarctation of the
African Americans have an increased need for combination
aorta can also produce secondary hypertension. Medical or surgical
therapy to attain and maintain BP goals.84 The Hypertension in
management of the underlying disorder usually normalizes BP.
African American Working Group of the International Society on
Nonpharmacologic treatment, particularly weight loss in those
Hypertension in Blacks has published treatment guidelines that are
who are overweight, is the cornerstone of therapy for essential
similar to the JNC7.84 Lifestyle modifications are recommended to
hypertension in children.81 The goal is to reduce the BP to below the
95th percentile for sex, age, and height, or below the 90th percentile if
concurrent conditions, such as chronic kidney disease, diabetes, or Treatment of Chronic Hypertension in Pregnancy
TABLE 15-7
target-organ damage, are present. ACE inhibitors, ARBs, β-blockers,
CCBs, and thiazide-type diuretics are all acceptable choices in chil- Drug/Class Comments
dren. ACE inhibitors, ARBs, and direct renin inhibitors are contrain- Methyldopa Preferred agent based on long-term followup
dicated in sexually active girls because of potential teratogenic effect, data supporting safety
and in those who might have bilateral renal artery stenosis or β-Blockers Generally safe, but intrauterine growth retarda-
unilateral stenosis in a solitary kidney. As with adults, consideration tion reported
for initial agents should be based on the presence of compelling Labetalol Increasingly preferred over methyldopa
indications or concurrent conditions that may warrant their use (e.g., because of fewer side effects
Clonidine Limited data available
ACE inhibitor or ARB for those with diabetes or microalbuminuria).
Calcium channel blockers Limited data available; no increase in major
Pregnancy1,82 Hypertension during pregnancy is a major cause of teratogenicity with exposure
maternal and neonatal morbidity and mortality. Hypertension dur- Diuretics Not first-line agents but probably safe in low
ing pregnancy is categorized as preeclampsia, eclampsia, gestational, doses if used chronically prior to conception
chronic, and superimposition of preeclampsia on chronic hyperten- Angiotensin-converting Contraindicated; major teratogenicity reported
enzyme inhibitors, angioten- with exposure (fetal toxicity and death)
sion. Preeclampsia, defined as a elevated BP greater than or equal to
sin II receptor blockers and
140/90 mm Hg that appears after 20 weeks gestation accompanied by
direct renin inhibitors
new-onset proteinuria (≥300 mg/24 hours), can lead to life-threaten-
 157
augment drug therapy. They also support thiazide-type diuretics as Dyslipidemia Dyslipidemia is considered a major CV risk factor.
first-line for most patients and selecting specific drug therapy to Controlling dyslipidemia is important to the overall care of patients

CHAPTER 15
treat compelling indications, if present. These guidelines aggres- with hypertension. Thiazide-type diuretics and β-blockers without
sively promote combination therapy. They recommend starting ISA may adversely affect serum cholesterol values, although these
with two drugs in patients with SBP values ≥15 mm Hg from goal. effects generally are transient and of no clinical consequence.87 α-
This aggressive approach is reasonable considering that overall goal Blockers have favorable effects (decreased low-density lipoprotein
BP attainment rates are low in African Americans. cholesterol and increased high-density lipoprotein cholesterol).
BP-lowering effects of antihypertensive classes varies in African However, because data from the ALLHAT show that α-blocker
Americans. Thiazide diuretics and CCBs seem to be particularly therapy does not reduce CV risk as much as thiazide-type diuretic
effective at lowering BP in African Americans. When either of these therapy, this benefit is not clinically applicable.35
two classes (especially thiazides) is used in combination with a β-

Hypertension
Metabolic Syndrome13,88,89 Metabolic syndrome is a cluster of
blocker, ACE inhibitor, or ARB, antihypertensive response is signifi-
multiple cardiometabolic risk factors. It was most recently defined
cantly increased. This may be a result of the low renin pattern of
as the presence of three of the following five criteria: abdominal
hypertension, which can result in less BP lowering with β-blockers,
obesity (waist circumference >40 inches in men, >35 inches in
ACE inhibitors, or ARBs when used as monotherapy compared to the
women), elevated triglycerides (≥150 mg/dL or receiving drug
effect in white patients. Interestingly, African Americans have a higher
treatment for elevated triglycerides), low high-density lipoprotein
risk of angioedema and cough from ACE inhibitors than do whites.84
cholesterol (<40 mg/dL in men, <50 mg/dL in women or receiving
Despite potential differences in antihypertensive effects, drug
drug treatment for low high-density lipoprotein), elevated BP
therapy selection should be based on evidence. Thiazide-type diuret-
(≥130/≥85 mm Hg or receiving drug treatment for high BP), and
ics are first-line agents based on the preponderance of evidence. A
elevated fasting blood glucose (≥100 mg/dL or receiving drug
subgroup analysis of African American patients from the ALLHAT
treatment for elevated glucose).13
also supports the first-line role of thiazide-type diuretics in treating
Regardless of the debate regarding whether or not metabolic
African American patients with hypertension.39 These agents just so
syndrome is a true “disease,” it is widely accepted that patients with
happen to also be very effective at controlling BP in this population.
metabolic syndrome are at significant increased risk of developing
ACE inhibitors, ARBs, and CCBs may also be used as first-line
CV disease and/or type 2 diabetes. Using an ACE inhibitor or ARB to
options. Other drug therapies should be used if a compelling indica-
treat patients with hypertension and the metabolic syndrome, espe-
tion is present, even if the antihypertensive effect may not be as great
cially patients with elevated fasting glucose but not yet type 2
as with another drug class (e.g., a β-blocker is first-line therapy for
diabetes, may be beneficial. A recent meta-analysis demonstrated
BP control in an African American patient who is post-MI).
that ARBs and ACE inhibitors are less likely then β-blockers or
thiazide-diuretics to be associated with progression to new-onset
Other Concomitant Conditions type 2 diabetes.89 However, studies specifically evaluating the most
Most patients with hypertension have some other coexisting condi- effective antihypertensive regimen in patients with metabolic syn-
tion(s) that may influence selection or use of drug therapy. The drome have not been done. In addition, an ALLHAT subgroup
influence of concomitant conditions should only be complementary analysis of patients with impaired fasting glucose showed that CV
to, and never in replacement of, drug therapy choices indicated by events were reduced more with chlorthalidone compared to lisino-
compelling indications. Under some circumstances, these are helpful pril.38 Thus, thiazides-type diuretics can be used in patients with
in deciding on a particular antihypertensive agent when more than metabolic syndrome, similar to ACE inhibitors, ARBs, or CCBs. In
one antihypertensive class is recommended. In some cases, an agent patients with elevated fasting glucose, or any patient at risk for
should be avoided because it may aggravate a concomitant disorder. developing type 2 diabetes, close monitoring of serum potassium
In other cases, an antihypertensive can be used to treat hypertension, should occur when treated with thiazide-type diuretics. If hypokale-
a compelling indication, and another concomitant condition. mia develops, or even subclinical hypokalemia (serum potassium
within the normal range, but at the low end of the normal range), in
Pulmonary Disease and Peripheral Arterial Disease85 β-
thiazide treated patients, the risk of developing type 2 diabetes
Blockers, especially nonselective agents, have been generally avoided
significantly increases.90 Therefore, treatment of thiazide-induced
in patients with hypertension and reactive airway disease (asthma or
hypokalemia, or even subclinical hypokalemia, should be considered
chronic obstructive pulmonary disease with a reversible obstructive
to maintain serum potassium in the mid to high end of the normal
component) because of a fear of inducing bronchospasm. This precau-
range (e.g., 4.0–5.0 mEq/L). This may reverse thiazide-induced
tion is more of a myth than a fact. Data suggests that cardioselective β-
glucose intolerance or possibly prevent onset of type 2 diabetes. This
blockers can safely be used in patients with asthma or chronic obstruc-
can be accomplished though the addition of an ACE inhibitor, ARB,
tive pulmonary disease.86 Consequently, cardioselective β-blockers
or potassium sparing diuretic, or with potassium supplementation
should be used to treat a compelling indication (i.e., post-MI, coro-
for cases of more severe hypokalemia.
nary disease, or heart failure) in patients with reactive airway disease.
Peripheral arterial disease, noncoronary atherosclerotic vascular Erectile Dysfunction91 Most antihypertensive agents are associ-
disease, is a coronary artery disease risk equivalent. The 2007 AHA ated with erectile dysfunction in men. However, it is not clear if
guidelines now recommend a BP goal of less than 130/80 mm Hg in erectile dysfunction associated with antihypertensive treatment is
this population. ACE inhibitors may be ideal in patients with solely a result of drug therapy or is a symptom of underlying CV
symptomatic lower-extremity peripheral arterial disease who also disease. Traditionally, β-blockers have been labeled as agents that
have hypertension, as they decrease CV events in these patients.85 significantly cause sexual dysfunction, and many practitioners have
CCBs may also be beneficial because of their vasodilatory effects on avoided prescribing them as a result. However, data supporting this
the peripheral arteries. β-Blockers have traditionally been considered notion are limited. A systematic review of 15 studies involving
problematic in patients with peripheral arterial disease because of 35,000 patients assessing β-blocker use for MI, heart failure, and
possible decreased peripheral blood flow secondary to unopposed hypertension found only a very slight increased risk erectile dys-
stimulation of α-receptors that results in vasoconstriction. However, function.92 In addition, prospective long-term data from the
β-blockers are not contraindicated in peripheral arterial disease and TOMHS (Treatment of Mild Hypertension Study) show no differ-
have not been shown to adversely affect walking capability.85 ence in the incidence of erectile dysfunction between diuretics and
 158
β-blockers versus ACE inhibitors and CCBs.93 Centrally acting serum half-life of most antihypertensive agents does not correlate
agents are associated with higher rates of sexual dysfunction and with the hypotensive duration of action. Moreover, diuretics lower
SECTION 2

should be avoided in men with erectile dysfunction. BP primarily through extrarenal mechanisms. Hydrochlorothiazide
Hypertensive men frequently have atherosclerotic vascular dis- and chlorthalidone are the two most frequently used thiazide diuret-
ease, which frequently results in erectile dysfunction. Consequently, ics in landmark clinical trials that have demonstrated reduced
erectile dysfunction may be mostly associated with chronic arterial morbidity and mortality. These agents are not equipotent on a
changes resulting from elevated BP and lack of control may increase milligram-per-milligram basis; chlorthalidone is 1.5 to 2.0 times
the risk of erectile dysfunction. These changes are even more more potent than hydrochlorothiazide.95 This is attributed to a
pronounced in hypertensive men with diabetes. longer half-life (45 to 60 hours vs. 8 to 15 hours) and longer duration
Erectile dysfunction in hypertension may be an important of effect (48 to 72 hours vs. 16 to 24 hours) with chlorthalidone.
Cardiovascular Disorders

marker for CV disease. A study of men prospectively screened for These differences in BP lowering do not appear to result in differ-
erectile dysfunction after being referred for nuclear stress test ences in CV outcomes. A small meta-analysis of five outcome-based
imaging showed that erectile dysfunction was a stronger predictor clinical trials evaluating CV events suggests there is no difference in
of severe coronary heart disease than traditional risk factors (age, long-term CV outcomes with chlorthalidone compared with other
smoking, hypertension, diabetes, and dyslipidemia).94 thiazide-type diuretics, including hydrochlorothiazide.96 It is well
accepted that CV benefits in hypertension apply to all thiazide-type
Individual Antihypertensive Agents1,7 diuretics, and benefits are considered a class effect.2
Diuretics are very effective in lowering BP when used in combi-
Diuretics9–11,30 Diuretics, preferably a thiazide, are first-line nation with most other antihypertensives. This additive response is
agents for hypertension.1,2 The best available evidence justifying this explained by two independent pharmacodynamic effects. First,
recommendation is from ALLHAT.30 Moreover, when combination when two drugs cause the same overall pharmacologic effect (BP
therapy is needed in hypertension to control BP, a diuretic is lowering) through different mechanisms of action, their combina-
recommended to be one of the agents used.1 There are four tion usually results in an additive or synergistic effect. This is
subclasses of diuretics that are used in the treatment of hyperten- especially relevant when a β-blocker, ACE inhibitor, or ARB is
sion: thiazides, loops, potassium-sparing agents, and aldosterone indicated in an African American, but does not elicit sufficient
antagonists (see Table 15–5). Potassium-sparing diuretics are weak antihypertensive effect. Adding a diuretic in this situation can often
antihypertensive agents but provide an additive effect when used in significantly lower BP. Second, a compensatory increase in sodium
combination with a thiazide or loop diuretic. Moreover, they and fluid retention may be seen with antihypertensive agents. This
counteract the potassium- and magnesium-losing properties of the problem is counteracted with the concurrent use of a diuretic.
other diuretic agents and possible glucose intolerance. Aldosterone Side effects of thiazide-type diuretics include hypokalemia, hypo-
antagonists (spironolactone and eplerenone) may be technically magnesemia, hypercalcemia, hyperuricemia, hyperglycemia, dyslipi-
considered potassium-sparing agents, but are more potent antihy- demia, and sexual dysfunction. Many of these side effects were
pertensives. However, they are viewed by the JNC7 as an indepen- identified when high-doses of thiazides were used in the past (e.g.,
dent class because of evidence supporting compelling indications. hydrochlorothiazide 100 mg/day). Current guidelines recommend
The exact hypotensive mechanisms of action of diuretics are limiting the dose of hydrochlorothiazide or chlorthalidone to 12.5 to
multifaceted. The drop in BP seen when diuretics are first started is 25 mg/day, which markedly reduces the risk for most metabolic side
caused by an initial diuresis. Diuresis causes reductions in plasma effects. Loop diuretics may cause the same side effects, although the
and stroke volume, which decreases cardiac output and BP. This effect on serum lipids and glucose is not as significant, and hypocal-
initial drop in cardiac output causes a compensatory increase in cemia may occur.
peripheral vascular resistance. With chronic diuretic therapy, extra- Hypokalemia and hypomagnesemia may cause muscle fatigue or
cellular fluid and plasma volume return to near pretreatment values. cramps. However, serious cardiac arrhythmias can occur in patients
However, peripheral vascular resistance decreases to values that are with severe hypokalemia and hypomagnesemia. Patients at greatest
lower than the pretreatment baseline. This reduction in peripheral risk for this are patients with left ventricular hypertrophy, coronary
vascular resistance is responsible for chronic antihypertensive effects. disease, post-MI, a history of arrhythmia, or those concurrently
Thiazide-type diuretics have additional actions that may further receiving digoxin. Low-dose therapy (i.e., 25 mg hydrochlorothia-
explain their antihypertensive effects. Thiazides mobilize sodium and zide or 12.5 mg chlorthalidone daily) rarely causes significant
water from arteriolar walls. This effect would lessen the amount of electrolyte disturbances. Efforts should be made to keep potassium
physical encroachment on the lumen of the vessel created by excessive in the therapeutic range by careful monitoring.
accumulation of intracellular fluid. As the diameter of the lumen Diuretic-induced hyperuricemia can precipitate gout. This side
relaxes and increases, there is less resistance to the flow of blood and effect may be especially problematic in patients with a previous
peripheral vascular resistance further drops. High dietary sodium history of gout and with thiazide-type diuretics. However, acute
intake can blunt this effect and a low salt intake can enhance this gout is unlikely in patients with no previous history of gout. If gout
effect. Thiazides are also postulated to cause direct relaxation of does occur in a patient who requires diuretic therapy, allopurinol
vascular smooth muscle. can be given to prevent gout and will not compromise the antihy-
Thiazides are the preferred type of diuretic for treating hyperten- pertensive effects of the diuretic. High doses of thiazide-type and
sion. In patients requiring diuresis to treat concurrent edema, such loop diuretics may increase fasting glucose and serum cholesterol
as in heart failure, a loop diuretic should be considered. Diuretics values. Diligent monitoring and treatment of diuretic-induced
should ideally be dosed in the morning if given once daily, and in hypokalemia, even if subclinical, will lessen the associated increase
the morning and afternoon when dosed twice daily to minimize risk in fasting glucose, and perhaps onset of type 2 diabetes.90
of nocturnal diuresis. However, with chronic use, thiazide-type Potassium-sparing diuretics can cause hyperkalemia, especially in
diuretics, potassium sparing diuretics, and aldosterone antagonists patients with chronic kidney disease or diabetes and in patients
rarely cause a pronounced diuresis. receiving concurrent treatment with an ACE inhibitor, nonsteroidal
The major pharmacokinetic differences between the various thia- antiinflammatory drugs, or potassium supplements. Hyperkalemia
zide-type diuretics are serum half-life and duration of diuretic effect. is especially problematic for the newest aldosterone antagonist
The clinical relevance of these differences is unknown because the eplerenone. This agent is a very selective aldosterone antagonist, and
 159
its propensity to cause hyperkalemia is greater than with the other chronic kidney disease or those on concomitant nonsteroidal antiin-
potassium sparing agents, and even spironolactone. Because of this flammatory drugs, potassium supplements, or potassium-sparing

CHAPTER 15
increased risk of hyperkalemia, eplerenone is contraindicated in diuretics are at risk for hyperkalemia. Judicious monitoring of serum
patients with impaired kidney function or type 2 diabetes with pro- potassium and creatinine values within 4 weeks of starting or increas-
teinuria (see Table 15–5). Although spironolactone may cause gyneco- ing the dose of an ACE inhibitor can often identify these abnormalities
mastia in up to 10% of patients, this occurs rarely with eplerenone. before they evolve into serious hyperkalemia.
Diuretics can be used safely with most other agents. However, A worrisome adverse effect of ACE inhibitor is acute kidney
concurrent administration with lithium may result in increased failure. Fortunately, this serious adverse effect is rare, occurring in
lithium serum concentrations. This interaction can predispose less than 1% of patients. Preexisting kidney disease increases the risk
patients to lithium toxicity. of this side effect. Bilateral renal artery stenosis or unilateral stenosis

Hypertension
of a solitary functioning kidney render patients dependent on the
ACE Inhibitors27,32,80 ACE inhibitors are a first-line agents for vasoconstrictive effect of angiotensin II on the efferent arteriole of
hypertension.1,2 The ALLHAT demonstrated less heart failure and the kidney, thus explaining why these patients are particularly
stroke with chlorthalidone than with lisinopril.30 However, other susceptible to acute kidney failure from ACE inhibitors. Slowly
outcome studies have demonstrated similar, if not better outcomes titrating the dose of ACE inhibitor and judicious kidney function
with ACE inhibitors than with thiazide diuretics.27,32 monitoring can minimize risk and allow for early detection of those
ACE facilitates production of angiotensin II which has a major with renal artery stenosis.
role in arterial BP regulation as depicted in Fig. 15–1. ACE is It is important to note that GFR decreases in patients treated with
distributed in many tissues and is present in several different cell ACE inhibitors or ARBs.65 This is attributed to the inhibition of
types, but its principal location is in endothelial cells. Thus the major angiotensin II vasoconstriction on the efferent arteriole. This decrease
site for angiotensin II production is in the blood vessels, not the in GFR often increases serum creatinine, and small increases should
kidney. ACE inhibitors block the ACE (also termed bradykinase), be anticipated when monitoring patients on ACE inhibitors. Modest
thus inhibiting conversion of angiotensin I to angiotensin II. Angio- elevations of either up to a 35% (for baseline creatinine values less
tensin II is a potent vasoconstrictor that also stimulates aldosterone than or equal to 3 mg/dL) or absolute increases less than 1 mg/dL, do
secretion, causing an increase in sodium and water reabsorption with not warrant changes.65 If larger increases occur, ACE inhibitor ther-
accompanying potassium loss. By blocking the ACE, vasodilation apy should be stopped or the dose reduced.
and a decrease in aldosterone occur. ACE inhibitors also block Angioedema is a serious potential complication of ACE inhibitor
degradation of bradykinin and stimulate the synthesis of other therapy. It occurs in less than 1% of the population, and is more
vasodilating substances (prostaglandin E2 and prostacyclin). The likely in African Americans and smokers. Symptoms include lip and
observation that ACE inhibitors lower BP in patients with normal tongue swelling and possibly difficulty breathing. Drug discontinu-
plasma renin activity suggests that bradykinin and perhaps tissue ation is needed for ACE inhibitor-associated angioedema. However,
production of ACE are important in hypertension. Increased brady- angioedema associated with laryngeal edema and/or pulmonary
kinin enhances the BP-lowering effects of ACE inhibitors, but also is symptoms occasionally occurs and requires treatment with epi-
responsible for the side effect of dry cough. ACE inhibitors effectively nephrine, corticosteroids, antihistamines and/or emergent intuba-
prevent or regress left ventricular hypertrophy by reducing the direct tions to support respiration. A history of angioedema, even if not
stimulation by angiotensin II on myocardial cells. from an ACE inhibitor, precludes use of another ACE inhibitor (it
There are many evidence-based uses for ACE inhibitors (see Fig. is a contraindication). Cross-reactivity between ACE inhibitors and
15–3). ACE inhibitors reduce CV morbidity and mortality in ARBs is small, but has been reported.53,99 An ARB can be used in a
patients with left ventricular dysfunction,48 and decrease progression patient with a history of ACE inhibitor-induced angioedema when
of chronic kidney disease.65 They should be first-line as disease there is a compelling indication for an ARB with careful monitoring
modifying therapy in all of these patients unless absolutely contrain- for a repeat occurrence of angioedema.
dicated. ACE inhibitors, or ARBs in certain patients, are first-line in A persistent dry cough develops in up to 20% of patients, and is
patients with diabetes and hypertension because of demonstrated pharmacologically explained by the inhibition of bradykinin break-
CV disease and kidney benefits. A regimen including an ACE down. This cough does not cause clinical illness, but is annoying to
inhibitor with a thiazide-type diuretic is considered first-line in patients. It should be clearly differentiated from a wet cough
recurrent stroke prevention base on proven benefits from the because of pulmonary edema, which may be a sign of uncontrolled
PROGRESS trial showing reduced risk of secondary stroke.31 In heart failure versus an ACE inhibitor-induced cough.
combination with β-blocker therapy, evidence shows that ACE ACE inhibitors, in addition to ARBs, are absolutely contraindica-
inhibitors further reduce CV risk in coronary disease, and in patients ted in pregnancy.1,83 Female patients of child-bearing age should be
post-MI.57,59,61,62 These benefits of ACE inhibitors occur in patients counseled regarding effective forms of birth control as ACE inhibi-
with atherosclerotic vascular even in the absence of left ventricular tors are associated major congenital malformations when exposed in
systolic dysfunction or heart failure, and have the potential to reduce the first trimester and fetopathy (group of conditions that includes
the development of new-onset type 2 diabetes.63 renal failure, renal dysplasia, hypotension, oligohydramnios, pulmo-
There are 10 ACE inhibitors on the U.S. market (see Table 15–5). nary hypotension, hypocalvaria, and death) when exposed in the
All except captopril, which has a much shorter half-life than the second and third trimester.83 Similar to diuretics, ACE inhibitors can
others, can be dosed once daily; captopril is dosed two or three increase lithium serum concentrations in patients on lithium ther-
times daily. In some patients, especially when higher doses are used, apy. Concurrent use of an ACE with a potassium-sparing diuretic
twice daily dosing is needed to maintain 24-hour effects with (including aldosterone antagonists), potassium supplements, or an
enalapril, benazepril, moexipril, quinapril, and ramipril. The ARB may result in excessive increases in potassium.
absorption of captopril, but not other ACE inhibitors, is reduced Starting doses of ACE inhibitors should be low, with even lower
when given with food. doses in patients at risk for orthostatic hypotension, or severe renal
ACE inhibitors are well tolerated,98 but are not absent of side effects. dysfunction (e.g., elderly, chronic kidney disease). Acute hypoten-
ACE inhibitors decrease aldosterone and can increase serum potassium sion may occur at the onset of ACE inhibitor therapy. Patients who
concentrations. Although this increase is usually small, and beneficial are sodium or volume depleted, in heart failure exacerbation, very
in thiazide-treated patients, hyperkalemia is possible. Patients with elderly, or on concurrent vasodilators or diuretics are at high risk
 160
for this effect. It is important to start with half the normal dose of of a thiazide-type diuretic to an ARB significantly increases antihy-
an ACE inhibitor for all patients with these risk factors, and use slow pertensive efficacy. Similar to ACE inhibitors, most ARBs have long
SECTION 2

dose titration. enough half-lives to allow for once-daily dosing. However, cande-
sartan, eprosartan, losartan, and valsartan have the shortest half-
Angiotensin Receptor Blockers ARBs are first-line agents for
lives and may require twice-daily dosing for sustained BP lowering.
hypertension.1,2 Angiotensin II is generated by two enzymatic path-
ARBs have the lowest incidence of side effects compared to other
ways: the RAAS, which involves ACE, and an alternative pathway that
antihypertensive agents.98 Because they do not affect bradykinin, they
uses other enzymes such as chymases (also known as “tissue ACE”).
do not have the potential to illicit a dry cough like ACE inhibitors.
ACE inhibitors inhibit only the effects of angiotensin II produced
Although these drugs have been termed “ACE inhibitors without the
through the RAAS, whereas ARBs inhibit angiotensin II from all
cough,” pharmacologic differences highlight that they could have
pathways. It is unclear how these differences affect tissue concentra-
Cardiovascular Disorders

very different effects on vascular smooth muscle and myocardial

tions of ACE. ACE inhibitors only partially block the effects of
tissue that can correlate to different effects on target-organ damage
angiotensin II, though the clinical significance of this is not known.
and CV risk reduction when compared with ACE inhibitors. It is
ARBs directly block the angiotensin II receptor subtype 1 receptor
possible that their effects may be superior to ACE inhibitors in
that mediates the known effects of angiotensin II in humans: vaso-
patients with type 2 diabetic nephropathy, but may be inferior to ACE
constriction, aldosterone release, sympathetic activation, antidiuretic
inhibitors in patients with more advanced heart disease (e.g., heart
hormone release, and constriction of the efferent arterioles of the
failure, post-MI). Unfortunately, there are no direct comparisons
glomerulus. Because they do not block the angiotensin II receptor
looking at long-term effects in patients with just hypertension.
subtype 2 receptor, the beneficial effects of angiotensin II receptor
Regardless, their role in patients with type 2 diabetic nephropathy is
subtype 2 stimulation (vasodilation, tissue repair, and inhibition of
well established and they also are very reasonable alternatives in
cell growth) remain intact when ARBs are used. Unlike ACE inhibi-
patients requiring an ACE inhibitor but who experience intolerable
tors, ARBs do not block the breakdown of bradykinin. Therefore,
side effects.
some of the beneficial effects of bradykinin, such as vasodilation
(which can enhance treatment of left ventricular dysfuntion), regres-
sion of myocyte hypertrophy and fibrosis, and increased levels of
tissue plasminogen activator, are not present with ARB therapy. CLINICAL CONTROVERSY
ARBs have outcomes data showing long-term reductions in Data demonstrates that risk of CV events is further reduced when
progression of target-organ damage in patients with hypertension an ARB is added to an ACE inhibitor in patients with left ventricu-
and certain compelling indications. In patients with type 2 diabetes lar dysfunction. Other data support this combination in patients
and nephropathy, progression of nephropathy has been shown to be with severe forms of nephrotic syndrome. However, using the
significantly reduced with ARB therapy.64 Some benefits appear to combination of an ACE with an ARB has not been well studied as
be independent of BP lowering, suggesting that the pharmacologic a standard treatment regimen in hypertension and incurs a signifi-
effects of ARBs on the efferent arteriole may result in progression of cantly higher risk of side effects (e.g., hyperkalemia).100
kidney disease. For patients with left ventricular dysfunction, the
CHARM studies showed that ARB therapy reduces risk of CV events
Like ACE inhibitors, ARBs may cause renal insufficiency, hyper-
when added to a stable regimen of a diuretic, ACE inhibitor, and β-
kalemia, and orthostatic hypotension. The same precautions that
blocker, or as alternative therapy in ACE-intolerant patients.53,54
apply to ACE inhibitors for patients with suspected bilateral renal
Importantly, the ELITE (Evaluation of Losartan in the Elderly)
artery stenosis, those on drugs that can raise potassium, and those on
studies show that losartan is not superior to captopril in left
drugs that increase risk of hypotension apply to ARBs. ARBs can be
ventricular dysfunction when compared head-to-head.51,52 One
used with caution in patients with a history of angioedema, but unlike
outcome study, the VALLIANT, also showed that an ARBs can
ACE inhibitors are not contraindicated. Angioedema is also less likely
reduce CV events in patients post-MI with left ventricular dysfunc-
to occur than with ACE inhibitors, but cross-reactivity has been
tion, but would be used mostly as an alternative to an ACE inhibitor
reported.53,99 An ARB should only be used in a patient with a history
for this use.58
of ACE inhibitor-induced angioedema when there is a compelling
ARBs have been compared head-to-head with CCBs. The MOSES
indication for an ARB with careful monitoring for a repeat occur-
demonstrated that eprosartan reduces the occurrence of recurrent
rence of angioedema. ARBs should not be used in pregnancy.83
stroke more than nitrendipine does in patients with a past medical
history of cerebrovascular disease.74 Using nitrendipine was a rea- Calcium Channel Blockers12,27 CCBs, both dihydropyridine
sonable comparator because the Syst-Eur had already demonstrated CCBs and nondihydropyridine CCBs, are first-line agents for hyper-
that nitrendipine reduces the occurrence of CV events, particularly tension.1,2 They have compelling indications in coronary disease and
stroke, in older patients with isolated systolic hypertension.12 These in diabetes. However, with these compelling indications, they are
data support the common notion that ARBs may have cerebropro- essentially in addition to, or in replacement of, other antihypertensive
tective effects that may explain CV event reductions. Another drug classes.
outcome study, the VALUE (Valsartan Long-term Use Evaluation) Previous data indicated that dihydropyridine CCBs may not
trial, showed that valsartan-based therapy is equivalent to amlo- provide as much protection against CV events when compared with
dipine-based therapy for the primary composite outcome of first conventional therapy (diuretics and β-blockers) or ACE inhibitors
CV event in patients with hypertension and additional CV risk in uncomplicated hypertension.27 However, newer data shows that
factors.33 However, occurrence of certain components of the pri- CCBs are likely to be as effective at lowering CV events as other
mary end point (stroke and MI) and new-onset type 2 diabetes was agents. In ALLHAT there was no difference in the primary outcome
lower in the valsartan group. Although patients treated with amlo- between chlorthalidone and amlodipine, and only the secondary
dipine had slightly lower mean BP values than valsartan treated outcome of heart failure was higher with amlodipine.30 A subgroup
patients, there was no difference in the primary end point. analysis of ALLHAT directly compared amlodipine to lisinopril and
Data from pooled analyses and direct comparisons have demon- demonstrated that there was no difference in the primary out-
strated that ARBs have a fairly flat dose–response curve, suggesting come.101 As discussed previously, the VALUE study also showed no
that increasing the dose above low or moderate doses is unlikely to difference in the primary outcome of first CV event in high-risk
result in a large degree of BP lowering.98 The addition of low doses patients between valsartan and amlodipine.33
 161
There may be differences in CV event reduction between dihy- lems occur mostly with high-doses or when used in patients with
dropyridine CCBs and nondihydropyridine CCBs. In patients with preexisting abnormalities in the cardiac conduction system. Heart

CHAPTER 15
hypertension and diabetes, dihydropyridine CCBs appear to be less failure has been reported in otherwise healthy patients as a conse-
cardioprotective than ACE inhibitors.64 Studies with the nondihy- quence of negative inotropic effects. Both drugs can cause anorexia,
dropyridine CCBs (diltiazem and verapamil) are limited, but the nausea, peripheral edema, and hypotension. Verapamil causes con-
NORDIL (Nordic Diltiazem) study found diltiazem to be equivalent stipation in approximately 7% of patients. This side effect also
to diuretics and β-blockers in reducing CV events.27 It is possible occurs with diltiazem, but to a lesser extent.
that these differences (beneficial with diltiazem and neutral with Verapamil and to a lesser extent diltiazem, can cause drug interac-
dihydropyridines) may relate to the sympathetic stimulation that tions because of their ability to inhibit the cytochrome P450 3A4
can occur with dihydropyridines. isoenzyme system. This inhibition can increase serum concentra-

Hypertension
Dihydropyridine CCBs are very effective in older patients with tions of other drugs that are metabolized by this isoenzyme system
isolated systolic hypertension. The Syst-Eur demonstrated that a long- (e.g., cyclosporine, digoxin, lovastatin, simvastatin, tacrolimus, theo-
acting dihydropyridine CCB reduced the risk of CV events markedly phylline). Verapamil and diltiazem should be given very cautiously
in isolated systolic hypertension.12 A long-acting dihydropyridine CCB with a β-blocker because there is an increased risk of heart block with
should be strongly considered in isolated systolic hypertension. these combinations. When a CCB is needed in combination with a
Contraction of cardiac and smooth muscle cells requires an β-blocker for BP lowering, a dihydropyridine should be selected,
increase in free intracellular calcium concentrations from the extra- because it will not increase risk of heart block. The hepatic metabo-
cellular fluid. When cardiac or vascular smooth muscle is stimulated, lism of CCBs, especially felodipine, nicardipine, nifedipine, and
voltage-sensitive channels in the cell membrane are opened, allowing nisoldipine, may be inhibited by ingesting large quantities of grape-
calcium to enter the cells. The influx of extracellular calcium into the fruit juice (≥1 quart daily).
cell releases stored calcium from the sarcoplasmic reticulum. As Many different formulations of verapamil and diltiazem are
intracellular free calcium concentration increases, it binds to a currently available (see Table 15–5). Although certain sustained-
protein, calmodulin, which then activates myosin kinase enabling release verapamil and diltiazem products may contain the same
myosin to interact with actin to induce contraction. CCBs work by active drug (e.g., Calan SR and Verelan), they are usually not AB
inhibiting influx of calcium across the cell membrane. There are two rated by the FDA as interchangeable on a mg-per-mg basis because
types of voltage-gated calcium channels: a high-voltage channel (L of different biopharmaceutical release mechanisms. However, the
type) and a low-voltage channel (T type). Currently available CCBs clinical significance of these differences is likely negligible.
only block the L-type channel, which leads to coronary and periph- Two sustained-release verapamil products (Covera HS and Ver-
eral vasodilation. elan PM) and one diltiazem product (Cardizem LA) are chrono-
The two subclasses of CCBs, dihydropyridines and nondihydropy- therapeutically designed to target the circadian BP rhythm. These
ridines (see Table 15–5) are pharmacologically very different from agents are primarily dosed in the evening (with the exception of
each other. Antihypertensive effectiveness is similar with both sub- Cardizem LA which may be dosed in the morning or evening) so
classes, but they differ in other pharmacodynamic effects. Nondihy- that drug is released during the early morning hours when BP first
dropyridines decrease heart rate and slow atrioventricular nodal starts to increase. The rationale behind chronotherapy in hyperten-
conduction. Similar to β-blockers, these drugs may also treat sion is that blunting the early morning BP surge may result in
supraventricular tachyarrhythmias (e.g., atrial fibrillation). Verapamil greater reductions in CV events than conventional dosing of regular
produces negative inotropic and chronotropic effects that are respon- antihypertensive products in the morning. However, evidence from
sible for its propensity to precipitate or cause systolic heart failure in the CONVINCE (Controlled Onset Verapamil Investigation of
high-risk patients. Diltiazem also has these effects but to a lesser extent Cardiovascular End Points) trial showed that chronotherapeutic
than verapamil. All CCBs (except amlodipine and felodipine) have verapamil was similar, but not better than, a thiazide-type diuretic/
negative inotropic effects. Dihydropyridines may cause a baroreceptor- β-blocker–based regimen with respect to CV events.28
mediated reflex tachycardia because of their potent peripheral vasodi-
lating effects. This effect appears to be more pronounced with the first β-Blockers27,28,48,59,62 β-Blockers have been used in several large
generation dihydropyridines (e.g., nifedipine) and is significantly outcome trials in hypertension. However, in most of these trials, a
diminished with the newer agents (e.g., amlodipine) and when given thiazide-type diuretic was the primary agents with a β-blocker added
in sustained-release dosage forms. Dihydropyridines do not alter on for additional BP lowering. Therefore, β-blockers are now only
conduction through the atrioventricular node and thus are not effec- considered appropriate first-line agents to treat specific compelling
tive agents in supraventricular tachyarrhythmias. indications (post-MI, coronary disease). They also are evidence-based
Among dihydropyridines, short-acting nifedipine may rarely as additional therapy for other compelling indications (heart failure
cause an increase in the frequency, intensity, and duration of angina and diabetes). Numerous trials have shown reduced CV risk when β-
in association with acute hypotension. This effect is most likely due blockers are used following an MI, during an acute coronary syn-
to a reflex sympathetic stimulation, and is likely obviated by using drome, or in chronic stable angina. Although once considered contra-
sustained-release formulations of nifedipine. For this reason, all indicated in heart failure, multiple studies have shown that carvedilol
other dihydropyridines have an intrinsically long-half-life or are and metoprolol succinate reduce mortality in patients with left
provided in sustained release formulations. Immediate-release ventricular dysfunction who are treated with a diuretic and ACE
nifedipine has been associated with an increased incidence of inhibitor.
adverse CV effects, is not approved for treatment of hypertension, For patients with hypertension but without compelling indica-
and should not be used to treat hypertension. Other side effects with tions, other primary agents (thiazide-type diuretics, ACE inhibitors,
dihydropyridines include dizziness, flushing, headache, gingival ARBs, and CCBs) should be used as the initial first-line agent before
hyperplasia, and peripheral edema. Side effects caused by vasodila- β-blockers. While this may be surprising to experienced clinicians,
tion, such as dizziness, flushing, headache, and peripheral edema, this recommendation is consistent with the 2007 AHA guidelines,
occur more frequently with all dihydropyridines than with the the 2007 European Society of Hypertension guidelines, and the 2006
nondihydropyridines because they are less-potent vasodilators. United Kingdom’s National Institute for Health and the Clinical
Diltiazem and verapamil can cause cardiac conduction abnor- Excellence guidelines.2,92,93 It is based on meta-analyses data that
malities such as bradycardia or atrioventricular block. These prob- suggest β-blocker–based therapy may not reduce CV events as well
 162
as these other agents when used as the initial drug to treat patients other effects. Propranolol is the most lipophilic drug and atenolol is
with hypertension and without a compelling indication for a β- the least lipophilic. It is unclear whether higher lipophilicity is
SECTION 2

blocker. associated with more central nervous system side effects (dizziness,
Several mechanisms of action have been proposed for β-blockers, drowsiness). However, the lipophilic properties can provide better
but none of them alone is consistently associated with a reduction effects for non-CV conditions such as migraine headache preven-
in arterial BP. β-Blockers have negative chronotropic and inotropic tion, essential tremor, and thyrotoxicosis. BP lowering is equal
cardiac effects that reduce cardiac output and explains some of the among β-blockers regardless of lipophilicity.
antihypertensive effect. However, cardiac output falls equally in
patients treated with β-blockers regardless of BP lowering.
β-Adrenoceptors are located on the surface membranes of juxta- CLINICAL CONTROVERSY
glomerular cells, and β-blockers inhibit these receptors and thus the
Cardiovascular Disorders

Many of the clinical trials included in the meta-analyses data that

release of renin. However, there is a weak association between
suggest β-blocker–based therapy may not reduce CV events as
plasma renin and antihypertensive efficacy of β-blocker therapy.
well as these other agents used atenolol dosed once daily.44–47
Some patients with low plasma renin concentrations do respond to
Atenolol has a half life of 6 to 7 hours and is nearly always dosed
β-blockers. Therefore, additional mechanisms must also account
once daily, whereas immediate-release forms of carvedilol and
for the antihypertensive effect of β-blockers. However, the ability of
metoprolol tartrate have 6- to 10- and 3- to 7-hour half-lives
β-blockers to reduce plasma renin and thus angiotensin II concen-
respectively, and are always dosed at least twice daily. Conse-
trations may play a major role in their ability to reduce CV risk.
quently, it is possible that these findings might only apply to
There are important pharmacodynamic and pharmacokinetic
atenolol and also that these findings may be a result of using
differences among β-blockers, but all agents provide a similar
atenolol once daily instead of twice daily.
degree of BP lowering. There are two pharmacodynamic properties
of the β-blockers that differentiate this class: cardioselectivity and
ISA. β-Blockers that possess a greater affinity for β1-receptors than Most side effects of β-blockers are an extension of their ability to
β2-receptors are cardioselective. antagonize β-adrenoceptors. β-Blockade in the myocardium can be
The β1- and β2-adrenoceptors are distributed throughout the associated with bradycardia, atrioventricular conduction abnormal-
body, but they concentrate differently in certain organs and tissues. ities (e.g., second- or third-degree heart block), and the develop-
There is a preponderance of β1-receptors in the heart and kidney, ment of acute heart failure. The decreases in heart rate may actually
and a preponderance of β2-receptors in the lungs, liver, pancreas, benefit certain patients with atrial arrhythmias (atrial fibrillation,
and arteriolar smooth muscle. β1-Receptor stimulation increases atrial flutter) and hypertension by both providing rate control and
heart rate, contractility, and renin release. β2-Receptor stimulation BP lowering. β-Blockers usually only produce heart failure if they
results in bronchodilation and vasodilation. Cardioselective β- are used in high initial doses in patients with preexisting left
blockers are not likely to provoke bronchospasm and vasoconstric- ventricular dysfunction or if started in these patients during an
tion. Insulin secretion and glycogenolysis are mediated by β2- acute heart failure exacerbation. Blocking β2-receptors in arteriolar
receptors. Blocking β2-receptors may reduce these processes and smooth muscle may cause cold extremities and may aggravate
cause hyperglycemia or blunt recovery from hypoglycemia. peripheral arterial disease or Raynaud’s phenomenon as a result of
Cardioselective β-blockers (e.g., atenolol, metoprolol) have clini- decreased peripheral blood flow. In addition, there is an increase of
cally significant advantages over nonselective β-blockers (e.g., pro- sympathetic tone during periods of hypoglycemia that may result in
pranolol, nadolol), and are generally preferred to treat hypertension. an increase in BP because of unopposed α-receptor-mediated
Cardioselective agents are safer than nonselective agents in patients vasoconstriction.
with asthma or diabetes. However, cardioselectivity is a dose-depen- Abrupt cessation of β-blocker therapy can produce unstable
dent phenomenon; at higher doses, cardioselective agents lose their angina, MI, or even death in patients with coronary disease. Abrupt
relative selectivity for β1-receptors and block β2-receptors as effec- cessation may also lead to rebound hypertension (a sudden increase
tively as they block β1-receptors. The dose at which cardioselectivity in BP to above pretreatment values). To avoid this, β-blockers
is lost varies from patient to patient. should always be tapered gradually over 1 to 2 weeks before
Some β-blockers (e.g., acebutolol, pindolol) have ISA and act as eventually discontinuing the drug. This acute withdrawal syndrome
partial β-receptor agonists. When they bind to the β-receptor, they is believed to be secondary to progression of underlying coronary
stimulate it, but far less than a pure β-agonist. If sympathetic tone is disease and hypersensitivity of β-adrenergic receptors as a result of
low, as it is during resting states, β-receptors are partially stimulated upregulation. In patients without coronary disease, abrupt discon-
by ISA β-blockers. Therefore, resting heart rate, cardiac output, and tinuation may present as tachycardia, sweating, and generalized
peripheral blood flow are not reduced when these type of β-blockers malaise, in addition to increased BP.
are used. Theoretically, ISA agents would appear to have advantages Like diuretics, β-blockers have been shown to increase serum
over β-blockers in certain patients with heart failure, or sinus cholesterol and glucose values, but these effects are transient and of
bradycardia. Unfortunately, they do not appear to reduce CV events questionable clinical significance. In patients with diabetes or dys-
as well as other β-blockers. In fact, they may increase risk post-MI or lipidemia, the reduction in CV events was as great with β-blockers
in those with coronary disease. Thus, agents with ISA are rarely as with an ACE inhibitor in the United Kingdom Prospective
needed and have little to no clinical utility. Diabetes Study,66 and far superior to placebo in the SHEP trial.9 In
Pharmacokinetic differences among β-blockers relate to first-pass the GEMENI (Glycemic Effects in Diabetes Mellitus: Carvedilol-
metabolism, route of elimination, degree of lipophilicity, and serum Metoprolol Comparison in Hypertension) trial, patients with diabe-
half-lives. Propranolol and metoprolol undergo extensive first-pass tes and hypertension who were randomized to metoprolol had an
metabolism, so the dose needed to attain β-blockade with either increase in hemoglobin A1c values, whereas patients randomized to
drug varies from patient to patient. Atenolol and nadolol have are carvedilol did not.102 This suggests that mixed α- and β-blocking
renally excreted. The dose of these agents may need to be reduced in effects of carvedilol may be preferential to metoprolol in patients
patients with moderate to severe chronic kidney disease. with uncontrolled diabetes. However, differences in hemoglobin A1c
β-Blockers, especially those with highly lipophilic properties, values were too small to make this application clinically relevant in
penetrate the central nervous system penetration and may cause all patients with diabetes that need treatment with a β-blocker.
 163
β-Blockers can slightly increase serum triglycerides and decrease CCB, although its effectiveness in combination with maximum doses
high-density lipoprotein cholesterol. β-Blockers with α-blocking of ACE inhibitors has not been adequately studied.

CHAPTER 15
properties produce no changes in these lipid values. Because these Many of the cautions and adverse effects seen with ACE inhibi-
are of questionable clinical significance, cardioselective agents, tors and ARBs apply to direct renin inhibitors (i.e., aliskiren).
which have less overall side effects, remain the β-blockers of choice Aliskiren should never be used in pregnancy because of the known
for most patients. teratogenic effects of using other drugs that block the RAAS system.
Angioedema has also been reported in patients treated with
 Alternative Agents The primary role of an alternative antihy- aliskiren. Increases in serum creatinine and serum potassium values
pertensive agent is to provide additional BP lowering in patients have been observed. The mechanisms of these adverse effects are
who are already treated with an agent from a drug class proven to likely similar to those with ACE inhibitors and ARBs. It is reason-

Hypertension
reduce CV events (diuretics, ACE inhibitors, ARBs, CCBs, or even able to use similar monitoring strategies by measuring serum
β-blockers). creatinine and serum potassium in patients treated with aliskiren.
This is particularly important in patients treated with the combina-
α1-Blockers.35 Prazosin, terazosin, and doxazosin are selective
tion of aliskiren and an ACE inhibitor or an ARB who are at higher
α1-receptor blockers. They work in the peripheral vasculature and
risk for hyperkalemia (e.g., chronic kidney disease).
inhibit the uptake of catecholamines in smooth muscle cells result-
ing in vasodilation and BP lowering. Central α2-Agonists. Clonidine, guanabenz, guanfacine, and meth-
Doxazosin was one of the original treatment arms of the ALLHAT. yldopa lower BP primarily by stimulating α2-adrenergic receptors in
However, it was stopped prematurely when statistically more second- the brain. This stimulation reduces sympathetic outflow from the
ary end points of stoke, heart failure, and CV events were seen with vasomotor center in the brain and increases vagal tone. It is also
doxazosin compared with chlorthalidone.35 There were no differences believed that peripheral stimulation of presynaptic α2-receptors may
in the primary end point of fatal coronary heart disease and nonfatal further reduce sympathetic tone. Reduced sympathetic activity
MI. These data suggest that thiazide-type diuretics are superior to α1- together with enhanced parasympathetic activity can decrease heart
blockers in preventing CV events in patients with hypertension. rate, cardiac output, total peripheral resistance, plasma renin activity,
Therefore, α1-blockers are alternative agents that should be used in and baroreceptor reflexes. Clonidine is often used in resistant hyper-
combination with primary antihypertensive agents. tension, and methyldopa is a first-line agent for pregnancy-induced
α1-Blockers can provide symptomatic benefits in men with benign hypertension.
prostatic hypertrophy. These agents block postsynaptic α1-adrenergic Chronic use of centrally acting α2-agonists results in sodium and
receptors located on the prostate capsule, causing relaxation and water retention. As with other centrally acting antihypertensives,
decreased resistance to urinary outflow. However, when used to lower depression can occur, especially with high doses. The incidence of
BP, they should only be in addition to primary antihypertensive orthostatic hypotension and dizziness is high, so they should be used
agents. very cautiously in the elderly. Lastly, clonidine has a relatively high
A potentially severe side effect of α1-blockers is a “first-dose” incidence of anticholinergic side effects (sedation, dry mouth, consti-
phenomenon that is characterized by transient dizziness or faintness, pation, urinary retention, and blurred vision). Thus it should gener-
palpitations, and even syncope within 1 to 3 hours of the first dose. ally be avoided for chronic antihypertensive therapy in the elderly.
This adverse reaction can also happen after dose increases. These Abrupt cessation of central α2-agonists may lead to rebound
episodes are accompanied by orthostatic hypotension and can be hypertension. This effect is thought to be secondary to a compensa-
obviated by taking the first dose and subsequent first increased doses tory increase in norepinephrine release after abrupt discontinuation.
at bedtime. Because orthostatic hypotension and dizziness may In addition, other effects such as nervousness, agitation, headache,
persist with chronic administration, these agents should be used and tremor can also occur, which may be exacerbated by concomi-
cautiously in elderly patients. Even though antihypertensive effects tant β-blocker use, particularly with clonidine. Thus, if clonidine is
are achieved through a peripheral α1-receptor antagonism, these to be continued it should be tapered. In patients who are receiving
agents cross the blood–brain barrier and may cause central nervous concomitant β-blocker therapy, the β-blocker should be gradually
system side effects. α1-Blockers also may cause priapism. Sodium discontinued first several days before gradual discontinuation of
and water retention can occur with chronic administration. Conse- clonidine.
quently, these agents are most effective when given in combination Methyldopa can cause hepatitis or hemolytic anemia, although
with a diuretic to maintain antihypertensive efficacy and minimize this is rare. Transient elevations in serum hepatic transaminases are
potential edema. occasionally seen with methyldopa therapy but are clinically irrele-
vant unless they are greater than three times the upper limit of
Aliskiren.103,104 Aliskiren is the first oral agent within a new
normal. Methyldopa should be quickly discontinued if persistent
antihypertensive drug class that directly inhibits renin.103 This drug
increases in serum hepatic transaminases or alkaline phosphatase
blocks the RAAS at its point of activation, which results in reduced
are detected because this may indicate the onset of a fulminate life-
plasma renin activity and BP lowering. It has a 24-hour half-life, is
threatening hepatitis. A Coombs-positive hemolytic anemia occurs
primarily eliminated through biliary excretion unchanged, and
in less than 1% of patients receiving methyldopa, although 20% of
provides 24-hour antihypertensive effects with once-daily dosing.
patients exhibit a positive direct Coombs test without anemia. For
The exact role of this drug class in the management of hypertension
these reasons, methyldopa has limited use in routine management
is unclear. Aliskiren is approved as monotherapy or in combination
of hypertension except in pregnancy.
therapy. However, because of the lack of long-term studies evaluating
CV event reduction and significant drug cost compared to generic Reserpine. Reserpine lowers BP by depleting norepinephrine from
agents with outcomes data, it should clearly be used as an alternative sympathetic nerve endings, and blocking transport of norepinephrine
therapy for the treatment of hypertension. Studies evaluating the ability into its storage granules. Norepinephrine release into the synapse
of aliskiren to lower CV events and decrease progression of diabetic following nerve stimulation is reduced and results in reduced sympa-
nephropathy are planned to start in 2007, but will not be completed for thetic tone, peripheral vascular resistance, and BP. Reserpine also
many years. Aliskiren provides BP reductions comparable to an ACE depletes catecholamines in the brain and the myocardium.
inhibitor, ARB, or CCB. It also has additive antihypertensive effects Reserpine has a slow onset of action and long-half life that allows
when used in combination with thiazides, ACE inhibitors, ARBs, or a for once-daily dosing. However, it may take 2 to 6 weeks before the
 164
maximal antihypertensive effect is seen. Because reserpine can cause drugs have little to no role in the management of hypertension. They
significant sodium and water retention, it should only be given in deplete norepinephrine from postganglionic sympathetic nerve ter-
SECTION 2

combination with a diuretic (preferably a thiazide). Reserpine’s minals and inhibit the release of norepinephrine in response to
strong inhibition of sympathetic activity results in increased para- sympathetic nerve stimulation, resulting in reduced cardiac output
sympathetic activity. This effect explains why side effects such as nasal and peripheral vascular resistance. Orthostatic hypotension is com-
stuffiness, increased gastric acid secretion, diarrhea, and bradycardia mon because reflex-mediated vasoconstriction is blocked. Long-
can occur. Depression has been reported, which is a consequence of term norepinephrine depletion leads to postsynaptic receptor super-
central nervous system depletion of catecholamines and serotonin. sensitivity. Consequently, concomitant use of sympathomimetics or
The initial reports of depression with reserpine were in the 1950s and tricyclic antidepressants may provoke hypertensive crisis. Erectile
are inconsistent with current definitions of depression. Regardless, dysfunction, diarrhea, and weight gain are also common.
Cardiovascular Disorders

reserpine-induced depression is dose-related. Moreover, very high

Agents in Development.104 Darusentan, clevidipine, and nebiv-
doses (above 1 mg daily) were frequently used in the 1950s, resulting
olol are new agents under study that provide significant reductions
in more depression. When reserpine is used in doses between 0.05
in BP and may be approved for hypertension in the near future.
and 0.25 mg daily (recommended doses), the rate of depression is
Darusentan is an endothelin (A) selective endothelin receptor
equal to that seen with β-blockers, diuretics, or placebo.9
antagonist. There currently are no antihypertensive agents available
Reserpine was used as a third-line agent in many of the landmark
that target the endothelin receptor. If this agent is approved, it will
clinical trials that have documented the benefit in treating hyperten-
likely be used in patients with resistant hypertension. Nebivolol is a
sion, including the VA Cooperative trials and most importantly, the
“third-generation” cardioselective β-blocker. It produces vasodila-
SHEP trial.9 An analysis of the SHEP data found that reserpine was
tion and improves endothelial function via the L-arginine–nitric
very well tolerated.
oxide pathway. Clevidipine is an ultrashort-acting, vascular-selec-
Direct Arterial Vasodilators. Hydralazine and minoxidil directly tive, dihydropyridine calcium antagonist. It is being developed for
relax arteriolar smooth muscle resulting in vasodilation and BP lower- intravenous use in patients with hypertensive crisis.
ing. Both agents cause potent reductions in perfusion pressure that
activates the baroreceptor reflexes. Activation of baroreceptors results PHARMACOECONOMIC CONSIDERATIONS
in a compensatory increase in sympathetic outflow, which leads to an
increase in heart rate, cardiac output, and renin release. Consequently, The cost of effectively treating hypertension is substantial. However,
tachyphylaxis can develop resulting in a loss of hypotensive effect with these costs can be offset by savings that would be realized by
continued use. This compensatory baroreceptor response can be reducing CV morbidity and mortality. Cost related to treating
counteracted by concurrent use of a β-blocker. target-organ damage (e.g., MI, end-stage kidney failure) can drasti-
All patients receiving hydralazine or minoxidil long-term for cally increase healthcare costs. The cost per life-year saved from
hypertension should first receive both a diuretic and a β-blocker. treating hypertension is estimated to be $40,000 for younger adults
Direct arterial vasodilators can precipitate angina in patients with and even less for older adults.105 Treatments that cost less than
underlying coronary disease unless the baroreceptor reflex mecha- $50,000 per quality-adjusted life-year saved generally are considered
nism is completely blocked with a β-blocker. Nondihydropyridine favorable by health economists.
CCBs can be used as an alternative to β-blockers in these patients, In a cost-minimization study that included the cost of drug acquisi-
but a β-blocker is preferred. The side effect of sodium and water tion, supplemental drugs, laboratory tests, clinic visits, and complica-
retention is significant with these drugs, and is minimized by using tions, the total costs of treating hypertension with either a diuretic, ACE-
a diuretic concomitantly. inhibitor, or CCB was under $1,500.106 Another cost-minimization
One side effect unique to hydralazine is a dose-dependent drug- analysis found that 86 middle-age or 29 elderly patients with hyperten-
induced lupus-like syndrome. Hydralazine is eliminated by hepatic sion would need to be treated to prevent 1 MI, stroke, or death.107
N-acetyltransferase. This enzyme displays genetic polymorphism, A comparative analysis of 133,624 patients with hypertension
and “slow acetylators” are especially prone to develop drug-induced ages 65 and older from a state prescription drug-assistance program
lupus with hydralazine. This syndrome is more common in women demonstrated that 40% of patients were prescribed pharmacother-
and is reversible upon discontinuation. Drug-induced lupus may be apy that was not necessarily recommended by the JNC7 guidelines
avoided by using less than 200 mg of hydralazine daily. Other side recommendations.108 If these 40% had drug-therapy modifications
effects of hydralazine include dermatitis, drug fever, peripheral made to follow evidence-based treatment, a reduction in costs of
neuropathy, hepatitis, and vascular headaches. For these reasons, $11.6 million would have been realized in the 2001 calendar year
hydralazine has limited usefulness in the treatment of hypertension. based on discounted prices. This was projected to increase to $20.5
However, it is still especially useful in patients with severe chronic million using usual Medicaid pricing limits.
kidney disease and in kidney failure. Thus it is crucial to identify ways to control the cost of care without
Because minoxidil is a more potent vasodilator than hydralazine, increasing the morbidity and mortality associated with uncontrolled
the compensatory increases in heart rate, cardiac output, renin hypertension. Using evidence-based pharmacotherapy will save costs
release, and sodium retention are even more dramatic. Sodium and not only by using the most effective agents. Thiazide-type diuretics
water retention can be so severe with minoxidil that heart failure are first-line treatment options in most patients without compelling
can be precipitated. It is even more important to coadminister a β- indications, and are very inexpensive. Just using thiazides, either as
blocker and a diuretic with minoxidil. A loop diuretic is often more monotherapy or in combination, is appropriate under almost all
effective than a thiazide in patients treated with minoxidil. A circumstances and aspects of hypertension management. When
troublesome side effect of minoxidil is hypertrichosis (hirsutism), needed, using other generic primary antihypertensive agents that can
presenting as increased hair growth on the face, arms, back, and be administered once daily should be considered.
chest. This usually ceases when the drug is discontinued. Minoxidil
is reserved for very-difficult-to-control hypertension and in patients HYPERTENSIVE URGENCIES
requiring hydralazine who experience drug-induced lupus. AND EMERGENCIES1,7
Other Agents. Guanethidine and guanadrel are postganglionic Both hypertensive urgencies and emergencies are characterized by
sympathetic inhibitors. Because of significant complications, these the presence of very elevated BP—greater than 180/120 mm Hg.
 165
However, the need for urgent or emergent antihypertensive therapy DBP falls below 110 mm Hg or a total of 0.7 mg clonidine has been
should be determined based on the presence of acute or immediately administered. A single dose may be all that is necessary. Labetalol can

CHAPTER 15
progressing target-organ injury, but not elevated BP alone. Urgen- be given in a dose of 200 to 400 mg, followed by additional doses
cies are not associated with acute or immediately progressing target- every 2 to 3 hours.
organ injury, whereas emergencies are. Examples of acute target- Oral or sublingual immediate-release nifedipine for acute BP
organ injury include encephalopathy, intracranial hemorrhage, acute lowering is dangerous. This approach produces a rapid reduction in
left ventricular failure with pulmonary edema, dissecting aortic BP. Use of immediate-release and should never be used for hyper-
aneurysm, unstable angina, and eclampsia or severe hypertension tensive urgencies because of reports of severe adverse events such
during pregnancy. nifedipine as MIs and strokes.109

 Hypertensive Urgency

Hypertension
Hypertensive Emergency
A common error with treating hypertensive urgency is initiating Hypertensive emergencies are those rare situations that require
overly aggressive antihypertensive therapy. This treatment likely has immediate BP reduction to limit new or progressing target-organ
been caused by the classification terminology “urgency.” Hyperten- damage (see Arterial Blood Pressure: Classification above). Hyper-
sive urgencies are ideally managed by adjusting maintenance ther- tensive emergencies require parenteral therapy, at least initially, with
apy by adding a new antihypertensive and/or increasing the dose of one of the agents listed in Table 15–8. The goal in hypertensive
a present medication. This is the preferred approach to these emergencies is not to lower BP to less than 140/90 mm Hg; rather, a
patients as it provides a more gradual reduction in BP. Very rapid reduction in mean arterial pressure of up to 25% within minutes to
reductions in BP to goal values should be discouraged because of hours is the initial target. If then stable, BP can be reduced to 160/
potential risks. Because autoregulation of blood flow in patients 100–110 mm Hg within the next 2 to 6 hours. Precipitous drops in
with hypertension occurs at a much higher range of pressure than in BP may lead to end-organ ischemia or infarction. If patients tolerate
normotensive persons, the inherent risks of reducing BP too precip- this reduction, additional gradual reductions toward goal BP values
itously include cerebrovascular accidents, MI, and acute kidney can be attempted after 24 to 48 hours. The exception to this guideline
failure. Hypertensive urgency requires BP reductions with oral is for patients with an acute ischemic stroke where maintaining an
antihypertensive agents to stage 1 values over a period of several elevated BP is needed for a much longer period of time.
hours to several days. All patients with hypertensive urgency should The clinical situation should dictate which intravenous medica-
be reevaluated within 7 days (preferably after 1 to 3 days). tion is used to treat hypertensive emergencies. Regardless, therapy
Acute administration of a short-acting oral antihypertensive (cap- should be provided in a hospital or emergency room setting with
topril, clonidine or labetalol) followed by careful observation for intraarticular BP monitoring. Table 15–8 lists special indications for
several hours to assure a gradual reduction in BP is an option for agents that can be used. Some of these agents are discussed in
hypertensive urgency. However, there are no data supporting this further detail below.
approach as being absolutely needed. Oral captopril is one of the Nitroprusside is widely considered the agent of choice for most
agents of choice and can be used in doses of 25 to 50 mg at 1- to 2- cases, but can be problematic in patients with chronic kidney disease.
hour intervals. The onset of action of oral captopril is 15 to 30 It is a direct-acting vasodilator that decreases peripheral vascular
minutes, and a marked fall in BP is unlikely to occur if no hypoten- resistance but does not increase cardiac output unless left ventricular
sive response is observed within 30 to 60 minutes. For patients with failure is present. Nitroprusside can be given to treat most hyperten-
hypertensive rebound following withdrawal of clonidine, 0.2 mg sive emergencies, but in aortic dissection, propranolol should be
clonidine can be given initially, followed by 0.2 mg hourly until the given first to prevent reflex sympathetic activation. Nitroprusside is

TABLE 15-8 Parenteral Antihypertensive Agents for Hypertensive Emergency

Drug Dose Onset (min) Duration (min) Adverse Effects Special Indications
Sodium nitro- 0.25–10 mcg/kg/min intravenous Immediate 1–2 Nausea, vomiting, muscle Most hypertensive emergencies;
prusside infusion (requires special delivery twitching, sweating, thiocya- caution with high intracranial
system) nate and cyanide pressure, azotemia, or in chronic
intoxication kidney disease
Nicardipine 5–15 mg/h intravenous 5–10 15–30; may exceed Tachycardia, headache, flush- Most hypertensive emergencies
hydrochloride 240 ing, local phlebitis except acute heart failure; cau-
tion with coronary ischemia
Fenoldopam 0.1–0.3 mcg/kg/min intravenous <5 30 Tachycardia, headache, nau- Most hypertensive emergencies;
mesylate infusion sea, flushing caution with glaucoma
Nitroglycerin 5–100 mcg/min intravenous infusion 2–5 5–10 Headache, vomiting, methe- Coronary ischemia
moglobinemia, tolerance
with prolonged use
Hydralazine 12–20 mg intravenous 10–20 60–240 Tachycardia, flushing, head- Eclampsia
hydrochloride 10–50 mg intramuscular 20–30 240–360 ache vomiting, aggravation
of angina
Labetalol hydro- 20–80 mg intravenous bolus every 5–10 180–360 Vomiting, scalp tingling, bron- Most hypertensive emergencies
chloride 10 min; 0.5–2.0 mg/min intrave- choconstriction, dizziness, except acute heart failure
nous infusion nausea, heart block,
orthostatic hypotension
Esmolol 250–500 mcg/kg/min intravenous 1–2 10–20 Hypotension, nausea, asthma, Aortic dissection; perioperative
hydrochloride bolus, then 50–100 mcg/kg/min first-degree heart block,
intravenous infusion; may repeat heart failure
bolus after 5 minutes or increase
infusion to 300 mcg/min
 166
metabolized to cyanide and then to thiocyanate, which is eliminated hypotension. Modifying other CV risk factors (e.g., smoking, dys-
by the kidneys. Therefore, serum thiocyanate levels should be moni- lipidemia, and diabetes) is also important.
SECTION 2

tored when infusions are continued longer than 72 hours. Nitroprus-

side should be discontinued if the concentration exceeds 12 mg/dL.
 COMBINATION ANTIHYPERTENSIVE
The risk of thiocyanate accumulation and toxicity is increased in
patients with impaired kidney function. THERAPY
Intravenous nitroglycerin dilates both arterioles and venous
Starting therapy with a combination of two drugs is recommended
capacitance vessels, thereby reducing both cardiac afterload and
in patients who are far from their BP goal, for patients where goal
preload which can decrease myocardial oxygen demand. It also
achievement may be difficult (e.g., those with BP goals of less than
dilates collateral coronary blood vessels and improves perfusion to
130/80 mm Hg, African Americans), and in patients with multiple
Cardiovascular Disorders

ischemic myocardium. These properties make intravenous nitro-

compelling indications for different antihypertensive agents. More-
glycerin ideal for the management of hypertensive emergency in the
over, combination therapy is often needed to control BP and most
presence of myocardial ischemia. Intravenous nitroglycerin is asso-
patients require two or more agents.1,21,42,65
ciated with tolerance when used over 24 to 48 hours, and can cause
Combination regimens for hypertension should ideally include a
severe headache.
diuretic, preferably a thiazide-type. This method will provide addi-
Fenoldopam and nicardipine are newer and more expensive
tional BP lowering as most patients respond well to a combination
alternative agents. Fenoldopam is a dopamine-1 agonist. It can
regimen that includes a diuretic. Clinicians should anticipate the
improve renal blood flow and may be especially useful in patients
need for three drugs to control BP in patients with aggressive BP
with kidney insufficiency. Nicardipine provides arterial vasodila-
goals of <130/80 mm Hg.65 Using low-dose combinations also
tion, and can treat cardiac ischemia similar to nitroglycerin, but
provides greater reductions in BP compared to high doses of single
may provide more predictable reductions in BP.
agents, with fewer drug-related side effects.98
The hypotensive response of hydralazine is less predictable than
Diuretics, when combined with several agents (especially an ACE
with other parenteral agents. Consequently, its major role is in the
inhibitor, ARB or β-blocker), can result in additive antihypertensive
treatment of eclampsia or hypertensive encephalopathy associated
effects. BP lowering from certain antihypertensive agents can activate
with renal insufficiency.
the RAAS as a compensatory mechanism to counteract BP changes,
and regulate fluid loss. Most alternative antihypertensive agents (i.e.,
EVALUATION OF THERAPEUTIC OUTCOMES reserpine, arterial vasodilators, and centrally acting agents) need to
be given with a diuretic to avoid sodium and water retention.
ACHIEVING GOALS Many fixed-dose combination products are commercially avail-
able (Table 15–9). Most of these products contain a thiazide-type
The most important strategy to prevent CV morbidity and mortality diuretic and have multiple dose strengths available. Individual dose
in hypertension is BP control to goal values. Routine goal BP values titration is more complicated with fixed-dose combination products,
should be attained in elderly patients and in those with isolated but this strategy can reduce the number of daily tablets/capsules
systolic hypertension, but actual BP lowering can occur at a very and can simplify regimens to improve adherence. This alone may
gradual pace over a period of several months to avoid orthostatic increase the likelihood of achieving or maintaining goal BP values.

TABLE 15-9 Fixed-Dose Combination Products

Combination Drugs (Brand Name) Strengths (mg/mg) Daily Frequency
ACE inhibitor with a thiazide diuretic Benazepril/hydrochlorothiazide (Lotensin HCT) 5/6.25, 10/12.5, 20/12.5, 20/25 1
Captopril/hydrochlorothiazide (Capozide) 25/15, 25/25, 50/15, 50/25 1 to 3
Enalapril/hydrochlorothiazide (Vaseretic) 5/12.5, 10/25 1
Lisinopril/hydrochlorothiazide (Prinzide, Zestoretic) 10/12.5, 20/12.5, 20/25 1
Moexipril/hydrochlorothiazide (Uniretic) 7.5/12.5, 15/25 1 or 2
Quinapril/hydrochlorothiazide (Accuretic) 10/12.5, 20/12.5, 20/25 1
ARB with a thiazide diuretic Candesartan/hydrochlorothiazide (Atacand HCT) 600/12.5, 600/25 1
Eprosartan/hydrochlorothiazide (Teveten HCT) 16/12.5, 32/12.5 1
Irbesartan/hydrochlorothiazide (Avalide) 75/12.5, 150/12.5, 300/12.5 1
Losartan/hydrochlorothiazide (Hyzaar) 50/12.5, 100/25 1
Olmesartan/hydrochlorothiazide (Benicar HCT) 20/12.5, 40/12.5, 40/25 1
Telmisartan/hydrochlorothiazide (Micardis HCT) 40/12.5, 80/12.5 1
Valsartan/hydrochlorothiazide (Diovan HCT) 80/12.5, 160/12.5 1
β-Blocker with a thiazide diuretic Atenolol/chlorthalidone (Tenoretic) 50/25, 100/25 1
Bisoprolol/hydrochlorothiazide (Ziac) 2.5/6.25, 5/6.25, 10/6.25 1
Propranolol/hydrochlorothiazide (Inderide) 40/25, 80/25 2
Propranolol LA/hydrochlorothiazide (Inderide LA) 80/50, 120/50, 160/50 1
Metoprolol/hydrochlorothiazide (Lopressor HCT) 50/25, 100/25 1 or 2
Nadolol/bendroflumethiazide (Corzide) 40/5, 80/5 1
Timolol/hydrochlorothiazide (Timolide) 10/25 1 or 2
ACE inhibitor with calcium channel blocker Amlodipine/benazepril (Lotrel) 2.5/10, 5/10, 10/20 1
Enalapril/pelodipine (Lexxel) 5/5 1
Trandolapril/verapamil (Tarka) 2/180, 1/240, 2/240, 4/240 1 or 2
ARB with calcium channel blocker Valsartan/amlodipine (Exforge) 5/160, 10/160, 5/320, 10/320 1
Olmesartan/amlodipine (AZOR) 5/20, 10/20, 5/40, 10/40 1
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
 167

TABLE 15-10 Causes of Resistant Hypertension More frequent evaluations are required in patients with a history of
poor control, nonadherence, progressive target-organ damage, or

CHAPTER 15
Improper blood pressure measurement
symptoms of adverse drug effects.
Volume overload
Self-measurements of BP or automatic ambulatory BP monitoring
• Excess sodium intake
• Volume retention from kidney disease
can be useful clinically to establish effective 24-hour control. This type
• Inadequate diuretic therapy of monitoring may become the standard of care in the future, but the
Drug-induced or other causes JNC7 and AHA recommends that ambulatory BP monitoring only be
• Nonadherence used in select situations such as suspected white coat hypertension. If
• Inadequate doses patients are measuring their BP at home, it is important that they
• Agents listed in Table 15-1 measure during the early morning hours for most days, and then at

Hypertension
Associated conditions different times of the day on alternative days of the week. Addition-
• Obesity, excess alcohol intake ally, patients should be instructed to measure BP two to three times
Secondary hypertension each time they measure BP, and to document all values accurately.

Toxicity
 RESISTANT HYPERTENSION
Patients should be monitored routinely for adverse drug effects
Resistant hypertension is the failure to achieve goal BP in patients (Table 15–11). Monitoring should typically occur 2 to 4 weeks after
who are adhering to full doses of an appropriate three-drug regimen starting a new agent or dose increases, and then every 6 to 12
that includes a diuretic.1 Patients with newly diagnosed hyperten- months in stable patients. Additional monitoring may be needed for
sion or who are not receiving drug therapy should not be considered other concomitant diseases if present (e.g., diabetes, dyslipidemia,
to have resistant hypertension.110 Difficult-to-control hypertension gout). Moreover, patients treated with an aldosterone antagonist
is persistently elevated BP despite treatment with two or three drugs (eplerenone or spironolactone), should have potassium concentra-
that does not meet the criteria for resistant hypertension (e.g., tions and kidney function assessed within 3 days and again at 1 week
maximum doses that includes a diuretic). after initiation to detect potential hyperkalemia.48 The occurrence
Table 15–10 lists several causes of resistant hypertension. Volume of an adverse drug event may require dosage reduction or substitu-
overload is a common cause, thus highlighting the importance of tion with an alternative antihypertensive agent.
diuretic therapy in the management of hypertension. In addition,
nonadherence to drug therapy and lifestyle modifications plays an ADHERENCE
important role. Patients should be closely evaluated to see if any of
these causes can be reversed. If nothing is identified, the principle of Lack of persistence with hypertension treatment is a major problem
drug therapy selection from the JNC7 and AHA guidelines should in the United States and is associated with significant increases in
still apply. Compelling indications, if present, should guide selec- costs as a result of development of complications. Because hyperten-
tion assuming these patients are on a diuretic. sion is a relatively asymptomatic disease, poor adherence is frequent,
Medications that have additive or synergistic effects when given particularly in patients newly treated. It has been estimated that only
in combination should ideally be used. In patients with severe up to 50% of patients with newly diagnosed hypertension are
chronic kidney disease (e.g., estimated GFR <30 mL/min 1.73 m2), continuing treatment at 1 year.111 Therefore, it is imperative to assess
a loop diuretic might be considered over a thiazide. patient adherence on a regular basis.
Identification of nonadherence should be followed up with appropri-
CLINICAL MONITORING ate patient education, counseling, and intervention. Once-daily regimens
are preferred in most patients to improve adherence. Although some
Routine ongoing monitoring to assess disease progression, the may believe that aggressive treatment may negatively impact quality of
desired effects of antihypertensive therapy (efficacy), and undesired life and thus adherence, several studies have found that most patients
adverse side effects (toxicity) is needed in all patients treated with actually feel better once their BP is controlled. Patients on antihyperten-
antihypertensive drug therapy. sive therapy should be questioned periodically about changes in their
general health perception, energy level, physical functioning, and overall
Disease Progression satisfaction with treatment. Lifestyle modifications should always be
recommended to provide additional BP lowering and other potential
Patients should be monitored for signs and symptoms of progres-
health benefits. Persistence with lifestyle modifications should be contin-
sive target-organ disease (see Table 15–1). A careful history for chest
ually encouraged in patients engaging in such endeavors.
pain (or pressure), palpitations, dizziness, dyspnea, orthopnea,
headache, sudden change in vision, one-sided weakness, slurred
speech, and loss of balance should be taken to assess for the presence TABLE 15-11 Select Monitoring for
of hypertensive complications. Other clinical monitoring parame- Antihypertensive Pharmacotherapy
ters that may be used to assess target-organ disease include fundu-
Class Parameters
scopic changes on eye examination, left ventricular hypertrophy on
electrocardiogram, proteinuria, and changes in kidney function. Diuretics Blood pressure, blood urea nitrogen (BUN)/serum
These parameters should be monitored periodically because any creatinine, serum electrolytes (potassium, mag-
nesium, sodium), uric acid (for thiazides)
sign of deterioration requires immediate assessment and followup.
Aldosterone antagonists Blood pressure, BUN/serum creatinine, serum
potassium
Efficacy Angiotensin-converting Blood pressure, BUN/serum creatinine, serum
Clinic-based BP monitoring remains the standard for managing enzyme inhibitors potassium
hypertension. BP response should be evaluated 2 to 4 weeks after Angiotensin receptor blockers Blood pressure, BUN/serum creatinine, serum
potassium
initiating or making changes in therapy. Once goal BP values are
Calcium channel blockers Blood pressure; heart rate
attained, assuming no signs or symptoms of acute target-organ
β-Blockers Blood pressure, heart rate
disease are present, BP monitoring can be done every 3 to 6 months.
 168
High Blood Pressure Research and the Councils on Clinical Cardiology
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SECTION 2

2788.
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controlled trial. Lancet 2005;366(9489):895–906. Added trial. Lancet 2003;362(9386):767–771.
35. ALLHAT officers and coordinators for the ALLHAT Collaborative 55. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on
Research Group. Diuretic versus alpha-blocker as first-step antihyper- morbidity and mortality in patients with severe heart failure. Randomized
tensive therapy: Final results from the Antihypertensive and Lipid- Aldactone Evaluation Study Investigators. N Engl J Med 1999;341(10):709–
Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hyper- 717.
tension 2003;42(3):239–246. 56. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone
36. Davis BR, Cutler JA, Gordon DJ, et al. Rationale and design for the blocker, in patients with left ventricular dysfunction after myocardial
Antihypertensive and Lipid Lowering Treatment to Prevent Heart infarction. N Engl J Med 2003;348(14):1309–1321.
Attack Trial (ALLHAT). ALLHAT Research Group. Am J Hypertens 57. Smith SC, Jr., Allen J, Blair SN, et al. AHA/ACC guidelines for
1996;9(4 Pt 1):342–360. secondary prevention for patients with coronary and other atheroscle-
37. Rahman M, Pressel S, Davis BR, et al. Renal outcomes in high-risk rotic vascular disease: 2006 update endorsed by the National Heart,
hypertensive patients treated with an angiotensin-converting enzyme Lung, and Blood Institute. J Am Coll Cardiol 2006;47(10):2130–2139.
inhibitor or a calcium channel blocker vs a diuretic: A report from the 58. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart both in myocardial infarction complicated by heart failure, left ventric-
Attack Trial (ALLHAT). Arch Intern Med 2005;165(8):936–946. ular dysfunction, or both. N Engl J Med 2003;349(20):1893–1906.
38. Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in 59. Fraker TO Jr, Fihn SD, writing on behalf of the 2002 Chronic Stable
antihypertensive treatment of type 2 diabetes, impaired fasting glu- Angina Writing Committee. 2007 Chronic angina focused updated of
cose concentration, and normoglycemia: Antihypertensive and Lipid- the ACC/AHA 2002 guidelines for the managment of patients with
Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch chronic stable angina: A report of the American College of Cardiology/
Intern Med 2005;165(12):1401–1409. American Heart Association Task Force on Practice Guidelines Writ-
39. Wright JT Jr, Dunn JK, Cutler JA, et al. Outcomes in hypertensive ing Group to Develop the Focused Update of the 2002 guidelines of the
black and nonblack patients treated with chlorthalidone, amlodipine, managment of patients with chronic stable angina. Circulation 2007;
and lisinopril. JAMA 2005;293(13):1595–1608. 116:Dec.
40. Turnbull F. Effects of different blood-pressure-lowering regimens on 60. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium
major cardiovascular events: Results of prospectively-designed over- antagonist vs a non-calcium antagonist hypertension treatment strat-
views of randomised trials. Lancet 2003;362(9395):1527–1535. egy for patients with coronary artery disease. The International Verap-
41. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke amil-Trandolapril Study (INVEST): A randomized controlled trial.
statistics—2007 update: A report from the American Heart Associa- JAMA 2003;290(21):2805–2816.
 170
61. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for 80. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and
the management of patients with ST-elevation myocardial infarc- new antihypertensive drugs in elderly patients: Cardiovascular mortal-
SECTION 2

tion—Executive summary: A report of the American College of Cardi- ity and morbidity the Swedish Trial in Old Patients with Hyperten-
ology/American Heart Association Task Force on Practice Guidelines sion-2 study. Lancet 1999;354(9192):1751–1756.
(Writing Committee to Revise the 1999 Guidelines for the Manage- 81. National High Blood Pressure Education Program Working Group on
ment of Patients with Acute Myocardial Infarction). Circulation High Blood Pressure in Children and Adolescents. The fourth report on
2004;110(5):588–636. the diagnosis, evaluation, and treatment of high blood pressure in
62. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline children and adolescents. Pediatrics 2004;114(2 Suppl 4th Report):555–
update for the management of patients with unstable angina and non-ST- 576.
segment elevation myocardial infarction—Summary article: A report of 82. Roberts JM, Pearson G, Cutler J, Lindheimer M. Summary of the
the American College of Cardiology/American Heart Association task NHLBI Working Group on Research on Hypertension During Preg-
Cardiovascular Disorders

force on practice guidelines (Committee on the Management of Patients nancy. Hypertension 2003;41(3):437–445.
With Unstable Angina). J Am Coll Cardiol 2002;40(7):1366–1374. 83. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital
63. Dagenais GR, Pogue J, Fox K, et al. Angiotensin-converting-enzyme malformations after first-trimester exposure to ACE inhibitors. N Engl
inhibitors in stable vascular disease without left ventricular systolic J Med 2006;354(23):2443–2451.
dysfunction or heart failure: A combined analysis of three trials. Lancet 84. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood
2006;368(9535):581–588. pressure in African Americans: Consensus statement of the Hyperten-
64. American Diabetes Association. Standards of medical care in diabe- sion in African Americans Working Group of the International Society
tes—2007. Diabetes Care 2006;30(Suppl 1):S4–S41. on Hypertension in Blacks. Arch Intern Med 2003;163(5):525–541.
65. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in 85. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice
adults with hypertension and diabetes: A consensus approach. National guidelines for the management of patients with peripheral arterial
Kidney Foundation Hypertension and Diabetes Executive Committees disease (lower extremity, renal, mesenteric, and abdominal aortic): A
Working Group. Am J Kidney Dis 2000;36(3):646–661. collaborative report from the American Association for Vascular
66. UK Prospective Diabetes Study Group. Efficacy of atenolol and capto- Surgery/Society for Vascular Surgery, Society for Cardiovascular Angi-
pril in reducing risk of macrovascular and microvascular complica- ography and Interventions, Society for Vascular Medicine and Biology,
tions in type 2 diabetes: UKPDS 39. BMJ 1998;317(7160):713–720. Society of Interventional Radiology, and the ACC/AHA Task Force on
67. Pahor M, Psaty BM, Alderman MH, et al. Therapeutic benefits of ACE Practice Guidelines (Writing Committee to Develop Guidelines for the
inhibitors and other antihypertensive drugs in patients with type 2 Management of Patients With Peripheral Arterial Disease): Endorsed
diabetes. Diabetes Care 2000;23(7):888–892. by the American Association of Cardiovascular and Pulmonary Reha-
68. National Kidney Foundation. K/DOQI clinical practice guidelines on bilitation; National Heart, Lung, and Blood Institute; Society for
hypertension and antihypertensive agents in chronic kidney disease. Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascu-
Am J Kidney Dis 2004;43(5 Suppl 1):S1–S290. lar Disease Foundation. Circulation 2006;113(11):e463–e654.
69. Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for 86. Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta-blockers
renoprotection in patients with non-diabetic chronic renal disease (REIN- in patients with reactive airway disease: A meta-analysis. Ann Intern
2): Multicentre, randomised controlled trial. Lancet 2005;365(9463):939– Med 2002;137(9):715–725.
946. 87. Lakshman MR, Reda DJ, Materson BJ, et al. Diuretics and beta-
70. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering blockers do not have adverse effects at 1 year on plasma lipid and
and antihypertensive drug class on progression of hypertensive kidney lipoprotein profiles in men with hypertension. Department of Veter-
disease: Results from the AASK trial. JAMA 2002;288(19):2421–2431. ans Affairs Cooperative Study Group on Antihypertensive Agents.
71. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin– Arch Intern Med 1999;159(6):551–558.
angiotensin system and other antihypertensive drugs on renal outcomes: 88. Eckel RH, Kahn R, Robertson RM, Rizza RA. Preventing cardiovascu-
Systematic review and meta-analysis. Lancet 2005;366(9502):2026–2033. lar disease and diabetes: A call to action from the American Diabetes
72. Nakao N, Yoshimura A, Morita H, et al. Combination treatment of Association and the American Heart Association. Diabetes Care
angiotensin-II receptor blocker and angiotensin-converting-enzyme 2006;29(7):1697–1699.
inhibitor in non-diabetic renal disease (COOPERATE): A randomised 89. Elliot WJ, Meyer PM. Incident diaebetes in clinical trials of antihyper-
controlled trial. Lancet 2003;361(9352):117–124. tensive drugs: A network analysis. Lancet 2007;369:201–207.
73. Dussol B, Moussi-Frances J, Morange S, et al. A randomized trial of 90. Zillich AJ, Garg J, Basu S, et al. Thiazide diuretics, potassium, and the
furosemide vs hydrochlorothiazide in patients with chronic renal failure development of diabetes. Hypertension 2006;48:219–224.
and hypertension. Nephrol Dial Transplant 2005;20(2):349–353. 91. Barksdale JD, Gardner SF. The impact of first-line antihypertensive
74. Schrader J, Luders S, Kulschewski A, et al. Morbidity and mortality drugs on erectile dysfunction. Pharmacotherapy 1999;19(5):573–581.
after stroke, eprosartan compared with nitrendipine for secondary 92. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of
prevention: Principal results of a prospective randomized controlled depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351–357.
study (MOSES). Stroke 2005;36(6):1218–1226. 93. Grimm RH Jr, Grandits GA, Prineas RJ, et al. Long-term effects on
75. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke sexual function of five antihypertensive drugs and nutritional hygienic
in patients with ischemic stroke or transient ischemic attack: A treatment in hypertensive men and women. Treatment of Mild Hyper-
statement for healthcare professionals from the American Heart Asso- tension Study (TOMHS). Hypertension 1997;29(1 Pt 1):8–14.
ciation/American Stroke Association Council on Stroke: Co-spon- 94. Min JK, Williams KA, Okwuosa TM, et al. Prediction of coronary heart
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line. Circulation 2006;113(10):e409–449. 95. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlor-
76. Gueyffier F, Bulpitt C, Boissel JP, et al. Antihypertensive drugs in very thalidone: Evidence supporting their interchangeability. Hypertension
old people: A subgroup meta-analysis of randomised controlled trials. 2004;43(1):4–9.
INDANA Group. Lancet 1999;353(9155):793–796. 96. Psaty BM, Lumley T, Furberg CD. Meta-analysis of health outcomes of
77. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated chlorthalidone-based vs nonchlorthalidone-based low-dose diuretic
isolated systolic hypertension in the elderly: Meta-analysis of outcome therapies. JAMA 2004;292(1):43–44.
trials. Lancet 2000;355(9207):865–872. 97. Grimm RH, Jr., Flack JM, Grandits GA, et al. Long-term effects on
78. Rastas S, Pirttila T, Viramo P, et al. Association between blood plasma lipids of diet and drugs to treat hypertension. Treatment of
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79. Bulpitt CJ, Beckett NS, Cooke J, et al. Results of the pilot study for the 98. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combina-
Hypertension in the Very Elderly Trial. J Hypertens 2003;21(12):2409– tion treatment with blood pressure lowering drugs: Analysis of 354
2417. randomised trials. BMJ 2003;326(7404):1427.
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99. Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema 105. Edelson JT, Weinstein MC, Tosteson AN, et al. Long-term cost-
associated with angiotensin-converting enzyme inhibitor use: Out- effectiveness of various initial monotherapies for mild to moderate

CHAPTER 15
come after switching to a different treatment. Arch Intern Med hypertension. JAMA 1990;263(3):407–413.
2004;164(8):910–913. 106. Hilleman DE, Mohiuddin SM, Lucas BD, Jr, et al. Cost-minimization
100. Phillips CO, Kashani A, Ko DK, et al. Adverse effects of combination analysis of initial antihypertensive therapy in patients with mild-to-
angiotensin II receptor blockers plus angiotensin–converting enzyme moderate essential diastolic hypertension. Clin Ther 1994;16(1):88–
inhibitors for left ventricular dysfunction. Arch Intern Med 2007; 102, discussion 187.
167(18):1930–1936. 107. Pearce KA, Furberg CD, Psaty BM, Kirk J. Cost-minimization and the
101. Leenen FH, Nwachuku CE, Black HR, et al. Clinical events in high-risk number needed to treat in uncomplicated hypertension. Am J Hyper-
hypertensive patients randomly assigned to calcium channel blocker tens 1998;11(5):618–629.
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sive and lipid-lowering treatment to prevent heart attack trial. Hyper- ing on hypertension: Can better care cost less? JAMA 2004;291(15):1850–
tension 2006;48(3):374–384. 1856.
102. Bakris GL, Fonseca V, Katholi RE, et al. Metabolic effects of carvedilol 109. Grossman E, Messerli FH, Grodzicki T, Kowey P. Should a moratorium
vs metoprolol in patients with type 2 diabetes mellitus and hyperten- be placed on sublingual nifedipine capsules given for hypertensive
sion: A randomized controlled trial. JAMA 2004;292(18):2227–2236. emergencies and pseudoemergencies? JAMA 1996;276(16):1328–1331.
103. Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet 2006;368 110. Moser M, Setaro JF. Clinical practice. Resistant or difficult-to-control
(9545):1449–1456. hypertension. N Engl J Med 2006;355(4):385–392.
104. Gradman AH, Vivas Y. New drugs for hypertension: What do they 111. Degli Esposti L, Valpiani G. Pharmacoeconomic burden of undertreat-
offer? Curr Hypertens Rep 2006;8(5):425–432. ing hypertension. Pharmacoeconomics 2004;22(14):907–928.
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 173

C HAP T E R

16 Heart Failure

ROBERT B. PARKER, JO E. RODGERS, AND LARISA H. CAVALLARI

ceptor blocker or the combination of hydralazine and isosorbide

KEY CONCEPTS dinitrate are reasonable alternatives. Patients with asymptomat-
ic left ventricular dysfunction and/or a previous myocardial in-
 Heart failure is a clinical syndrome caused by the inability of the farction (stage B of the American College of Cardiologists/
heart to pump sufficient blood to meet the metabolic needs of American Heart Association [ACC/AHA] classification scheme)
the body. Heart failure can result from any disorder that reduc- should also receive ACE inhibitors, with the goal of preventing
es ventricular filling (diastolic dysfunction) and/or myocardial symptomatic heart failure and reducing mortality.
contractility (systolic dysfunction). The leading causes of heart
failure are coronary artery disease and hypertension. The pri-  The β-blockers carvedilol, metoprolol CR/XL, and bisoprolol
mary manifestations of the syndrome are dyspnea, fatigue, and prolong survival, decrease hospitalizations and the need for
fluid retention. transplantation, and cause “reverse remodeling” of the left ven-
tricle. These agents are recommended for all patients with a re-
 Heart failure is a progressive disorder that begins with myocar- duced left ventricular ejection fraction. Therapy must be
dial injury. In response to the injury, a number of compensatory instituted at low doses, with slow upward titration to the target
responses are activated in an attempt to maintain adequate dose.
cardiac output, including activation of the sympathetic nervous
system (SNS) and the renin–angiotensin–aldosterone system  Although chronic diuretic therapy frequently is used in heart
(RAAS), resulting in vasoconstriction and sodium and water re- failure patients, it is not mandatory. Diuretic therapy along with
tention, as well as ventricular hypertrophy/remodeling. These sodium restriction is required only in those patients with pe-
compensatory mechanisms are responsible for the symptoms ripheral edema and/or pulmonary congestion. Many patients
of heart failure and contribute to disease progression. will need continued diuretic therapy to maintain euvolemia af-
ter fluid overload is resolved.
 Our current understanding of heart failure pathophysiology is
best described by the neurohormonal model. Activation of en- Digoxin does not improve survival in patients with heart failure
dogenous neurohormones, including norepinephrine, angioten- but does provide symptomatic benefits. Digoxin doses should
sin II, aldosterone, vasopressin, and numerous proinflammatory be adjusted to achieve plasma concentrations of 0.5 to 1.0 ng/
cytokines, plays an important role in ventricular remodeling and mL; higher plasma concentrations are not associated with ad-
the subsequent progression of heart failure. Importantly, phar- ditional benefits but may be associated with increased risk of
macotherapy targeted at antagonizing this neurohormonal acti- toxicity.
vation has slowed the progression of heart failure and improved

Aldosterone antagonism with low-dose spironolactone reduces
survival.
mortality in patients with New York Heart Association (NYHA)
 Most patients with symptomatic heart failure should be routinely classes III and IV heart failure and thus should be strongly con-
treated with an angiotensin-converting enzyme (ACE) inhibitor, sidered in these patients, provided that potassium and renal
a β-blocker, and a diuretic. The benefits of these medications on function can be carefully monitored. Aldosterone antagonists
slowing heart failure progression, reducing morbidity and mortal- should also be considered soon after myocardial infarction in pa-
ity, and improving symptoms are clearly established. Patients tients with left ventricular dysfunction and either heart failure or
should be treated with a diuretic if there is evidence of fluid re- diabetes.
tention. Treatment with digoxin may also be considered to im-
 The combination of hydralazine and nitrates improves the
prove symptoms and reduce hospitalizations.
composite end point of mortality, hospitalizations for heart fail-
 In patients with heart failure, ACE inhibitors improve survival, ure, and quality of life in African Americans who receive stan-
slow disease progression, reduce hospitalizations, and improve dard therapy. The addition of hydralazine and nitrates is
quality of life. The doses for these agents should be targeted at reasonable in patients with persistent symptoms despite opti-
those shown in clinical trials to improve survival. When ACE in- mized therapy with an ACE inhibitor (or angiotensin receptor
hibitors are contraindicated or not tolerated, an angiotensin II re- blocker) and β-blocker.
 No therapy for acute decompensated heart failure studied to
date has been shown conclusively to influence mortality. Treat-
Learning objectives, review questions, ment goals are directed toward restoration of systemic oxygen
and other resources can be found at transport and tissue perfusion, relief of pulmonary edema, and
www.pharmacotherapyonline.com. limitation of further cardiac damage. Maximizing oral therapy
and using combinations of short-acting intravenous medica-

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 174
tions with different cardiovascular actions are often needed to in men has not changed over the last 40 years, but has decreased by
optimize cardiac output, relieve pulmonary edema, and limit approximately one-third in women.5 These differences in heart
SECTION 2

myocardial ischemia. Invasive hemodynamic monitoring may failure incidence may be a result of sex-based differences in the
be required to provide immediate feedback on treatment effi- cause of heart failure as myocardial infarction is the leading cause in
cacy and adverse effects. men, whereas hypertension is the leading etiology in women.
Heart failure is the most common hospital discharge diagnosis in
Pharmacists should play an important role as part of a multidis-
individuals older than age 65 years. Annual hospital discharges for
ciplinary team to optimize therapy in heart failure. The pharma-
heart failure now total more than 1 million, a 174% increase over
cist should be responsible for such activities as optimizing
the last two decades.4 Heart failure also has a tremendous economic
regimens for heart failure drug therapy (namely, ensuring that
impact, which is expected to increase markedly as the baby boom
appropriate drugs at appropriate doses are used), educating pa-
Cardiovascular Disorders

generation ages. Current estimates suggest annual expenditures for

tients about the importance of adherence to their heart failure
heart failure of approximately $33 billion, with the majority of these
regimen (including pharmacologic and dietary interventions),
costs spent on hospitalized patients.4 Thus, heart failure is a major
screening for drugs that may exacerbate or worsen heart failure,
medical problem, with substantial economic impact that is expected
and monitoring for adverse drug effects and drug interactions.
to become even more significant as the population ages.
Despite prodigious advances in our understanding of the etiology,
pathophysiology, and pharmacotherapy of heart failure, the progno-
  Heart failure is a progressive clinical syndrome that can result sis for patients with this disorder remains grim. Although the mortal-
from any disorder that impairs the ability of the ventricle to fill with ity rates have declined over the last 50 years, the overall 5-year survival
or eject blood, thus rendering the heart unable to pump blood at a remains approximately 50% for all patients with a diagnosis of heart
rate sufficient to meet the metabolic demands of the body.1 Heart failure, with mortality increasing with symptom severity.5 For heart
failure is the final common pathway for numerous cardiac disorders failure patients younger than age 65 years, 80% of men and 70% of
including those affecting the pericardium, heart valves, and myocar- women will die within 8 years. Death is classified as sudden in
dium. Diseases that adversely affect ventricular diastole (filling), approximately 40% of patients,1,6 implicating serious ventricular
ventricular systole (contraction), or both can lead to heart failure. arrhythmias as the underlying cause in many patients with heart
For many years it was believed that reduced myocardial contractility, failure. Factors affecting the prognosis of patients with heart failure
or systolic dysfunction (i.e., reduced left ventricular ejection fraction include, but are not limited to, age, gender, LVEF, renal function,
[LVEF]), was the sole disturbance in cardiac function responsible for blood pressure, heart failure etiology, and drug or device therapy.
heart failure. However, it is now recognized that large numbers of Recent models incorporating these and other factors enable clinicians
patients with the heart failure syndrome have relatively normal to develop reliable estimates of an individual patient’s prognosis.7
systolic function (i.e., normal LVEF). This is now referred to as heart
failure with preserved LVEF and is believed to be primarily caused by
diastolic dysfunction of the heart.1 Recent estimates suggest 20% to ETIOLOGY
60% of patients with heart failure have preserved LVEF with distur-
bances in relaxation (lusitropic) properties of the heart, or diastolic   Heart failure can result from any disorder that affects the
dysfunction.2 However, regardless of the etiology of heart failure, the ability of the heart to contract (systolic function) and/or relax
underlying pathophysiologic process and principal clinical manifes- (diastolic dysfunction); Table 16–1 lists the common causes of heart
tations (fatigue, dyspnea, and volume overload) are similar and failure.8 Heart failure with impaired systolic function (i.e., reduced
appear to be independent of the initial cause. Historically, this LVEF) is the classic, more familiar form of the disorder, but current
disorder was commonly referred to as congestive heart failure; the estimates suggest up to 50% of patients with heart failure have
preferred nomenclature is now heart failure because a patient can preserved left ventricular systolic function with presumed diastolic
have the clinical syndrome of heart failure without having symptoms dysfunction.2 In contrast to systolic heart failure that is usually
of congestion. This chapter focuses on treatment of patients with caused by previous myocardial infarction (MI), patients with pre-
systolic dysfunction (with or without concurrent diastolic dysfunc- served LVEF typically are elderly, female, obese, and have hyperten-
tion), whereas Chap. 20 focuses on the treatment of heart failure with sion, atrial fibrillation, or diabetes.2 Recent data indicate that survival
preserved LVEF (diastolic dysfunction).
TABLE 16-1 Causes of Heart Failure
EPIDEMIOLOGY Systolic dysfunction (decreased contractility)
• Reduction in muscle mass (e.g., myocardial infarction)
Heart failure is an epidemic public health problem in the United • Dilated cardiomyopathies
States. Approximately 5 million Americans have heart failure with • Ventricular hypertrophy
an additional 550,000 cases diagnosed each year. Unlike most other • Pressure overload (e.g., systemic or pulmonary hypertension, aortic or
cardiovascular diseases, the incidence, prevalence, and hospitaliza- pulmonic valve stenosis)
tion rates associated with heart failure are increasing and are • Volume overload (e.g., valvular regurgitation, shunts, high-output states)
expected to continue to increase over the next few decades as the Diastolic dysfunction (restriction in ventricular filling)
• Increased ventricular stiffness
population ages. A large majority of patients with heart failure are
• Ventricular hypertrophy (e.g., hypertrophic cardiomyopathy, other examples
elderly, with multiple comorbid conditions that influence morbid-
above)
ity and mortality.3,4 The incidence of heart failure doubles with each • Infiltrative myocardial diseases (e.g., amyloidosis, sarcoidosis, endomyocardial
decade of life and affects nearly 10% of individuals older than age 75 fibrosis)
years. Heart failure is more common in men than in women until • Myocardial ischemia and infarction
age 65 years, reflecting the greater incidence of coronary artery • Mitral or tricuspid valve stenosis
disease in men.4 As such, improved survival of patients after • Pericardial disease (e.g., pericarditis, pericardial tamponade)
myocardial infarction is a likely contributor to the increased inci-
Data from Colucci W, Braunwald E. Pathophysiology of heart failure. In: Zipes DP, Libby P, Bonow
dence and prevalence of heart failure.3 Recent results from the RO, Braunwald E, eds. Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed. Philadelphia:
Framingham Heart Study showed that the incidence of heart failure Elsevier Saunders, 2005:509–538.
 175
2
is similar in patients with impaired or preserved LVEF. Frequently, Heart rate is controlled by the autonomic nervous system. Stroke
systolic and diastolic dysfunction coexist. The common cardiovascu- volume, or the volume of blood ejected during systole, depends on

CHAPTER 16
lar diseases, such as MI and hypertension, can cause both systolic and preload, afterload, and contractility.8 As defined by the Frank-
diastolic dysfunction; thus many patients have heart failure as a Starling mechanism, the ability of the heart to alter the force of
result of reduced myocardial contractility and abnormal ventricular contraction depends on changes in preload. As myocardial sarco-
filling. Heart failure with preserved LVEF is discussed in Chap. 20. mere length is stretched, the number of cross-bridges between thick
 Coronary artery disease is the most common cause of systolic and thin myofilaments increases, resulting in an increase in the
heart failure, accounting for nearly 70% of cases.3 Myocardial force of contraction. The length of the sarcomere is determined
infarction leads to reduction in muscle mass as a consequence of primarily by the volume of blood in the ventricle; therefore, left
death of affected myocardial cells. The degree to which contractility ventricular end-diastolic volume is the primary determinant of

Heart Failure
is impaired will depend on the size of the infarction. In an attempt preload. In normal hearts, the preload response is the primary
to maintain cardiac output, the surviving myocardium undergoes a compensatory mechanism such that a small increase in end-diastolic
compensatory remodeling, thus beginning the maladaptive process volume results in a large increase in cardiac output. Because of the
that initiates the heart failure syndrome and leads to further injury relationship between pressure and volume in the heart, left ventric-
to the heart. This is discussed in greater detail in Pathophysiology ular end-diastolic pressure is often used in the clinical setting to
below. Myocardial ischemia and infarction also affect the diastolic estimate preload. The hemodynamic measurement used to estimate
properties of the heart by increasing ventricular stiffness and slow- left ventricular end-diastolic pressure is the pulmonary artery occlu-
ing ventricular relaxation. Thus, myocardial infarction frequently sion pressure (PAOP). Afterload is a more complex physiologic
results in systolic and diastolic dysfunction. concept that can be viewed pragmatically as the sum of forces
Impaired systolic function is a cardinal feature of dilated cardio- preventing active forward ejection of blood by the ventricle. Major
myopathies. Although the cause of reduced contractility frequently components of global ventricular afterload are ejection impedance,
is unknown, abnormalities such as interstitial fibrosis, cellular wall tension, and regional wall geometry. In patients with left
infiltrates, cellular hypertrophy, and myocardial cell degeneration ventricular systolic dysfunction, an inverse relationship exists
are seen commonly on histologic examination. Genetic causes of between afterload (or SVR) and stroke volume such that increasing
dilated cardiomyopathies may also occur.9 afterload causes a decrease in stroke volume (Fig. 16–1). Contractil-
Pressure or volume overload causes ventricular hypertrophy, ity is the intrinsic property of cardiac muscle describing fiber
which attempts to return contractility to a near-normal state. If the shortening and tension development.
pressure or volume overload persists, the remodeling process results
in alterations in the geometry of the hypertrophied myocardial cells COMPENSATORY MECHANISMS IN
and is accompanied by increased collagen deposition in the extra- HEART FAILURE
cellular matrix. Thus, both systolic and diastolic function may be
impaired.8 Examples of pressure overload include systemic or pul-  Heart failure is a progressive disorder initiated by an event that
monary hypertension and aortic or pulmonic valve stenosis. impairs the ability of the heart to contract and/or relax. The index
Hypertension remains an important cause and/or contributor to event may have an acute onset, as with myocardial infarction, or the
heart failure in many patients, particularly women, the elderly, and onset may be slow, as with long-standing hypertension. Regardless of
African Americans.1 The role of hypertension should not be under- the index event, the decrease in the heart’s pumping capacity results
estimated because hypertension is an important risk factor for in the heart having to rely on compensatory responses to maintain
ischemic heart disease and thus is also present in a high percentage an adequate cardiac output.10 These compensatory responses include
of the patients with this disorder. Volume overload may occur in the (a) tachycardia and increased contractility through sympathetic
presence of valvular regurgitation, shunts, or high-output states nervous system (SNS) activation, (b) the Frank-Starling mechanism,
such as anemia or pregnancy. Table 16–1 lists less-common causes whereby an increase in preload results in an increase in stroke
of diastolic dysfunction, which include infiltrative myocardial dis- volume, (c) vasoconstriction, and (d) ventricular hypertrophy and
eases, mitral or tricuspid valve stenosis, and pericardial disease. remodeling. These compensatory responses are intended to be short-
Because ischemic heart disease and/or hypertension contribute so term responses to maintain circulatory homeostasis after acute
significantly to the development of heart failure in the majority of reductions in blood pressure or renal perfusion. However, the
patients, it is important to emphasize that heart failure is a largely
preventable disorder. Thus, control of blood pressure and appropri-
ate management of other risk factors for cardiovascular disease (e.g.,
smoking cessation, treatment of lipid disorders, diabetes manage-
ment, dietary modification) are important strategies for clinicians
to implement to reduce their patients’ risk of heart failure.

PATHOPHYSIOLOGY
NORMAL CARDIAC FUNCTION
To understand the pathophysiologic processes in heart failure, a basic
understanding of normal cardiac function is necessary. Cardiac out-
put (CO) is defined as the volume of blood ejected per unit time (L/
min) and is the product of heart rate (HR) and stroke volume (SV): FIGURE 16-1. Relationship between stroke volume and systemic vascu-
lar resistance. In an individual with normal left ventricular (LV) function,
CO = HR × SV increasing systemic vascular resistance has little effect on stroke volume.
As the extent of LV dysfunction increases, the negative, inverse relation-
The relationship between CO and mean arterial pressure (MAP) is:
ship between stroke volume and systemic vascular resistance becomes
MAP = CO × systemic vascular resistance (SVR) more important (B to A).
 176

TABLE 16-2 Beneficial and Detrimental Effects of the Compensatory Responses in Heart Failure
SECTION 2

Compensatory Response Beneficial Effects of Compensation Detrimental Effects of Compensation

+
Increased preload (through Na and water retention) Optimize stroke volume via Frank-Starling mechanism Pulmonary and systemic congestion and edema formation
Increased MVO2
Vasoconstriction Maintain BP in face of reduced CO Increased MVO2
Shunt blood from nonessential organs to brain and heart Increased afterload decreases stroke volume and further
activates the compensatory responses
Tachycardia and increased contractility (because of SNS Helps maintain CO Increased MVO2
activation) Shortened diastolic filling time
β1-receptor downregulation, decreased receptor sensitivity
Cardiovascular Disorders

Precipitation of ventricular arrhythmias

Increased risk of myocardial cell death
Ventricular hypertrophy and remodeling Helps maintain CO Diastolic dysfunction
Reduces myocardial wall stress Systolic dysfunction
Decreases MVO2 Increased risk of myocardial cell death
Increased risk of myocardial ischemia
Increased arrhythmia risk
Fibrosis
BP, blood pressure; CO, cardiac output; MVO2, myocardial oxygen demand; SNS, sympathetic nervous system.

persistent decline in cardiac output in heart failure results in long- glomerular cells in the kidney. As shown in Fig. 16–2, renin is
term activation of these compensatory responses resulting in the responsible for conversion of angiotensinogen to angiotensin I.
complex functional, structural, biochemical, and molecular changes Angiotensin I is converted to angiotensin II by angiotensin-convert-
important for the development and progression of heart failure. The ing enzyme (ACE). Angiotensin II may also be generated via non–
beneficial and detrimental effects of these compensatory responses ACE-dependent pathways. Angiotensin II feeds back on the adrenal
are described below and are summarized in Table 16–2. gland to stimulate aldosterone release, thereby providing an addi-
tional mechanism for sodium and water retention in the kidney. As
Tachycardia and Increased Contractility intravascular volume increases secondary to sodium and water reten-
tion, left ventricular volume and pressure (preload) increase, sarco-
The change in heart rate and contractility that rapidly occurs in
meres are stretched, and the force of contraction is enhanced.8 While
response to a drop in cardiac output is primarily a result of release of
the preload response is the primary compensatory mechanism in
norepinephrine (NE) from adrenergic nerve terminals, although
normal hearts, the chronically failing heart usually has exhausted its
parasympathetic nervous system activity is also diminished. Cardiac
preload reserve.8 As shown in Fig. 16–3, increases in preload will
output increases with heart rate until diastolic filling becomes com-
increase stroke volume only to a certain point. Once the flat portion
promised, which in the normal heart is at 170 to 200 beats per
of the curve is reached, further increases in preload will only lead to
minute. Loss of atrial contribution to ventricular filling also can
pulmonary or systemic congestion, a detrimental result.8 Figure 16–3
occur (atrial fibrillation, ventricular tachycardia), reducing ventricu-
also shows that the curve is flatter in patients with left ventricular
lar performance even more. Because ionized calcium is sequestered
dysfunction. Consequently, a given increase in preload in a patient
into the sarcoplasmic reticulum and pumped out of the cardiac
with heart failure will produce a smaller increment in stroke volume
myocyte during diastole, shortened diastolic time also results in a
than in an individual with normal ventricular function.
higher average intracellular calcium concentration during diastole,
increasing actin–myosin interaction, augmenting the active resis-
tance to fibril stretch, and reducing lusitropy. Conversely, the higher
Vasoconstriction and Increased Afterload
average calcium concentration translates into greater filament inter- Vasoconstriction occurs in patients with heart failure to help redis-
action during systole, generating more tension.8 In addition, poly- tribute blood flow away from nonessential organs to coronary and
morphisms in genes coding for adrenergic receptors (e.g., β1 and α2c cerebral circulations to support blood pressure, which may be
receptors) appear to alter the response to endogenous NE and reduced secondary to a decrease in cardiac output (mean arterial
increase the risk for the development of heart failure.11 pressure = CO × SVR).8 A number of neurohormones likely contrib-
Increasing heart rate greatly increases myocardial oxygen ute to the vasoconstriction, including NE, angiotensin II, endo-
demand. If ischemia is induced or worsened, both diastolic and thelin-1, and arginine vasopressin (AVP).8 Vasoconstriction impedes
systolic function may become impaired, and stroke volume can forward ejection of blood from the ventricle, further depressing
drop precipitously. cardiac output and heightening the compensatory responses.
Because the failing ventricle usually has exhausted its preload reserve
Fluid Retention and Increased Preload (unless the patient is intravascularly depleted), its performance is
exquisitely sensitive to changes in afterload (see Fig. 16–1). Thus,
Augmentation of preload is another compensatory response that is
increases in afterload often potentiate a vicious cycle of continued
rapidly activated in response to decreased cardiac output. Renal
worsening and downward spiraling of the heart failure state.
perfusion in heart failure is reduced because of depressed cardiac
output and redistribution of blood away from nonvital organs. The
kidney interprets the reduced perfusion as an ineffective blood vol-
Ventricular Hypertrophy and Remodeling 8,10
ume, resulting in activation of the renin–angiotensin–aldosterone  Although the signs and symptoms of heart failure are closely
system (RAAS) in an attempt to maintain blood pressure and increase associated with the items described above, the progression of heart
renal sodium and water retention. Reduced renal perfusion and failure appears to be independent of the patient’s hemodynamic
increased sympathetic tone also stimulate renin release from juxta- status. It is now recognized that ventricular hypertrophy and
 177

CHAPTER 16
Angiotensinogen

Renin from the kidney

Angiotensin I Bradykinin

ACE (kininase II)

FIGURE 16-2. Physiology of the renin–angiotensin–
Chymase and
aldosterone system. Renin produces angiotensin I
other non–ACE- Angiotensin II
from angiotensinogen. Angiotensin I is cleaved to

Heart Failure
dependent pathways
Vasodilatory angiotensin II by angiotensin-converting enzyme
Inactive
prostaglandins
kinins
Histamine (ACE). Angiotensin II has a number of physiologic
actions that are detrimental in heart failure. Note
that angiotensin II can be produced in a number
of tissues, including the heart, independent of
Vasoconstriction ↑ Aldosterone
ACE activity. ACE is also responsible for the
↑ NE
↑ Sympathetic breakdown of bradykinin. Inhibition of ACE results
activity in accumulation of bradykinin that, in turn,
Fibrosis ↑ Na/H2O retention
Fibrosis
enhances the production of vasodilatory prosta-
glandins. (NE, norepinephrine.)

remodeling are key components in the pathogenesis of progressive lar remodeling. Although these mediators produce deleterious
myocardial failure. Ventricular hypertrophy is a term used to effects on the heart, their increased circulating and tissue concentra-
describe an increase in ventricular muscle mass. Cardiac or ventric- tions also serve as an important reminder that heart failure is a
ular remodeling is a broader term describing changes in both systemic, as well as cardiac, disorder.
myocardial cells and extracellular matrix that result in changes in Pressure overload (and probably hormonal activation) associated
the size, shape, structure, and function of the heart. Ventricular with hypertension produces a concentric hypertrophy (increase in
hypertrophy and remodeling can occur in association with any the ventricular wall thickness without chamber enlargement). Con-
condition that causes myocardial injury including MI, cardiomyop- versely, eccentric left ventricular hypertrophy (myocyte lengthening
athy, hypertension, and valvular heart disease. with increased chamber size with minimal increase in wall thick-
Cardiac remodeling is a complex process that affects the heart at ness) characterizes the hypertrophy seen in patients with systolic
the molecular and cellular levels. Figure 16–4 shows key elements in dysfunction or previous MI. As the myocytes undergo change, so do
the process. Collectively, these events result in progressive changes various components of the extracellular matrix. For example, there
in myocardial structure and function such as cardiac hypertrophy, is evidence for collagen degradation, which may lead to slippage of
myocyte loss, and alterations in the extracellular matrix. The pro- myocytes, fibroblast proliferation, and increased fibrillar collagen
gression of the remodeling process leads to reductions in myocar- synthesis, resulting in fibrosis and stiffening of the entire myocar-
dial systolic and/or diastolic function that, in turn, result in further dium. Thus, a number of important ventricular changes that occur
myocardial injury, perpetuating the remodeling process and the with remodeling include changes in the geometry of the heart from
decline in ventricular dysfunction. Angiotensin II, NE, endothelin, elliptical to spherical, increases in ventricular mass (from myocyte
aldosterone, vasopressin and numerous inflammatory cytokines, as hypertrophy), and changes in ventricular composition (especially
well as substances under investigation, that are activated both the extracellular matrix) and volumes, all of which likely contribute
systemically and locally in the heart play an important role in to the impairment of cardiac function. If the event that produces
initiating the signal–transduction cascade responsible for ventricu- cardiac injury is acute (e.g., MI), the ventricular remodeling process
begins immediately. However, it is the progressive nature of this
Normal
process that results in continual worsening of the heart failure state,
4.0 and thus is now the major focus for identification of therapeutic
Mild to moderate targets. In fact, it is believed that all the heart failure therapies that
Cardiac index (L/min/m2)

left ventricular are associated with decreased mortality and/or slowing the progres-
3.0 dysfunction sion of the disease produce this effect largely through their ability to
slow or reverse the ventricular remodeling process, a process often
referred to as reverse remodeling. Thus, although ventricular hyper-
trophy and remodeling may have some beneficial effects by helping
2.0
maintain cardiac output, they also are believed to play an essential
Hypoperfusion

role in the progressive nature of heart failure.

1.5 Severe left

ventricular
THE NEUROHORMONAL MODEL OF
dysfunction HEART FAILURE AND THERAPEUTIC
Congestion INSIGHTS IT PROVIDES8,10
5 10 15 20 25
  Over the years, several different paradigms have guided our
Pulmonary artery occlusion pressure (mm Hg) understanding of the pathophysiology and treatment of heart failure.
FIGURE 16-3. Relationship between cardiac output (shown as cardiac The early paradigm is often called the cardiorenal model, where the
index which is cardiac output [CO]/body surface area [BSA]) and preload problem was viewed as excess sodium and water retention, and
(shown as pulmonary artery occlusion pressure). diuretic therapy was the main therapeutic approach. The next para-
 178

Myocardial injury
SECTION 2

Chronic activation of hemodynamic and neurohormonal

compensatory responses
Cardiovascular Disorders

Alterations in
Cardiac extracellular matrix Myocyte loss from Abnormal myocardial LV dilation
hypertrophy including interstitial necrosis and apoptosis energetics and sphericity
fibrosis

Ventricular remodeling

Progressive systolic and

diastolic dysfunction

FIGURE 16-4. Key components of the pathophysiology of cardiac remodeling. Myocardial injury (e.g., myocardial
infarction) results in the activation of a number of hemodynamic and neurohormonal compensatory responses in an
attempt to maintain circulatory homeostasis. Chronic activation of the neurohormonal systems results in a cascade of
events that affect the myocardium at the molecular and cellular levels. These events lead to the changes in ventricular
size, shape, structure, and function known as ventricular remodeling. The alterations in ventricular function result in further
deterioration in cardiac systolic and diastolic function which further promotes the remodeling process. (LV, left ventricle.)

digm was the cardiocirculatory model, which focused on impaired medications in attenuating this progression, it must be emphasized
cardiac output (viewed as being a result of both reduced pumping that this model does not completely explain heart failure progression.
capacity of the heart and systemic vasoconstriction). This paradigm For example, drug therapies that target the neurohormonal perturba-
focused on positive inotropes and, later, vasodilators as the primary tions in heart failure usually only slow the progressive nature of the
therapies to overcome reductions in cardiac output. Although the disorder rather than completely stop it. Ongoing research will likely
therapeutic approaches associated with these paradigms provided identify additional targets for drug therapy.
some symptomatic benefits to patients with heart failure, they did
little to slow progression of the disease. In fact, the detrimental effects
of positive inotropic drugs on survival highlighted the inadequacy of
Angiotensin II10
the cardiocirculatory model to explain the progressive nature of heart Of the neurohormones and autocrine/paracrine factors that play an
failure. The first studies with ACE inhibitors were initiated with the important role in the pathophysiology of heart failure, angiotensin
thought that they might be effective because of their balanced II is probably the best understood. Although circulating angiotensin
(arterial and venous) vasodilation. Subsequent realization that ACE II produced from ACE activity is the most familiar route for
inhibitors were providing benefit beyond their vasodilating effects, generation of angiotensin II, recent evidence indicates that this
followed by the positive results with β-adrenergic receptor blockers hormone is synthesized directly in the myocardium through non–
and aldosterone antagonists, has led to the current paradigm used to ACE-dependent pathways. This tissue production of angiotensin II
describe heart failure: the neurohormonal model. This model recog- also plays an important role in heart failure pathophysiology.
nizes that there is an initiating event (e.g., MI, long-standing hyper- Angiotensin II has multiple actions that contribute to its detrimen-
tension) that leads to decreased cardiac output and begins the “heart tal effects in heart failure. Angiotensin II increases systemic vascular
failure state,” but then the problem moves beyond the heart, and it resistance directly by promoting potent vasoconstriction and indi-
essentially becomes a systemic disease whose progression is mediated rectly by causing release of AVP and endothelin-1. Angiotensin II
largely by neurohormones and autocrine/paracrine factors. Although also facilitates release of NE from adrenergic nerve terminals,
the former paradigms still guide us to some extent in the sympto- heightening SNS activation. It promotes sodium retention through
matic management of the disease (e.g., diuretics and digoxin), it is the direct effects on the renal tubules and by stimulating aldosterone
latter paradigm that helps us understand disease progression and, release. Its vasoconstriction of the efferent glomerular arteriole
more importantly, the ways to slow disease progression. In the helps to maintain perfusion pressure in patients with severe heart
sections that follow, important neurohormones and autocrine/para- failure or impaired renal function. Thus, in patients dependent on
crine factors are described with respect to their role in heart failure angiotensin II for maintenance of perfusion pressure, initiation of
and its progression. The benefits of current and investigational drug an ACE inhibitor or angiotensin receptor type I blocker (ARB)
therapies can be better understood through a solid understanding of causes efferent arteriole vasodilation, decreased perfusion pressure,
the neurohormones they regulate/affect. Although the neurohor- and decreased glomerular filtration. This explains the risk of tran-
monal model provides a logical framework for our current under- sient impairment in renal function associated with initiation of ACE
standing of heart failure progression and the role of various inhibitor or ARB therapy. Finally, angiotensin II, and many of the
 179
neurohormones released in response to angiotensin II, play a central evidence that the direct cardiac effects of aldosterone play an impor-
role in stimulating ventricular hypertrophy, remodeling, myocyte tant role in heart failure pathophysiology.

CHAPTER 16
apoptosis (programmed cell death), oxidative stress, inflammation,
and alterations in the extracellular matrix. Clinical data suggest that Natriuretic Peptides18
blocking angiotensin II-mediated effects contributes substantially to
The natriuretic peptide family has three members, atrial natriuretic
the prolonged survival of ACE inhibitor- and ARB-treated heart
peptide, B-type natriuretic peptide (BNP), and C-type natriuretic
failure patients.12,13 The favorable effects of ACE inhibitors and
peptide. Atrial natriuretic peptide is stored mainly in the right
ARBs on hemodynamics, symptoms, quality of life, and survival in
atrium, whereas BNP is found primarily in the ventricles. Both are
heart failure highlight the importance of angiotensin II in the
released in response to pressure or volume overload. C-type natri-
pathophysiology of heart failure.
uretic peptide is found mainly in the brain and has very low plasma

Heart Failure
concentrations. Atrial natriuretic peptide and BNP plasma concen-
Norepinephrine8,10 trations are elevated in patients with heart failure and are thought to
Many of the detrimental effects of NE in heart failure are described balance the effects of the renin–angiotensin system by causing
above. It plays a central role in the tachycardia, vasoconstriction, natriuresis, diuresis, vasodilation, decreased aldosterone release,
and increased contractility observed in heart failure. Plasma NE decreased hypertrophy, and inhibition of the SNS and RAAS.
concentrations are elevated in correlation with the degree of heart The development of easily performed commercial assays for BNP
failure, and patients with the highest plasma NE concentrations and the related biologically inactive peptide, N-terminal prohormone
have the poorest prognosis. In addition to the detrimental effects BNP, resulted in significant attention to the role of these peptides as a
described, excessive SNS activation causes downregulation of β1- biomarker for prognostic, diagnostic, and therapeutic use. In patients
receptors, with a subsequent loss of sensitivity to receptor stimula- with chronic heart failure, the degree of elevation in BNP levels is
tion. Evidence suggests that genetic variations in the β1- and α2c- closely associated with increased mortality, risk of sudden death, symp-
receptors, which are targets for NE’s actions, may modify the extent toms, and hospital readmission. Current data indicate BNP is more
of receptor downregulation and increase the risk of heart failure.11 sensitive than NE for predicting morbidity and mortality in heart
Excess catecholamines increase the risk of arrhythmias and can failure patients. Accurate diagnosis of acute decompensated heart
cause myocardial cell loss by stimulating both necrosis and apopto- failure in acute care settings is often difficult because many of the
sis. Finally, NE contributes to ventricular hypertrophy and remod- symptoms (e.g., dyspnea) mimic those of other disorders, such as
eling. The detrimental effects of SNS activation are further pulmonary disease or obesity. The best-established clinical application
highlighted by the clinical trials of chronic therapy with β-agonists, of BNP testing is in the urgent care setting where the BNP assay is useful
phosphodiesterase inhibitors, and other drugs that cause SNS acti- when combined with clinical evaluation for discriminating dyspnea
vation, as they have been shown uniformly to increase mortality in secondary to heart failure from other causes. The BNP assay may also
heart failure. Conversely, β-blockers, ACE inhibitors, and digoxin be useful in the diagnosis of heart failure in the outpatient setting and
all help to decrease SNS activation through various mechanisms, used as a marker to guide titration of heart failure drug therapy.
and are beneficial in heart failure. Thus, it is clear that NE plays a However, the usefulness of the assay in these situations remains uncer-
critical role in the pathophysiology of the heart failure state. tain and the results of ongoing studies may help clarify the role of BNP
testing in these patients. Finally, administration of recombinant human
Aldosterone14,15 BNP (nesiritide) for short-term management of acute heart failure
resulted in hemodynamic and symptomatic improvement, further
Aldosterone-mediated sodium retention and its key role in volume
supporting the role of BNP in heart failure pathophysiology.
overload and edema has long been recognized as an important
component of the heart failure syndrome. Circulating aldosterone is
increased in heart failure as a consequence of stimulation of its
Arginine Vasopressin19
synthesis and release from the adrenal cortex by angiotensin II and AVP is a pituitary peptide hormone that plays an important role in
because of decreased hepatic clearance secondary to reduced hepatic regulation of renal water and solute excretion. AVP secretion is
perfusion. Although its enhancement of sodium retention is an directly linked to changes in plasma osmolality, thus attempting to
important component of heart failure symptoms, recent studies maintain body fluid homeostasis. The physiologic effects of AVP are
indicate direct effects of aldosterone on the heart that may be even mediated through the V1a and V2 receptors. V1a receptors are located
more important in heart failure pathophysiology. Chief among these in vascular smooth muscle and in myocytes where AVP stimulation
is the ability of aldosterone to produce interstitial cardiac fibrosis results in vasoconstriction and increased cardiac contractility,
through increased collagen deposition in the extracellular matrix of respectively. V2 receptors are located in the collecting duct of the
the heart. This cardiac fibrosis may decrease systolic function, and kidney where AVP stimulation causes reabsorption of free water.
also impair diastolic function by increasing the stiffness of the Plasma concentrations of AVP are elevated in patients with heart
myocardium. Current research shows that extraadrenal production failure supporting current research that indicates AVP plays a role
of aldosterone in the heart, kidneys, and vascular smooth muscle also in the pathophysiology of heart failure. Important effects associated
contributes to the progressive nature of heart failure through target with increased circulating AVP concentrations include (a) increased
organ fibrosis and vascular remodeling. Induction of a systemic renal free water reabsorption in the face of plasma hypoosmolality
proinflammatory state and increased oxidative stress are other resulting in volume overload and hyponatremia; (b) increased
important direct detrimental actions of aldosterone. Aldosterone arterial vasoconstriction which contributes to reduced cardiac out-
also may increase the risk of ventricular arrhythmias through a put; and (c) stimulation of remodeling by cardiac hypertrophy and
number of mechanisms, including creation of reentrant circuits as a extracellular matrix collagen deposition.
result of fibrosis, inhibition of cardiac NE reuptake, depletion of Given the importance of AVP in heart failure, recent efforts have
intracellular potassium and magnesium, and impairment of para- focused on the development of AVP antagonist drugs for treatment
sympathetic traffic. Recent studies demonstrate that the aldosterone of acute and chronic heart failure. By blocking the AVP receptor,
antagonists spironolactone16 and eplerenone17 produce significant these agents primarily increase free water excretion (i.e., an
reductions in mortality in patients with heart failure, without appre- “aquaretic” effect). The oral V2 receptor antagonist tolvaptan
ciable effects on diuresis or hemodynamics, providing substantial increased serum sodium and urine output without affecting heart
 180
rate, blood pressure, renal function, or other electrolytes in patients TABLE 16-3 Drugs That May Precipitate or Exacerbate
hospitalized for hyponatremia from various causes (hyponatremia Heart Failure
SECTION 2

due to heart failure in approximately 33% of patients).20 In another

Negative inotropic effect
clinical trial, the addition of oral tolvaptan to diuretic therapy in
Antiarrhythmics (e.g., disopyramide, flecainide, propafenone, and others)
patients hospitalized for worsening heart failure had no effect on
β-Blockers (e.g., propranolol, metoprolol, atenolol, and others)
mortality or the composite end point of cardiovascular death or Calcium channel blockers (e.g., verapamil, diltiazem)
hospitalization for heart failure.21 However, tolvaptan did produce Itraconazole
short-term reductions in body weight, edema, and patient-assessed Terbinafine
dyspnea without causing any serious adverse events.22 These results Cardiotoxic
suggest that AVP antagonists may be useful in the treatment of heart Doxorubicin
Cardiovascular Disorders

failure patients with volume overload. Unlike diuretics, they appear Daunomycin
to reduce excess fluid volume without affecting hemodynamics, Cyclophosphamide
renal function, or electrolytes. Thus, these agents may offer a new Trastuzumab
therapeutic approach to currently available drug therapies. Imatinib
Ethanol
Amphetamines (e.g., cocaine, methamphetamine)
Other Circulating Mediators23 Sodium and water retention
In addition to neurohormones, several proinflammatory cytokines Nonsteroidal antiinflammatory drugs
are under extensive investigation for their role in heart failure Cyclooxygenase-2 inhibitors
pathophysiology. Tumor necrosis factor-α (TNF-α), interleukin Rosiglitazone and pioglitazone
Glucocorticoids
(IL)-6 -6), and IL-1β have all been shown to be elevated in heart
Androgens and estrogens
failure, with a direct relationship between the degree of elevation
Salicylates (high dose)
and the severity of heart failure. Of these cytokines, TNF-α is best Sodium-containing drugs (e.g., carbenicillin disodium, ticarcillin disodium)
studied for its pathophysiologic role in heart failure. TNF-α pro-
duces multiple deleterious actions including negative inotropic
effects, uncoupling α-adrenergic receptors from adenylyl cyclase are a common and growing problem in patients with heart failure.
(thus reducing β-receptor-mediated responses), increasing myocar- Hospitalization for heart failure exacerbation consumes large
dial cell apoptosis, and stimulating remodeling via several mecha- amounts of healthcare dollars and significantly impairs the patient’s
nisms. Although these findings clearly implicate a role for TNF-α in quality of life, thus there is great interest in identifying, and then
the pathophysiology of heart failure, clinical trials evaluating anti– remedying, factors that increase the risk of decompensation. In
TNF-α therapies (e.g., etanercept and infliximab) have been disap- patients with heart failure, appropriate therapy can often maintain
pointing, with no improvement in outcomes demonstrated. them in a “compensated” state, indicating that they are relatively
The endothelin peptides are potent vasoconstrictors that may be symptom-free. However, there are many aggravating or precipitating
involved in heart failure pathophysiology through a number of factors that may cause a previously compensated patient to develop
mechanisms. Endothelin-1, the best characterized of these peptides, is worsened symptoms necessitating hospitalization. Factors that may
synthesized by endothelial and vascular smooth muscle cells with the precipitate or exacerbate heart failure typically do so by one or more
release of endothelin-1 enhanced by NE, angiotensin II, and inflam- of the following mechanisms: (a) negative inotropic effects; (b) direct
matory cytokines. Like other peptides and hormones described ear- cardiotoxicity; or (c) increased sodium and/or water retention
lier, endothelin-1 plasma concentrations are elevated in heart failure (Table 16–3). The resulting symptoms are typically those associated
and are correlated directly with the severity of hemodynamic abnor- with volume overload, but in more severe cases hypoperfusion may
mality, symptoms, and mortality. Its arterial and venous constrictive also be present.
effects increase preload and afterload, and its vasoconstriction of both Noncompliance with prescribed heart failure medications or with
efferent and afferent renal arterioles may decrease renal plasma flow dietary recommendations (e.g., sodium intake and fluid restriction)
and induce sodium retention. Endothelin-1 has direct cardiotoxic are common causes of heart failure exacerbation.25 For example,
and arrhythmogenic effects and is a potent stimulator of cardiac 43% of patients admitted with an acute decompensation of chronic
myocyte hypertrophy. The putative role of endothelin in heart failure heart failure were assessed as having dietary sodium excess, 34% had
led to the development of a number of endothelin-receptor antago- excess fluid intake (defined as >2.5 L/day), and approximately 24%
nists. Although these agents improved hemodynamics, no benefit on had drug noncompliance that may have contributed to their
morbidity or mortality has been demonstrated and further clinical decompensation (although not necessarily defined as the primary
development is unlikely. cause of decompensation).
The role of inflammation and endothelial dysfunction has gener- Cardiac events may also precipitate heart failure exacerbations.
ated significant interest in the use of statins in patients with heart Myocardial ischemia and infarction are potentially reversible causes
failure. In addition to lowering cholesterol and reducing the risk of that must be carefully considered because nearly 70% of heart
death and other atherosclerotic vascular diseases, the proposed pleio- failure patients have coronary artery disease. It should be noted that
tropic effects (e.g., antiinflammatory, improved endothelial function, myocardial ischemia can either be a cause or consequence of heart
promotion of angiogenesis) may be beneficial in heart failure.24 failure decompensation. Revascularization should be considered in
Although some observational studies and short-term prospective appropriate patients. Atrial fibrillation occurs in up to 30% of
clinical trials indicate beneficial effects, others have failed to demon- patients with heart failure, and is associated with increased morbid-
strate significant improvement with statin therapy. Ongoing trials to ity and mortality.26,27 Atrial fibrillation can exacerbate heart failure
assess effects on mortality will help clarify the role of statin therapy. through rapid ventricular response and loss of atrial contribution to
ventricular filling. Conversely, heart failure can precipitate atrial
FACTORS PRECIPITATING/EXACERBATING fibrillation by worsening atrial distension resulting from ventricular
HEART FAILURE volume overload. Control of ventricular response, maintenance of
sinus rhythm in appropriate patients, and prevention of throm-
Although significant advancements have been made in treatment, boembolism are important elements in the treatment of heart
symptom exacerbations, to the point that hospitalization is required, failure patients with atrial fibrillation.
 181
A number of noncardiac events may also be associated with heart tion) or right ventricular failure (systemic congestion). Although
failure decompensation. Pulmonary infections frequently cause wors- most patients initially have left ventricular failure, the ventricles

CHAPTER 16
ening of heart failure. Many of these events would be preventable with share a septal wall, and because left ventricular failure increases the
more widespread use of the pneumococcal and influenza vaccines. workload of the right ventricle, both ventricles eventually fail and
Recent studies suggest that anemia occurs frequently in patients with contribute to the heart failure syndrome. Because of the complex
heart failure and that it is an independent predictor of death and nature of this syndrome, it has become exceedingly more difficult to
hospitalization for heart failure, regardless of left ventricular systolic attribute a specific sign or symptom as caused by either right or left
function.28 The exact cause of anemia in heart failure patients is ventricular failure. Therefore, the numerous signs and symptoms
uncertain but likely involves reduced response to erythropoietin, the associated with this disorder are collectively attributed to heart
presence of inhibitors to hematopoiesis, and/or impaired iron supply. failure, rather than due to dysfunction of a specific ventricle.

Heart Failure
Correction of anemia with erythropoietin analogs is associated with
improved symptoms and exercise capacity but some have expressed CLINICAL PRESENTATION OF HEART FAILURE
concern that raising hemoglobin concentrations may increase the risk
General
of thromboembolism or other cardiovascular events. Therefore, the
results of ongoing clinical trials evaluating survival are needed to ■ Patient presentation may range from asymptomatic to cardio-
determine the role of this therapy in heart failure. genic shock
What should be evident is that many of the precipitating Symptoms
factors are preventable, particularly through appropriate pharma- ■ Dyspnea, particularly on exertion
cist intervention. Specifically, patient education and counseling by a
■ Orthopnea
pharmacist should help to decrease the most common reason for
heart failure exacerbation: noncompliance with dietary sodium and ■ Paroxysmal nocturnal dyspnea
water restrictions, drug therapy, or both. Pharmacists also should be ■ Exercise intolerance
able to identify and address inadequate heart failure therapy, poorly
■ Tachypnea
controlled hypertension, and administration of drugs that may
worsen heart failure (see Table 16–3). Use of medications such as ■ Cough
antiarrhythmic agents and selected calcium channel blockers are ■ Fatigue
important precipitants of exacerbations. It should be noted that the ■ Nocturia
cyclooxygenase-2 (COX-2) inhibitor celecoxib and nonsteroidal
■ Hemoptysis
antiinflammatory drugs (NSAIDs) have similar effects on renal
function.29 Thus, both NSAIDs and COX-2 inhibitors should be ■ Abdominal pain
used judiciously in heart failure patients. The thiazolidinedione ■ Anorexia
hypoglycemic drugs, rosiglitazone and pioglitazone, are associated ■ Nausea
with the development of weight gain and edema that may exacer-
■ Bloating
bate heart failure. Current guidelines indicate these agents should
not be used in patients with New York Heart Association (NYHA) ■ Poor appetite, early satiety
class III or IV heart failure and recent evidence suggests rosiglita- ■ Ascites
zone may increase the risk of myocardial infarction.1,30,31 It can be
■ Mental status changes
argued that heart failure exacerbations caused by noncompliance,
inadequate/inappropriate drug therapy, and poorly controlled Signs
hypertension are all preventable and amenable to pharmacist inter- ■ Pulmonary rales
vention. Thus the value of the pharmacist’s role in careful and ■ Pulmonary edema
repeated education of patients and in monitoring of the drug
■ S3 gallop
regimen should not be underestimated. Attention to these factors
may make an important contribution to reducing the risk of ■ Cool extremities
hospitalization and improving the patient’s quality of life. ■ Pleural effusion
■ Cheyne-Stokes respiration
32 ■ Tachycardia
CLINICAL PRESENTATION
■ Narrow pulse pressure
SIGNS AND SYMPTOMS ■ Cardiomegaly
 The primary manifestations of heart failure are dyspnea and ■ Peripheral edema
fatigue, which lead to exercise intolerance, and fluid overload, that ■ Jugular venous distension
can result in pulmonary congestion and peripheral edema. The ■ Hepatojugular reflux
presence of these signs and symptoms may vary considerably from
patient to patient, such that some patients have dyspnea but no ■ Hepatomegaly
signs of fluid retention whereas others may have marked volume Laboratory Tests
overload with few complaints of dyspnea or fatigue. However, many ■ BNP >100 pg/mL
patients may have both dyspnea and volume overload. Clinicians
■ Electrocardiogram may be normal or it could show numerous
should remember that symptom severity often does not correlate
abnormalities including acute ST-T–wave changes from myo-
with the degree of left ventricle dysfunction. Patients with a low
cardial ischemia, atrial fibrillation, bradycardia, left ventricu-
LVEF (less than 20% to 25%) may be asymptomatic, whereas
lar hypertrophy
patients with preserved LVEF may have significant symptoms. It is
also important to note that symptoms can vary considerably over ■ Serum creatinine may be increased because of hypoperfusion.
time in a given patient. Historically, signs and symptoms are Preexisting renal dysfunction can contribute to volume over-
classified as being a result of left ventricular (pulmonary conges- load.
 182

■ Complete blood count useful to determine if heart failure is a internal jugular vein with the patient at a 45° angle is the preferred
result of reduced oxygen-carrying capacity method for assessing JVD. The presence of JVD more than 4 cm
SECTION 2

above the sternal angle suggests systemic venous congestion. In

■ Chest radiography is useful for detection of cardiac enlarge- patients with mild systemic congestion, JVD may be absent at rest,
ment, pulmonary edema, and pleural effusions but application of pressure to the abdomen will cause an elevation
■ Echocardiogram assesses left ventricle size, valve function, of JVD (hepatojugular reflux).
pericardial effusion, wall motion abnormalities, and ejection Peripheral edema is a cardinal finding in heart failure. Edema
fraction usually occurs in dependent parts of the body, and thus is seen as
■ Hyponatremia, serum sodium <130 mEq/L, is associated with ankle or pedal edema in ambulatory patients, although it may be
reduced survival and may indicate worsening volume over- manifested as sacral edema in bedridden patients. Adults typically
Cardiovascular Disorders

load and/or disease progression have a 10-lb fluid weight gain before trace peripheral edema is
evident; therefore, patients with acute decompensated heart failure
Pulmonary congestion arises as the left ventricle fails and is unable may have no clinical evidence of systemic congestion except weight
to accept and eject the increased blood volume that is delivered to it. gain. Consequently, body weight is the best short-term end point
Consequently, pulmonary venous and capillary pressures rise, leading for evaluating fluid status. Nonfluid weight gain or loss of muscle
to interstitial and bronchial edema, increased airway resistance, and mass as a result of cardiac cachexia are potential confounders for
dyspnea. The associated signs and symptoms may include (a) dyspnea long-term use of weight as a marker for fluid status. Ascites is
(with or without exertion), (b) orthopnea, (c) paroxysmal nocturnal another common sign of systemic congestion.
dyspnea, and (d) pulmonary edema. Exertional dyspnea occurs when Heart failure patients may exhibit signs and symptoms of low
there is a reduction in the level of exertion that causes breathlessness. cardiac output alone or in addition to volume overload. The primary
This is typically described as more breathlessness than was associated complaint associated with such poor perfusion is fatigue. Patients
previously with a specific activity (e.g., vacuuming, stair climbing). As may also complain of poor appetite or early satiety because of limited
heart failure progresses, many patients eventually have dyspnea at perfusion of the gastrointestinal tract. Conversely, patients with such
rest. gastrointestinal complaints may simply be experiencing gut edema.
Orthopnea is dyspnea that occurs with assumption of the supine More subjective measures of low cardiac output include worsening
position. It occurs within minutes of recumbency and is a result of renal function, cool extremities, and narrow pulse pressure.
reduced pooling of blood in the lower extremities and abdomen.
Orthopnea is relieved almost immediately by sitting upright and DIAGNOSIS1
typically is prevented by elevating the head with pillows. An increase
in the number of pillows required to prevent orthopnea (e.g., a No single test is available to confirm the diagnosis of heart failure.
change from “two-pillow” to “three-pillow” orthopnea) suggests Because the syndrome of heart failure can be caused or worsened by
worsening heart failure. Attacks of paroxysmal nocturnal dyspnea multiple cardiac and noncardiac disorders, accurate diagnosis is
typically occur after 2 to 4 hours of sleep; the patient awakens from essential for development of therapeutic strategies. Heart failure is
sleep with a sense of suffocation. The attacks are caused by severe often initially suspected in a patient based on their symptoms. These
pulmonary and bronchial congestion, leading to shortness of breath will often include dyspnea, exercise intolerance, fatigue, and/or fluid
and wheezing. The reasons these attacks occur at night are unclear retention. However, it must be emphasized that signs and symptoms
but may include (a) reduced pooling of blood in the lower extrem- lack sensitivity for diagnosing heart failure since these symptoms are
ities and abdomen (as with orthopnea), (b) slow resorption of frequently found with many other disorders. Even in patients with
interstitial fluid from sites of dependent edema, (c) normal reduc- known heart failure, there is poor correlation between the presence
tion in sympathetic activity that occurs with sleep (e.g., less support or severity of symptoms and hemodynamic abnormality.
for the failing ventricle), and (d) normal depression in respiratory A complete history and physical examination targeted at identify-
drive that occurs with sleep. ing cardiac or noncardiac disorders or behaviors that may cause or
Rales (crackling sounds heard on auscultation) are present in the hasten heart failure development or progression are essential in the
lung bases as a result of transudation of fluid into alveoli. The rales initial evaluation of a symptomatic patient. A careful medication
typically are bibasilar, but if heard unilaterally, they are usually history should also be obtained with a focus on use of ethanol,
right-sided. Rales are not present in most patients with chronic tobacco, illicit drugs (e.g., cocaine or methamphetamine), vitamins
heart failure even though there is volume overload. This is thought and supplements (including herbal or “natural” supplements),
to be a consequence of a compensatory increase in lymphatic NSAIDs, and antineoplastic agents (anthracyclines, cyclophospha-
drainage. Detection of rales is usually indicative of a rapid onset of mide, trastuzumab, imatinib). Particular attention should be paid
worsening heart failure rather than the amount of excess fluid to cardiovascular risk factors and to other disorders that can cause
volume. A third heart sound, or S3 gallop, is heard frequently in or exacerbate heart failure. Because coronary artery disease is the
patients with left ventricular failure and may be caused by elevated cause of heart failure in nearly 70% of patients, careful attention and
atrial pressure and altered distensibility of the ventricle. evaluation of the possibility of coronary disease is essential, espe-
Pulmonary edema is the most severe form of pulmonary conges- cially in men. If coronary artery disease is detected, appropriate
tion, and is caused by accumulation of fluid in the interstitial spaces revascularization procedures may then be considered. The patient’s
and alveoli. In heart failure patients, it is the result of increased volume status should be documented by assessing the body weight,
pulmonary venous pressure. The patient experiences extreme JVD, and presence or absence of pulmonary congestion and periph-
breathlessness and anxiety and may cough pink, frothy sputum. eral edema. Laboratory testing may assist in identification of disor-
Pulmonary edema can be terrifying for the patient, causing a feeling ders that cause or worsen heart failure. The initial evaluation should
of suffocation or drowning. Patients with pulmonary edema may include a complete blood count, serum electrolytes (including
also report any of the above mentioned signs or symptoms of calcium and magnesium), tests of renal and hepatic function,
pulmonary congestion. urinalysis, lipid profile, hemoglobin A1c, thyroid function tests,
Systemic congestion is associated with a number of signs and chest radiography, and 12-lead electrocardiogram (ECG). There are
symptoms. Jugular venous distension (JVD) is the simplest and no specific ECG findings associated with heart failure, but findings
most reliable sign of fluid overload. Examination of the right may help detect coronary artery disease or conduction abnormali-
 183

CHAPTER 16
Common Examples

Hypertension, coronary artery or other

Stage A
atherosclerotic vascular disease,
Patients at high risk
diabetes, obesity, metabolic syndrome
for developing heart failure

Development of structural heart

disease

Heart Failure
Stage B Previous MI, left ventricular
Progression of Heart Failure

Patients with structural hypertrophy, left ventricular systolic

heart disease but no HF dysfunction
signs or symptoms
HF symptoms develop

Stage C Left ventricular systolic dysfunction and

Patients with structural symptoms such as dyspnea, fatigue, and
heart disease and current or reduced exercise tolerance.
previous symptoms

Treatment-resistant symptoms
Patients with treatment refractory
symptoms at rest despite maximal
Stage D
medical therapy (e.g., patients requiring
Refractory HF requiring
recurrent hospitalization or who cannot be
specialized interventions
discharged without mechanical assist
devices or inotropic therapy)

FIGURE 16-5. ACC/AHA heart failure staging

system. (HF, heart failure; MI, myocardial
infarction.) (Adapted with permission from
Circulation 2005;112:154–234.)

ties that could affect prognosis and guide treatment decisions. treatment strategies.1 The system is comprised of four stages (Fig.
Measurement of BNP may also assist in differentiating dyspnea 16–5). This staging system differs from the NYHA functional classi-
caused by heart failure from other causes.18 fication (Table 16–4) with which most clinicians are familiar. The
Although the history, physical examination, and laboratory tests NYHA system is primarily intended to classify symptomatic heart
can provide important clues to the underlying cause of heart failure, failure according to the clinician’s subjective evaluation and does not
the echocardiogram is the single most useful test in the evaluation recognize preventive measures or the progression of the disorder. A
of a patient with heart failure. The echocardiogram is used to patient’s symptoms can change frequently over a short period of
evaluate abnormalities in the pericardium, myocardium, or heart time as a result of changes in, medications, diet, or intercurrent
valves and to quantify the LVEF to determine if systolic or diastolic illnesses. For example, a patient with NYHA class IV symptoms with
dysfunction is present. marked volume overload could rapidly improve to class II or III with
aggressive diuretic therapy. In spite of these limitations, this system
can be useful for monitoring patients and is widely used in heart
TREATMENT failure studies. In contrast, and consistent with the progressive
nature of heart failure, a patient’s ACC/AHA heart failure stage could
Chronic Heart Failure not improve (e.g., go from stage C to stage B) even though the

■ DESIRED OUTCOMES
The goals of therapy in management of chronic heart failure are to TABLE 16-4 New York Heart Association Functional Classification
improve the patient’s quality of life; relieve or reduce symptoms; Functional class
prevent or minimize hospitalizations for exacerbations of heart I Patients with cardiac disease but without limitations of physical activity. Ordinary
failure; slow progression of the disease process; and prolong survival. physical activity does not cause undue fatigue, dyspnea, or palpitation.
Although these goals are still important, identification of risk factors II Patients with cardiac disease that results in slight limitations of physical activity.
for heart failure development and recognition of its progressive Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina.
nature have led to increased emphasis on preventing the develop- III Patients with cardiac disease that results in marked limitation of physical activity.
ment of this disorder. With this in mind, the American College of Although patients are comfortable at rest, less-than-ordinary activity will lead to
Cardiology/American Heart Association (ACC/AHA) guidelines for symptoms.
IV Patients with cardiac disease that results in an inability to carry on physical activity
the evaluation and management of chronic heart failure use a staging
without discomfort. Symptoms of congestive heart failure are present even at
system that recognizes not only the evolution and progression of the
rest. With any physical activity, increased discomfort is experienced.
disorder, but also emphasizes risk factor modification and preventive
 184
patient’s symptoms could fluctuate from NYHA class IV to class I. In preserved LVEF, and management of patients with heart failure and
addition, the ACC/AHA staging system provides a more comprehen- a number of comorbid diseases. The HFSA guidelines will be
SECTION 2

sive framework for evaluation, prevention, and treatment of heart periodically updated on the HFSA website (www.hfsa.org). Finally,
failure. the European Society of Cardiology published guidelines for the
management of both acute34 and chronic heart failure.35 Although
■ GENERAL MEASURES minor differences exist between the recommendations in the Amer-
ican and European guidelines, they are in general agreement in their
The complexity of the heart failure syndrome necessitates a compre- overall approach. Clinicians caring for patients with heart failure
hensive approach to management that includes accurate diagnosis, should be familiar with these guidelines but should also remember
identification and treatment of risk factors (e.g., diabetes, hyperten- that these are only guidelines and that management and treatment
sion, coronary artery disease), elimination or minimization of
Cardiovascular Disorders

must be individualized for each patient.

precipitating factors, appropriate pharmacologic and nonpharma-
cologic therapy, and close monitoring and followup.
The first step in management of chronic heart failure is to Treatment of Stage A Heart Failure
determine the etiology (see Table 16–1) and/or any precipitating (See Fig. 16–6)
factors. Treatment of underlying disorders, such as hyperthyroid- Patients in stage A do not have structural heart disease or heart failure
ism, may obviate the need for treatment of heart failure. Patients symptoms but are at high risk for developing heart failure because of
with valvular diseases may derive significant benefit from valve the presence of risk factors. The emphasis here is on identification and
replacement or repair. Revascularization or antiischemic therapy in modification of these risk factors to prevent the development of
patients with coronary disease may reduce heart failure symptoms. structural heart disease and subsequent heart failure. Commonly
Drugs that aggravate heart failure (see Table 16–3) should be encountered risk factors include hypertension, diabetes, obesity, met-
discontinued if possible. abolic syndrome, smoking, and coronary artery disease. Although
Restriction of physical activity reduces cardiac workload and is each of these disorders individually increases risk, they frequently
recommended for virtually all patients with acute congestive symp- coexist in many patients and act synergistically to foster the develop-
toms. However, once the patient’s symptoms have stabilized and ment of heart failure. Effective control of blood pressure reduces the
excess fluid is removed, restrictions on physical activity are discour- risk of developing heart failure by approximately 50%, thus current
aged. In fact, current guidelines indicate that exercise training hypertension treatment guidelines should be followed.36 Control of
programs in stable heart failure patients improve exercise tolerance, hyperglycemia reduces the risk of end-organ damage and the risk of
functional capacity, and may slow heart failure progression.1 developing heart failure. Appropriate management of coronary dis-
Because a major compensatory response in heart failure is ease and its associated risk factors is also important, including
sodium and water retention, restriction of dietary sodium and fluid treatment of hyperlipidemia according to published guidelines and
intake are important nonpharmacologic interventions. Mild (<3 g smoking cessation.37 Although treatment must be individualized,
per day) to moderate (<2 g per day) sodium restriction, in conjunc- ACE inhibitors or ARBs should be strongly considered for antihyper-
tion with daily measurement of weight, should be implemented to tensive therapy in patients with multiple vascular risk factors.1
minimize volume retention and allow use of lower and safer diuretic Diuretics and β-blockers may also useful in this setting.
doses. The typical American diet contains 3 to 6 g of sodium per day
so most patients would need to reduce their intake by approxi-
mately 50%. This can often be accomplished by not adding salt to
Treatment of Stage B Heart Failure
prepared foods and eliminating foods high in sodium (e.g., salt-
(See Fig. 16–6)
cured meats, salted snack foods, pickles, soups, delicatessen meats, Patients in stage B have structural heart disease, but do not have heart
and processed foods). In patients with hyponatremia (serum Na failure symptoms. This group includes patients with left ventricular
<130 mEq/L) or those with persistent volume retention despite high hypertrophy, recent or remote MI, valvular disease, or reduced LVEF
diuretic doses and sodium restriction, daily fluid intake should be (less than 40%). These individuals are at risk for developing heart
limited to 2 L per day from all sources. failure and treatment is targeted at minimizing additional injury and
Other important general measures include patient and family preventing or slowing the remodeling process. In addition to the
counseling on the signs and symptoms of heart failure, detailed treatment measures outlined in stage A, ACE inhibitors and β-block-
instructions on the importance of appropriate medication use and ers are important components of therapy. Patients with a previous MI
compliance, and the need for close monitoring and followup to should receive both ACE inhibitors and β-blockers, regardless of the
reinforce compliance and minimize the risk of heart failure exacer- LVEF.1 Similarly, patients with a reduced LVEF should also receive
bations and subsequent hospitalization. both these agents, whether or not they have had a MI.1 ARBs are an
effective alternative in patients intolerant to ACE inhibitors.1
■ GENERAL APPROACH TO TREATMENT
 Current ACC/AHA treatment guidelines are organized around Treatment of Stage C Heart Failure
the four identified stages of heart failure and the treatment recom- (See Fig. 16–7)
mendations are summarized below (Figs. 16–6 and 16–7).1 This     Patients with structural heart disease and previous or
staging system emphasizes the progressive nature of the disorder current heart failure symptoms are classified in stage C. In addition
and targets treatment to prevent and/or slow the progression of to treatments in stages A and B, most patients in stage C should be
heart failure. Clinicians are reminded that, in addition to the ACC/ routinely treated with three medications: a diuretic, an ACE inhibi-
AHA, other cardiology professional societies have developed guide- tor, and a β-blocker (see Drug Therapies for Routine Use below).
lines for evaluation and treatment of heart failure. The Heart Failure The benefits of these medications on slowing heart failure progres-
Society of America (HFSA) issued practice guidelines in 2006.33 The sion, reducing morbidity and mortality, and improving symptoms
HFSA and ACC/AHA guidelines are very similar with regard to care are clearly established. Aldosterone receptor antagonists, ARBs,
and treatment of patients with chronic heart failure. In addition, the digoxin, and hydralazine-isosorbide dinitrate are also useful in
HFSA guidelines provide a thorough discussion of other areas selected patients. Nonpharmacologic therapy with devices such as
including acute decompensated heart failure, heart failure with an implantable cardiac-defibrillator (ICD) or cardiac resynchroni-
 185

CHAPTER 16
Stage A Stage B

Control CV risk factors

All treatments under Stage A

Does the HTN, diabetes, or

patient smoke? atherosclerotic disease?

Heart Failure
Yes Yes Previous MI and/or asymptomatic left
ventricular remodeling (LVH or
Encourage Treat according to LVEF < 40%)
smoking cessation current guidelines
Yes

Initiate and titrate

Does patient have atherosclerotic ACE inhibitor†‡ or ARB‡
vascular (coronary, cerebral, peripheral) (†Class IIa, Evidence A—if low EF with or without MI)
disease or diabetes? (‡Class IIa, Evidence B—if HTN and LVH)
Yes and
-blocker
ACE inhibitor or ARB (Class I, Evidence A—MI with or without low EF,
(Class IIA, Evidence A (ACE inhibitor)) Evidence C—no MI with low EF)
(Class IIA, Evidence C (ARB))
ACE inhibitor intolerant

ARB
(Class I, Evidence B—if post-MI with low EF)
(Class IIa, Evidence C—if low EF only )

FIGURE 16-6. Treatment algorithm for patients with ACC/AHA stages A and B heart failure. (ACE, angiotensin-converting enzyme; ARB,
angiotensin receptor blocker; CV, cardiovascular; EF, ejection fraction; HTN, hypertension; LVEF, left ventricular ejection fraction; LVH, left
ventricular hypertrophy; MI, myocardial infarction.) (Adapted with permission from Circulation 2005;112:154–234.)

zation therapy (CRT) with a biventricular pacemaker is also indi- from sudden death, whereas death from pump failure is more
cated in certain patients in stage C (see Nonpharmacologic Therapy frequent in those with advanced heart failure. Many of these
below). Other general measures are also important, including mod- patients have complex and frequent ventricular ectopic beats,
erate sodium restriction, daily weight measurement, immunization although it remains unknown whether these ectopic beats contrib-
against influenza and pneumococcus, modest physical activity, and ute to the risk of malignant arrhythmias or merely serve as markers
avoidance of medications that can exacerbate heart failure. Recent for individuals at higher risk for sudden death. Drugs that attenuate
evidence suggests that careful followup and patient education that disease progression such as β-blockers and aldosterone antagonists
reinforces dietary and medication compliance can prevent clinical reduce the risk of sudden death. However, empiric treatment with
deterioration and reduce hospitalization.1 class I antiarrhythmic agents, although they can suppress ventricu-
lar ectopic beats, adversely affect survival.38 The role of the ICD
Treatment of Stage D Heart Failure compared to amiodarone for primary prevention of sudden death
was evaluated in Sudden Cardiac Death in Heart Failure Trial
Stage D heart failure includes patients with symptoms at rest that
(SCD-HeFT). Placement of an ICD was superior to amiodarone or
are refractory despite maximal medical therapy. This includes
placebo for reducing mortality in patients with NYHA class II or III
patients who undergo recurrent hospitalizations or who cannot be
heart failure and LVEF ≤35%, regardless of the etiology of heart
discharged from the hospital without special interventions. These
failure.39 Importantly, this study also found that amiodarone had no
individuals have the most advanced form of heart failure and should
be considered for specialized therapies including mechanical circu- benefit compared to placebo and thus this drug, because of its
latory support, continuous intravenous positive inotropic therapy, multiple adverse effects, drug interactions, and lack of effect on
cardiac transplantation, or hospice care. The approach to treatment mortality, should not be used for primary prevention of sudden
of patients with stage D heart failure is discussed in more detail in death. However, because of the neutral effects of amiodarone on
Acute Decompensated Heart Failure below. survival, it is often used in heart failure patients with atrial fibrilla-
tion to maintain sinus rhythm and/or to prevent ICD discharges. In
cardiac arrest survivors with a reduced LVEF, the ICD is superior to
■ NONPHARMACOLOGIC THERAPY antiarrhythmic drug therapy for improving survival.40 Thus, the
Sudden cardiac death, primarily as a consequence of ventricular ACC/AHA guidelines recommend the ICD for both primary and
tachycardia and fibrillation, is responsible for 40% to 50% of the secondary prevention to improve survival in patients with current
mortality in heart failure patients. In general, patients in the earlier or previous heart failure symptoms and reduced LVEF. Chapter 19
stages of heart failure with milder symptoms are more likely to die thoroughly reviews ICD therapy.
 186

Stage C
SECTION 2

Initiate and titrate Yes

ACE inhibitor and -blocker* Fluid retention Initiate and titrate diuretic

No Symptoms
ARA‡ (Class I, Evidence B)
improve once
Cardiovascular Disorders

ARB (Class IA, Evidence A if ACE-inhibitor intolerant) euvolemic?

(Class IIa, Evidence A if already taking ARB for alternative indication)
(Class IIb, Evidence B if persistently symptomatic on ACE-inhibitor and -blocker) Yes
Digoxin (Class IIa, Evidence B†)

Hydralazine/ISDN (Class IIa, Evidencce A if African American and NYHA classes III to IV) Long-term
(Class IIb, Evidence C if ACE-inhibitor/ARB intolerant) monitoring

Any time during therapy . . .

Yes
Persistent volume overload? Aggressive diuretic therapy

No
Yes ARB
Persistent HTN? Hydralazine/ISDN
Amlodipine or felodipine
No
Yes Nitrates
Concomitant angina Amlodipine or felodipine

* If not already receiving this therapy for previous MI, LV dysfunction, or other indication.
‡ If NYHA classes III to IV.
† Indication is to reduce hospitalization.

FIGURE 16-7. Treatment algorithm for patients with ACC/AHA stage C heart failure. (ACE, angiotensin-converting enzyme; ARA,
aldosterone receptor antagonist; ARB, angiotensin receptor blocker; HTN, hypertension; ISDN, isosorbide dinitrate; LV, left ventricle; MI,
myocardial infarction.) (Adapted with permission from Circulation 2005;112:154–234.)

Recent studies demonstrate that CRT offers a promising heart failure symptoms (i.e., stage C). In general, these patients
approach to selected patients with chronic heart failure.41,42 Delayed should receive combined therapy with an ACE inhibitor or ARB and
electrical activation of the left ventricle, characterized on the ECG a β-blocker, plus a diuretic if there is evidence of fluid retention.
by a QRS duration that exceeds 120 msec, occurs in approximately Initiation of digoxin therapy can be considered at any time for
one-third of patients with moderate to severe systolic heart failure. symptom reduction, to decrease hospitalizations, or slow ventricu-
Because the left and right ventricles normally activate simulta- lar response in patients with concomitant atrial fibrillation. An
neously, this delay results in asynchronous contraction of the aldosterone receptor antagonist should also be considered in
ventricles, which contributes to the hemodynamic abnormalities of selected patients.1
heart failure. Implantation of a specialized biventricular pacemaker
 Diuretics 43,44 The compensatory mechanisms in heart failure
to restore synchronous activation of the ventricles can improve
stimulate excessive sodium and water retention, often leading to
ventricular contraction and hemodynamics. Recent trials show
pulmonary and systemic congestion. Diuretic therapy, in addition
improvements in exercise capacity, NYHA classification, quality of
to sodium restriction, is recommended in all patients with clinical
life, hemodynamic function, hospitalizations, and mortality with
evidence of fluid retention. Once fluid overload has been resolved,
CRT.41,42 A CRT is currently indicated only in NYHA classes III to
many patients require chronic diuretic therapy to maintain
IV patients receiving optimal medical therapy and with a QRS
euvolemia. Among the drugs used to manage heart failure, diuretics
duration ≥120 msec and LVEF ≤35%. Combined CRT and ICD
are the most rapid in producing symptomatic benefits. Because
devices are available and can be used if the patient meets the
diuretics do not alter disease progression or prolong survival, they
indications for both devices.
are not considered mandatory therapy. Thus patients who do not
have fluid retention would not require diuretic therapy.
■ PHARMACOLOGIC THERAPY The primary goal of diuretic therapy is to reduce symptoms
associated with fluid retention, improve exercise tolerance and
Drug Therapies for Routine Use quality of life, and reduce hospitalizations from heart failure. They
   
Figure 16–7 is a treatment algorithm for accomplish this by decreasing pulmonary and peripheral edema
management of patients with reduced LVEF and current or prior through reduction of preload. Although preload is a determinant of
 187
cardiac output, the Frank-Starling curve (see Fig. 16–3) shows that TABLE 16-5 Loop Diuretics—Use in Heart Failure
patients with congestive symptoms have reached the flat portion of

CHAPTER 16
Furosemide Bumetanide Torsemide
the curve. A reduction in preload improves symptoms but has little
effect on the patient’s stroke volume or cardiac output until the Usual daily dose (oral) 20–160 mg/day 0.5–4 mg/day 10–80 mg/day
steep portion of the curve is reached. However, diuretic therapy Ceiling dosea
must be used judiciously because overdiuresis can lead to a reduc- Normal renal function 80–160 mg 1–2 mg 20–40 mg
tion in cardiac output and symptoms of dehydration. C Lcr - 20–50 mL /min 160 mg 2 mg 40 mg
C Lcr < 20 mL /min 400 mg 8–10 mg 100 mg
Diuretic therapy is usually initiated in low doses in the outpatient
Bioavailability 10%–100% 80%–90% 80%–100%
setting, with dosage adjustments based on symptom assessment and
average: 50%
daily body weight. Change in body weight is a sensitive marker of Affected by food Yes Yes No

Heart Failure
fluid retention or loss, and it is recommended that patients monitor Half-life 0.3–3.4 h 0.3–1.5 h 3–4 h
their status by taking daily morning body weights. Patients who gain
CLcr, creatine clearance.
a pound per day for several consecutive days, or 3 to 5 lb in a week, a
Ceiling dose: single dose above which additional response is unlikely to be observed.
should contact their healthcare provider for instructions (which Adapted from Am J Med Sci 2000;319:38–50.
often will be to increase the diuretic dose temporarily). Such action
often will allow patients to prevent a decompensation that requires
to give progressively higher doses. The appropriate chronic dose is
hospitalization. One study demonstrated a significant reduction in
that which maintains the patient at a stable dry weight without
emergency department visits with a protocol that directed patients
symptoms of dyspnea. Table 16–5 lists ranges of doses of loop
to self-adjust their diuretic dose based on changes in heart failure
diuretics and recommended ceiling doses.
symptoms and daily body weight.45 Hypotension or worsening renal
function (e.g., increases in serum creatinine) may be indicative of  ACE Inhibitors ACE inhibitors are the cornerstone of pharma-
volume depletion and necessitate a reduction in the diuretic dose. cotherapy for patients with heart failure. By blocking the conversion
Assessing for volume depletion is particularly important before of angiotensin I to angiotensin II by ACE, the production of
ACE inhibitor or β-blocker initiation or dose up-titration as overdi- angiotensin II and, in turn, aldosterone is decreased, but not com-
uresis may predispose patients to hypotension and other adverse pletely eliminated.13 This decrease in angiotensin II and aldosterone
effects with increases in ACE inhibitor or β-blocker doses. attenuates many of the deleterious effects of these neurohormones,
including ventricular remodeling, myocardial fibrosis, myocyte
Thiazide Diuretics. Thiazide diuretics such as hydrochlorothi-
apoptosis, cardiac hypertrophy, norepinephrine release, vasocon-
azide block sodium and chloride reabsorption in the distal convo-
striction, and sodium and water retention.13 Thus, ACE inhibitor
luted tubule (approximately 5% to 8% of filtered sodium).
therapy plays an important role in preventing RAAS-mediated pro-
Consequently, the thiazides are relatively weak diuretics and infre-
gressive worsening of myocardial function. The endogenous vasodi-
quently are used alone in heart failure. However, as reviewed in
lator bradykinin, which is inactivated by ACE, is also increased by
Treatment: Acute Decompensated Heart Failure below, under
ACE inhibitors, along with the release of vasodilatory prostaglandins
Diuretic Resistance, thiazides or the thiazide-like diuretic metola-
and histamine.13 The precise contribution of the effects of ACE
zone can be used in combination with loop diuretics to promote a
inhibitors on bradykinin and vasodilatory prostaglandins is unclear.
very effective diuresis. In addition, thiazide diuretics may be pre-
However, the persistence of clinical benefits with ACE inhibitors
ferred in patients with only mild fluid retention and elevated blood
despite angiotensin II and aldosterone levels returning to pretreat-
pressure because of their more persistent antihypertensive effects
ment levels suggests this is a potentially important effect.13
compared to loop diuretics.
Numerous placebo-controlled clinical trials involving more than
Loop Diuretics. Loop diuretics are usually necessary to restore 7,000 patients with reduced LVEF have documented the favorable
and maintain euvolemia in heart failure. They act by inhibiting a effects of ACE inhibitor therapy on symptoms, NYHA functional
Na-K-2Cl transporter in the thick ascending limb of the loop of classification, clinical status, exercise tolerance, and quality of life.13
Henle, where 20% to 25% of filtered sodium normally is reab- When compared with placebo, patients treated with ACE inhibitors
sorbed. Because loop diuretics are highly bound to plasma proteins, have fewer treatment failures, hospitalizations, and increases in
they are not highly filtered at the glomerulus. They reach the tubular diuretic dosages.13
lumen by active transport via the organic acid transport pathway. More importantly, these trials show that ACE inhibitors improve
Competitors for this pathway (probenecid or organic by-products survival by 20% to 30% compared to placebo.13 In addition, the
of uremia) can inhibit delivery of loop diuretics to their site of Studies of Left Ventricular Dysfunction (SOLVD) Prevention and
action and decrease effectiveness. Loop diuretics also induce a Treatment trials indicate the survival benefit is maintained long-
prostaglandin-mediated increase in renal blood flow, which con- term (12 years) in patients who were treated with enalapril.46 In
tributes to their natriuretic effect. Coadministration of NSAIDs addition to improving survival, ACE inhibitors also reduce the
blocks this prostaglandin-mediated effect and can diminish diuretic combined risk of death or hospitalization, slow the progression of
efficacy. Excessive dietary sodium intake may also reduce the heart failure, and reduce the rates of reinfarction.13 The benefits of
efficacy of loop diuretics. Unlike thiazides, loop diuretics maintain ACE inhibitor therapy are independent of the etiology of heart
their effectiveness in the presence of impaired renal function, failure (ischemic versus nonischemic) and are observed in patients
although higher doses may be necessary to obtain adequate delivery with mild, moderate, or severe symptoms.
of the drug to the site of action. The most common cause of heart failure is ischemic heart disease,
Heart failure is one of the disease states in which the maximal where MI results in loss of myocytes, followed by ventricular
response to loop diuretics is reduced. This is believed to result from dilation and remodeling. Captopril, ramipril, and trandolapril all
a decrease in the rate of diuretic absorption and/or increased benefit post-MI patients, whether they are initiated early (within 36
proximal or distal tubule reabsorption of sodium, possibly due to hours) and continued for 4 to 6 weeks or started later and adminis-
increased activity of the Na-K-2Cl transporter.43 As a consequence, tered for several years.13 Collectively, these studies indicate that ACE
doses above the recommended ceiling doses produce no additional inhibitors after MI improve overall survival, decrease development
diuresis. Thus, once the ceiling dose is reached, it is recommended of severe heart failure, and reduce reinfarction and heart failure
to give the diuretic more frequently for additional effect rather than hospitalization rates.13 The benefit occurs within the first few days
 188
of therapy and persists during long-term treatment. The effects are ACE inhibitor doses proven beneficial in clinical trials, but if these
most pronounced in higher-risk patients, such as those with symp- doses are not tolerated, lower doses can be used with the knowledge
SECTION 2

tomatic heart failure or reduced LVEF, with 20% to 30% reductions that there are likely only small differences in mortality outcomes
in mortality reported in these patients.13 Post-MI patients without between the high and low doses. Also, initiation of β-blocker therapy
heart failure symptoms or decreases in LVEF (stage B) should also should not be delayed until target ACE inhibitor doses are achieved
receive ACE inhibitors to prevent the development of heart failure as the addition of a β-blocker is proven to reduce mortality, whereas
and to reduce mortality.1,13,47 that is not the case with increasing ACE inhibitor doses.
In addition to their benefits in patients with established heart In summary, the evidence that ACE inhibitors improve symp-
failure, ACE inhibitors also are effective for preventing the develop- toms, slow disease progression, and decrease mortality in patients
ment of heart failure and reducing cardiovascular risk. Enalapril with heart failure and reduced LVEF (stage C) is unequivocal.
Cardiovascular Disorders

decreases the risk of hospitalization for worsening heart failure and Current guidelines indicate these patients should receive ACE
reduces the composite end point of death and heart failure hospital- inhibitors, unless contraindications are present.1 Moreover, ACE
ization in patients with asymptomatic left ventricular dysfunction.48 inhibitors should also be used to prevent the development of heart
The development of diabetes mellitus, an important risk factor for failure in at-risk patients (i.e., stages A and B).1
cardiovascular disease that also increases morbidity and mortality in
heart failure patients, is reduced by enalapril in patients with  β-Blockers There is overwhelming evidence from multiple
chronic heart failure.49 In patients with established atherosclerotic randomized, placebo-controlled clinical trials that β-blockers
vascular disease (e.g., coronary, cerebral, or peripheral circulations) reduce morbidity and mortality in patients with heart failure. As
and normal LVEF, ACE inhibitors reduce the development of new- such, the ACC/AHA guidelines on the management of heart failure
onset heart failure and diabetes, cardiovascular death, overall mor- recommend that β-blockers should be used in all stable patients
tality, MI, and stroke.50 with heart failure and a reduced left ventricular ejection fraction in
The clear benefit of ACE inhibitors is evident in the Joint Commis- the absence of contraindications or a clear history of β-blocker
sion for Accreditation of Healthcare Organizations (JCAHO) and intolerance.1 Patients should receive a β-blocker even if their symp-
Centers for Medicare and Medicaid Services (CMS) selection of ACE toms are mild or well controlled with diuretic and ACE inhibitor
inhibitor use in patients with heart failure and decreased LVEF as a therapy. Importantly, it is not essential that ACE inhibitor doses be
key quality measure. Despite the overwhelming benefit demonstrated optimized before a β-blocker is started because the addition of a β-
with these agents, there is substantial evidence that they are blocker is likely to be of greater benefit than an increase in ACE
underused and underdosed.51,52 These data indicate that significant inhibitor dose.1 β-Blockers are also recommended for asympto-
numbers of heart failure patients do not receive ACE inhibitors, and matic patients with a reduced left ventricular ejection fraction (stage
of those who are receiving these agents, many are taking lower-than- B) to decrease the risk of progression to heart failure.
recommended doses.52 Also, for patients receiving an ACE inhibitor β-Blockers have been studied in more than 20,000 patients with
at hospital discharge, use significantly decreases over time and heart failure in placebo-controlled trials. Three β-blockers have been
patients who were not prescribed ACE inhibitors at discharge were shown to significantly reduce mortality compared to placebo:
unlikely to have therapy initiated in the outpatient setting.51 The most carvedilol, metoprolol controlled-release/extended-release (CR/XL),
common reasons cited for underuse or underdosing are concerns and bisoprolol. Each was studied in a large population with the
about safety and adverse reactions to ACE inhibitors, especially in primary end point of mortality. Carvedilol was the first β-blocker
patients with underlying renal dysfunction or hypotension. The use of shown to improve survival in heart failure. In the U.S. Carvedilol
ACE inhibitors in patients with renal insufficiency is particularly Heart Failure Study, 1,094 patients were randomized to carvedilol or
relevant because it is present in 25% to 50% of heart failure patients placebo in addition to standard therapy, including an ACE inhibitor,
and is associated with an increased risk of mortality.53 Several recent digoxin, and diuretic. The study was stopped early because of a 65%
studies in different patient populations, including post-MI patients reduction in the risk of death with carvedilol.58 Nearly 4,000 patients
with decreased left ventricular function and patients with stable were randomized to metoprolol CR/XL (Toprol-XL) or placebo in
coronary artery disease and preserved left ventricular function, indi- the Metoprolol CR/XL Randomized Intervention Trial in Congestive
cate that ACE inhibitors may be more effective in those patients with Heart Failure (MERIT-HF), the largest β-blocker mortality trial to
renal insufficiency.54–56 Because many heart failure patients have date.59 This trial was also stopped early because of a significant
concomitant disorders (e.g., diabetes, hypertension, previous MI) survival benefit with β-blockade. Specifically, metoprolol was associ-
that also may be favorably affected by ACE inhibitors, renal dysfunc- ated with a 34% reduction in total mortality, a 41% reduction in
tion should not be an absolute contraindication to ACE inhibitor use sudden death, and a 49% reduction in death from worsening heart
in patients with left ventricular dysfunction. However, these patients failure. Bisoprolol was studied in more than 2,600 patients enrolled
should be monitored carefully for the development of worsening in the Cardiac Insufficiency Bisoprolol Study (CIBIS) II.60 The study
renal function and/or hyperkalemia with special attention to risk was also stopped prematurely because of a 34% reduction in total
factors associated with this complication of ACE inhibitor therapy.1 mortality with bisoprolol compared to placebo. Bisoprolol was also
An important practical consideration is determining the proper associated with a 44% reduction in sudden death and a 26%
dose of an ACE inhibitor. The ability to achieve target doses shown reduction in death because of worsening heart failure. Multiple post-
to be effective in clinical trials is often limited by hypotension and/or hoc subgroup analyses of data from the MERIT-HF and CIBIS II
a decline in renal function. Clinical trials establishing the efficacy of trials suggest that the benefits of β-blockade occur regardless of heart
these agents titrated drug doses to a predetermined target rather than failure etiology or disease severity.
according to therapeutic response. Although data on the dose- The majority of participants in MERIT-HF and CIBIS II had
dependent effects of ACE inhibitors in patients with heart failure are either class II or class III heart failure, and β-blockers became
limited, higher doses may reduce the risk of hospitalization com- standard therapy in patients with class II or III disease after these
pared to lower doses, but there do not appear to be significant trials were published. However, the efficacy and safety of β-blockers
differences in mortality.57 In many positive trials of other heart in patients with class IV heart failure were unclear until publication
failure therapies (e.g., β-blockers, aldosterone antagonists), interme- of the Carvedilol, Prospective, Randomized, Cumulative Survival
diate ACE inhibitor doses were generally used as background ther- (COPERNICUS) trial.61 This trial randomized nearly 2,300 clinically
apy. These results emphasize that clinicians should attempt to use stable patients who had symptoms at rest or with minimal exertion
 189
to carvedilol or placebo. Like the other studies, COPERNICUS was Components that are critical for successful β-blocker therapy
stopped prematurely after carvedilol produced a 35% relative reduc- include appropriate patient selection, drug initiation and titration,

CHAPTER 16
tion in mortality. Carvedilol was well tolerated in this population, and patient education. β-Blockers should be initiated in stable
with fewer participants receiving carvedilol compared to placebo patients who have no or minimal evidence of fluid overload.1
requiring permanent discontinuation of study medication. Although β-blockers are typically started in the outpatient setting,
Data supporting the use of β-blockers in asymptomatic patients there are data indicating that initiation of a β-blocker prior to
with left ventricular systolic dysfunction (stage B) come from a discharge in patients who are hospitalized for decompensated heart
study of carvedilol in post-MI patients with a decreased LVEF.62 failure increases β-blocker usage compared with outpatient initia-
While the primary end point of all-cause mortality or hospital tion without increasing the risk of serious adverse effects.69 How-
admission for cardiovascular problems was similar in the carvedilol ever, β-blockers should not be started in patients who are

Heart Failure
and placebo groups, carvedilol significantly reduced all-cause mor- hospitalized in the intensive care unit or recently required intrave-
tality alone compared to placebo. Cardiovascular mortality and nous inotropic support. In unstable patients, other heart failure
nonfatal MI were also lower among carvedilol-treated patients. therapy should be optimized and then β-blocker therapy reevalu-
In addition to improving survival, β-blockers improve multiple ated once stability is achieved.
other end points. All the large clinical trials demonstrated 15% to Initiation of a β-blocker at normal doses in patients with heart
20% reductions in all-cause hospitalization and 25% to 35% reduc- failure may to lead to symptomatic worsening or acute decompen-
tions in hospitalizations for worsening heart failure with β-blocker sation owing to the drug’s negative inotropic effect. For this reason,
therapy.60,63,64 Studies also show consistent improvements in left β-blockers are listed as drugs that may exacerbate or worsen heart
ventricular systolic function with β-blockers, with increases in failure (see Table 16–3). To minimize the likelihood for acute
LVEF of 5 to 10 units (e.g., from an ejection fraction of 20% to 25% decompensation, β-blockers should be started in very low doses
or 30%) after several weeks to months of therapy. β-Blockers have with slow upward dose titration. Table 16–6 describes the starting
also been shown to decrease ventricular mass, improve the spheric- and target doses. Of note, the smallest commercially available tablet
ity of the ventricle, and reduce systolic and diastolic volumes (left of bisoprolol is a scored 5-mg tablet. Because the recommended
ventricular end-systolic volume and left ventricular end-diastolic starting dose of 1.25 mg/day is not readily available, bisoprolol is the
volume).65,66 These effects are often collectively called reverse remod- least commonly used of the three agents and, in fact, is not approved
eling, referring to the fact that they return the heart toward more by the Food and Drug Administration (FDA) for use in heart
normal size, shape, and function. failure. Thus, therapy is generally limited to either carvedilol or
The effects of β-blockers on symptoms and exercise tolerance metoprolol CR/XL, and there is no compelling evidence that one
varies among studies. Many studies show improvements in NYHA drug is superior to the other. A controlled-release formulation of
functional class, patient symptom scores, or quality-of-life assess- carvedilol (carvedilol CR) that allows once-daily dosing was recently
ments (such as the Minnesota Living with Heart Failure Question- FDA-approved, and pharmacokinetic studies demonstrate similar
naire), and exercise performance, as assessed by the 6-minute walk degrees of drug exposure with the controlled- and immediate-
test.63–65 Other investigators find significant reductions in mortality release formations of the drug.70 Carvedilol CR should be consid-
with β-blockers but no significant improvement in symptoms.67 As ered in patients with difficulty maintaining adherence to the imme-
such, it is important to educate patients that β-blocker therapy is diate-release formulation.
expected to positively influence disease progression and survival β-Blocker doses should be doubled no more often than every 2
even if there is little to no symptomatic improvement. weeks, as tolerated, until the target or maximally tolerated dose is
The majority of participants in β-blocker trials were on ACE reached. Target doses are those associated with reductions in mor-
inhibitors at baseline as the benefits of ACE inhibitors were proven tality in placebo-controlled clinical trials. It is important to make
prior to β-blocker trials. Whether the strategy of starting a β-blocker every effort to titrate doses up to target whenever possible in order
prior to an ACE inhibitor is safe and effective has been debated. This to provide maximal survival benefits. In addition, there is evidence
issue was addressed in CIBIS III, in which patients with mild to that response to β-blockers is dose dependent, with greater reduc-
moderate symptoms were randomized to initial therapy with either tions in hospitalization rates and improvements in LVEF at higher
bisoprolol or enalapril.68 The two strategies produced similar rates of doses. However, even low doses appear to prolong survival com-
death or hospitalization. However, the trial failed to satisfy the pared to placebo, and thus, any dose of β-blocker is likely to provide
prespecified statistical criterion for noninferiority of initial therapy some benefit.71 Data with metoprolol suggest that heart rate may
with a β-blocker compared to an ACE inhibitor. In the absence of serve as a guide to the degree of β-blockade and that lower β-
more compelling evidence, ACE inhibitors should be started first in blocker doses might be considered reasonable if the reduction in
most patients. Initiating a β-blocker first may be advantageous for heart rate indicates a good response to β-blocker therapy.71
patients with evidence of excessive SNS activity (e.g., tachycardia) Good communication between the patient and healthcare pro-
and may also be appropriate for patients whose renal function or vider(s) is particularly important for successful therapy. Patients
potassium concentrations preclude starting an ACE inhibitor at that
time. However, the risk for decompensation during β-blocker initia- TABLE 16-6 Initial and Target Doses for β-Blockers Used in
tion may be greater in the absence of preexisting ACE inhibitor Treatment of Heart Failure
therapy, and careful monitoring is essential.
Drug Initial Dosea Target Dose
The mechanism by which β-blockers exert their therapeutic
benefit is unclear. β-Blockers antagonize the detrimental effects of Bisoprolol b
1.25 mg daily 10 mg daily
the SNS described earlier in the chapter. To this end, potential Carvedilol b 3.125 mg bid 25 mg bid c
mechanisms to explain the favorable effects of β-blockers in heart Metoprolol succinate CR/XLb 12.5-25 mg daily d 200 mg daily
failure include antiarrhythmic effects, attenuating or reversing ven- a
Doses should be doubled approximately every 2 weeks, or as tolerated by the patient, until the
tricular remodeling, decreasing myocyte death from catecholamine- highest tolerated or target dose is reached.
b
induced necrosis or apoptosis, preventing fetal gene expression, Regimens proven in large trials to reduce mortality.
c
Target dose for patients who weigh >85 kg is 50 mg bid.
improving left ventricular systolic function, decreasing heart rate d
In Metroprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), the
and ventricular wall stress thereby reducing myocardial oxygen majority of class II patients were given 25 mg daily, whereas the majority of class III patients were
demand, and inhibiting plasma renin release.1 given 12.5 mg daily as their starting dose.
 190
should understand that dose up-titration is a long, gradual process Although a number of ARBs are currently available, the primary
and that achieving the target dose is important to maximize the clinical trials supporting the use of these agents in heart failure used
SECTION 2

benefits of therapy. Patients should also be aware that response to either valsartan or candesartan.72 The Valsartan Heart Failure Trial
therapy may be delayed and that heart failure symptoms may actually (Val-HeFT) evaluated whether the addition of valsartan to standard
worsen during the initiation period. In the event of worsening background heart failure therapy (which included an ACE inhibitor
symptoms, patients who understand the potential benefits of long- in 93% and a β-blocker in 35% of patients) improved survival.74 The
term β-blocker therapy may be more likely to continue treatment. addition of valsartan had no effect on all-cause mortality but pro-
In summary, the data provide clear evidence that β-blockers slow duced a 13% reduction in morbidity and mortality (principally as a
disease progression, decrease hospitalizations, and improve survival in result of reductions in heart failure hospitalizations). Subgroup
heart failure. β-Blockers have also been shown to improve quality of analysis showed that the benefits were greatest in those patients not
Cardiovascular Disorders

life in many patients with heart failure, although this is not a universal receiving background ACE inhibitor therapy. Based on these results,
finding. Based on these data, β-blockers are recommended as standard valsartan is now approved for use in patients with NYHA classes II to
therapy for all patients with systolic dysfunction, regardless of the IV heart failure. The Valsartan in Acute Myocardial Infarction
severity of their symptoms. Clinical trial experience shows that target (VALIANT) trial compared the effect of valsartan, captopril, and the
β-blocker doses can be achieved in the majority of patients provided combination of the two agents in post-MI patients with symptomatic
that appropriate initiation, titration, and education are implemented. heart failure, reduced left ventricular systolic function, or both, in a
noninferiority trial design.47 The primary end point of total mortality
occurred in 19.3% of patients receiving valsartan and captopril,
Drug Therapies to Consider for 19.5% of captopril-treated patients, and 19.9% of the valsartan
Selected Patients group. Thus, in this high-risk post-MI population, valsartan was as
 Angiotensin II Receptor Blockers The use of ARBs in heart effective as captopril in reducing the risk of death, but combination
failure has generated great interest and controversy.72 The crucial therapy only increased the risk of adverse effects and did not improve
role of the RAAS in heart failure development and progression is well survival compared to monotherapy with either agent. Based on these
established, as are the benefits of inhibiting this system with ACE findings, valsartan is now approved for use in post-MI patients with
inhibitors. Although ACE inhibitors decrease angiotensin II produc- left ventricular failure or left ventricular dysfunction.
tion in the short-term, these agents do not completely suppress The Candesartan in Heart Failure: Assessment of Reduction in
generation of this hormone. With chronic administration of ACE Mortality and Morbidity (CHARM) trials were designed as three
inhibitors, ACE escape, characterized by increases in circulating studies to compare candesartan with placebo in patients with sympto-
angiotensin II and aldosterone, often occurs.12,73 In addition, angio- matic heart failure (Table 16–7).75 Both the CHARM-Added (patients
tensin II can be formed in a number of tissues, including the heart, receiving background ACE-inhibitor therapy)76 and CHARM-Alter-
through non–ACE-dependent pathways (e.g., chymase, cathepsin, native (patients intolerant of ACE-inhibitor therapy)77 trials found
and kallikrein).12 Therefore, blockade of the detrimental effects of significant reductions in the primary end point of cardiovascular death
angiotensin II by ACE inhibition is incomplete. In addition, trouble- or hospitalization for heart failure in patients receiving candesartan,
some adverse effects of ACE inhibitors such as cough are linked to although the benefit was modest in CHARM-Added. No significant
accumulation of bradykinin.13 The ARBs block the angiotensin II benefit of candesartan was observed in CHARM-Preserved (patients
receptor subtype 1 (AT1), preventing the deleterious effects of with LVEF >40%).78 Overall, candesartan was well tolerated but its use
angiotensin II, regardless of its origin. Because ARBs do not inhibit was associated with an increased risk of hypotension, hyperkalemia,
the ACE enzyme, these agents do not appear to affect bradykinin.12,73 and renal dysfunction. On the basis of these results, candesartan is now
By inhibiting both the formation of angiotensin II and its effects on approved for use in heart failure.
the AT1 receptor, combination therapy with an ACE inhibitor plus Although ACE inhibitors remain first-line therapy in patients
an ARB offers a theoretical advantage over either agent used alone with stage C heart failure and reduced LVEF, the current ACC/AHA
through more complete blockade of the deleterious effects of angio- guidelines recommend the use of ARBs in patients who are unable
tensin II. Also, by directly blocking AT1 receptors, ARBs would allow to tolerate ACE inhibitors.1 Similarly, ARBs are alternatives to ACE
unopposed stimulation of AT2 receptors, causing vasodilation and inhibitors in patients with stages A and B heart failure.1 Cough and
inhibition of ventricular remodeling.12 Because bradykinin-related angioedema are the most common causes of ACE inhibitor intoler-
adverse effects of ACE inhibitors such as angioedema and cough lead ance. Caution should be exercised when ARBs are used in patients
to drug discontinuation in some patients, the potential for an ARB to with angioedema from ACE inhibitors as some cross-reactivity has
produce similar clinical benefits with fewer side effects is of great been reported.77,79 ARBs are not an alternative in patients with
interest. Whether ARBs add incremental benefit to current estab- hypotension, hyperkalemia, or renal insufficiency secondary to ACE
lished therapies or are superior (or equivalent) to ACE inhibitors is inhibitors because they are as likely to cause these adverse effects.
the focus of several clinical trials.72 Also, the combined use of ACE inhibitors, ARBs, and aldosterone

TABLE 16-7 Clinical Trials of Candesartan in Heart Failure

Results (%)
Adjusted
Trial Drug Patient Population Primary End Point Drug Placebo Hazard Ratio P Value
CHARM-Added Candesartan vs. placebo Symptomatic HF and EF ≤40% on CV death or hospital 37.9 42.3 0.85 0.01
ACE inhibitors admission for HF
CHARM-Alternative Candesartan vs. placebo Symptomatic HF and EF ≤40%, CV death or hospital 33.0 40.0 0.70 <0.0001
ACE-inhibitor intolerant admission for HF
CHARM-Preserved Candesartan vs. placebo Symptomatic HF and EF ≤40% CV death or hospital 22.0 24.3 0.86 0.051
admission for HF
CHARM-Overall Candesartan vs. placebo Combined from above 3 trials All-cause mortality 23.0 25 0.90 0.032
ACE, angiotensin-converting enzyme; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity trial; CV, cardiovascular; EF, ejection fraction; HF, heart failure.
 191
17
antagonists is not recommended because of the increased risk of patients with left ventricular dysfunction after MI. To be eligible
renal dysfunction and hyperkalemia.1 The specific drugs and doses for study participation, patients had to have either evidence of heart

CHAPTER 16
proven to be effective in clinical trials should be used. failure or diabetes. More than 6,600 patients were randomized
The role of ARBs as an adjunct to ACE inhibitors remains within 3 to 14 days of MI to eplerenone, titrated to 50 mg/day, or
controversial. The CHARM-Added trial found the addition of can- placebo in addition to standard therapy, which usually included an
desartan to ACE inhibitor and β-blocker therapy produced incre- ACE inhibitor, β-blocker, aspirin, and diuretics. As occurred in
mental reductions in cardiovascular death and hospitalizations for RALES, patients with serum creatinine concentrations greater than
heart failure, but did not improve overall survival.76 In contrast, 2.5 mg/dL or serum potassium concentrations greater than 5 mEq/
neither the VALIANT nor the Val-HeFT trials found additional L were excluded. Treatment with eplerenone was associated with a
benefit from the addition of valsartan to ACE-inhibitor treat- significant 15% relative reduction in the risk for death from any

Heart Failure
ment.47,74 These results suggest the addition of an ARB to optimal cause and a 15% reduction in the risk of hospitalization from heart
heart failure therapy (ACE inhibitors, β-blockers, diuretics, etc.) failure. Serious hyperkalemia occurred in 5.5% of eplerenone-
offers, at best, marginal benefits with increased risk of adverse effects. treated patients and 3.9% of placebo-treated patients. Eplerenone
The current guidelines indicate that the addition of an ARB can be was not associated with gynecomastia.
considered in patients who remain symptomatic despite receiving The benefits of aldosterone antagonists in heart failure are not
conventional heart failure pharmacotherapy. Some clinicians suggest just a result of the inhibition of aldosterone’s actions in the heart
that the addition of an aldosterone antagonist to ACE inhibitor and resulting in inhibition of aldosterone-mediated cardiac fibrosis and
β-blocker therapy is preferred over that of an ARB. The proven ventricular remodeling. Recent evidence points to an important role
survival benefit of aldosterone antagonists in patients with NYHA of aldosterone antagonists in attenuating the systemic proinflam-
classes III to IV heart failure (Randomized Aldactone Evaluation matory state and oxidative stress caused by aldosterone.14,80 And
Study [RALES] trial) and in post-MI patients with left ventricular while spironolactone historically has been viewed as a diuretic, this
systolic dysfunction (Eplerenone Post-Acute Myocardial Infarction is believed to contribute little to its benefits in heart failure, in part,
Heart Failure Efficacy and Survival Study [EPHESUS] trial), as because the doses used have minimal diuretic effect.16 Thus, as with
discussed in the following section, supports this approach.16,17 ACE inhibitors and β-blockers, the data on aldosterone antagonists
also support the neurohormonal model of heart failure.

Aldosterone Antagonists Spironolactone and eplerenone are The clinical trial data suggest that the use of aldosterone antago-
aldosterone antagonists that work by blocking the mineralocorticoid nists in heart failure is associated with minimal risk. However, data
receptor, the target site for aldosterone. In the kidney, aldosterone from clinical practice suggest otherwise. In particular, an observa-
antagonists inhibit sodium reabsorption and potassium excretion. tional study of approximately 1.3 million elderly patients in the
Although the diuretic effects with low doses of aldosterone antago- Ontario Drug Benefit Program found that the spironolactone pre-
nists are minimal, the potassium-sparing effects can have significant scription rate increased approximately fourfold immediately after
consequences as discussed below. In the heart, aldosterone antago- the publication of RALES.82 The increase in the prescription rate
nists inhibit cardiac extracellular matrix and collagen deposition, was accompanied by nearly threefold increases in the rate of
thereby attenuating cardiac fibrosis and ventricular remodeling.80 hospital admissions and the rate of death related to hyperkalemia.
Spironolactone also interacts with androgen and progesterone recep- Further evidence of spironolactone-induced hyperkalemia comes
tors, which may lead to gynecomastia and other sexual side effects in from small case series showing that 25% to 35% of patients treated
some patients. Such adverse effects are less frequent with eplerenone outside the controlled clinical trial setting develop hyperkalemia
owing to its low affinity for the progesterone and androgen receptors. (>5 mEq/L) and that 10% to 12% develop serious hyperkalemia.83,84
Evidence that ACE inhibitors incompletely suppress aldosterone Potential factors contributing to the high incidence of hyperkale-
provided the impetus for examining the benefits of adding an mia in clinical practice include the initiation of aldosterone antago-
aldosterone antagonist to ACE inhibitor therapy.81 RALES random- nists in patients with impaired renal function or high potassium
ized more than 1,600 patients with current or recent class IV heart concentrations and the failure to decrease or stop potassium supple-
failure to aldosterone blockade with spironolactone 25 mg/day or ments when starting aldosterone antagonists. Other risk factors for
placebo.16 Patients were also treated with standard therapy, usually hyperkalemia include diabetes, older age, inadequate laboratory
including an ACE inhibitor, loop diuretic, and digoxin. Those with monitoring, and concomitant use of high-dose ACE inhibitors, β-
a serum creatinine concentration above 2.5 mg/dL or a serum blockers, NSAIDs, or cyclooxygenase-2 inhibitors. The ACC/AHA
potassium concentration above 5 mEq/L were excluded. The study recently recommended strategies to minimize the risk for hyperkale-
was stopped prematurely after an average followup of 24 months mia with aldosterone antagonists in heart failure.1 Table 16–8 sum-
because of a significant 30% reduction in the primary end point of marizes these strategies. Chief among these recommendations is to
total mortality with spironolactone. Spironolactone reduced mor- avoid aldosterone antagonists in patients with renal dysfunction. It is
tality as a consequence of both progressive heart failure and sudden important to emphasize here that serum creatinine may overestimate
cardiac death. Spironolactone also produced a 35% reduction in renal function in the elderly and in patients with decreased muscle
hospitalizations for worsening heart failure and significant sympto- mass, in whom creatinine clearance should serve as a guide for the
matic improvement, as assessed by changes in NYHA functional appropriateness of aldosterone antagonist therapy. The risk for
class. The low dose of spironolactone was well tolerated in RALES. hyperkalemia is dose dependent, and the morbidity and mortality
The most common adverse effect was gynecomastia, which reductions with aldosterone antagonists in clinical trials occurred at
occurred in 10% of men on spironolactone, compared to 1% of low doses (i.e., spironolactone 25 mg/day and eplerenone 50 mg/
men on placebo, and led to treatment discontinuation in 2% of day). Therefore, the doses of aldosterone antagonists should be
patients. There were statistically (but not clinically) significant limited to those associated with beneficial effects so as to decrease the
increases in serum creatinine (by 0.05 to 0.10 mg/dL) and potas- risk for hyperkalemia.
sium concentrations (by 0.30 mEq/L) with spironolactone. The Only 10% of RALES participants were taking β-blockers at
incidence of serious hyperkalemia (>6 mEq/L) was minimal and did baseline because the benefits of β-blockers in heart failure were not
not differ between spironolactone- and placebo-treated groups. appreciated fully at the time the trial began.16 β-Blockers inhibit
More recently, the EPHESUS trial evaluated the effect of selective plasma renin release and may provide additional suppression of the
antagonism of the mineralocorticoid receptor with eplerenone in renin–angiotensin–aldosterone system when used with ACE inhib-
 192

TABLE 16-8 Recommended Strategies for Reducing the Risk for chronic heart failure. The results of the Digitalis Investigational
Hyperkalemia with Aldosterone Antagonists Group (DIG) trial helped clarify the role of digoxin in this setting.85
SECTION 2

The view of digoxin has also shifted over the past decade. Although it
• Avoid starting aldosterone antagonists in patients with any of the following:
was historically considered useful in heart failure because of its
• Serum creatinine concentration >2.0 in women or >2.5 mg/dL in men or a
positive inotropic effects, it now seems clear that its real benefits in
creatinine clearance <30 mL/min
• Recent worsening of renal function heart failure are related to its neurohormonal modulating effects.
• Serum potassium concentration ≥5.0 mEq/L The efficacy of digoxin in patients with heart failure and supraven-
• History of severe hyperkalemia tricular tachyarrhythmias such as atrial fibrillation is well established
• Start with low doses (12.5 mg/day for spironolactone and 25 mg/day for and widely accepted. Its role in heart failure patients with normal
eplerenone), especially in the elderly and in those with diabetes or a creatinine sinus rhythm has been considerably more controversial. Until the
Cardiovascular Disorders

clearance <50 mL/min 1980s, most data supporting efficacy of digoxin in these patients came
• Decrease or discontinue potassium supplements when starting an aldosterone from anecdotal evidence and seriously flawed or uncontrolled studies.
antagonist Since then, a number of clinical trials have shown that digoxin
• Avoid concomitant use of NSAIDs or COX-2 inhibitors improves LVEF, quality of life, exercise tolerance, and heart failure
• Avoid concomitant use of high-dose ACE inhibitors or ARBs
symptoms.86,87 However, these studies involved small numbers of
• Avoid triple therapy with an ACE inhibitor, ARB, and aldosterone antagonist
• Monitor serum potassium concentrations and renal function within 3 days and 1
patients followed for short time periods with many of the patients
week after the initiation or dose titration of an aldosterone antagonist or any other being withdrawn from preexisting digoxin treatment upon entering
medication that could affect potassium homeostasis; thereafter, potassium con- the trial. Although these trials demonstrated hemodynamic and
centrations and renal function should be monitored monthly for the first 3 symptomatic improvement in heart failure patients receiving digoxin,
months, and then every 3 months an unresolved issue was the unknown effect of digoxin on mortality.
• If potassium exceeds 5.5 mg/dL at any point during therapy, discontinue any This was of particular concern given the increased mortality seen with
potassium supplementation or, in the absence of potassium supplements, reduce other positive inotropic drugs, and finally led to organization and
or stop aldosterone antagonist therapy performance of the DIG trial to determine the effects of digoxin on
• Counsel patients to survival in patients with heart failure in sinus rhythm.85
• Limit intake of high-potassium-containing foods and salt substitutes
The DIG trial was a double-blind, randomized, placebo-controlled
• Avoid the use of over-the-counter nonsteroidal antiinflammatory drugs
trial with the primary end point of all-cause mortality.85 Patients (n =
• Temporarily discontinue aldosterone antagonist therapy if diarrhea develops
or diuretic therapy is interrupted 6,800) with heart failure symptoms and an ejection fraction of 45% or
less were eligible and were followed for a mean of 37 months. Most
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; COX, cyclooxygenase; patients received background therapy with diuretics and ACE inhibi-
NSAIDs, nonsteroidal antiinflammatory drugs.
Adapted from Hunt SA, Abraham WT, Chin MH et al. Circulation 2005;112:e154–235.
tors. The mean serum digoxin concentration achieved was 0.8 ng/mL
after 12 months of therapy. No significant difference in all-cause
itors. Thus, there has been some speculation about whether spiro- mortality was found between patients receiving digoxin and placebo
nolactone will provide further benefit in patients receiving both (34.8% and 35.1%, respectively). A trend toward lower mortality as a
ACE inhibitors and β-blockers. However, data from EPHESUS consequence of worsening heart failure was observed in the digoxin
provide some clarity to this issue, as the majority of EPHESUS group, although this was offset by a trend toward an increased
participants were on β-blockers at baseline and the trial still mortality from other cardiovascular causes (presumably arrhythmias)
demonstrated significant reductions in mortality with the addition in patients receiving digoxin. Hospitalizations for worsening heart
of eplerenone.17 failure were reduced 28% by digoxin compared to placebo (P <
Current guidelines state that it is reasonable to add an aldoster- 0.001), whereas hospitalizations for other cardiovascular causes were
one antagonist to standard therapy in select patients provided that increased in the digoxin group. In all, 64.3% of digoxin-treated
potassium and renal function can be carefully monitored.1 Based on patients were hospitalized compared to 67.1% of patients receiving
data from RALES and EPHESUS, low-dose aldosterone antagonists placebo (P = 0.006). Therefore, DIG is the first trial to show that a
may be appropriate for two groups of patients: those with moder- positive inotropic agent does not increase mortality and actually
ately severe to severe heart failure who are receiving standard decreases morbidity in patients with heart failure.
therapy and those with left ventricular dysfunction early after MI.1 Although digoxin does not improve survival in heart failure
For patients who fall outside the populations studied in these patients, multiple post-hoc analyses of data from studies evaluating
clinical trials, there are no clear guidelines on aldosterone antago- the effect of digoxin withdrawal have helped clarify the role of
nist use. Trials to address the efficacy of aldosterone antagonism in digoxin use for patients in sinus rhythm.86 Collectively, these studies
patients with mild to moderate heart failure symptoms or in suggested the drug produces important symptomatic benefits and
patients with preserved left ventricular systolic function are ongo- that digoxin withdrawal increased the risk of treatment failure and
ing. Although there are currently no data on the use of aldosterone deterioration of exercise capacity and ejection fraction. Furthermore,
antagonists in patients with class I, class II, or stable class III heart the risk of symptomatic exacerbation of heart failure after digoxin
failure, it might be reasonable to consider their use in these patients discontinuation was highest in patients with the most severe symp-
who require potassium supplementation. The premise for use in toms.86 Based on this evidence, digoxin can be beneficial in patients
this setting would be that it might be possible to reduce or eliminate with symptomatic or stage C heart failure and reduced LVEF in
potassium supplementation while potentially providing additional addition to standard therapy to reduce heart failure hospitalizations.
benefit with respect to altering the disease course. Furthermore, digoxin should not be used in patients with a normal
LVEF, sinus rhythm, and no history of heart failure symptoms,

Digoxin In 1785, William Withering was the first to report because the risk is not balanced by any known benefit.1
extensively on the use of foxglove (Digitalis purpurea) for the treat- Two retrospective analyses of the combined PROVED/RADI-
ment of dropsy (i.e., edema). Although digitalis glycosides have been ANCE database88 and the DIG Trial database89 offer additional
in clinical use for more than 200 years, not until the 1920s were they insights into the clinical benefit of low serum digoxin concentra-
clearly demonstrated to have a positive inotropic effect on the heart. tions. While all patients in the Prospective Randomized Study of
Furthermore, it was not until the late 1980s that clinical trials were Ventricular Failure and Efficacy of Digoxin (PROVED) and Ran-
conducted to critically evaluate the role of digoxin in the therapy of domized Assessment of Digoxin on Inhibitors of the Angiotensin
 193
Converting Enzyme (RADIANCE) trials who continued to take  Nitrates and Hydralazine Nitrates and hydralazine were
digoxin did significantly better than those who were withdrawn, combined originally in the treatment of heart failure because of

CHAPTER 16
those who had plasma digoxin concentrations between 0.5 and 0.9 their complementary hemodynamic actions. Nitrates, by serving as
ng/mL were just as likely to be free of worsening heart failure as nitric oxide donors, activate guanylate cyclase to increase cyclic
those with higher plasma concentrations. Retrospective analysis of guanosine monophosphate in vascular smooth muscle. This results
the DIG trial database suggests that a serum digoxin concentration in venodilation and reductions in preload. Hydralazine is a direct-
of 0.5 to 0.8 ng/mL may be associated with a reduction in mortality, acting vasodilator that acts predominantly on arterial smooth mus-
whereas higher concentrations may increase mortality.89 In another cle to reduce SVR and increase stroke volume and cardiac output
post-hoc analysis of the DIG trial, digoxin therapy was associated (see Fig. 16–1). Hydralazine also has antioxidant properties and
with an increased risk of death in women, but not in men.90 This appears to prevent nitrate tolerance.98 Evidence also suggests that

Heart Failure
finding was refuted in another analysis of the same data which the combination of hydralazine and nitrates may exert beneficial
demonstrated that a beneficial effect of digoxin was evident at effects beyond their hemodynamic actions by interfering with the
serum concentrations from 0.5 to 0.9 ng/mL, whereas serum con- biochemical processes associated with heart failure progression.1,99
centrations greater than or equal to 1.2 ng/mL were harmful.91 More The efficacy of the combination of hydralazine and isosorbide
recently, the most comprehensive reanalysis of the DIG trial data- dinitrate (ISDN) was evaluated in three large, randomized heart
base found that serum concentrations of 0.5 to 0.9 ng/mL were failure trials. The first trial predated the use of ACE inhibitors and β-
associated with lower mortality, all-cause hospitalizations, and heart blockers in heart failure and found that the combination of hydral-
failure hospitalizations, whereas serum concentrations greater than azine 75 mg and ISDN 40 mg, each given four times daily, reduced
or equal to 1 ng/mL were associated with lower heart failure mortality in patients receiving diuretics and digoxin compared to
hospitalizations with no effect on mortality. Serum concentrations placebo.100 However, a subsequent trial comparing the combination
of 0.5 to 0.9 ng/mL had no interaction with LVEF greater than 45% with an ACE inhibitor demonstrated greater mortality reduction
or gender.92 Of the 7,788 patients randomized in the DIG trial, 988 with the ACE inhibitor.101 Post-hoc analysis of these trials suggested
patients had a LVEF greater than 45%; digoxin had no effect on that the combination of hydralazine and ISDN was particularly
mortality or hospitalization in these patients.93 effective in African Americans, and led to examining the efficacy of
These results suggest that most of the benefit from digoxin is adding the combination to standard therapy in this racial group.
achieved at low plasma concentrations and little additional effect is The African American Heart Failure Trial (A-HeFT) randomized
achieved with higher doses. Thus, for most patients, the target 1,050 self-identified African Americans with class III or IV heart
digoxin plasma concentration should be 0.5 to 1.0 ng/mL. This more failure to hydralazine plus ISDN or placebo, each in addition to
conservative target would also be expected to decrease the risk of standard therapy, usually including an ACE inhibitor (or ARB), β-
adverse effects from digoxin toxicity; in fact, more recent assessment blocker, and diuretic, with or without digoxin and spironolactone.99
of the rate of digoxin toxicity suggests a significant decline in the The trial used a fixed dose combination product, BiDil®, that
overall incidence.94 In most patients with normal renal function, this contains hydralazine 37.5 mg and ISDN 20 mg. Therapy was initi-
plasma concentration range can be achieved with a daily dose of ated as a single tablet given three times daily, then titrated to two
0.125 mg. Patients with decreased renal function, the elderly, and tablets (hydralazine 75 mg/ISDN 40 mg) three times daily if toler-
those who are receiving interacting drugs (e.g., amiodarone) should ated. The trial was terminated early after a mean followup of 10
receive 0.125 mg every other day. In patients with atrial fibrillation months because of a significant (43%) reduction in all-cause mortal-
and a rapid ventricular response, the historic practice of increasing ity in patients receiving hydralazine/ISDN compared to placebo. The
digoxin doses (and concentrations) until rate control is achieved is primary composite end point of mortality, hospitalizations for heart
no longer recommended. Digoxin alone is often ineffective to control failure, and quality of life was also significantly improved with the
ventricular response in patients with atrial fibrillation and increasing combination product. Based on these results, BiDil® was approved
the dose only increases the risk of toxicity. Digoxin combined with a by the FDA to treat heart failure exclusively in African Americans.
β-blocker or amiodarone is superior to either agent alone for control- The mechanism for the beneficial effects of hydralazine/ISDN is
ling ventricular response in patients with atrial fibrillation and heart believed to relate to an increase in nitric oxide bioavailability second-
failure.95 Consequently, target digoxin plasma concentrations are the ary to nitric oxide donation from ISDN and a hydralazine-mediated
same regardless of whether the patient is in sinus rhythm or atrial reduction in oxidative stress.98 Nitric oxide attenuates myocardial
fibrillation. Several equations and nomograms have been proposed remodeling and may play a protective role in heart failure.102 It is
to estimate digoxin maintenance doses based on estimated renal suggested that African Americans have less nitric oxide than do non-
function for a particular patient and population pharmacokinetic African Americans, and thus, may derive particular benefit from
parameters. These methods are extensively reviewed elsewhere.96 therapy that enhances nitric oxide bioavailability. Whether the bene-
Recently, investigators developed a digoxin dosing nomogram that fits of adding hydralazine/ISDN to standard therapy extend to non-
targets a lower digoxin plasma concentration.97 In the absence of African Americans remains to be determined.
supraventricular tachyarrhythmias, a loading dose is not indicated Guidelines from the Heart Failure Society of America recom-
because digoxin is a mild inotropic agent that will produce gradual mend the addition of hydralazine and ISDN as part of standard
effects over several hours, even after loading. therapy, including ACE inhibitors, in African Americans with
Digoxin’s place in the pharmacotherapy of chronic heart failure moderately severe to severe heart failure.33 The addition of hydral-
can be summarized for two patient groups. In patients with heart azine and ISDN is also reasonable in patients of other ethnicities
failure and supraventricular tachyarrhythmias such as atrial fibrilla- who continue to have symptoms despite optimized therapy with an
tion, it should be considered early in therapy to help control ACE inhibitor (or ARB) and β-blocker.1 For patients who are
ventricular response rate. For patients in normal sinus rhythm, unable to tolerate an ACE inhibitor because of cough or angio-
although digoxin does not improve survival, its effects on symptom edema, an ARB is recommended as the first-line alternative.1
reduction and clinical outcomes are evident in patients with mild to Hydralazine and ISDN is appropriate as first-line therapy in patients
severe heart failure. Consequently, it should be used in conjunction unable to tolerate either an ACE inhibitor or ARB because of renal
with other standard heart failure therapies, including diuretics, ACE insufficiency, hyperkalemia, or possibly hypotension.
inhibitors, and β-blockers, in patients with symptomatic heart There are several potential obstacles to successful therapy with
failure to reduce hospitalizations. hydralazine and ISDN in heart failure. First is the need for frequent
 194
dosing, with the fixed-dose combination dosed three times daily hypertension. The presence of atrial fibrillation in patients with
and the individual drugs dosed four times daily in clinical trials. heart failure is associated with a worse long-term prognosis.1 The
SECTION 2

Second, adverse effects are common with hydralazine/ISDN, with combination of atrial fibrillation and heart failure may exert a
headache, dizziness, and gastrointestinal distress occurring more number of detrimental effects, including increased risk of throm-
frequently with hydralazine/ISDN than with placebo in clinical boembolism secondary to stasis of blood in the atria, a reduction in
trials.99,100 A third potential obstacle is the increased cost of the cardiac output because of loss of the atrial contribution to ventric-
fixed-dose combination product compared to the individual drugs ular filling, and hemodynamic compromise from the rapid ventric-
purchased separately, which may preclude the use of the combina- ular response. Moreover, heart failure exacerbations and atrial
tion product in some patients. Treatment with the two separate fibrillation are closely linked and it is often difficult to determine
drugs rather than the combination product may compromise which disorder caused the other. For example, worsening heart
Cardiovascular Disorders

adherence to therapy. Thus, if therapy with hydralazine and ISDN is failure results in volume overload which, in turn, causes atrial
deemed appropriate, patients may need continual reinforcement to distension and increases the risk of atrial fibrillation. Similarly, atrial
maintain good medication adherence, especially if the individual fibrillation with a rapid ventricular response can reduce cardiac
drugs are used. It is important to recognize that none of the above output and lead to heart failure exacerbation. Thus, optimal man-
trials incorporated a nitrate-free interval in the dosing regimen. agement of both conditions is required with careful attention paid
to control of ventricular response and anticoagulation for stroke
prevention (see Chap. 19).95
Treatment of Concomitant Disorders Recent studies suggest that ACE inhibitors, ARBs, and β-blockers
Heart failure is often accompanied by other disorders whose natural decrease the incidence of atrial fibrillation in patients with heart
history or therapy may affect morbidity and mortality. In selected failure, providing further support for their use in these patients.103,104
patients, optimal management of these concomitant disorders may Digoxin is frequently used to slow ventricular response in patients
have a profound impact on heart failure symptoms and outcomes. with heart failure and atrial fibrillation. However, it is more effective
at rest than with exercise and it does not affect the progression of
Hypertension Although ischemic heart disease has replaced
heart failure. β-Blockers are more effective than digoxin and have the
hypertension as the most common cause of heart failure, still nearly
added benefits of improving morbidity and mortality. Combination
two-thirds of heart failure patients have current hypertension or a
therapy with digoxin and a β-blocker may be more effective for rate
previous history of hypertension.1 Hypertension can contribute
control than either agent used alone. Calcium channel blockers with
directly to the development of heart failure and also contributes
negative inotropic effects, such as verapamil or diltiazem, should be
indirectly by increasing the risk of coronary artery disease. Pharma-
avoided. Amiodarone is a reasonable alternative for rate control in
cotherapy of hypertension in patients with heart failure should
those patients who are not responding to digoxin and/or β-blockers
initially involve agents that can treat both disorders such as ACE
or who have contraindications to these agents.95 Appropriate selec-
inhibitors, β-blockers, and diuretics. If control of hypertension is
tion of antithrombotic therapy that considers the presence of risk
not achieved after optimizing treatment with these agents, the
factors for thromboembolism in an individual patient is also
addition of an ARB, aldosterone antagonist, isosorbide dinitrate/
required.95
hydralazine, or a second-generation calcium channel blocker such
Because of the close association between atrial fibrillation, heart
as amlodipine (or possibly felodipine) should be considered. Medi-
failure exacerbations, and hospitalizations, many clinicians prefer
cations that should be avoided include the calcium channel blockers
maintenance of sinus rhythm with antiarrhythmic drugs to the rate-
with negative inotropic effects (e.g., verapamil, diltiazem, and most
control approach in the treatment of patients with both disorders.
dihydropyridines) and direct-acting vasodilators (e.g., minoxidil)
However, it must be noted that the benefits of restoring and
that cause sodium retention.
maintaining sinus rhythm remain unclear in this population and is
Angina Coronary artery disease is the most common heart failure not without risk. Although the Atrial Fibrillation Follow-up Inves-
etiology. Consequently, appropriate management of coronary disease tigation of Rhythm Management (AFFIRM) study showed no
and its risk factors is an important strategy for the prevention and difference in outcomes between the rhythm control and rate control
treatment of heart failure. Coronary revascularization should be approaches, less than 10% of the patients in this study had signifi-
strongly considered in patients with both heart failure and angina.1 cant left ventricular dysfunction.105 Several ongoing clinical trials
Pharmacotherapy of angina in patients with heart failure should use should help clarify the best approach to these difficult-to-manage
drugs that can successfully treat both disorders. Nitrates and β- patients. In general, amiodarone is the preferred agent if the rhythm
blockers are effective antianginal agents and are the preferred agents control approach is taken. Although it has many noncardiac toxici-
for patients with both disorders as they may improve hemodynamics ties, amiodarone does not have cardiodepressant or significant
and clinical outcomes.1 It should be noted that the antianginal proarrhythmic effects and appears to be safe in heart failure.
effectiveness of these agents may be significantly limited if fluid Dofetilide also appears to be safe and effective in this population.
retention is not controlled with diuretics. Similar to their use in Class I antiarrhythmics should be avoided.95
hypertension, both amlodipine and felodipine appear to be safe to use
Diabetes Diabetes is highly prevalent in the heart failure popula-
in this setting. Optimization of other treatments for secondary pre-
tion, with current estimates indicating it is present in approximately
vention of coronary and other atherosclerotic vascular disease should
one-third of heart failure patients.30,106 As an important risk factor
also be considered.37 Although their precise role in the treatment of
for coronary artery disease, diabetes directly contributes to the
heart failure awaits the results of additional studies, initial evidence
development of heart failure. Importantly though, diabetes is a risk
suggests statins might decrease the risk of heart failure hospitaliza-
factor for heart failure independent of coronary artery disease or
tions and death, regardless of heart failure etiology.24
hypertension, is associated with hastened heart failure progression,
Atrial Fibrillation Atrial fibrillation is the most frequently and is a significant predictor of mortality in patients with heart
encountered arrhythmia and it is commonly found in patients with failure.106
heart failure, affecting 10% to 30% of patients.1 The high incidence Pharmacotherapy of diabetes in heart failure patients is compli-
of atrial fibrillation in the heart failure population is not surprising cated by concerns about adverse effects associated with metformin
as each of these two disorders predisposes to the other and they and the thiazolidinedione (TZD) drugs (rosiglitazone and pioglita-
share many risk factors, including coronary artery disease and zone). The beneficial effects of these agents on glucose control and
 195
cardiovascular risk factors lead to their widespread use in patients ies suggest that torsemide is absorbed reliably and is associated with
with heart failure in spite of the warnings in the product labeling better outcomes than the more variably absorbed furosemide.108,109

CHAPTER 16
against their use.106 The metformin product labeling states that it is Torsemide is preferred in patients with persistent fluid retention
contraindicated for use in patients with heart failure requiring despite high doses of other loop diuretics. And while the costs of
pharmacologic treatment because of the purported risk of lactic torsemide exceed those of furosemide, pharmacoeconomic analyses
acidosis. However, data from retrospective analyses involving more suggest that the costs of care are similar or less with torsemide.109
than 3,000 patients suggest that metformin is safe (no reports of These data require confirmation in controlled, double-blinded clin-
lactic acidosis) in patients with heart failure.107 In addition, these ical trials but provide preliminary evidence that the more reliably
reports show that metformin treatment is associated with decreased absorbed loop diuretics may be superior to furosemide.
mortality and hospitalizations compared to conventional antihy- The loop diuretics exhibit a ceiling effect in heart failure, meaning

Heart Failure
perglycemic therapy.107 Consequently, some clinicians suggest that that once the ceiling dose is reached, no additional response is
the contraindication to metformin use in heart failure should be achieved by increasing the dose. Thus, when this dose is reached,
reexamined. However, the lack of prospective data about the safety additional diuresis is achieved by giving the drug more often (twice
and efficacy of metformin in patients with heart failure indicates daily or occasionally three times daily) or by giving combination
that if the drug is used, it should be used cautiously with careful diuretic therapy. Table 16–5 lists the ceiling doses. Multiple daily
monitoring of volume status and renal function. Although the dosing achieves a more sustained diuresis throughout the day. When
mechanism(s) are presently unclear, the TZDs are associated with dosed two or three times daily, the first dose is usually given first thing
weight gain, peripheral edema, and heart failure. The TZD package in the morning and the final dose in late afternoon/early evening.
insert indicates these agents should not be used in patients with class Diuretics cause a variety of metabolic abnormalities, with severity
III or IV heart failure because they may cause intravascular volume related to the potency of the diuretic. Chapter 15 has a detailed
expansion and heart failure exacerbation. Most clinical trials with discussion on the adverse effects of diuretic therapy. Hypokalemia
these drugs excluded patients with moderate to severe heart failure, is the most common metabolic disturbance with thiazide and loop
thus the evidence supporting this precaution comes mainly from diuretics, which in heart failure patients may be exacerbated by
retrospective analyses and case reports. Because of the potential risk, hyperaldosteronism. Hypokalemia increases the risk for ventricular
a recent consensus statement indicates TZDs should not be used in arrhythmias in heart failure and is especially worrisome in patients
patients with NYHA class III or class IV heart failure.30 TZDs should receiving digoxin. Hypokalemia is often accompanied by hypo-
be used cautiously in patients with class I or II symptoms, with close magnesemia. Because adequate magnesium is necessary for entry of
observation needed to detect weight gain, edema formation, or potassium into the cell, cosupplementation with both magnesium
heart failure exacerbation.30 and potassium may be necessary to correct the hypokalemia. Con-
comitant ACE inhibitor (or ARB) and/or aldosterone antagonist
Drug Class Information therapy may help to minimize diuretic-induced hypokalemia
because these drugs tend to increase serum potassium concentra-
 Diuretics44 Loop diuretics, as described earlier, represent the
tion through their inhibitory effect on aldosterone secretion. None-
typical diuretic therapy for patients with heart failure because of
theless, the serum potassium concentration should be monitored
their potency and, as such, are the only diuretics discussed here.
closely in heart failure patients and supplemented appropriately
There are currently three loop diuretics available that are used
when needed. In addition to metabolic abnormalities, a recent post-
routinely: furosemide, bumetanide, and torsemide. They share
hoc analysis of the DIG trial suggested that chronic diuretic use was
many similarities in their pharmacodynamics, with their differences
associated with increased risk of mortality and hospitalization.110
being largely pharmacokinetic in nature. Table 16–5 shows the
These findings must be interpreted with caution because this trial
relevant information on the loop diuretics. Following oral adminis-
was not designed to evaluate outcomes associated with diuretic
tration, the peak effect with all the agents occurs in 30 to 90 minutes,
therapy. However, they do serve to remind clinicians of the impor-
with duration of 2 to 3 hours (slightly longer for torsemide).
tance of appropriate patient selection and monitoring when using
Following intravenous administration, the diuretic effect begins
diuretic therapy.
within minutes. All three drugs are highly (>95%) bound to serum
albumin and enter the nephron by active secretion in the proximal  Angiotensin-Converting Enzyme Inhibitors A number of
tubule. The magnitude of effect is determined by the peak concen- ACE inhibitors are available currently in the United States; Table
tration achieved in the nephron, and there is a threshold concentra- 16–9 summarizes those commonly used in the treatment of patients
tion that must be achieved before any diuresis is seen. with heart failure. Although ACE inhibitors vary in their chemical
The biggest difference between the agents is bioavailability. Bio- structure (e.g., sulfhydryl- vs. non–sulfhydryl-containing agents)
availability of bumetanide and torsemide is essentially complete and tissue affinity, the major differences in the ACE inhibitors are
(80% to 100%), whereas furosemide bioavailability exhibits marked not in these pharmacologic properties but in their pharmacokinetic
intra- and interpatient variability. Furosemide bioavailability ranges properties.13 Although it appears that mortality reduction with ACE
from 10% to 100%, with an average of 50%. Thus, if bioequivalent inhibitors is probably a drug class effect, not all ACE inhibitors that
intravenous and oral doses are desired, oral furosemide doses are FDA approved for treatment of heart failure have been evaluated
should be approximately double that of the intravenous dose, for their effects on mortality in heart failure. Thus it seems most
whereas intravenous and oral doses are the same for torsemide and prudent to use those agents that have been documented to reduce
bumetanide. Coadministration of furosemide and bumetanide with morbidity and mortality because the dose required for this effect has
food can decrease bioavailability significantly, whereas food has no been documented.1 Table 16–9 also summarizes the target doses for
effect on bioavailability of torsemide. The intraabdominal conges- survival benefit.
tion that can occur in heart failure also may slow the rate (and thus To minimize the risk of hypotension and renal insufficiency, ACE
decrease the peak concentration) of furosemide, which can reduce inhibitor therapy should be started with low doses followed by
the diuretic’s efficacy. Thus furosemide is most problematic with gradual titration to the target doses as tolerated.1 Asymptomatic
respect to rate and extent of absorption and the factors that hypotension should not be considered a contraindication to initia-
influence it, whereas torsemide has the least-variable bioavailability. tion of an ACE inhibitor although initiation or dose increases in
Recent data suggest that these differences in bioavailability and patients with systolic blood pressures less than 90 to 100 mm Hg
variability may have clinical implications. For example, several stud- should be done cautiously. Renal function and serum potassium
 196

TABLE 16-9 Angiotensin-Converting Enzyme Inhibitors Routinely Used for the Treatment of Heart Failure
SECTION 2

Target Dosing—
Generic Name Brand Name Initial Dose Survival Benefit a Prodrug Elimination b
Captopril Capoten 6.25 mg tid 50 mg tid No Renal
Enalapril Vasotec 2.5–5 mg bid 10 mg bid Yes Renal
Lisinopril Zestril, Prinivil 2.5–5 mg daily 20–40 mg dailyc No Renal
Quinapril Accupril 10 mg bid 20–40 mg bidd Yes Renal
Ramipril Altace 1.25–2.5 mg bid 5 mg bid Yes Renal
Fosinopril Monopril 5-10 mg daily 40 mg dailyd Yes Renal/hepatic
Trandolapril Mavik 0.5–1 mg daily 4 mg daily Yes Renal/hepatic
Cardiovascular Disorders

Perindopril Aceon 2 mg daily 8–16 mg dailyd Yes Renal/hepatic

a
Target doses associated with survival benefits in clinical trials.
b
Primary route of elimination.
c
Note that in the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial (Circulation 1999;100:2312–2318), no significant difference in mortality was found between low dose (~5 mg/day) and high
dose (~35 mg/day) lisinopril therapy.
d
Effects on mortality have not been evaluated.

should be evaluated within 1 to 2 weeks after therapy is started with Adverse Effects. The primary adverse effects of ACE inhibitor
subsequent periodic assessments, especially after dose increases. therapy are secondary to their major pharmacologic effects of
Careful attention to appropriate doses of diuretics is important as suppressing angiotensin II and increasing bradykinin. The reduc-
fluid overload may blunt the beneficial effects of ACE inhibitors and tions in angiotensin II are associated with hypotension and func-
overdiuresis increases the risk of hypotension and renal insuffi- tional renal insufficiency which are the most common adverse
ciency. After titration of the drug to the target dose, most patients effects observed with ACE inhibitors. Hypotension may be asymp-
tolerate chronic therapy with few complications. Although symp- tomatic or manifested as dizziness, lightheadedness, presyncope, or
toms may improve within a few days of initiating therapy, it may take syncope. It occurs most commonly early in therapy or after an
weeks to months before the full benefits are apparent. Even if increase in dose, although it may occur at any time during treat-
symptoms do not improve, long-term ACE inhibitor therapy should ment. Risk factors for hypotension include hyponatremia (serum
be continued to reduce the risk of mortality and hospitalization. sodium <130 mEq/L), hypovolemia, and overdiuresis.1 The occur-
Because ACE inhibitors were the first agents to show improvements rence of hypotension may be minimized by initiating therapy with
in heart failure survival and were frequently used as background lower ACE inhibitor doses and/or temporarily withholding or
therapy in clinical trials of other medications, they are often used as reducing the dose of diuretic, and liberalizing salt and fluid intake.1
the initial therapy in patients with left ventricular systolic function. An often overlooked solution to hypotension is to space the admin-
Traditionally, after titration of the ACE inhibitor dose, the addition of istration times of vasoactive medications (e.g., diuretics and β -
β-blockers was considered. The expected ACE inhibitor-mediated blockers) throughout the day so that these medications are not all
decrease in blood pressure made some clinicians reluctant to initiate administered at or near the same time. Many patients who experi-
β-blocker therapy. Because of the impressive benefits of β-blockers, ence symptomatic hypotension early in therapy are still good
initiation of β-blocker therapy should not be delayed in patients who candidates for long-term treatment if risk factors for low blood
fail to reach target ACE inhibitor doses.1 Because activation of the SNS pressure are addressed.
occurs before that of the RAAS and is an important stimulus for RAAS Functional renal insufficiency is manifested as increases in serum
activation, there is debate over whether ACE inhibitors or β-blockers creatinine and blood urea nitrogen. As cardiac output and renal
should be used as initial therapy. The results of the previously blood flow decline, renal perfusion is maintained by the vasocon-
discussed CIBIS III trial did not provide compelling evidence to strictor effect of angiotensin II on the efferent arteriole. Patients most
support initiation of β-blockers prior to ACE inhibitors.68 Conse- dependent on this system for maintenance of renal perfusion (and
quently, in most patients, ACE inhibitors should be the initial therapy, therefore most likely to develop functional renal insufficiency with
but it is important to remember that the greatest benefit is seen when ACE inhibitors) are those with severe heart failure, hypotension,
both an ACE inhibitor and β-blocker are used. hyponatremia, volume depletion, bilateral renal artery stenosis, and
Because of the high prevalence of coronary artery disease in concomitant use of NSAIDs.113 Sodium depletion, usually secondary
patients with heart failure, aspirin is frequently coadministered with to diuretic therapy, is the most important factor in the development
ACE inhibitors. Several retrospective cohort analyses suggest that of functional renal insufficiency with ACE inhibitor therapy. Renal
aspirin may attenuate the hemodynamic and mortality benefits of insufficiency therefore can be minimized in many cases by reduction
ACE inhibitors.111 The postulated mechanism of this interaction in diuretic dosage or liberalization of sodium intake. Increases in
involves opposing effects on synthesis of vasodilatory prostaglan- serum creatinine of 10% to 20% from baseline are commonly
dins. The ACE inhibitor–mediated increase in bradykinin increases observed after initiation of ACE inhibitor therapy. In some patients,
the synthesis of vasodilatory prostaglandins that have favorable the serum creatinine will return to baseline levels without a reduc-
hemodynamic benefits in heart failure. Because of aspirin’s effect on tion in ACE inhibitor dose.113 Increases in serum creatinine of >0.5
prostaglandin synthesis, this potentially beneficial action of ACE mg/dL if the baseline creatinine is <2.0 mg/dL or >1.0 mg/dL if the
inhibitors may be negated. However, in contrast with studies that creatinine is >2.0 mg/dL, should prompt clinicians to reconsider
showed an ACE inhibitor-aspirin interaction, other investigators ACE therapy and evaluate potential causes for the abrupt decline in
have found no interaction, even in patients without coronary artery renal function.113 Because renal dysfunction with ACE inhibitors is
disease or with impaired renal function.111,112 Because there is no secondary to alterations in renal hemodynamics, it is almost always
prospective evidence confirming an interaction between these reversible upon discontinuation of the drug.113
agents, it is currently recommended that the decision to use each of Careful dose titration can minimize the risks of hypotension and
these medications be made based on whether an individual patient transient worsening of renal function. Thus usual initial doses
has indications for each drug. Use of aspirin doses of 160 mg per day should be about one-fourth the final target dose with slow upward
or less should be considered. dose titration over several days based on blood pressure and serum
 197
creatinine. In certain patients, especially those hospitalized patients Adverse Effects. The ARBs have a low incidence of adverse
who seem to be at high risk for hypotension or worsening of renal effects. Because they do not affect bradykinin, they are not associated

CHAPTER 16
function, it also may be advisable to initiate therapy with a short- with cough and have a lower risk of angioedema than ACE inhibi-
acting agent such as captopril. This will help minimize the duration tors. However, because of reports of recurrences of ACE inhibitor-
of adverse effects should they occur. Once stabilized on ACE related angioedema after ARB administration, ARBs should be used
inhibitor therapy with captopril, the patient can then be switched to cautiously in any patient with a history of angioedema.77,79 The
a longer-half-life drug. major adverse effects are related to suppression of the RAAS. The
Retention of potassium with ACE inhibitor therapy can occur incidence and risk factors for developing hypotension, decreases in
and is caused by the reduced feedback of angiotensin II to stimulate renal function, and hyperkalemia with the ARBs is similar to that of
aldosterone release. Hyperkalemia is most likely to occur in patients ACE inhibitors.12 Thus, ARBs are not alternatives in patients who

Heart Failure
with renal insufficiency and in those taking concomitant potassium develop these complications from ACE inhibitors. Careful monitor-
supplements, potassium-containing salt substitutes, or potassium- ing is required when an ARB is used with another inhibitor of the
sparing diuretic therapy (including an aldosterone antagonist), RAAS (e.g., ACE inhibitor or aldosterone antagonist) as this combi-
especially if they have diabetes.113 The more widespread use of nation increases the risk of these adverse effects. Similar to the ACE
aldosterone antagonists (e.g., spironolactone) in patients with heart inhibitors, the ARBs are contraindicated in the second and third
failure may increase the risk of hyperkalemia.82 trimesters of pregnancy and should be avoided in the first trimester
ACE inhibitors are also associated with other important adverse because of increased risk of fetal/neonatal morbidity and mortality.
effects. A dry, hacking cough occurs with a similar frequency (5% to Neither candesartan nor valsartan are metabolized by the cyto-
15% of patients) with all the agents and is related to bradykinin chrome P450 (CYP) system, so no pharmacokinetic drug–drug
accumulation. The cough is usually nonproductive, occurs within interactions with these agents are expected.
the first few months of therapy, resolves within 1 to 2 weeks of drug
 β-Blockers Metoprolol CR/XL, carvedilol, and bisoprolol are
discontinuation, and reappears with rechallenge. Because cough
the only β-blockers shown to reduce mortality in large heart failure
occurs in up to 40% of patients with heart failure, independent of
trials. Metoprolol and bisoprolol selectively block the β1-receptor,
ACE inhibitor use, it is important to rule out other potential causes
whereas carvedilol blocks the β1, β2, and α1-receptors and also
of cough, such as pulmonary congestion. Because cough is a
possesses antioxidant effects. Although there is no clear evidence
bradykinin-mediated effect, replacement of ACE inhibitor therapy
that these pharmacologic differences result in differences in efficacy
with an ARB would be reasonable in those patients who cannot
among agents, they may aid in selection of a specific agent. For
tolerate the cough. Angioedema is a rare, but potentially life-
example, carvedilol is expected to have greater antihypertensive
threatening complication that is also believed to be related to
effects than the other agents because of its α-receptor blocking
bradykinin accumulation. It may occur more frequently in African
properties and may be preferred in patients with poorly controlled
Americans than in other populations.1 Use of ACE inhibitors is
blood pressure. Conversely, metoprolol or bisoprolol may be pre-
contraindicated in patients with a history of angioedema. ARBs may
ferred in patients with low blood pressure or dizziness and in
be an alternative therapy in patients with ACE inhibitor-induced
patients with significant airway disease.
angioedema, although caution is advised as rare cross-reactivity is
Bisoprolol is eliminated approximately 50% by renal elimination,
reported.1,77,79 ACE inhibitors are contraindicated during the sec-
whereas metoprolol and carvedilol are essentially completely
ond and third trimesters of pregnancy because of the increased risk
metabolized and undergo extensive hepatic first-pass metabolism.
of fetal renal failure, intrauterine growth retardation, and other
Both metoprolol and carvedilol are also substrates for the CYP2D6,
congenital defects. A recent analysis using a Medicaid database of
which is known to be polymorphic. The 7% of the white population
nearly 30,000 patients suggests that first trimester use of ACE
and 1% to 2% of the Asian American and African American
inhibitors should also be avoided as the risk of major congenital
populations who are CYP2D6-poor metabolizers would be expected
defects was increased 2.7-fold in infants exposed to these agents
to have higher plasma concentrations than anticipated at the usual
during the first trimester.114
doses of carvedilol and metoprolol. However, given that β-blockers
 Angiotensin II Receptor Blockers Although ACE inhibi- have a wide therapeutic index, it is unclear whether the poor
tors remain the agents of first choice to treat stage C heart failure metabolizer phenotype would result in more pronounced hemody-
with reduced LVEF, ARBs approved for the treatment of heart namic effects.
failure are now the recommended alternatives in patients who are There is fairly strong evidence that benefits of β-blockers in heart
unable to tolerate an ACE inhibitor.1 Although seven ARBs are failure are not a class effect. Specifically, in a study powered for
currently on the market, only two, candesartan and valsartan, are mortality reduction, there was no difference in survival between the
approved for the treatment of heart failure. The use of these two nonselective β-blocker bucindolol and placebo.115 Although there
agents is supported by clinical trial data that document a target has been considerable debate over why bucindolol failed to provide
dose associated with improved survival and other important out- a survival benefit, it may be related to the drug’s ancillary properties
comes in patients with decreased LVEF.47,74,75 Thus, candesartan or or differences among β-blocker trials in the characteristics of study
valsartan are the preferred agents in patients with heart failure, participants. These data emphasize the importance of confining β-
whether used alone or in combination with ACE inhibitors. ARBs blocker use to one of the agents with proven survival benefits,
are also alternative to ACE inhibitors in patients with stages A or B especially given the diversity among β-blockers in their receptor
heart failure.1 sensitivities and ancillary properties.
The clinical use of ARBs is also similar to that of ACE inhibitors. There has been much debate over whether one β-blocker is
Therapy should be initiated at low doses (candesartan 4 to 8 mg superior to another. Specifically, it has been hypothesized that
once daily; valsartan 20 to 40 mg twice daily) and then titrated to nonselective blockade with carvedilol might produce greater bene-
target doses (candesartan 32 mg once daily; valsartan 160 mg twice fits than β1-selective blockade. This hypothesis is based on observa-
daily).1 Blood pressure, renal function, and serum potassium should tions that the β1-receptor is downregulated, and the β2- and α1-
be evaluated within 1 to 2 weeks after initiation of therapy and after receptors account for a larger proportion of total cardiac adrenergic
increases in dose and these end points used to guide subsequent receptors in the failing heart. Only one trial with a mortality end
dose changes. It is not necessary to reach target ARB doses before point has provided a head-to-head comparison of carvedilol and a
adding a β-blocker. β1-selective blocker. The Carvedilol or Metoprolol European Trial
 198
(COMET) compared carvedilol 25 mg twice daily and immediate- Importantly, concerns of masking symptoms of hypoglycemia or
release metoprolol 50 mg twice daily and found a significant 17% worsening glycemic control should not preclude β-blockers use in
SECTION 2

lower mortality rate in patients treated with carvedilol.116 However, patients with diabetes. Indeed, post-hoc analysis of heart failure
concerns regarding the formulation and dose of metoprolol used in trials shows that β-blockers are well tolerated and significantly
COMET limit the conclusions that can be drawn from these reduce morbidity and mortality in patients with diabetes and heart
findings. Specifically, the study used the immediate-release formu- failure.119 β-Blockers should be used cautiously in patients with
lation of metoprolol (metoprolol tartrate) not the sustained-release diabetes and recurrent hypoglycemia.
formation (metoprolol succinate) shown to reduce mortality com-
pared to placebo.59 The efficacy of the immediate-release formula- Digoxin Digoxin exerts its positive inotropic effect by binding to
tion in reducing mortality in heart failure has not been proven. sodium- and potassium-activated adenosine triphosphatase (Na-K-
Cardiovascular Disorders

Metoprolol CR/XL provides more consistent plasma concentrations ATPase or sodium pump). Inhibition of Na-K-ATPase decreases
over a 24-hour period and appears to provide more favorable effects outward transport of sodium and leads to increased intracellular
on heart rate variability, autonomic balance, and blood pressure, sodium concentrations. Higher intracellular sodium concentrations
suggesting that this formulation might be superior to immediate- favor calcium entry and reduce calcium extrusion from the cell
release metoprolol.117 The target dose of metoprolol also differed through effects on the sodium–calcium exchanger. The result is
between COMET and MERIT-HF. The target dose in COMET was increased storage of intracellular calcium in the sarcoplasmic reticu-
100 mg/day (50 mg twice daily), whereas the target dose of meto- lum, and with each action potential, a greater release of calcium to
prolol in MERIT-HF was 200 mg/day. Many question whether the activate contractile elements. Digoxin also has beneficial neurohor-
degree of β-blockade achieved in COMET with immediate-release monal actions. These effects occur at low plasma concentrations,
metoprolol 50 mg twice daily is comparable to that achieved with where little inotropic effect is seen, and are independent of inotropic
metoprolol CR/XL 200 mg/day in MERIT-HF or carvedilol 25 mg activity. Unlike other positive inotropes that increase intracellular
twice daily in COMET. Thus, the debate over β-blocker superiority cyclic adenosine monophosphate (cAMP), digoxin attenuates the
continues, and although some clinicians would argue superiority of excessive SNS activation present in heart failure patients. Although
carvedilol, it seems clear that what is most important is that one of the precise mechanism is unknown, a digoxin-mediated reduction in
the three β-blockers proven to reduce mortality is used. central sympathetic outflow and improvement in impaired barore-
ceptor function appear to play an important role. Because mortality
Adverse Effects. Possible adverse effects with β-blocker use in and progression of heart failure are linked to the extent of SNS
heart failure include bradycardia or heart block, hypotension, activation, these sympathoinhibitory effects may be an important
fatigue, impaired glycemic control in diabetic patients, broncho- component of the clinical response to the drug. Chronic heart failure
spasm in patients with asthma, and worsening heart failure. Clini- is also marked by autonomic dysfunction, most notably suppression
cians should monitor vital signs and carefully assess for signs and of the parasympathetic (vagal) system. Digoxin increases parasympa-
symptoms of worsening heart failure during β-blocker initiation and thetic activity in heart failure patients and leads to a decrease in heart
up-titration. Hypotension is more common with carvedilol because rate, thus enhancing diastolic filling. The vagal effects also result in
of its α1-receptor–blocking properties. Bradycardia and hypotension slowed conduction and prolongation of atrioventricular node refrac-
generally are asymptomatic and require no intervention; however, β- toriness, thus slowing the ventricular response in patients with atrial
blocker dose reduction is warranted in symptomatic patients. fibrillation. Because atrial fibrillation is a common complication of
Fatigue usually resolves after several weeks of therapy, but sometimes heart failure, the combined positive inotropic, neurohormonal, and
requires dose reduction. In diabetic patients, β-blockers may worsen negative chronotropic effects of digoxin can be particularly beneficial
glucose tolerance and can mask the tachycardia and tremor (but not for such patients. The overall response to digoxin is usually an
sweating) that accompany hypoglycemia. In addition, nonselective increase in cardiac index and a decrease in PAOP with relatively little
agents such as carvedilol may prolong insulin-induced hypoglycemia change in arterial blood pressure.86,87,96
and slow recovery from a hypoglycemic episode. Despite this, there
is evidence that carvedilol produces better glycemic control in Pharmacokinetics. Numerous studies of digoxin pharmacoki-
diabetic patients compared to immediate-release metoprolol and netics have been published; Table 16–10 summarizes them. Digoxin
may improve insulin sensitivity.118 Diabetic patients should be
warned of these potential adverse effects, and blood glucose should TABLE 16-10 Clinical Pharmacokinetics of Digoxin
be monitored with initiation, adjustment, and discontinuation of β- Oral bioavailability
blocker therapy. Adjustment of hypoglycemic therapy may be neces- Tablets 0.5–0.9 (0.65) a
sary with concomitant β-blocker use in diabetics. Elixir 0.75–0.85 (0.80)
Up-titration should be avoided if the patient experiences signs of Capsules 0.9–1.0 (0.95)
worsening heart failure, including volume overload and poor perfu- Onset of action
sion. Fluid overload may be asymptomatic and manifest solely as an Oral 1.5–6 h
increase in body weight. Mild fluid overload may be managed by Intravenous 15–30 min
intensifying diuretic therapy. The treatment of moderate to severe Peak effect
congestion is discussed in the section on acute decompensated heart Oral 4–6 h
Intravenous 1.5–4 h
failure. Once the patient has been stabilized, dose titration may
Terminal half-life
continue as tolerated until the target or highest tolerated dose is
Normal renal function 36 h
reached. Anuric patients 5 days
Absolute contraindications to β-blocker use include uncontrolled Volume of distribution at steady state 7.3 L /kg
bronchospastic disease, symptomatic bradycardia, advanced heart Fraction unbound in plasma 0.75–0.80
block without a pacemaker, and acute decompensated heart failure. Fraction excreted unchanged in urine 0.65–0.70
However, β-blockers may be tried with caution in patients with a
Range and mean value in parentheses.
asymptomatic bradycardia or well-controlled asthma. Particular Data from Schentag JJ, Bang AJ, Kozinski-Tober JL. Digoxin. In: Burton ME, Shaw LM, Schentag JJ,
caution is warranted in patients with marked bradycardia (<55 Evans WE, eds. Applied Pharmacokinetics and Pharmacodynamics: Principles of Therapeutic Drug
beats/min) or hypotension (systolic blood pressure <80 mm Hg). Monitoring, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006:410–439.
 199

TABLE 16-11 Digoxin Drug Interactions

CHAPTER 16
Drugs Mechanism/Effect Suggested Clinical Management
Amiodarone Inhibits P-glycoprotein resulting in decrease in renal and nonrenal clearance; Monitor SDC and adverse effects; anticipate the need to
can increase SDC by 70%–100% reduce the dose by 50%
Antacids Concurrent administration may decrease digoxin bioavailability by 20%–35% Space doses at least 2 h apart or avoid concurrent use if
possible
Cholestyramine, colestipol Bind digoxin in gut and decrease bioavailability 20%–35%; may also decrease Space doses at least 2 h apart or avoid concurrent colestipol
enterohepatic recycling use if possible
Diuretics Thiazides or loop diuretics may cause hypokalemia and hypomagnesemia, Monitor and replace electrolytes if necessary
thereby increasing the risk of digitalis toxicity

Heart Failure
Erythromycin, clarithromycin, Alter gut bacterial flora; bioavailability and SDC increase 40%–100% in Monitor SDC and anticipate the need to reduce the dose;
tetracycline approximately 10% of patients who extensively metabolize digoxin in the avoid concurrent use if possible
gut; may also be caused by inhibition of P-glycoprotein by macrolides
Ketoconazole, itraconazole Decrease in renal and nonrenal clearance by inhibition of P-glycoprotein; SDC Monitor SDC and anticipate the need to reduce the dose by
may increase by 50%–100% 50%
Kaolin-pectin Large dose (30–60 mL) may decrease digoxin bioavailability by approximately Space doses at least 2 h apart or avoid concurrent use if
60% possible
Metoclopramide Increase in gut mobility may decrease bioavailability of slow dissolving tablets; Effect is minimized by administration of digoxin capsules
unknown significance
Neomycin, sulfasalazine Decrease in bioavailability by 20%–25% sulfasalazine Space doses at least 2 h apart or avoid concurrent use if
possible
Propafenone Decrease in renal clearance; SDC may increase 30%–40% Monitor SDC and anticipate the need to reduce the dose
Quinidine Inhibits P-glycoprotein resulting in decrease in renal and nonrenal clearance; Monitor SDC and adverse effects; anticipate the need to
also displacement of digoxin from tissue-binding sites with decrease in the reduce dose by 50%
volume of distribution; SDC generally increases about twofold
Spironolactone Decrease in renal and nonrenal clearance; also interference with some digoxin Monitor SDC and anticipate the need to reduce dose; check
assays thus increasing apparent SDC assay for interference
Verapamil Inhibits P-glycoprotein resulting in decrease in renal and nonrenal clearance, Monitor SDC and anticipate the need to reduce the dose by
SDC may increase 70%–100% 50%; consider using another calcium channel blocker
SDC, serum digoxin concentration.

has a large volume of distribution and is extensively bound to for sudden cardiac death, presumably as a consequence of ventricular
various tissues, most notably to Na-K-ATPase in skeletal and arrhythmias. Patients who are at increased risk of toxicity include
cardiac muscles. Because it does not distribute appreciably to body those with impaired renal function, decreased lean body mass, the
fat, loading doses of digoxin (when necessary) should be calculated elderly, and those taking interacting drugs. Hypokalemia, hypo-
based on estimates of lean body weight. There is a long “distribution magnesemia, and hypercalcemia will predispose patients to cardiac
phase” after administration of oral or intravenous digoxin, resulting manifestations of digoxin toxicity. Thus, concomitant therapy with
in a lag time before maximum pharmacologic response is observed diuretics may lead to electrolyte abnormalities and increase the likeli-
(Table 16–10). Transiently elevated serum digoxin concentrations hood of cardiac arrhythmias. Similarly, hypothyroidism, myocardial
during the distribution phase are not associated with increased ischemia, and acidosis will also increase the risk of cardiac adverse
therapeutic or adverse effects, although they can mislead the clini- effects. Although digoxin toxicity is commonly associated with plasma
cian who is unaware of the timing of blood sampling relative to the concentrations greater than 2 ng/mL, clinicians should remember that
previous digoxin dose. Consequently, blood samples for measure- digoxin toxicity is based on the presence of symptoms rather than a
ment of serum digoxin concentrations should be collected at least 6 specific plasma concentration.96 Usual treatment of digoxin toxicity
hours, and preferably 12 hours or more, after the last dose.
In patients with normal renal function, 60% to 80% of a dose of
digoxin is eliminated unchanged in urine via glomerular filtration and TABLE 16-12 Signs and Symptoms of Digoxin Toxicity
tubular secretion. The terminal half-life of digoxin is approximately Noncardiac (mostly CNS) adverse effects
1.5 days in subjects with normal renal function but approximately 5 Anorexia, nausea, vomiting, abdominal pain
days in anuric patients (see Table 16–10). Recent evidence indicates Visual disturbances
that the drug efflux transporter P-glycoprotein plays an important role Halos, photophobia, problems with color perception (i.e., red-green or yellow-green
in the bioavailability, renal and nonrenal clearance, and drug interac- vision), scotomata
tions with digoxin. Table 16–11 summarizes clinically important Fatigue, weakness, dizziness, headache, neuralgia, confusion, delirium, psychosis
pharmacokinetic/pharmacodynamic drug interactions. An extensive Cardiac adverse effects a,b
review of the pharmacokinetics and pharmacodynamics of digoxin is Ventricular arrhythmias
Premature ventricular depolarizations, bigeminy, trigeminy, ventricular tachycardia,
available.96
ventricular fibrillation
Adverse Effects. Although digoxin can produce a variety of car- Atrioventricular (AV) block
diac and noncardiac adverse effects, it is usually well tolerated by most First degree, second degree (Mobitz type I), third degree
AV junctional escape rhythms, junctional tachycardia
patients (Table 16–12).86,87 Noncardiac adverse effects frequently
Atrial arrhythmias with slowed AV conduction or AV block
involve the CNS or gastrointestinal systems but also may be nonspe- Particularly paroxysmal atrial tachycardia with AV block
cific (e.g., fatigue or weakness). Cardiac manifestations include Sinus bradycardia
numerous different arrhythmias that are believed to be caused by
a
multiple electrophysiologic effects (Table 16–12). Cardiac arrhythmias Some adverse effects may be difficult to distinguish from the signs/symptoms of heart failure.
b
Digoxin toxicity has been associated with almost every known rhythm abnormality (only the more
may be the first evidence of toxicity in a patient (before any noncardiac common manifestations are listed).
symptoms occur). Rhythm disturbances are of particular concern Reprinted and adapted from Prog Cardiovasc Dis, Vol. 44, Eichorn EJ, Gheorghiade M, Pages 251–
because patients with chronic heart failure are already at increased risk 266, Copyright 2002, with permission from Elsevier.
 200
includes drug withdrawal or dose reduction and treatment of cardiac Patients with worsening chronic heart failure associated with reduced
arrhythmias and electrolyte abnormalities. In patients with life-threat- or preserved left ventricular function comprise approximately 70% of
SECTION 2

ening digoxin toxicity, purified digoxin-specific Fab antibody frag- heart failure hospital admissions. These patients can become refrac-
ments should be administered. Serum digoxin concentrations will not tory to available oral therapy and decompensate following a relatively
be reliable until the antidote has been eliminated from the body.87 mild insult (e.g., dietary indiscretion), medical noncompliance, or a
noncardiac concurrent illness (e.g., infection). A new cardiac event,
such as recurrent MI, atrial fibrillation, myocarditis, or acute valvular
insufficiency also can cause a stable patient to decompensate. Sec-
TREATMENT ondly, de novo heart failure may occur following a large myocardial
infarction or sudden increase in blood pressure in the setting of left
Acute Decompensated
Cardiovascular Disorders

ventricular dysfunction and represents approximately 25% of admis-

Heart Failure sions. A third group of patients with severe left ventricular systolic
dysfunction associated with progressive worsening of cardiac output
 As discussed previously, the number of patients with heart failure and refractoriness to therapy represents approximately 5% of heart
is substantial and continues to increase. Although mortality from failure admissions.125 Additional insight into the clinical characteris-
heart failure has improved, the growing number of patients with the tics of decompensated heart failure patients unexpectedly indicates
disorder and the progressive nature of the syndrome have led to that a high percentage of patients present with hypertension and
substantial increases in hospitalizations for heart failure.4 Recent preserved systolic function.126
data indicate approximately 1 million patients are hospitalized Several studies provide a better understanding of the prognostic
annually for heart failure, resulting in significant morbidity, mortal- factors associated with decompensated heart failure. Data from the
ity, and consumption of large quantities of healthcare resources.4 Acute Decompensated Heart Failure Registry (ADHERE), a registry
Inpatient admission for heart failure exacerbations is associated of hospitalized patients with a primary diagnosis of decompensated
with an increased risk of subsequent hospitalization and decreased heart failure, found blood urea nitrogen greater than or equal to 43
survival.120 The economic impact of heart failure is considerable mg/dL to be the best individual predictor of in-hospital mortality,
with cost driven primarily by hospitalization and inpatient care.4 followed by systolic blood pressure less than 115 mm Hg and then
A number of descriptive terms have been used to characterize by serum creatinine greater than or equal to 2.75 mg/dL. Using
patients with worsening heart failure requiring hospitalization. Patients these three parameters, patients were identified as low, intermedi-
with persistent symptoms or refractory heart failure requiring special- ate, high, and very high risk with an in-hospital mortality of 2%,
ized interventions despite optimal standard therapy such as ACE 6%, 13%, and 20%, respectively.127 Additional studies confirm an
inhibitors and β-blockers are classified as stage D in the ACC/AHA increase in in-hospital mortality in patients with low systolic blood
classification scheme. These patients typically fall into the category of pressure and worsening renal function on admission.128,129 Hypona-
NYHA class III or IV heart failure, with symptoms upon minimal tremia, elevations in troponin I, ischemic etiology, and poor func-
exertion or at rest.1 The terms decompensated heart failure or exacerba- tional capacity are additional negative prognostic factors.125
tion of heart failure refer to those patients with new or worsening signs
or symptoms, which are usually caused by volume overload and/or ■ GENERAL APPROACH TO TREATMENT
hypoperfusion and lead to additional medical care, such as emergency
room visits and hospitalizations. The term acute heart failure may be  The overall goals of therapy in the patient with decompensated
misleading as it more often refers to the patient with a sudden onset of heart failure are to relieve congestive symptoms or optimize volume
signs or symptoms of heart failure in the setting of previously normal status, as well as treat symptoms of low cardiac output, so that the
cardiac function. This section of the chapter focuses on the manage- patient can be discharged in a compensated state on oral drug therapy.
ment of patients with acute decompensated heart failure. Clinical Although diuretic, vasodilator, and positive inotrope therapy can be
syndromes within decompensated heart failure include systemic vol- very effective at achieving these goals, their efficacy must be balanced
ume overload, low output, and acute pulmonary edema. It is important against the potential for serious toxicity. Thus, another important goal
to recognize that such patients may present with impaired or preserved is to minimize the risks of pharmacologic therapy. Maintenance of
left ventricular function and a variety of etiologies may be responsible vital organ perfusion to preserve renal function and prevention of
for the primary disease process. The clinical course of heart failure additional myocardial injury, diuretic-induced electrolyte depletion,
manifests as periods of relative stability with an increasing frequency in hypotension from vasodilators, and myocardial ischemia and arrhyth-
episodes of decompensation as the underlying disease progresses.121 mias from positive inotropes are all important goals.
Despite the considerable morbidity and mortality associated with In addition, all patients should be evaluated for potential etiolo-
decompensated heart failure, the first randomized placebo-controlled gies and precipitating factors, including atrial fibrillation and other
trials in this patient population were published in 2002.122,123 In arrhythmias, worsening hypertension, myocardial ischemia or
addition, it was not until recently that guidelines were generated infarction, anemia, hypothyroidism or hyperthyroidism, and other
focusing specifically on managing decompensated heart failure. Cur- causes. Medications, including noncardiac medications, which may
rently, the ACC/AHA guidelines focus a portion of their recommen- worsen cardiac function, should also be considered as precipitating
dations for chronic heart failure on the decompensated patient, but or contributing factors. Patients who may benefit from revascular-
the HFSA and the European Society of Cardiology have published ization should also be identified. Prior to discharge, optimization of
separate guidelines for evaluating and treating decompensated heart chronic oral therapy and patient education are critical to preventing
failure.1,34,124 Because available drug therapies differ between Europe future hospitalizations. When available and appropriate, patients
and the United States, the HFSA guidelines are the focus of the should be referred to a heart failure disease management pro-
remainder of this chapter. gram.124 A careful history and physical examination are key compo-
nents in the diagnosis of decompensated heart failure. The history
should focus on the potential etiologies of heart failure, the presence
■ PATHOPHYSIOLOGY AND of any precipitating factors, onset, duration, and severity of symp-
CLINICAL PRESENTATION toms, and a careful medication history. Current guidelines recom-
Patients requiring intensive therapy for decompensated heart failure mend making the diagnosis of decompensated heart failure based
may have a variety of underlying etiologies and clinical presentations. primarily on signs and symptoms.124 With congestion representing
 201
the more common presentation of heart failure, orthopnea is the TABLE 16-13 Recommendations for Hospitalizing Patients
main symptom of fluid overload that best correlates with elevated

CHAPTER 16
Presenting with Acute Decompensated Heart Failure
pulmonary pressures.129 Important elements of the physical exami-
Recommendation Clinical Circumstances
nation include assessment of vital signs and weight, cardiac auscul-
tation for heart sounds and murmurs, pulmonary exam for the Hospitalization Evidence of severely decompensated heart failure, including
presence of rales, and evaluation for the presence of peripheral recommended • Hypotension
edema. The jugular venous pressure is the most reliable indicator of • Worsening renal function
• Altered mentation
the patient’s volume status and should be carefully evaluated on
Dyspnea at rest
admission and closely followed during hospitalization as an indica-
• Typically reflected by resting tachypnea
tor of the efficacy of diuretic therapy.129 An S3 gallop also represents • Less commonly reflected by oxygen saturation <90%

Heart Failure
ventricular filling and has high diagnostic specificity for heart failure Hemodynamically significant arrhythmia
decompensation. Other physical findings, such as pulmonary crack- • Including new onset of rapid atrial fibrillation
les and lower-extremity edema, have low specificity and sensitivity Acute coronary syndromes
for the diagnosis of decompensated heart failure.124 The develop- Hospitalization should Worsened congestion
ment of a bedside assay for plasma BNP has focused considerable be considered • Even without dyspnea
attention on the use of BNP as an aid in the diagnosis of suspected • Typically reflected by a weight gain of ≥5 kg
heart failure. Plasma BNP is positively correlated with the degree of Signs and symptoms of pulmonary or systemic congestion
left ventricular dysfunction and heart failure and this assay is now • Even in the absence of weight gain
frequently used in acute care settings to assist in the differential Major electrolyte disturbance
Associated comorbid conditions
diagnosis of dyspnea (heart failure vs. asthma, chronic obstructive
• Pneumonia
pulmonary disease, or infection). A low BNP concentration has a • Pulmonary embolus
96% predictive value for excluding heart failure as an etiology when • Diabetic ketoacidosis
evaluating patients presenting with dyspnea. In addition, an ele- • Symptoms suggestive of transient ischemic accident
vated prehospital discharge BNP concentration is associated with an or stroke
increased risk of worse long-term outcome. It is important to note Repeated implantable cardioverter-defibrillator firings
that any disease process that increases right heart pressures will Previously undiagnosed heart failure with signs and
elevate BNP, including pulmonary emboli, chronic obstructive lung symptoms of systemic or pulmonary congestion
disease, and primary pulmonary hypertension. Also, BNP levels Adapted from Adams KF, Lindenfield J, Arnold JMO, et al. HFSA 2006 comprehensive heart failure
may be mildly increased with increasing age, female gender, and practice guidelines. J Card Fail 2006;12:e1–e122.
renal dysfunction, whereas concentrations may be lower with obe-
sity.129 Additional research will better characterize the role of BNP at a low dose prescribed to achieve a trough serum concentration of
measurement in the diagnosis and treatment of heart failure. When 0.5 to 1.0 ng/mL.1
the diagnosis of decompensated heart failure is uncertain, current There are two general approaches to maximize therapy in the
guidelines recommend obtaining a BNP concentration in conjunc- decompensated heart failure patient. One is to use simple clinical
tion with assessing signs and symptoms. parameters (signs and symptoms, blood pressure, renal function)
Hospitalization should occur or should be considered depending on and the second is to use invasive hemodynamic monitoring in
each patient’s presenting symptoms and physical examination. addition to these clinical parameters. In all decompensated heart
Table 16–13 describes the clinical presentation of patients in whom failure patients, close monitoring is essential for assuring optimal
hospitalization should occur or should be considered. Most patients response to therapy while avoiding adverse effects. Daily monitoring
do not require admission to an intensive care unit and are admitted should include weight, strict fluid intake and output, and heart
to a monitored unit or general medical floor. Admission to an failure signs and symptoms to assess clinical efficacy of drug therapy.
intensive care unit may be required if the patient experiences Foley catheter placement is not recommended unless close monitor-
hemodynamic instability requiring frequent monitoring of vital ing of urine output is needed. As safety end points, monitoring for
signs, invasive hemodynamic monitoring, or rapid titration of electrolyte depletion, symptomatic hypotension, and renal dysfunc-
intravenous medications with concurrent monitoring to assure safe tion should be assessed frequently. Although many of the above
and effective outcomes. parameters may be monitored daily, some will need to be monitored
The first step in the management of decompensated heart failure more frequently as dictated by the patient’s clinical status. Vital signs
is to ascertain that optimal treatment with oral medications has should be assessed multiple times throughout the day at a frequency
been achieved. If fluid retention is evident on physical examination, that is appropriate for a given patients’ level of stability. Orthostatic
aggressive diuresis should be accomplished. Although increasing the blood pressure should be assessed at least once daily.124 Table 16–14
dose of oral diuretic may be effective in some cases, the use of summarizes the recommendations for monitoring.
intravenous diuretics frequently is necessary. Every effort should be
made to optimally treat the patient with an ACE inhibitor. β-
Blocker therapy should generally be continued during the hospital
■ PRINCIPLES OF THERAPY BASED ON
admission unless recent dose initiation or up-titration was respon- CLINICAL PRESENTATION
sible for the decompensated state. In such cases, β-blocker therapy Appropriate medical management of the patient presenting with
may need to be temporarily held or dose reduced. Appropriateness decompensated heart failure is aided by determination of whether the
of initiating this therapy prior to hospital discharge will be discussed patient has signs and symptoms of fluid overload (“wet” heart failure)
later in this chapter. Discontinuation of ACE inhibitor or β-blocker or low cardiac output (“dry” heart failure).129,130 As previously dis-
therapy occasionally may be necessary in the setting of cardiogenic cussed, most patients present with fluid overload (or the “wet”
shock or symptomatic hypotension. Certain therapies may also profile). Symptoms consistent with pulmonary congestion include
need to be temporarily held in the setting of renal dysfunction, orthopnea and dyspnea with minimal exertion and those of systemic
especially in the setting of oliguria or hyperkalemia (e.g., ACE congestion include gastrointestinal discomfort, ascites, and peripheral
inhibitor, ARB, and/or aldosterone antagonist) or elevated serum edema. Patients with no or minimal fluid overload (or the “dry”
digoxin concentrations. Most patients should be receiving digoxin category of decompensated heart failure) may have symptoms that
 202

TABLE 16-14 Monitoring Recommendations for Patients mended. However, invasive hemodynamic monitoring often pro-
Hospitalized with Acute Decompensated vides essential information necessary to achieve optimal drug
SECTION 2

Heart Failure therapy in patients with a confusing or complicated clinical picture

and during dose titration of rapidly acting medications. And thus,
Value Frequency Specifics
such monitoring should be considered in patients who are refrac-
Weight At least daily Determine after voiding in the morning tory to initial therapy, whose volume status is unclear, or who has
Account for possible increased food intake clinically significant hypotension such as a systolic blood pressure
as a result of improved appetite less than 80 mm Hg, or worsening renal function despite therapy.
Fluid intake/ At least daily Strict documentation necessary
Such monitoring is required to document adequate hemodynamic
output
Vital signs More than daily Including orthostatic blood pressure
response to inotropic therapy prior to committing to chronic
Cardiovascular Disorders

Signs At least daily Edema, acites, pulmonary rales, hepatomeg- outpatient inotropic therapy.124 Finally, assessment of hemody-
aly, increased jugular venous pressure, namic parameters is required to document adequate reversal of
hepatojugular reflux, liver tenderness pulmonary hypertension prior to cardiac transplantation.129
Symptoms At least daily Orthopnea, paroxysmal nocturnal dyspnea, Invasive hemodynamic monitoring is usually performed with a
nocturnal cough, dyspnea, fatigue flow-directed pulmonary artery or Swan-Ganz catheter placed per-
Electrolytes At least daily Potassium, magnesium, sodium cutaneously through a central vein and advanced through the right
Renal function At least daily blood urea nitrogen, serum creatinine side of the heart and into the pulmonary artery. Inflation of a
Adapted from Adams KF, Lindenfield J, Arnold JMO, et al. HFSA 2006 comprehensive heart failure balloon proximal to the end port allows the catheter to “wedge,”
practice guidelines. J Card Fail 2006;12:e1–e122. yielding the PAOP, which estimates the pulmonary venous (left
atrial) pressure and, in the absence of intracardiac shunt, mitral
are more difficult to distinguish. This is a syndrome of low cardiac valve disease or pulmonary disease, the left ventricular diastolic
output and is characterized principally by extreme fatigue and tired- pressure. Additionally, cardiac output may be measured and sys-
ness as well as other symptoms not commonly attributed to cardiac temic vascular resistance (SVR) calculated. Table 16–15 lists the
causes such as poor appetite, nausea, and early satiety. It is important normal values for hemodynamic parameters.
to recognize that gastrointestinal symptoms may be associated with In addition to the clinical presentation, invasive hemodynamic
congestion rather than low cardiac output to the gastrointestinal monitoring helps in the selection of appropriate medical therapy as
tract. Moreover, these patients frequently exhibit worsening renal well as in the classification of patients into specific subsets. These
function and a decline in serum sodium level. Many patients will hemodynamic subsets were first proposed for patients with left ven-
present with signs and symptoms of both types of advanced heart tricular dysfunction following an acute MI but also are applicable to
failure. In these patients, low-output symptoms may not be obvious patients with acute or severe heart failure from other causes (Fig.
until congestion is optimally treated. Figure 16–8 outlines a suggested 16–9).132 This hemodynamic classification has four subsets and is
treatment approach based on whether the patient has signs and based on a cardiac index above or below 2.2 L/min/m2 and a PAOP
symptoms of fluid overload and/or low cardiac output. above or below 18 mm Hg. Figure 16–10 is a treatment algorithm
based on hemodynamic subsets. In addition to using the above
■ PRINCIPLES OF THERAPY BASED ON profiles or categories to stratify patients with decompensated heart
HEMODYNAMIC SUBSETS failure, these four hemodynamic profiles are predictive for outcome
with patients in the wet-warm profile having a twofold greater risk of
Patients with decompensated heart failure may have critically
death and those in the wet-cold profile having a 2.5-fold increased
reduced cardiac output, usually with low arterial blood pressure and
risk of death at 1 year compared to dry-warm patients.129
systemic hypoperfusion resulting in organ system dysfunction (i.e.,
cardiogenic shock). They also may have pulmonary edema with Subset I Patients in hemodynamic subset I have a cardiac index
hypoxemia, respiratory acidosis, and markedly increased work of and PAOP within generally acceptable ranges and have the lowest
breathing. With cardiopulmonary support, response to interven- mortality of any subset. These patients do not need immediate
tions should be assessed promptly to allow for timely adjustments in specific interventions other than maximizing oral therapy and
treatment. Because cardiopulmonary support must be instituted monitoring. It should be emphasized that patients with significant
and adjusted rapidly, immediate assessment of the results of an left ventricular dysfunction may still present in subset I because
intervention limits risks and makes adjustments in therapy more normal compensatory mechanisms and/or appropriate drug ther-
prompt. ECG monitoring, continuous pulse oximetry, urine flow apy may at least partially correct an otherwise abnormal hemody-
monitoring, and automated blood pressure recording are now the namic profile.
minimal noninvasive standard of care for critically ill patients with
Subset II As shown in Fig. 16–9, patients in subset II have an
cardiopulmonary decompensation. Peripheral or femoral arterial
adequate cardiac index but a PAOP greater than 18 mm Hg. These
catheters may be used for continuous and accurate assessment of
patients are likely to have pulmonary congestion (i.e., “wet” heart
arterial pressure.
failure) secondary to increased hydrostatic pressure in the pulmo-
nary capillaries but no evidence of peripheral hypoperfusion. The
Hemodynamic Monitoring primary goal of therapy in these patients is to reduce pulmonary
The role of invasive hemodynamic monitoring for improving out- congestion by lowering PAOP which is associated with improved
comes in patients with decompensated heart failure remains contro- outcomes. Accordingly, the therapeutic goal in this setting is to
versial. The Evaluation Study of Congestive Heart Failure and reduce filling pressures without reducing cardiac output, increasing
Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial heart rate, or further activating neurohormones. And thus, it is
assessed the role of invasive hemodynamic monitoring in the critically important that PAOP not be decreased excessively so as to
management of patients hospitalized for heart failure. The use of a cause a significant decrease in cardiac index. Although the normal
pulmonary artery catheter had no impact on survival after hospital range of PAOP is 5 to 12 mm Hg for individuals without cardiac
discharge.131 It is important to note that patients with a clear dysfunction, higher pressures of 15 to 18 mm Hg frequently are
indication for pulmonary artery catheter were excluded from this necessary for heart failure patients to optimize cardiac index while
trial. Thus, the routine use of invasive monitoring is not recom- avoiding pulmonary congestion. Generally, the PAOP can be low-
 203

CHAPTER 16
ADHF

Evaluate and optimize chronic therapy

D/C meds that worsen HF
Assess for signs/symptoms of fluid
overload and/or low cardiac output
syndrome
Low cardiac output (“cold”)
Fluid overload (“wet”) Adequate volume status

Heart Failure
IV loop diuretic Fluid overload (“wet”)
± IV vasodilators +
Low cardiac output (“cold”) SBP < 90mm Hg
Symptomatic hypotension
Symptom relief? SBP < 90 mm Hg Worsening renal function
Symptomatic hypotension
Worsening renal function
Unresponsive/intolerant IV
vasodilators

Yes No No Yes No Yes

Increase loop IV inotropes IV vasodilators IV inotropes

diuretic dose Consider IV
Loop diuretic loop diuretics
continuous infusion Symptom relief? Symptom relief?
Add second diuretic Symptom relief?
Ultrafiltration No Yes No Yes
No Yes
Symptom relief? Add IV Consider
inotropes IV
vasodilators*
Yes No or

IV inotropes

Symptom relief?

Yes No

Consider invasive
hemodynamic monitoring
See Fig. 16–10

Optimize chronic oral therapy

* Depending on SBP

FIGURE 16-8. General treatment algorithm for acute decompensated heart failure (ADHF) based on clinical
presentation. IV vasodilators that may be used include nitroglycerin, nesiritide, or nitroprusside. Metolazone or
spironolactone may be added if the patient fails to respond to loop diuretics and a second diuretic is required. IV inotropes
that may be used include dobutamine or milrinone. (D/C, discontinue; HF, heart failure; SBP, systolic blood pressure.)
(Reprinted and adapted from J Cardiac Fail, Vol. 12, Pages e1–e122, Copyright 2006, with permission from Elsevier.)

TABLE 16-15 Hemodynamic Monitoring: Normal Values ered to the range of 15 to 18 mm Hg with relatively little decrease in
cardiac index because the Frank-Starling curve is flatter at higher
Central venous (right atrial) pressure, mean <5 mm Hg
PAOP values, particularly in patients with heart failure. Intravenous
Right ventricular pressure 25/0 mm Hg
administration of agents that reduce preload (i.e., loop diuretics,
Pulmonary artery pressure 25/10 mm Hg
Pulmonary artery pressure, mean <18 mm Hg nitroglycerin, or nesiritide) is the most appropriate acute therapy to
Pulmonary artery occlusion pressure, mean <12 mm Hg achieve the therapeutic goal for patients in subset II. These agents
Systemic arterial pressure 120/80 mm Hg will produce a very rapid decrease in preload, although signs and
Mean arterial pressure 90–110 mm Hg symptoms of pulmonary congestion may take longer to resolve.
Cardiac index 2.8–4.2 L/min/m2 Current guidelines recommend loop diuretics as first-line ther-
Stroke volume index 30–65 mL/b/m2 apy for management of heart failure patients admitted with fluid
Systemic vascular resistance 900–1,400 dyne.sec.cm–5 overload and that such agents should typically be administered
Pulmonary vascular resistance 150–250 dyne.sec.cm–5 intravenously. The rate of diuresis should achieve a desirable vol-
Arterial oxygen content 20 mL/dL
ume status without causing a rapid reduction in intravascular
Mixed venous oxygen content 15 mL/dL
volume resulting in symptomatic hypotension or renal dysfunction.
Arteriovenous oxygen content difference 3–5 mL/dL
Electrolyte depletion should be monitored for closely, especially
 204

5.0 Current guidelines recommend intravenous inotropes for symp-

tom relief or end-organ dysfunction in patients with left ventricular
SECTION 2

dysfunction and low cardiac output syndrome. Such therapy may be

4.0 especially useful in patients with low systolic blood pressure (less
Cardiac index (L/min/m2)

Subset I Subset II than 90 mm Hg) or symptomatic hypotension in the setting of

(normal) (pulmonary congestion) adequate filling pressures. As previously discussed (see Subset II
3.0 above), inotropic therapy may be considered in patients who do not
tolerate or respond to intravenous vasodilators or patients with
2.2 L/min/m2 worsening renal function. As with vasodilators, inotrope administra-
2.0 tion requires frequent blood pressure monitoring as well as continu-
Cardiovascular Disorders

Subset IV ous monitoring for arrhythmias. If arrhythmias arise, dose reduction

Subset III or discontinuation of inotropic therapy should occur. Also, these
(pulmonary congestion
1.0 (hypoperfusion)
and hypoperfusion) agents should be avoided in patients with low left-heart filling
18 mm Hg pressures. Given the potential risks associated with inotropic ther-
apy, vasodilators should be considered prior to using inotropes.124
10 20 30 40 In general, inotropic therapy should not be used in the broad
Pulmonary artery occlusion pressure (mm Hg) decompensated heart failure population. They are useful to increase
FIGURE 16-9. Hemodynamic subsets of heart failure based on cardiac cardiac output in the patients described above. These agents may be
index and pulmonary artery occlusion pressure. (Adapted with permis- used to “bridge” patients with cardiogenic shock to heart transplan-
sion from N Engl J Med 1976;295:1356–1362.) tation or left ventricular assist device. Inotropes may also be used as
palliative therapy to improve functional status and quality of life in
when a high dose or diuretic combination therapy is used. In patients who are not considered optimal candidates for these
addition to sodium restriction (less than 2 g daily), supplemental definitive therapies.124
oxygen should be administered as needed for hypoxemia. In
Subset IV Patients with a cardiac index of less than 2.2 L/min/m2
patients with moderate hyponatremia (less than 130 mEq/L), fluid
and a PAOP higher than 18 mm Hg are in hemodynamic subset IV.
restriction (less than 2 L daily) should be considered, and in patients
These patients have the worst prognosis of any subset and illustrate
with worsening or severe hyponatremia (less than 125 mEq/L),
the typical hemodynamic profile for the patient hospitalized for
stricter fluid restriction may be necessary.124
severe heart failure.
Intravenous vasodilators may be considered in addition to
Because of severe pump failure, these patients cannot maintain an
diuretics for rapid symptom resolution and may be especially useful
adequate cardiac index despite the elevated left ventricular filling
in patients with acute pulmonary edema or severe hypertension, as
pressure and increased myocardial fiber stretch. These patients will
well as in patients who fail to respond to aggressive treatment with
present with signs and symptoms of both “wet” and low-output heart
diuretics. It is essential to avoid use of vasodilators in patients with
failure. The treatment goals are to alleviate these signs and symptoms
symptomatic hypotension, and frequent blood pressure monitoring
by increasing cardiac index above 2.2 L/min/m2 and reducing PAOP
is essential for the safe use of these agents. In addition, these agents
to 15 to 18 mm Hg while maintaining an adequate mean arterial
should not be used in patients with low left-heart filling pressures.
pressure. Thus therapy will involve a combination of agents used for
If symptomatic hypotension occurs with vasodilator therapy, the
subset II and subset III patients to achieve these goals (i.e., combina-
dose should be reduced or the agent discontinued. If patients fail to
tion of diuretic plus positive inotrope). These targets may be difficult
respond to the above therapies or experience worsening renal
to achieve and will necessitate careful monitoring and individualiza-
function, intravenous inotropic therapy should be considered.124
tion of drug therapy. Nitroprusside is a particularly useful agent in
Subset III Patients in hemodynamic subset III have a cardiac this setting because of its mixed arterial–venous vasodilating effects.
index of less than 2.2 L/min/m2 but without an abnormally elevated In the presence of significant hypotension, inotropic agents with
PAOP (see Fig. 16–9). These patients usually present without vasopressor activity may be required initially to achieve an adequate
evidence of pulmonary congestion, but the low cardiac index results perfusion pressure to essential organs and can then be combined, if
in signs and symptoms of peripheral hypoperfusion (i.e., decreased necessary, with diuretics and/or vasodilators to obtain the desired
urine output, weakness, peripheral vasoconstriction, weak pulses). hemodynamic effects and clinical response.
The mortality rate of subset III patients is reported to be four times
higher than that of patients without hypoperfusion.132 Although the
treatment goal is to alleviate signs and symptoms of hypoperfusion
■ PHARMACOLOGIC THERAPY OF ACUTE
by increasing cardiac index and perfusion to essential organs, DECOMPENSATED HEART FAILURE
therapy will differ among patients. If the PAOP is significantly  Unfortunately, the treatment of decompensated heart failure has
below 15 mm Hg, initial therapy will be to administer intravenous not improved substantially in the past decade in large part because
fluids to provide a more optimal left ventricular filling pressure of of the lack of clinical trial data in this population. The pharmaco-
15 to 18 mm Hg and consequently improve cardiac index. When therapeutic agents used to treat patients with decompensated heart
there is only mild left ventricular dysfunction, intravenous fluid failure rarely, if ever, produce a single cardiovascular action. Even
administration may be all that is necessary to achieve a cardiac index when intended for a single purpose (e.g., a positive inotrope), other
above 2.2 L/min/m2. However, many patients will have significant drug effects (tachycardia, vasodilation, or vasoconstriction) may
left ventricular dysfunction and a depressed Frank-Starling relation- either add to the therapeutic effect or cause adverse events that
ship despite adequate preload (i.e., PAOP of 15 to 18 mm Hg). In negate or even outweigh the intended therapeutic benefit. It often
these patients, intravenously administered positive inotropic agents can be difficult to anticipate how an individual patient will respond
(e.g., dobutamine, milrinone) and/or arterial vasodilators (e.g., to a given intervention. For this reason, hemodynamic monitoring
nitroprusside or nitroglycerin) are often necessary to achieve an can be useful, and many drugs are considered first-line therapy due
adequate cardiac index. It is noteworthy that some positive inotro- in part to their short half-lives and ease of titration. The description
pic medications also will have arterial vasodilating activity (see of expected drug actions outlined below should be viewed as a
specific drug classes that follow). general guide to the clinician, who must continuously reassess the
 205

CHAPTER 16
Subset II
Subset I IV loop diuretic
No additional ± thiazide
specific intervention ± IV vasodilator
(to achieve PAOP of 15–18 mmHg)

Subset III Subset IV

Heart Failure
PAOP<15 PAOP
Adequate
mm Hg 15–18 mm Hg
arterial pressure?

Fluids until Adequate Yes No

No
PAOP arterial pressure?
15–18 mm Hg

Yes No IV loop diuretic Dopamine

(to achieve
PAOP 15–18 mm Hg)
Cl>2.2
L/min/m2?
Dobutamine Dopamine
or milrinone
Milrinone Achieve adequate
or arterial pressure
Yes dobutamine ±
Achieve adequate IV vasodilator
arterial pressure

No additional
CI>2.2 L/min/m2?
specific intervention

Yes No
CI>2.2 L/min/m2?

IV nitroglycerin Add dobutamine

Yes No or milrinone (if
not already done)
Add IV vasodilator
±
No additional Add IV loop diuretic
specific intervention IV vasodilator

(to achieve PAOP 15–18 mm Hg)

FIGURE 16-10. General treatment algorithm for patients with advanced/decompensated heart failure based on hemodynamic
monitoring and hemodynamic subsets. IV vasodilators that may be used include nitroglycerin, nesiritide, or nitroprusside. See text
for details. (CI, cardiac index; PAOP, pulmonary artery occlusive pressure.)

patient for desired outcomes. Table 16–16 contains a summary of NE, and AVP elevations and the expected consequences of arteriolar
the expected hemodynamic effects of the various drugs discussed and coronary constriction, tachycardia, and increased PAOP and
below (see also Chap. 25). myocardial oxygen consumption. Unlike arterial dilators and posi-
tive inotropic agents, diuretics do not cause an upward shift in the
Diuretics44,133,134 Frank-Starling curve or increase cardiac index significantly in most
patients (see Table 16–16). Excessive preload reduction with diuret-
Intravenous loop diuretics, including furosemide, bumetanide, and
ics can lead to a decline in cardiac output (see Fig. 16–3). Conse-
torsemide, are used in the management of decompensated heart
quently, diuretics must be used judiciously to obtain the desired
failure, with furosemide being the most widely studied and used
improvement in symptoms of congestion while avoiding a reduc-
agent in this setting. Bolus administration of diuretics decreases
tion in cardiac output, symptomatic hypotension, or worsening
preload within 5 to 15 minutes by functional venodilation and later
renal function. Although counterintuitive, renal function may also
(>20 minutes) via sodium and water excretion, thereby improving
improve in the setting of diuresis.
pulmonary congestion. However, the acute reduction in venous
return may severely compromise effective preload in patients with Diuretic Resistance Occasionally, patients respond poorly to
significant diastolic dysfunction or intravascular depletion. This large doses of loop diuretics, and heart failure is the most common
results in a reflex increase in sympathetic activation, renin release, clinical setting in which diuretic resistance is observed. Data from
 206

TABLE 16-16 Usual Hemodynamic Effects of Intravenous Agents diuretic with a distal tubule blocker such as metolazone or hydro-
Commonly Used for Treatment of Advanced or chlorothiazide can produce a synergistic diuretic effect. The syner-
SECTION 2

Decompensated Heart Failurea gism is not a pharmacokinetic interaction but is related to the
increased delivery of sodium to the distal convoluted tubule.
Drug Dose HR MAP PAOP CO SVR
Enhanced sodium delivery to (and reabsorption in) the distal tubule
Dopamine 0.5–3 mcg/kg/min 0 0 0 0/+ – can then be blocked by the thiazide-type diuretic. Thus, when
Dopamine 3–10 mcg/kg/min + + 0 + 0 thiazide-type diuretics are added to a loop diuretic, they block more
Dopamine >10 mcg/kg/min + + + + + than their normal 5% to 8% of filtered sodium, and the combina-
Dobutamine 2.5–20 mcg/kg/min 0/+ 0 – + –
tion results in synergistic natriuresis.
Milrinone 0.375–0.75 mcg/ 0/+ 0/– – + –
kg/min
The loop diuretic–thiazide combination generally should be
Cardiovascular Disorders

Nitroprusside 0.25–3 mcg/kg/min 0/+ 0/– – + – reserved for the inpatient setting, where the patient can be moni-
Nitroglycerin 5–200 mcg/min 0/+ 0/– – 0/+ 0/– tored closely, because it can induce a profound diuresis with severe
Furosemide 20–80 mg, repeated 0 0/– – 0 0 electrolyte and volume depletion. When used in the outpatient
as needed up to setting, very low doses or only occasional doses of the thiazide-type
six times per day diuretic should be used along with close followup (weight, vital
Enalaprilat 1.25–2.5 mg q6-8h 0 0/– – + + signs, dizziness) to avoid serious adverse events.
Nesiritide bolus: 2 mcg/kg; 0 0/– – + – Current guidelines support each of the above mentioned options
infusion 0.01 for managing patients who do not initially respond to diuretic
mcg/kg/min 0
therapy. Further restricting sodium and fluid (e.g., less than 1 g and
+, increase; –, decrease; 0, no change; CO, cardiac output; HR, heart rate; MAP, mean arterial less than 1 L per day, respectively) beyond that which is routine may
pressure; PAOP, pulmonary artery occlusion pressure; SVR, systemic vascular resistance. also prove useful in managing diuretic refractory patients. Such
a
See text for a more detailed description of the interpatient variability in response.
severe fluid restrictions also will be helpful in managing moderate to
severe hyponatremia. Ultrafiltration is an additional therapeutic
retrospective analyses suggest that diuretics, especially aggressive
option in the diuretic refractory patient. This topic is discussed
diuretic administration, may be harmful. The use of diuretics is
within Mechanical Circulatory Support below.
associated with a dose-dependent increase in mortality.135 Recent
evidence also suggests that high diuretic doses are associated with a
decline in renal function in decompensated heart failure.134,136 Thus, Positive Inotropic Agents137,138
the need for increased exposure to diuretics in the setting of diuretic Drugs that increase intracellular cAMP are the only positive inotropic
resistance is concerning. agents currently approved for the treatment of acute heart failure. β-
The mechanisms responsible for diuretic resistance in heart Agonists activate adenylate cyclase through stimulation of β-adrener-
failure patients appear to be both pharmacokinetic and pharmaco- gic receptors, with the enzyme then catalyzing the conversion of
dynamic. The bioavailability of furosemide is relatively normal in adenosine triphosphate to cAMP. Phosphodiesterase inhibitors raise
heart failure patients, but the rate of absorption is prolonged cAMP concentrations by reducing its degradation. Consequently,
approximately twofold, and peak concentrations are about half of both drug classes increase intracellular cAMP, which enhances phos-
normal. Because loop diuretics have a sigmoidal-shaped urine pholipase (and, subsequently, phosphorylase) activity, increasing the
concentration–response curve, prolonged absorption may result in rate and extent of calcium influx during systole and enhancing
concentrations that fail to reach the steep portion of this curve, contractility. Additionally, cAMP enhances reuptake of calcium by
resulting in diminished responsiveness. Despite normal pharmaco- the sarcoplasmic reticulum during diastole, improving active relax-
kinetics following intravenous administration, diuretic resistance is ation. Table 16–17 summarizes the receptor activities of the β-
also observed with this route, suggesting an important pharmacody- agonists. Although rarely used in management of heart failure, the
namic component to diuretic resistance. The decreased responsive- receptor effects of epinephrine, NE, and isoproterenol are provided
ness in heart failure patients is explained in part by the high for reference.
concentrations of sodium reaching the distal tubule as a result of the Digoxin has little, if any, place in the acute treatment of patients
blockade of sodium reabsorption in the loop of Henle. As a with decompensated heart failure who are hemodynamically unsta-
consequence, the distal tubule hypertrophies, increasing its ability ble. The delay in peak inotropic effect, limited inotropic effect, long
to reabsorb sodium. In addition, low cardiac output, reduced renal duration of action, and potential toxicity (arrhythmic, vasoconstric-
perfusion, and subsequent decreased delivery of drug to the kidney tive, neurologic) are disadvantages in the acute setting. However, in
may also contribute to resistance. patients with acute decompensation who are taking digoxin as part
Several maneuvers can be attempted to overcome diuretic resis- of their chronic therapy, it is generally unnecessary to adjust the
tance. Treatment of heart failure with other agents (e.g., positive dose or discontinue its use unless changes in renal function increase
inotropes or afterload reducers) may improve diuresis by increasing the risk of toxicity.
cardiac output and renal perfusion. Administration of low doses of Although a number of parenteral agents have been used for the
dopamine with the hope of enhancing diuresis is also a common treatment of patients with decompensated heart failure, dobuta-
practice. However, data suggest that addition of dopamine to mine and milrinone have emerged as the two drugs most commonly
furosemide provides no additional diuresis.124 Larger intravenous
bolus doses of diuretics may achieve concentrations closer to the top
TABLE 16-17 Relative Effects of Adrenergic Drugs on Receptors
of the concentration–response curve, or a continuous intravenous
infusion may be used to maintain more constant concentrations in Drug α1 β1 β2 Dopamine1
the steep portion of the concentration–response curve. Studies of Norepinephrine ++++ ++++ 0 0
continuous-infusion furosemide suggest a greater natriuretic effect Epinephrine ++++ ++++ ++ 0
and no difference in metabolic adverse effects when compared with Dopaminea ++++ ++++ ++ ++
the same total daily dose given by intravenous bolus.124 Continuous Isoproterenol 0 ++++ ++++ 0
infusions also may limit adverse hemodynamic events. Dobutamineb + ++++ ++ 0
Another approach to improving diuresis is addition of a second a
See text for a more detailed description of the dose-dependent hemodynamic effects.
diuretic with a different mechanism of action. Combining a loop b
Combined effects of the commercially available racemic mixture (see text).
 207
administered. These drugs differ in their mechanism of action and During intravenous administration, there is an increase in stroke
resulting pharmacologic effects and provide advantages and disad- volume (and, therefore, cardiac output) with little change in heart

CHAPTER 16
vantages in any given patient. rate (see Table 16–16). Despite the increase in cardiac index, mean
arterial pressure may remain constant as a result of a concomitant
Dobutamine Dobutamine, a synthetic catecholamine, is a β1- and
decrease in arteriolar resistance. In contrast, the vasodilating effects
β2-receptor agonist with some α1-agonist effects (see Table 16–17).
may predominate and lead to a decrease in blood pressure and a
Unlike dopamine, dobutamine does not cause release of NE from
reflex tachycardia. Like dobutamine, milrinone lowers PAOP by
nerve terminals. The overall hemodynamic effects of dobutamine are
venodilation and thus is particularly useful in patients with a low
the result of its effects on adrenergic receptors and reflex-mediated
cardiac index and an elevated left ventricular filling pressure. Such a
actions. Its β2-receptor-mediated effects are greater than those of
reduction in preload, however, can be hazardous for patients
dopamine, and β2-receptor-mediated vasodilation will tend to offset

Heart Failure
without excessive filling pressure (especially those with symptoms
some of the α1-receptor-mediated vasoconstriction. Thus the net
of “dry” heart failure), leading to a decrease in cardiac index. Such
vascular effect is usually vasodilation. The positive inotropy is pri-
an effect would blunt the improvement in cardiac output that
marily a β1-receptor mediated effect. Cardiac β1-receptor stimula-
would otherwise be produced by the positive inotropic and arterial
tion by dobutamine causes an increase in contractility but generally
dilating actions. Milrinone should be used cautiously as a single
no significant change in heart rate and may provide an explanation
agent in severely hypotensive heart failure patients because it will
for the apparently more modest chronotropic actions of dobutamine
not increase, and may even decrease, arterial blood pressure. The
compared with dopamine.
results of controlled studies comparing dobutamine with milrinone
The overall hemodynamic effects of dobutamine are those of a
indicate that these agents produce generally similar hemodynamic
potent inotropic agent with vasodilating action. Initial doses of 2.5 to
effects. A clinically insignificant but greater increase in heart rate
5 mcg/kg per minute can be increased progressively to 20 mcg/kg/min
with dobutamine is the most consistent difference in these studies.
based on clinical and hemodynamic responses. The onset of action is
Milrinone has a longer terminal elimination half-life than adrener-
within minutes; however, peak effects may take 10 minutes to become
gic agonists. The average milrinone half-life in healthy subjects is
evident. Dobutamine has a half-life of 2 minutes. Cardiac index is
about 1 hour and approximately 3 hours in patients with heart
increased because of inotropic stimulation, arterial vasodilation, and
failure. This long elimination half-life may be a disadvantage in this
a variable increase in heart rate. Because of the offsetting changes in
patient population because a loading dose may be necessary to obtain
arteriolar resistance and cardiac index, dobutamine usually will cause
a prompt initial response, minute-to-minute titrations in dose can-
relatively little change in mean arterial pressure although these effects
not be made based on response, and adverse effects (arrhythmias or
may be variable. This is compared with the more consistent increase
hypotension) will persist longer after drug discontinuation. The
observed with dopamine. Dobutamine’s vasodilating action usually
usual loading dose for milrinone is 50 mcg/kg administered over 10
can decrease PAOP, making it particularly useful in the presence of
minutes. However, if rapid hemodynamic changes are unnecessary,
low cardiac index and an elevated left ventricular filling pressure, or
the loading dose should be eliminated because of the risk of hypoten-
detrimental in the presence of a reduced filling pressure. Unfortu-
sion. Thus, most patients are simply started on the maintenance
nately, an increase in oxygen consumption with dobutamine has been
infusion without a preceding bolus dose. The maintenance infusion
demonstrated in patients with both ischemic and nonischemic car-
for milrinone is 0.25 mcg/kg/min (up to 0.75 mcg/kg/min). Mil-
diomyopathy. The major adverse effect of dobutamine is tachycardia.
rinone is excreted unchanged in urine, and thus, its infusion rate
Although concern over attenuation of dobutamine’s hemodynamic
should be decreased by 50% to 70% in patients with significant renal
effects has been raised with prolonged administration, some effect is
impairment.
likely still retained. And thus, dobutamine dose should be tapered
The most notable adverse events associated with milrinone are
rather than abruptly discontinued.
arrhythmia, hypotension, and thrombocytopenia. Although the
In some patients, dobutamine (or milrinone) dose reduction or
incidence of thrombocytopenia associated with milrinone therapy is
discontinuation results in acute decompensation and these patients
rare, patients should still have platelet counts determined before
may then require placement of an indwelling intravenous catheter
and during therapy.
for continuous therapy. This approach may be used to “bridge”
The combination of dobutamine and milrinone is expected to
patients awaiting cardiac transplantation, and may also be used to
produce additive effects on cardiac index and PAOP reduction,
facilitate the discharge of patients who are not transplant candi-
suggesting this regimen as an option in patients who have dose-
dates, but who cannot be weaned from inotrope therapy. In this
limiting adverse effects with either class of drugs. It is unclear,
latter group, the use of continuous outpatient dobutamine therapy
however, if this combination provides a therapeutic advantage over
is for palliative use only and should only be considered after
the combination of a positive inotrope and a traditional pure
multiple unsuccessful attempts to maximize oral therapy and dis-
vasodilator such as nitroprusside.
continue inotrope therapy. Although effective for symptom pallia-
One study with milrinone points out the risk associated with
tion, it should be realized that the risk of mortality is likely
routine administration of inotropic therapy to a broad population of
increased. In contrast, the use of regularly scheduled intermittent
patients admitted to the hospital with an acute exacerbation of heart
dobutamine infusions at home or in an outpatient clinic is not
failure. Although this approach is not supported by clinical trial data,
recommended in the current guidelines.124
many patients without signs or symptoms of hypoperfusion receive
Milrinone Milrinone is a bipyridine derivative that inhibits phos- milrinone or other inotropic therapy with the belief that the hemo-
phodiesterase III, an enzyme responsible for the breakdown of dynamic effects may shorten hospitalization and improve clinical
cAMP to adenosine monophosphate. Milrinone has supplanted the outcomes. Designed to evaluate this strategy, the Outcomes of a
use of amrinone, the prototype drug for milrinone, because of the Prospective Trial of Intravenous Milrinone for Exacerbations of
more frequent occurrence of thrombocytopenia with amrinone. Chronic Heart Failure (OPTIME-CHF) trial was a randomized,
Both positive inotropic and arterial and venous vasodilating effects double-blind trial comparing the effects of milrinone and placebo in
contribute to the therapeutic response in heart failure patients; patients hospitalized with an acute exacerbation of chronic heart
hence milrinone has been referred to as an inodilator. The relative failure who, in the investigator’s opinion, did not require inotropic
balance of these pharmacologic effects may vary with dose and therapy.122 The 949 patients received a 48-hour infusion of milrinone
underlying cardiovascular pathology. 0.5 mcg/kg/min with no loading dose or placebo. No difference
 208
between milrinone and placebo was found in the primary end point tension), worsening ischemia in some patients with coronary dis-
of the number of days patients were hospitalized for cardiovascular ease. As with dobutamine and milrinone, arrhythmogenesis is also
SECTION 2

causes within 60 days of randomization. However, adverse events more common at higher doses.
were more common in the milrinone group. Sustained hypotension
requiring intervention (10.7% vs. 3.2%; P < 0.001) and new onset of
atrial fibrillation or flutter (4.6% vs. 1.5%; P = 0.004) occurred more Vasodilators134,140
frequently in patients receiving milrinone. Activation of the SNS, the RAAS, AVP, and other mediators all
Recently, data from the ADHERE Registry (n = 15,230) was used cause vasoconstriction and increased SVR. In patients with heart
to compare in-hospital mortality with intravenous nitroglycerin, failure, stroke volume varies inversely with SVR such that an
nesiritide, milrinone, and dobutamine. After adjusting for baseline increase in peripheral resistance leads to a severe decline in stroke
Cardiovascular Disorders

parameters that predict in-hospital mortality, both dobutamine- volume and cardiac output (see Fig. 16–1).
and milrinone-treated patients had a higher in-hospital mortality Vasodilators typically are described by their prominent site of
when compared to patients receiving either nitroglycerin or nesiri- action (arterial or venous). Arterial vasodilators act as impedance-
tide (P < 0.005). There was no difference in in-hospital mortality reducing agents, reducing afterload and a reflexive increase in
between nitroglycerin- and nesiritide-treated patients (P = 0.58). cardiac output. Venodilators act as preload reducers by increasing
In-hospital mortality was higher in patients receiving dobutamine venous capacitance, reducing symptoms of pulmonary congestion
compared to milrinone (P = 0.027).139 in patients with high cardiac filling pressures. Mixed vasodilators act
These results add to the growing concern about the use of on both resistance and capacitance vessels, reducing congestive
inotropic drugs in patients with decompensated heart failure and symptoms while increasing cardiac output. Nitroprusside, nitro-
strongly suggest that milrinone, and probably other inotropes, glycerin, and nesiritide are the most commonly used intravenous
should not be routinely used for the treatment of acute heart failure vasodilating agents in decompensated heart failure.
exacerbations. Although the routine use of milrinone should be
Nitroprusside Sodium nitroprusside, a mixed arterial–venous
discouraged, clinicians should be aware that inotropic therapy may
vasodilator, acts on vascular smooth muscle, increasing synthesis of
be needed in selected patients such as those with low cardiac output
nitric oxide to produce its balanced vasodilating action. As such, it
states with organ hypoperfusion or with cardiogenic shock. Gener-
both increases cardiac index and decreases venous pressure. Nitro-
ally, milrinone should be considered for patients who are receiving
prusside’s effects on these parameters are qualitatively similar to those
chronic β-blocker therapy because its positive inotropic effect does
produced by dobutamine and phosphodiesterase inhibitors, despite
not involve stimulation of β-receptors. In contrast to dobutamine,
the fact that it has no direct inotropic activity (see Table 16–16).
milrinone’s positive hemodynamic effects persist despite concomi-
However, nitroprusside generally causes a greater decrease in
tant β-blocker therapy.
PAOP, SVR, and blood pressure than these agents. Mean arterial
Dopamine Although dopamine generally should be avoided in the pressure may remain fairly constant but often decreases depending
treatment of decompensated heart failure, the only clinical scenario on the relative increase in cardiac output and reduction in arteriolar
where its pharmacologic actions may be preferable to dobutamine or tone. Hypotension is an important dose-limiting adverse effect of
milrinone is in the patient with marked systemic hypotension or nitroprusside and other vasodilators. Consequently, this drug is
cardiogenic shock in the face of elevated ventricular filling pressures, used primarily in patients who have a significantly elevated SVR and
where dopamine in doses greater than 5 mcg/kg per minute may be often requires invasive hemodynamic monitoring.
necessary to raise central aortic pressure. However, there are no data Patients with normal left ventricular function will not have an
to support this commonly employed practice. increase in stroke volume when SVR falls because the normal
Dopamine, the endogenous precursor of NE, exerts its effects by ventricle is fairly insensitive to small changes in afterload. Conse-
directly stimulating adrenergic receptors, as well as causing release quently, these patients experience a significant decrease in blood
of NE from adrenergic nerve terminals. Dopamine produces dose- pressure after administration of arterial vasodilators. This explains
dependent hemodynamic effects because of its relative affinity for why nitroprusside is a potent antihypertensive agent in patients
α 1-, β 1-, β 2-, and D1- (vascular dopaminergic) receptors (see Table without heart failure but causes less hypotension and reflex tachycar-
16–17). The following dose-dependent actions are intended as a dia in patients with left ventricular dysfunction. Nonetheless, even a
general guide to the clinician. modest increase in heart rate could have adverse consequences in
Positive inotropic effects mediated primarily by β 1-receptors patients with underlying ischemic heart disease and/or resting tachy-
become more prominent with dopamine doses of 2 to 5 mcg/kg/ cardia, and close monitoring is necessary during therapy.
min. Cardiac index is increased because of an increase in stroke Nitroprusside has been studied extensively and shown to be
volume and a variable increase in heart rate, which is partially dose effective in the short-term management of patients with severe heart
dependent. There is usually little change in SVR, presumably failure in a variety of settings (i.e., acute MI, valvular regurgitation,
because neither vasodilation (D1- and β2-receptor mediated) nor after coronary bypass surgery, decompensated chronic heart fail-
vasoconstriction (α1-receptor mediated) predominates. At doses ure). Generally, nitroprusside will not worsen, and may improve,
between 5 and 10 mcg/kg/min, chronotropic and α1-receptor– the balance between myocardial oxygen demand and supply. This is
mediated vasoconstricting effects become more prominent. Mean mainly a result of a decrease in oxygen demand caused by the
arterial pressure usually increases because of an increase in both lowering of left ventricular wall tension and a possible increase in
cardiac index and SVR (see Table 16–16). The vasoconstricting subendocardial blood flow resulting from decreased left ventricular
effects of higher doses could indirectly limit the increase in cardiac end-diastolic pressure. However, an excessive decrease in systemic
index by increasing afterload and PAOP, thus complicating the arterial pressure can reduce coronary perfusion and worsen
management of patients with preexisting high afterload. In such ischemia, leading to increased risk of coronary steal.
patients, alternative agents (dobutamine, milrinone) or the addition Nitroprusside has a rapid onset of action and a duration of action
of diuretics and/or vasodilators may be necessary. of less than 10 minutes, necessitating its administration by continu-
Dopamine, particularly at higher doses, may alter several param- ous intravenous infusion. This allows for precise dose titration based
eters that increase myocardial oxygen demand (increased heart rate, on measured clinical and hemodynamic parameters. It, like other
contractility, and systolic pressure) and potentially decrease myo- vasodilators used in heart failure, should be initiated at a low dose
cardial blood flow (coronary vasoconstriction and increased wall (0.1 to 0.2 mcg/kg/min) to avoid excessive hypotension and then
 209
increased by small increments (0.1 to 0.2 mcg/kg/min) every 5 to 10 The Vasodilation in the Management of Acute CHF (VMAC)
minutes as needed and tolerated. Effective doses usually range from trial was a randomized, double-blind trial that compared the effects

CHAPTER 16
0.5 to 3.0 mcg/kg/min. A rebound phenomenon has been reported of nesiritide, IV nitroglycerin, and placebo in patients with decom-
after abrupt withdrawal of nitroprusside in patients with heart failure pensated heart failure and dyspnea who were receiving standard
and is apparently caused by reflex neurohormonal activation during background therapy.123 Patients received pulmonary artery cathe-
therapy. If renal perfusion pressure is compromised by the drug, salt terization at the discretion of the investigators. The primary end
and water retention can contribute to volume expansion and tachy- points were the patient’s self-assessment of dyspnea (all patients)
phylaxis; this is seen typically only in patients with chronic hyperten- and the change in PAOP at 3 hours after the start of the study drug
sion, baseline azotemia, or when therapeutic augmentation of infusion (only in patients with a pulmonary artery catheter) com-
cardiac output during therapy is minimal. When stopping nitroprus- pared to placebo. Although nesiritide reduced dyspnea at 3 hours

Heart Failure
side and switching to oral drugs, it is usually advisable to taper doses compared to placebo, no difference between nesiritide and nitro-
slowly. Nitroprusside can cause cyanide and thiocyanate toxicity, but glycerin was found.
these are very unlikely when doses less than 3 mcg/kg/min are The precise role of nesiritide in the pharmacotherapy of decom-
administered for less than 3 days, except in patients with a serum pensated heart failure remains controversial. Some of this contro-
creatinine level greater than 3 mg/dL. versy centers on the marginal lack of improvement in mortality or
Given the potent pulmonary vasodilatory effects of nitroprusside other clinical outcomes with nesiritide compared to nitroglycerin
as well as its short half-life, this agent is frequently used to deter- (or nitroprusside) balanced against nesiritide’s significantly greater
mine reversibility of pulmonary hypertension in patients being costs (~$450 for a 24-hour nesiritide infusion compared to $10 to
assessed for heart transplantation. This is the most common use of $15 for nitroglycerin). In addition, two recent meta-analyses suggest
nitroprusside for the management of decompensated heart failure. an increased risk of worsening renal function, as well as an increase
in mortality with nesiritide.141,142 The authors of these studies
Nitroglycerin Intravenous nitroglycerin is often considered the
concluded that these finding are hypothesis generating and should
preferred agent for preload reduction in patients with severe heart
be further investigated. More recently, the safety of nesiritide in 303
failure. Because of its short half-life, intravenous nitroglycerin is
patients with a low LVEF (<40%) who were undergoing coronary
administered by continuous infusion. Its major hemodynamic
artery bypass surgery was evaluated in the multicenter, randomized,
actions are reductions in preload and PAOP via functional venodila-
placebo-controlled Nesiritide Administered Peri-Anesthesia in
tion and mild arterial vasodilation that is particularly evident in
Patients Undergoing Cardiac Surgery (NAPA) study.143 Patients
patients with heart failure and elevated SVR or when given in doses
received intravenous nesiritide 0.01 mcg/kg/min or placebo in the
approaching 200 mcg/min (see Table 16–16). Intravenous nitroglyc-
perianesthesia period and the infusion continued for 24 to 96 hours
erin is used primarily as a preload reducer for patients with pulmo-
at the investigator’s discretion. Serum creatinine increased and
nary congestion. In higher doses, nitroglycerin displays potent
glomerular filtration rate decreased after surgery compared with
coronary vasodilating properties and beneficial effects on myocardial
preoperative values in both treatment groups. However, the changes
oxygen demand and supply, making it the vasodilator of choice for
in creatinine and glomerular filtration rate were significantly greater
patients with severe heart failure and ischemic heart disease.
in placebo-treated patients. In contrast, the mean hospital length of
Nitroglycerin should be initiated at a dose of 5 to 10 mcg/min
stay was significantly shorter and the 180-day mortality rate was
(0.1 mcg/kg/min) and increased every 5 to 10 minutes as necessary
significantly lower in the nesiritide group. To clarify these issues
and tolerated. Hypotension and an excessive decrease in PAOP are
about the safety and efficacy of nesiritide, its manufacturer is
important dose-limiting side effects. Maintenance doses usually
conducting an additional prospective randomized controlled trial.
vary from 35 to 200 mcg/min (0.5 to 3.0 mcg/kg/min). Tolerance to
the hemodynamic effects of nitroglycerin may develop over 12 to 72
hours of continuous administration, but some patients have a ■ MECHANICAL CIRCULATORY SUPPORT144
sustained response. Neither nitroglycerin nor nitroprusside should Intraaortic Balloon Pump
be used in the presence of elevated intracranial pressure because
The intraaortic balloon pump (IABP) is a frequently used form of
either may worsen cerebral edema in this setting.
mechanical circulatory assistance and typically is employed in
Nesiritide Nesiritide is the first new drug approved for the treat- patients with advanced heart failure who do not respond adequately
ment of decompensated heart failure since milrinone. Manufac- to drug therapy, such as those with intractable myocardial ischemia
tured by recombinant techniques, it is identical to the endogenous or patients in cardiogenic shock. The IABP consists of a polyethy-
human BNP secreted by the ventricular myocardium in response to lene balloon mounted on a catheter that is usually inserted percuta-
volume overload. Exogenous administration of nesiritide mimics neously into the femoral artery and the balloon is then advanced
the vasodilatory and natriuretic actions of the endogenous peptide into the descending thoracic aorta. During counterpulsation, the
by stimulating the natriuretic peptide receptor A which leads to balloon is synchronized with the ECG so that it inflates during
increased levels of cyclic guanosine monophosphate in target tis- diastole and displaces aortic blood thus increasing aortic diastolic
sues. Nesiritide produces dose-dependent venous and arterial vaso- pressure and coronary perfusion. The balloon deflates just prior to
dilation, increases in cardiac output, natriuresis, and diuresis, and the opening of the aortic valve during systole and causes a sudden
decreases cardiac filling pressures, SNS and RAAS activity. Unlike decrease in aortic pressure, allowing the left ventricle to pump
nitroglycerin or dobutamine, tolerance does not develop to nesirit- against reduced arterial impedance. IABP support results in
ide’s pharmacologic actions. It does not affect cAMP or stimulate β- increased cardiac index, coronary artery perfusion, and myocardial
receptors, mechanisms that are thought to contribute to the myo- oxygen supply accompanied by decreased myocardial oxygen
cardial toxicity associated with the positive inotropic drugs. Thus, demand. Thus, it is particularly useful for short-term use in patients
nesiritide does not have the proarrhythmic effects associated with with decompensated heart failure in the setting of myocardial
dobutamine. Nesiritide is eliminated by several pathways including ischemia (evolving infarction, patients awaiting emergency coro-
the natriuretic peptide receptor C on target tissues, proteolytic nary bypass surgery). It is also used in hemodynamically unstable
cleavage by neutral endopeptidase, and renal filtration. Its elimina- patients who are unresponsive to inotropic therapy to stabilize them
tion half-life of 18 minutes is considerably longer than that of other prior to insertion of a left ventricular assist device that will serve as
vasodilators or β-agonists. a bridge to transplantation. Generally, intravenous vasodilators and
 210
inotropic agents are used in conjunction with the IABP to maximize Small studies suggest that ultrafiltration is an effective method to
hemodynamic and clinical benefits. remove fluid in heart failure patients and that early initiation prior
SECTION 2

to intravenous diuretics is effective and safe in reducing hospital

Ventricular Assist Devices length of stay and readmission in diuretic resistant patients.
Recently, the Ultrafiltration versus IV Diuretics for Patients Hospi-
A number of ventricular assist devices are available or under
talized for Acute Decompensated Congestive Heart Failure
investigation. These pumps are surgically implanted and assist, or in
(UNLOAD) trial investigated the effects of early ultrafiltration alone
some cases replace, the pumping functions of the right and/or left
compared to intravenous diuretics alone in 200 patients hospital-
ventricles. A left ventricular assist device (LVAD) removes blood
ized for decompensated heart failure and evidence of fluid overload.
directly from the left ventricle or the left atrium and pumps it to the
The primary end point of weight loss after 48 hours was significantly
aorta. The right ventricular assist device works similar to the LVAD
Cardiovascular Disorders

greater in the ultrafiltration group (5.0 kg) than in the diuretic

and may be used alone or in conjunction with the LVAD.
group (3.1 kg). There was no significant difference between the two
LVADs can be used in the short-term (days to a couple of weeks)
treatment groups in the dyspnea score at 48 hours, another primary
for temporary stabilization of a patient awaiting an intervention to
end point. Compared with the diuretic group, the net fluid loss was
correct the underlying cardiac dysfunction. Alternatively, these
significantly greater in the ultrafiltration group (4.6 L vs. 3.3 L) after
devices can be used in the long-term (several months to a couple of
48 hours. After 90 days, the incidence and duration of rehospitaliza-
years) as a bridge to heart transplantation. More recently, perma-
tion and the incidence of unscheduled office or emergency depart-
nent device implantation has become an option for patients who are
ment visits were significantly lower in patients who were treated
not heart transplantation candidates.
using ultrafiltration than in patients who were treated with intrave-
The REMATCH (Randomized Evaluation of Mechanical Assis-
nous diuretics.147
tance for the Treatment of Congestive Heart Failure) trial random-
ized 129 patients with decompensated heart failure to LVAD or
optimal medical therapy. LVAD patients experienced improved 2- ■ SURGICAL THERAPY
year survival; however, only 23% of these patients were alive at 2
Orthotopic cardiac transplantation remains the best therapeutic
years, compared to only 8% in the medically managed group.145
option for patients with chronic, irreversible NYHA class IV heart
The REMATCH trial was responsible for the approval of the use of
failure, with a 10-year survival of approximately 50% in well-selected
these devices as “destination” therapy, destination being the last
patients.148 Unfortunately, the shortage of acceptable donor hearts has
therapeutic option for a given patient. It also raised awareness
resulted in long waiting times for transplantation, with many patients
regarding some of the limitations of these devices. Complications
succumbing to their disease prior to transplantation. Another large
with LVADs include bleeding, air embolism, and right ventricular
percentage of patients are rejected from consideration for transplanta-
failure, as well as those complications associated with a major
tion because of age, concurrent illnesses, psychosocial factors, and
surgical procedure, including infection. In addition, these pumps
other reasons. See Chap. 92 for additional details on cardiac transplan-
can cause hemolysis, thrombosis, renal and hepatic dysfunction,
tation. The shortage of donor hearts has prompted development of
and arrhythmias. Finally, device malfunction may occur. Contro-
new surgical techniques, including ventricular aneurysm resection,
versy exists regarding the cost of such procedures given the already
mitral valve repair, and myocardial cell transplantation, which have
significant economic impact of this disease state on the healthcare
resulted in variable degrees of symptomatic improvement. Further
system. Although only a small number of patients were studied,
development of these and other techniques may offer additional
recent research suggests that prolonged unloading of the left ventri-
options in patients who are not transplantation candidates.
cle with an LVAD in combination with drug therapy to induce
reverse remodeling can produce sustained recovery in left ventricle
function and amelioration of symptoms.146 ■ PREPARATION FOR HOSPITAL DISCHARGE
For complete heart replacement therapy, the total artificial heart
For patients who are hospitalized with decompensated heart failure,
systems continue to be investigated; however, embolic complica-
all factors contributing to decompensation should be addressed.
tions, as well as the large size of the currently available systems, are
Patients should be near if not at optimal fluid status, transitioned
limiting their use. Inserted percutaneously, catheter-based LVADs
from intravenous to oral diuretic therapy. Both the patient and
are a more recent advancement. Although these small pumps may
family should receive appropriate education (see details below).
offer an advantage as they avoid the need for open-heart surgery, the
Chronic drug therapy should be optimized and appropriate fol-
technology is still in developmental stages.
lowup clinic appointments scheduled. Typically, patients should be
seen in the clinic in 7 to 10 days following hospital discharge. For
Ultrafiltration patients with recurrent hospital admissions, additional discharge
Renal dysfunction often occurs in the setting of decompensated criteria should be considered (Table 16–18).124
heart failure, and thus, renal replacement therapy may be necessary. Patient education is essential in the discharge process and should
Ultrafiltration provides an additional modality for fluid removal by be multidisciplinary involving input from dietitians, pharmacists,
rapidly removing salt and water (up to 500 mL/h) in a predictable and other healthcare providers. Teaching should promote self-care
manner. It reduces PAOP and increases cardiac output and diuresis by incorporating identification of specific positive and negative
without adversely affecting blood pressure, heart rate, or renal behaviors. By having a better understand of the key concepts of the
function. Also, ultrafiltration is proposed to be safer than diuretics disease and its management, patient self-care should improve and
because removal of sodium and water is isotonic. Potential candi- future hospitalizations may be avoided.124
dates for ultrafiltration include patients with diuretic resistance, Although all patients should benefit from education, those with
renal impairment with diuretic administration, and renal impair- more severe symptoms (NYHA class III or IV) require the most
ment despite inotropic therapy. Complications of ultrafiltration intensive counseling. During a hospitalization, only essential educa-
include those associated with central venous access, such as infec- tion is recommended, which should be supplemented within a
tion, as well as those associated with rapid volume removal and couple of weeks after discharge in the clinic setting. Patients recently
intravascular depletion. Electrolyte depletion is not significant, but hospitalized for heart failure should be considered for referral to a
still requires close monitoring. disease-management program.
 211

TABLE 16-18 Discharge Criteria for Patients with Heart Failure ing high doses versus low doses of ACE inhibitors experienced cost
saving as a consequence of fewer heart failure hospitalizations.152

CHAPTER 16
Recommended for all • Exacerbating factors addressed
More recent pharmacoeconomic studies have focused on the
heart failure • At least near-optimal volume status achieved
impact of newer heart failure therapies or those used as alternatives
patients • Transition from intravenous to oral diuretic successfully
completed to standard therapy. ARBs have been shown to be cost effective in
• Patient and family education completed patients not receiving ACE inhibitors.153 Eplerenone is a cost-effec-
• At least near-optimal pharmacologic therapy achieved tive therapy in patients with post-MI heart failure.154 Fixed-dose
• Followup clinic visit scheduled, usually for 7–10 days combination hydralazine and isosorbide dinitrate is cost-effective in
after discharge black patients with severe heart failure.155 Other cost-effective studies
Should be considered • Oral medication regimen stable for 24 hours have focused on device therapy. Prophylactic ICD implantation in
for patients with • No intravenous vasodilator or inotropic agent for 24 hours

Heart Failure
heart failure patients with systolic dysfunction is cost-effective.156
advanced heart • Ambulation before discharge to assess functional Although cost-effectiveness of CRT has been suggested, it was found
failure or recurrent capacity after therapy
to be sensitive to changes in several key variables. Thus investigators
admissions for • Plans for postdischarge management (scale present in
cautioned that such therapy should not be considered in patients
heart failure home, visiting nurse or telephone followup generally
no longer than 3 days after discharge) with any comorbid illnesses that may shorten life expectancy.157
• Referral for disease management Finally, LVADs as a bridge to heart transplantation were found to be
cost-ineffective unless costs associated with their implantation
Adapted from Adams KF, Lindenfield J, Arnold JMO, et al. HFSA 2006 comprehensive heart failure
decrease or their clinical benefits increase.158
practice guidelines. J Card Fail 2006;12:e1–e122.
As the management of heart failure has become increasingly
complex, the development of disease-management programs
For patients with end-stage disease, quality of life and prognosis
approaches that use multidisciplinary teams has been studied exten-
should be discussed with the patient and caregivers. The patient’s
sively. These programs use several broad approaches, including
clinical status should be optimally managed prior to discussing end-
heart failure specialty clinics and/or home-based interventions.
of-life care. If possible, this discussion should occur while the
Most are multidisciplinary and may include physicians, advanced
patient is still able to participate in the decision-making process.
practice nurses, dieticians, and pharmacists. In general, the pro-
End-of-life care should be considered in patients with persistent
grams focus on optimization of drug and nondrug therapy, patient
symptoms at rest despite multiple attempts to optimize therapy as
and family education and counseling, exercise and dietary advice,
evidenced by frequent hospitalizations (three or more per year),
intense followup by telephone or home visits, and monitoring and
ongoing limited quality of life, requiring intermittent or continuous
management of signs and symptoms of decompensation. In general,
intravenous therapy, or consideration of assist devices as destina-
multidisciplinary disease management programs reduce heart fail-
tion therapy. In such cases, inactivation of an ICD should be
ure and all-cause hospitalizations, mortality, and costs.159
discussed and patients may be considered for hospice services.124
Pharmacists can play an important role in the multidisciplinary
Integration of a palliative care approach may be necessary. As
team management of heart failure.160,161 Compared to conventional
clinical status deteriorates and medical therapies become ineffective,
treatment, pharmacist interventions, that included medication eval-
healthcare providers should transition from focusing on mortality
uation and therapeutic recommendations, patient education, and
reduction to palliative care.149
followup telephone monitoring, reduced hospitalizations for heart
failure. Adherence to guideline-recommended therapy was also
■ PHARMACOECONOMIC CONSIDERATIONS improved by pharmacist intervention. A recent study found that
Heart failure imposes a tremendous economic burden on the pharmacist intervention improved medication adherence and
healthcare system. In patients older than age 65 years, it is the most reduced emergency department visits and hospitalizations in low-
common reason for hospitalization, with hospital admission rates income patients with heart failure.162 Thus, the role and cost benefits
for this disorder continuing to increase. Heart failure is also associ- of pharmacist involvement in the multidisciplinary care of heart
ated with unacceptably high readmission rates during the 3 to 6 failure patients are now apparent and should include optimizing
months after initial discharge. Current estimates of costs of heart doses of heart failure drug therapy, screening for drugs that exacer-
failure treatment in the United States approach $30 billion with bate heart failure, monitoring for adverse drug effects and drug
most of the costs associated with hospitalization.1,4 The prevalence interactions, educating patients, and patient followup.
of heart failure and the costs associated with patient care are
expected to increase as the population ages and as survival from ■ CURRENT CONTROVERSIES
ischemic heart disease is improved. Thus approaches to improve the
1. For patients with chronic heart failure who remain sympto-
quality and cost-effectiveness of care for these patients may have a
matic despite standard therapy (ACE inhibitor, β-blocker,
significant impact on healthcare costs.
diuretic, digoxin), which additive therapy should be used is
Studies to assess the cost-effectiveness of drug therapy for heart
uncertain. Agents that can be considered are aldosterone antag-
failure were recently reviewed.150 Many studies provide direct cost
onists, ARBs, or hydralazine/nitrates. Drug selection should be
estimates, demonstrating an economic value when employing stan-
based on patient-specific criteria (e.g., renal function, ethnicity)
dard heart failure therapies, specifically ACE inhibitors, β-blockers,
that will influence the benefits and risks of each agent.
and digoxin. Much of the economic benefit of these therapies is a
result of a reduction in hospitalization. While the clinical and 2. The African American Heart Failure Trial confirmed that the
economic benefits of these therapies are well-recognized, standard addition of a fixed-dose combination of isosorbide dinitrate
heart failure therapies are often underprescribed. A recent study and hydralazine to standard background therapy improved
found that more optimal use of evidence-based therapies with a 10% survival in African American patients with heart failure.
increase in the use of ACE inhibitors, β-blockers, digoxin, and Whether isosorbide/hydralazine is beneficial in non-African
spironolactone would result in cost savings as a consequence of a American patients is unknown.
reduction in hospitalization.151 In addition, prescribing optimal 3. The optimal pharmacotherapy for patients with acute decom-
doses that approach target doses shown in clinical trials to affect pensated heart failure who are refractory to diuretic therapy is
outcomes would have a similar impact. For example, patients receiv- controversial. Recent meta-analyses suggest that nesiritide use
 212
is associated with worsening renal function and increased risk of arrhythmias and digoxin toxicity. Serum potassium monitor-
mortality. However, the safety of other vasodilators, such as ing is also required because of the risk of hyperkalemia associated
SECTION 2

nitroglycerin or nitroprusside, is not well established and the with ACE inhibitors, ARBs, and aldosterone antagonists. A serum
use of positive inotropes is associated with poor outcomes. potassium ≥4.0 mEq/L should be maintained with some evidence
suggesting it should be ≥4.5 mEq/L.163 Assessment of renal function
(blood urea nitrogen and serum creatinine) is also an important end
EVALUATION OF THERAPEUTIC OUTCOMES point for monitoring diuretic and ACE inhibitor therapy. Common
causes of worsening renal function in patients with heart failure
CHRONIC HEART FAILURE include overdiuresis, adverse effects of ACE inhibitor or ARB
therapy, and hypoperfusion.
Although mortality is an important end point, it does not give a
Cardiovascular Disorders

complete measure of the overall effects of the disease on patient

outcomes because many patients are hospitalized repeatedly for ACUTE DECOMPENSATED HEART FAILURE
heart failure exacerbations and continue to survive. Thus some of Assessment of adequacy of therapy in the acute decompensated
the more important therapeutic outcomes in heart failure manage- heart failure patient can be separated into two general categories:
ment, such as prolonged survival or prevention or slowing of the initial improvement of physiologic parameters and safe discharge
progression of heart failure, cannot be quantified in an individual from the intensive care unit following conversion to a chronic oral
patient. However, after appropriate diagnostic evaluation to deter- therapeutic regimen. Both goals must be achieved because hemody-
mine the etiology of heart failure, ongoing clinical assessment of namic improvement has not correlated with prolonged symptom
patients typically focuses on three general areas: (a) evaluation of improvement or enhanced survival.
functional capacity, (b) evaluation of volume status, and (c) labora- Initial stabilization requires achievement of adequate arterial oxy-
tory evaluation. gen saturation and content. Cardiac index and blood pressure must
The evaluation of functional capacity should focus on the pres- be sufficient to ensure adequate organ perfusion, as assessed by alert
ence and severity of symptoms the patient experiences during mental status, creatinine clearance sufficient to prevent metabolic
activities of daily living and how their symptoms affect these azotemic complications, hepatic function adequate to maintain syn-
activities. Questions directed toward the patient’s ability to perform thetic and excretory functions, a stable heart rate and rhythm
specific activities may be more informative than general questions (predominately sinus rhythm, rate-stabilized atrial fibrillation or
about what symptoms the patient may be experiencing. For exam- flutter, or paced rhythm), absence of ongoing myocardial ischemia
ple, ask patients if they can participate in exercise, climb stairs, get or infarction, skeletal muscle and skin blood flow sufficient to
dressed without stopping, check the mail, or clean the house. prevent ischemic injury, and normal arterial pH (7.34 to 7.47) with
Another important component of assessment of functional capacity a normal serum lactate concentration. Although these goals are
is to ask patients what activities they would like to do but are now achieved most often with a cardiac index greater than 2.2 L/min/m2,
unable to perform. a mean arterial blood pressure greater than 60 mm Hg, and a PAOP
Assessment of volume status is a vital component of the ongoing of 15 mm Hg or greater, the absolute values are highly variable and
care of patients with heart failure. This evaluation provides the depend on chronicity of illness, efficacy of chronic compensatory
clinician important information about the adequacy of diuretic mechanisms, previous chronic therapy, and concurrent illness.
therapy. Because the cardinal signs and symptoms of heart failure are Discharge from the intensive care unit requires maintenance of the
caused by excess fluid retention, the efficacy of diuretic treatment is preceding parameters in the absence of ongoing intravenous infusion
readily evaluated by the disappearance of these signs and symptoms. therapy, mechanical circulatory support, or positive-pressure venti-
The physical examination is the primary method for the evaluation lation. Some patients may achieve this goal with markedly lower
of fluid retention and specific attention should be focused on the blood pressure or higher filling pressure than suggested earlier;
patient’s body weight, extent of jugular venous distension, presence hence numerical goals cannot always be substituted for clinical
of hepatojugular reflux, presence and severity of pulmonary conges- status. Nonpharmacologic treatments aimed at the precipitants of a
tion, and peripheral edema. Specifically, in a patient with pulmonary patient’s heart failure exacerbation include permanent pacing, CRT
congestion, monitoring is indicated for resolution of rales and with or without ICD, coronary angioplasty or valvuloplasty, peri-
pulmonary edema and improvement or resolution of dyspnea on cardial drainage, cardiac surgery (coronary bypass, valve replace-
exertion, orthopnea, and paroxysmal nocturnal dyspnea. For ment or reconstruction, closure of intracardiac shunts), or even
patients with systemic congestion, a decrease or disappearance of cardiac transplantation, to achieve initial stabilization, definitive
peripheral edema, jugular venous distension, and hepatojugular therapy, or both.
reflux is sought. Other therapeutic outcomes include an improve-
ment in exercise tolerance and fatigue, decreased nocturia, and a
decrease in heart rate. Clinicians also will want to monitor blood
pressure and ensure that the patient does not develop symptomatic
ABBREVIATIONS
hypotension as a result of drug therapy. Body weight is a sensitive
ACE: angiotensin-converting enzyme
marker of fluid loss or retention, and patients should be counseled to
weigh themselves daily, reporting changes to their healthcare pro- ARB: angiotensin receptor blocker
vider so that adjustments can be made in diuretic doses. It should be AVP: arginine vasopressin
noted, particularly with β-blocker therapy, that symptoms may BNP: B-type natriuretic peptide
worsen initially and that it may take weeks to months of treatment
cAMP: cyclic adenosine monophosphate
before patients notice improvement in symptoms. Also, patients and
healthcare providers should be aware that heart failure progression COX-2: cyclooxygenase-2
may be slowed even though symptoms have not resolved. CRT: cardiac resynchronization therapy
Routine monitoring of serum electrolytes and renal function is HFSA: Heart Failure Society of America
required in patients with heart failure. Assessment of serum potas-
sium is especially important because hypokalemia is a common IABP: intraaortic balloon pump
adverse effect of diuretic therapy and is associated with an increased ICD: implantable cardioverter-defibrillator
 213
JVD: jugular venous distension 19. Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney
Int 2006;69:2124–2130.

CHAPTER 16
LVAD: left ventricular assist device
20. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral
LVEF: left ventricular ejection fraction vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med
MI: myocardial infarction 2006;355:2099–2112.
21. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral
NE: norepinephrine tolvaptan in patients hospitalized for worsening heart failure: The
NSAID: nonsteroidal antiinflammatory drug EVEREST Outcome Trial. JAMA 2007;297:1319–1331.
22. Gheorghiade M, Konstam MA, Burnett JC, Jr, et al. Short-term clinical
NYHA: New York Heart Association
effects of tolvaptan, an oral vasopressin antagonist, in patients hospi-
PAOP: pulmonary artery occlusion pressure talized for heart failure: The EVEREST Clinical Status Trials. JAMA

Heart Failure
RAAS: renin–angiotensin–aldosterone system 2007;297:1332–1343.
23. Mann DL. Inflammatory mediators and the failing heart: Past, present,
SNS: sympathetic nervous system and the foreseeable future. Circ Res 2002;91:988–998.
SVR: systemic vascular resistance 24. Laufs U, Custodis F, Bohm M. HMG-CoA reductase inhibitors in
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TNF-α: tumor necrosis factor-α
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CHAPTER 16
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88. Adams KF, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low 111. Teo KK, Yusuf S, Pfeffer M, et al. Effects of long-term treatment with
serum digoxin concentrations in heart failure. J Am Coll Cardiol angiotensin-converting-enzyme inhibitors in the presence or absence
2002;39:946–953. of aspirin: A systematic review. Lancet 2002;360:1037–1043.
89. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin 112. McAlister FA, Ghali WA, Gong Y, et al. Aspirin use and outcomes in a
concentration and outcomes in patients with heart failure. JAMA community-based cohort of 7352 patients discharged after first hospi-
2003;289:871–878. talization for heart failure. Circulation 2006;113:2572–2578.
90. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the 113. Schoolwerth AC, Sica DA, Ballermann BJ, Wilcox CS. Renal consider-
effect of digoxin for the treatment of heart failure. N Engl J Med ations in angiotensin converting enzyme inhibitor therapy: A statement

Heart Failure
2002;347:1403–1411. for healthcare professionals from the Council on the Kidney in Cardio-
91. Adams KF Jr, Patterson JH, Gattis WA, et al. Relationship of serum vascular Disease and the Council for High Blood Pressure Research of
digoxin concentration to mortality and morbidity in women in the the American Heart Association. Circulation 2001;104:1985–1991.
digitalis investigation group trial: A retrospective analysis. J Am Coll 114. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital
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92. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in J Med 2006;354:2443–2451.
mortality and hospitalization in heart failure: A comprehensive post 115. A trial of the beta-blocker bucindolol in patients with advanced
hoc analysis of the DIG trial. Eur Heart J 2006;27:178–186. chronic heart failure. N Engl J Med 2001;344:1659–1667.
93. Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and 116. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of
mortality in diastolic heart failure: The ancillary digitalis investigation carvedilol and metoprolol on clinical outcomes in patients with
group trial. Circulation 2006;114:397–403. chronic heart failure in the Carvedilol or Metoprolol European Trial
94. Bauman JL, Didomenico RJ, Galanter WL. Mechanisms, manifesta- (COMET): Randomised controlled trial. Lancet 2003;362:7–13.
tions, and management of digoxin toxicity in the modern era. Am J 117. Aquilante CL, Terra SG, Schofield RS, et al. Sustained restoration of
Cardiovasc Drugs 2006;6:77–86. autonomic balance with long- but not short-acting metoprolol in
95. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines patients with heart failure. J Card Fail 2006;12:171–176.
for the management of patients with atrial fibrillation: A report of the 118. Bakris GL, Fonseca V, Katholi RE, et al. Metabolic effects of
American College of Cardiology/American Heart Association Task Force carvedilol vs metoprolol in patients with type 2 diabetes mellitus and
on Practice Guidelines and the European Society of Cardiology Commit- hypertension: A randomized controlled trial. JAMA 2004;292:2227–
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Developed in collaboration with the European Heart Rhythm Associa- bility of metoprolol CR/XL in patients with diabetes and chronic heart
tion and the Heart Rhythm Society. Circulation 2006;114:e257–e354. failure: Experiences from MERIT-HF. Am Heart J 2005;149:159–167.
96. Schentag J, Bang A, Kozinski-Tober J. Digoxin. In: Burton M, Shaw L, 120. Mehra MR. Optimizing outcomes in the patient with acute decompen-
Schentag J, Evans W, eds. Applied Pharmacokinetics and Pharmacody- sated heart failure. Am Heart J 2006;151:571–579.
namics, 4th ed. Baltimore: Lippincott Williams & Wilkins, 2006:411–439. 121. Felker GM, Adams KF Jr, Konstam MA, et al. The problem of
97. Bauman JL, DiDomenico RJ, Viana M, Fitch M. A method of deter- decompensated heart failure: Nomenclature, classification, and risk
mining the dose of digoxin for heart failure in the modern era. Arch stratification. Am Heart J 2003;145:S18–S25.
Intern Med 2006;166:2539–2545. 122. Cuffe MS, Califf RM, Adams KF, et al. Short-term intravenous mil-
98. Daiber A, Mulsch A, Hink U, et al. The oxidative stress concept of rinone for acute exacerbation of chronic heart failure: A randomized
nitrate tolerance and the antioxidant properties of hydralazine. Am J controlled trial. JAMA 2002;287:1541–1547.
Cardiol 2005;96:25i–36i. 123. The VMAC Investigators. Intravenous nesiritide vs nitroglycerin for
99. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide treatment of decompensated congestive heart failure: A randomized
dinitrate and hydralazine in blacks with heart failure. N Engl J Med controlled trial. JAMA 2002;287:1531–1540.
2004;351:2049–2057. 124. Adams KF, Lindenfeld J, Arnold JMO, et al. Evaluation and manage-
100. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on ment of patients with acute decompensated heart failure. J Card Fail
mortality in chronic congestive heart failure. Results of a Veterans 2006;12:e86–e103.
Administration Cooperative Study. N Engl J Med 1986;314:1547–1552. 125. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syn-
101. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with dromes: Current state and framework for future research. Circulation
hydralazine-isosorbide dinitrate in the treatment of chronic congestive 2005;112:3958–3968.
heart failure. N Engl J Med 1991;325:303–310. 126. Adams KF Jr, Fonarow GC, Emerman CL, et al. Characteristics and
102. Prabhu SD. Nitric oxide protects against pathological ventricular outcomes of patients hospitalized for heart failure in the United States:
remodeling: Reconsideration of the role of NO in the failing heart. Circ Rationale, design, and preliminary observations from the first 100,000
Res 2004;94:1155–1157. cases in the Acute Decompensated Heart Failure National Registry
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tion of renin-angiotensin system prevents new-onset atrial fibrillation. 127. Fonarow GC, Adams KF Jr, Abraham WT, et al. Risk stratification for
Am Heart J 2006;152:217–222. in-hospital mortality in acutely decompensated heart failure: Classifi-
104. Nasr IA, Bouzamondo A, Hulot JS, et al. Prevention of atrial fibrilla- cation and regression tree analysis. JAMA 2005;293:572–580.
tion onset by beta-blocker treatment in heart failure: A meta-analysis. 128. Gheorghiade M, Abraham WT, Albert NM, et al. Systolic blood pressure
Eur Heart J 2007;28:457–462. at admission, clinical characteristics, and outcomes in patients hospital-
105. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control ized with acute heart failure. JAMA 2006;296:2217–2226.
and rhythm control in patients with atrial fibrillation. N Engl J Med 129. Nohria A, Mielniczuk LM, Stevenson LW. Evaluation and monitoring of
2002;347:1825–1833. patients with acute heart failure syndromes. Am J Cardiol 2005;96:32G-
106. Masoudi FA, Inzucchi SE. Diabetes mellitus and heart failure: Epidemiology, 40G.
mechanisms, and pharmacotherapy. Am J Cardiol 2007;99:113B–132B. 130. Nohria A, Lewis E, Stevenson LW. Medical management of advanced
107. Roberts F, Ryan GJ. The safety of metformin in heart failure. Ann heart failure. JAMA 2002;287:628–640.
Pharmacother 2007;41:642–646. 131. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of conges-
108. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized tive heart failure and pulmonary artery catheterization effectiveness:
trial of torsemide compared with furosemide therapy for patients with The ESCAPE trial. JAMA 2005;294:1625–1633.
heart failure. Am J Med 2001;111:513–520. 132. Forrester JS, Diamond G, Chatterjee K, Swan HJC. Medical therapy of
109. Young M, Plosker GL. Torasemide: A pharmacoeconomic review of its acute myocardial infarction by application of hemodynamic subsets. N
use in chronic heart failure. Pharmacoeconomics 2001;19:679–703. Engl J Med 1976;295:1356–1362.
 216
133. Brater DC. Diuretic therapy in congestive heart failure. Congest Heart official adult heart transplantation report—2006. J Heart Lung Trans-
Fail 2000;6:197–210. plant 2006;25:869–879.
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134. Stough WG, O’Connor CM, Gheorghiade M. Overview of current 149. Hauptman PJ, Havranek EP. Integrating palliative care into heart
noninodilator therapies for acute heart failure syndromes. Am J failure care. Arch Intern Med 2005;165:374–378.
Cardiol 2005;96:41G–46G. 150. Lee WC, Chavez YE, Baker T, Luce BR. Economic burden of heart
135. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to failure: A summary of recent literature. Heart Lung 2004;33:362–371.
mortality in advanced heart failure. Am J Cardiol 2006;97:1759–1764. 151. Shibata MC, Nilsson C, Hervas-Malo M, et al. Economic implications
136. Butler J, Forman DE, Abraham WT, et al. Relationship between heart of treatment guidelines for congestive heart failure. Can J Cardiol
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hospitalized patients. Am Heart J 2004;147:331–338. 152. Schwartz JS, Wang YR, Cleland JG, et al. High- versus low-dose angioten-
137. Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of sin converting enzyme inhibitor therapy in the treatment of heart failure:
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dobutamine, dopamine, and milrinone in the management of acute An economic analysis of the Assessment of Treatment with Lisinopril and
heart failure syndromes. Am J Cardiol 2005;96:47G–58G. Survival (ATLAS) trial. Am J Manag Care 2003;9:417–424.
138. Lehtonen LA, Antila S, Pentikainen PJ. Pharmacokinetics and pharmacody- 153. Smith DG, Cerulli A, Frech FH. Use of valsartan for the treatment of
namics of intravenous inotropic agents. Clin Pharmacokinet 2004;43:187– heart-failure patients not receiving ACE inhibitors: A budget impact
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139. Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in 154. Croom KF, Plosker GL. Eplerenone: A pharmacoeconomic review of
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vasoactive medications: An analysis from the Acute Decompensated Heart macoeconomics 2005;23:1057–1072.
Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57–64. 155. Angus DC, Linde-Zwirble WT, Tam SW, et al. Cost-effectiveness of
140. Dorsch MP, Rodgers JE. Nesiritide: Harmful or harmless? Pharmaco- fixed-dose combination of isosorbide dinitrate and hydralazine ther-
therapy 2006;26:1465–1478. apy for blacks with heart failure. Circulation 2005;112:3745–3753.
141. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening 156. Sanders GD, Hlatky MA, Owens DK. Cost-effectiveness of implantable
renal function with nesiritide in patients with acutely decompensated cardioverter-defibrillators. N Engl J Med 2005;353:1471–1480.
heart failure. Circulation 2005;111:1487–1491. 157. Feldman AM, de Lissovoy G, Bristow MR, et al. Cost effectiveness of
142. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term cardiac resynchronization therapy in the Comparison of Medical
risk of death after treatment with nesiritide for decompensated heart Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION)
failure: A pooled analysis of randomized controlled trials. JAMA trial. J Am Coll Cardiol 2005;46:2311–2321.
2005;293:1900–1905. 158. Clegg AJ, Scott DA, Loveman E, et al. Clinical and cost-effectiveness of
143. Mentzer RM Jr, Oz MC, Sladen RN, et al. Effects of perioperative left ventricular assist devices as a bridge to heart transplantation for
nesiritide in patients with left ventricular dysfunction undergoing people with end-stage heart failure: A systematic review and economic
cardiac surgery: The NAPA Trial. J Am Coll Cardiol 2007;49:716–726. evaluation. Eur Heart J 2006;27:2929–2938.
144. Boehmer JP, Popjes E. Cardiac failure: Mechanical support strategies. 159. Holland R, Battersby J, Harvey I, et al. Systematic review of multidis-
Crit Care Med 2006;34:S268–S277. ciplinary interventions in heart failure. Heart 2005;91:899–906.
145. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left 160. Gattis WA, Hasselblad V, Whellan DJ, O’Connor CM. Reduction in
ventricular assistance for end-stage heart failure. N Engl J Med heart failure events by the addition of a clinical pharmacist to the heart
2001;345:1435–1443. failure management team. Arch Intern Med 1999;159:1939–1945.
146. Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug 161. Whellan DJ, Gaulden L, Gattis WA, et al. The benefit of implementing
therapy for the reversal of heart failure. N Engl J Med 2006;355:1873– a heart failure disease management program. Arch Intern Med
1884. 2001;161:2223–2228.
147. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus 162. Murray M, Young J, Hoke S, et al. Pharmacist intervention to improve
intravenous diuretics for patients hospitalized for acute decompen- medication adherence in heart failure. A randomized trial. Ann Intern
sated heart failure. J Am Coll Cardiol 2007;49:675–683. Med 2007;146:714–725.
148. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the Interna- 163. Macdonald JE, Struthers AD. What is the optimal serum potassium
tional Society for Heart and Lung Transplantation: Twenty-third level in cardiovascular patients? J Am Coll Cardiol 2004;43:155–161.
 217

C HAP T E R

17 Ischemic Heart Disease

ROBERT L. TALBERT

to three-vessel involvement with significant left ventricular dys-

KEY CONCEPTS function is best managed with revascularization.

 Ischemic heart disease (IHD) is primarily caused by coronary ath-  Percutaneous transluminal coronary angioplasty and coronary
erosclerotic plaque formation that leads to an imbalance between artery bypass graft produce similar results overall but certain
oxygen supply and demand resulting in myocardial ischemia. patient subsets (e.g., diabetics) should have coronary artery by-
pass grafting done.
 Chest pain is the cardinal symptom of myocardial ischemia
caused by coronary artery disease (CAD).  The clinical performance measures for chronic stable CAD rec-
ommended by the American College of Cardiology and the
 Risk factor identification and modification are important interven- American Heart Association include blood pressure measure-
tions for individual patients with known or suspected IHD and as ment, lipid profile, symptom and activity assessment, smoking
a population-based policy to reduce the impact of this disease. cessation, antiplatelet therapy, drug therapy for lowering low-
 Major risk factors that can be altered include dyslipidemia (high density lipoprotein cholesterol, β-blocker therapy for prior myo-
total and low-density lipoprotein cholesterol, low high-density cardial infarction, angiotensin-converting enzyme inhibitor ther-
lipoprotein cholesterol, and high triglycerides), smoking, glyce- apy, and screening for diabetes.
mic control in diabetes mellitus, hypertension, and adoption of
therapeutic lifestyle changes (exercise, weight reduction and
reduced cholesterol and fat in the diet). Reduction in inflam- Ischemic heart disease (IHD) caused by atherosclerosis of the epicar-
mation may also play an important role. dial vessels leading to coronary heart disease (CHD) is the main
etiology of IHD. This process begins early in life, often not being
 Most patients with CAD should be receiving antiplatelet therapy. clinically manifest until the middle-aged years and beyond. IHD may
Chronic stable angina should be managed initially with β-block- present as an acute coronary syndrome (acute coronary syndrome
ers because they provide better symptomatic control, at least as includes unstable angina, non–ST-segment elevation myocardial
well as nitrates or calcium channel blockers, and decrease the infarction or ST-segment elevation myocardial infarction; see Chap.
risk of recurrent myocardial infarction and CAD mortality. 18), chronic stable exertional angina pectoris, and ischemia without
 Nitroglycerin and other nitrate products are useful for prophylaxis clinical symptoms. Coronary artery vasospasm (variant or Prinz-
of angina when patients are undertaking activities know to pro- metal angina) produces similar symptoms but is not caused by
voke angina; however, when angina is occurring on a regular, atherosclerosis. Other manifestations of atherosclerosis include heart
routine basis, chronic prophylactic therapy should be instituted. failure, arrhythmias, cerebrovascular disease (stroke), and peripheral
vascular disease. The American Heart Association, the American
 Although calcium channel blockers are effective as monother- College of Cardiology, and the European Society of Cardiology have
apy, they are generally used in combination with β-blockers or published management guidelines for stable and unstable angina.1–3
as monotherapy if patients are intolerant of β-blockers; most
patients with moderate to severe angina will require two drugs
to control their symptoms. Ranolazine is a second-line drug to EPIDEMIOLOGY
be used with β-blockers and certain calcium channel blockers.
The American Heart Association (AHA) estimates that 79,400,000
Pharmacologic management is as effective as revascularization American adults have one or more types of cardiovascular disease
(percutaneous transluminal coronary angioplasty, coronary ar- (CVD) based on data from 1999 through 2004.4 Nearly 2,400
tery bypass graft, etc.) if one or two vessels are involved and Americans die of CVD each day, or an average of 1 death every 33
there are no differences in survival, recurrent myocardial infarc- seconds. In 2004, the death rates from CVD were 448.9 (per 100,000)
tion, or other measures of effectiveness. for black males, 335.7 for white males, 331.6 for black females, and

Multivessel involvement, especially if the patient has left main 239.3 for white females.4 CHD was responsible for 52% of deaths
coronary artery disease or left main equivalent disease, or two- from CVD. Men die earlier from IHD and acute myocardial infarc-
tion than women, and aging of both sexes is associated with a higher
incidence of these afflictions. The disparity in mortality from IHD
between men and women decreases with aging, being about four to
Learning objectives, review questions, five times more common in men from the age of the mid-30s to a
and other resources can be found at preponderance of female deaths in the very elderly.
www.pharmacotherapyonline.com. The syndrome of angina pectoris is reported to occur with an
average annual incidence rate (number of new cases per time period/

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 218
total number of persons in the population for the same time period) of TABLE 17-2 Grading of Angina Pectoris by the Canadian
approximately 1.5% (range: 0.1 to 5/1,000) depending on the patient’s Cardiovascular Society Classification System
SECTION 2

age, gender, and risk-factor profile.5 The presenting manifestation in

Class Description of Stage
women is more commonly angina, whereas men more frequently have
myocardial infarction as the initial event. Estimates of the incidence Class I Ordinary physical activity does not cause angina, such as walking,
and prevalence of angina are not entirely accurate because of waxing climbing stairs. Angina occurs with strenuous, rapid, or prolonged
and waning of symptoms; angina may disappear in up to 30% of exertion at work or recreation.
Class II Slight limitation or ordinary activity. Angina occurs on walking or
patients with angina that is less severe and of recent onset.
climbing stairs rapidly, walking uphill, walking or stair climbing after
Data from the Framingham study show that the prevalence in a
meals, or in cold, or in wind, or under emotional stress, or only
1970 cohort followed for 10 years was approximately 1.5% for women during the few hours after wakening. Walking more than 2 blocks on
Cardiovascular Disorders

and 4.3% for men ages 50 to 59 years at inception.5 The annual rate the level and climbing more than 1 flight of ordinary stairs at a
of new episodes of angina range from 28.3 to 33 per 1,000 population normal pace and in normal condition.
for nonblack men, 22.4 to 39.5 for black men, 14.1 to 22.9 for Class III Marked limitations of ordinary physical activity. Angina occurs on
nonblack women, and 15.3 to 35.9 for black women in the age range walking 1 to 2 blocks on the level and climbing 1 flight of stairs in
of 65 to 84 years or older.4 AHA estimates that the prevalence of normal conditions and at a normal pace.
angina was 8.9 million in 2004.4 Other interesting trends noted Class IV Inability to carry on any physical activity without discomfort—anginal
included a 21% decline in the incidence of cardiovascular disease in symptoms may be present at rest.
women, but only a 6% decline in men over two cohorts from 1950 From Campeau L. Grading of angina [letter]. Circulation 1976;54:522–523, with permission.
and 1970. Cardiovascular mortality was reduced by 59% in women
and 53% in men from the same cohorts. The risk of developing An important determinate of outcome for the angina patient is the
ischemic heart disease is not the same worldwide. Countries such as number of vessels obstructed. Twelve-year survival from the Coro-
Japan and France are on the low end of the spectrum, whereas nary Artery Surgery Study (CASS) for patients with zero-, one-, two-,
Finland, Northern Ireland, Scotland, and South Africa have very high and three-vessel disease was 88%, 74%, 59%, and 40%, respectively.9
rates of IHD.6,7 Other factors that increase the risk of death in medically managed
Angina may be classified according to symptom severity, disabil- patients include the presence of heart failure (or markers such as
ity induced, or a specific activity scale (Tables 17–1 and 17–2). The poor ventricular wall motion and low ejection fraction), smoking,
specific activity scale developed by Goldman and coworkers8 may be left main or left main equivalent coronary artery disease, diabetes,
preferable because it has been shown to be equal to or better than and prior myocardial infarction. Twelve-year survival for patients
the New York Heart Association or Canadian Cardiovascular Soci- with at least one diseased vessel and ejection fractions in the ranges
ety functional classifications for reproducibility and provides better of ≥50%, 35% to 49%, and 0% to 34% is 73%, 54%, and 21%,
agreement with exercise treadmill testing. respectively. Of particular note, patients with left main coronary
artery disease (or left main equivalent) are at extremely high risk and
TABLE 17-1 Criteria for Determination of the Specific Activity constitute a unique group for therapeutic consideration.10 In the
Scale Functional Class CASS, at 15 years of followup, 37% of the surgery group and 27% of
the medical group are surviving; median survival is 13.3 years versus
Any
6.7 years, respectively (P <0.0001). If systolic function was normal,
Yes No
then median survival and percent surviving were not different
1. Can you walk down a flight of steps without stopping Go to 2 Go to 4 between the surgery and medical groups (median survival of about
(4.5–5.2 MET)? 15 years). Patients screened but not randomized to CASS had similar
2. Can you carry anything up a flight of 8 steps without Go to 3 Class III
survival rates, suggesting that results from randomized patients may
stopping (5–5.5 MET)? Or can you:
be applicable to more generalized populations as a measure of
a. Have sexual intercourse without stopping (5–5.2 MET)
b. Garden, rake, weed (5.6 MET)
external reliability.
c. Roller skate, dance foxtrot (5–6 MET)
d. Walk at a 4-miles/h rate on level ground (5–6 MET)
3. Can you carry at least 24 lb up 8 steps (10 MET)? Or Class I Class II
ETIOLOGY AND PATHOPHYSIOLOGY
can you:
a. Carry objects that weigh at least 80 lb (18 MET) The pathophysiology that underlies this disease process is dynamic,
b. Do outdoor work, shovel snow, spade soil (7 MET) evolutionary, and complex. An understanding of the determinants
c. Do recreational activities such as skiing, basketball, of myocardial oxygen demand (MVO2), regulation of coronary
touch football, squash, handball (7–10 MET) blood flow, the effects of ischemia on the mechanical and metabolic
d. Jog/walk 5 miles/h (9 MET) function of the myocardium, and how ischemia is recognized are
4. Can you shower without stopping (3.6–4.2 MET)? Or Class III Go to 5 important to understanding the rationale for the selection and use
can you: of pharmacotherapy for IHD.
a. Strip and make bed (3.9–5 MET)  Ischemia may be defined as lack of oxygen and decreased or
b. Mop floors (4.2 MET) no blood flow in the myocardium. In contrast, anoxia, defined as
c. Hang washed clothes (4.4 MET)
the absence of oxygen to the myocardium, results in continued
d. Clean windows (3.7 MET)
perfusion with washout of acid by-products of glycolysis, thereby
e. Walk 2.5 miles/h (3–3.5 MET)
f. Bowl (3–4.4 MET) preserving the mechanical and metabolic status of the heart to a
g. Play golf, walk and carry clubs (4.5 MET) greater extent than does ischemia for short periods of time.
h. Push a power lawnmower (4 MET)
5. Can you dress without stopping because of symptoms Class III Class IV DETERMINANTS OF OXYGEN DEMAND
(2–2.3 MET)?
The major determinants of MVO2 are (a) heart rate, (b) contractility,
MET, metabolic equivalents of activity.
From Goldman L, Hashimoto B, Cook F, et al. Comparative reproducibility and validity of systems
and (c) intramyocardial wall tension during systole. Overall,
for assessing cardiovascular functional class: Advantages of a new specific activity scale. Circulation intramyocardial wall tension is thought to be the most important
1981;64:1228, with permission. among these three factors. As the consequences of IHD are a result
 219
of increased demand in the face of a fixed supply of oxygen in most and myocardial oxygen demand are tightly coupled in a rapidly
situations, alterations in MVO2 are critically important in producing responsive system.

CHAPTER 17
ischemia and for interventions intended to alleviate ischemia. MVO2 Atherosclerotic lesions encroaching on the luminal cross-sectional
cannot be directly measured in patients; however, an indirect assess- area of the larger epicardial vessels (R1) transform the relationships
ment that correlates reasonably well with MVO2 as determined in among R1, R2, and blood flow. As resistance increases in R1 owing
experimental animal models is the tension–time index. This is a to occlusion, R2 can vasodilate to maintain coronary blood flow.
measure of the area under the curve of the left ventricular (LV) This response is inadequate with greater degrees of obstruction, and
pressure curve. Tension in the ventricle wall is a function of the the coronary flow reserve afforded by R2 vasodilation is insufficient
radius of the LV and intraventricular pressure. These factors are to meet oxygen demand (also referred to as autoregulation). The
related through the Laplace law, which states that wall stress is related extent of functional obstruction is important in the limitation of

Ischemic Heart Disease

directly to the product of intraventricular pressure and internal coronary blood flow, and the presence of relatively severe stenosis
radius and inversely to wall thickness multiplied by a factor of two. (>70%) may provoke ischemia and symptoms at rest, whereas less-
Increasing systemic blood pressure or ventricular dilation would severe stenosis may allow a reserve of coronary blood flow for
increase wall tension and oxygen demand whereas ventricular hyper- exertion.11
trophy would tend to minimize increasing MVO2. Clinical applica- The diameter of the lesion impeding blood flow through a vessel
tion of these principles has led to the use of the double product (DP), is important, but other factors such as length of the lesion and the
which is heart rate (HR) multiplied by systolic blood pressure (SBP) influence of pressure drop across an area of stenosis also affect
(DP = HR × SBP). Although this is a clinically useful indirect coronary blood flow and function of the collateral circulation.
estimate of MVO2, it does not consider changes in contractility (an Resistance to flow in a vessel is directly related to length of the
independent variable), and because only changes in pressure are obstructing lesion, but resistance is inversely related to the diameter
considered with the double product, volume loading of the LV and of the vessel to the fourth power. Consequently, diameter is much
increased MVO2 related to ventricular dilation are underestimated. more important. As blood flows across a stenotic lesion the pressure
drops (energy losses) as a result of friction between blood and the
REGULATION OF CORONARY BLOOD FLOW lesion and to the abrupt turbulent expansion as blood emerges from
the stenosis. This pressure drop is dynamic and directly related to
Although coronary blood flow is influenced by multiple factors, the flow giving rise to a resistance that is not fixed, but rather fluctuates,
caliber of the resistance vessels delivering blood to the myocardium as flow is changed. This relationship can dramatically affect collat-
and MVO2 are the prime determinants in the occurrence of eral blood flow and its response to exercise, resulting in what has
ischemia. The anatomy of the vascular bed will affect oxygen supply been called “coronary steal.” A similar situation may also occur
and, subsequently, myocardial metabolism and mechanical function. when the epicardial or subepicardial vessels “steal” blood flow from
the endocardium in the presence of a stenotic lesion.
Anatomic Factors Large and small coronary arteries may undergo dynamic changes
The normal coronary system (Fig. 17–1 illustrates normal anatomy) in coronary vascular resistance and coronary blood flow. Dynamic
consists of large epicardial or surface vessels (R1) that normally offer coronary obstruction can occur in normal vessels and vessels with
little intrinsic resistance to myocardial flow and intramyocardial stenosis in which vasomotion or spasm may be superimposed on a
arteries and arterioles (R2), which branch into a dense capillary fixed stenosis. Although it is possible that these changes may be
network (about 4,000 capillaries per mm2) to supply basal blood “active” in small coronary arteries, it is also possible that the
flow of 60 to 90 mL/min per 100 g of myocardium. R1 and R2 are in observed changes may reflect collapse owing to poststenotic intralu-
series and total resistance is the algebraic sum; however, under minal pressure drop or increased intramyocardial compressive
normal circumstances, the resistance in R2 is much greater. Myocar- forces associated with inadequate ventricular relaxation.
dial blood flow is inversely related to arteriolar resistance and Collateral blood flow exists to a certain extent from birth as
directly related to the coronary driving pressure. The arterioles native collaterals, but persisting ischemia may promote collateral
dynamically alter their intrinsic tone in response to demands for growth as developed collaterals. These two types of collaterals differ
oxygen and other factors, and as a result, myocardial oxygen delivery in anatomy and in their ability to regulate coronary blood flow.
Collateral development is dependent on the severity of obstruction,
the presence of various growth factors (basic fibroblast growth
factor [β-FGF] and vascular endothelial growth factor), endogenous
vasodilators (e.g., nitrous oxide, prostacyclin), hormones such as
estrogen, and, potentially, exercise. Collateral development is highly
species dependent and this should be considered when reading
experimental literature.

Metabolic Regulation
Coronary blood flow is closely tied to the oxygen needs of the heart.
Changes in oxygen balance lead to very rapid changes in coronary
blood flow. Although a number of mediators may contribute to these
changes, the most important ones are likely to be adenosine, other
nucleotides, nitric oxide, prostaglandins, CO2, and H+. Adenosine,
which is formed from adenosine triphosphate and adenosine mono-
phosphate under conditions of ischemia and stress, is a potent
vasodilator that links decreased perfusion to metabolically induced
vasodilation or “reactive hyperemia.” The synthesis and release of
FIGURE 17-1. Coronary anatomy. (From Tintinalli JE, Kelen GD, Stap- adenosine into coronary sinus venous effluent occurs within seconds
czynski JR, eds. Tintinalli’s Emergency Medicine: A Comprehensive Study after coronary artery occlusion, and approximately 30% of the hyper-
Guide, 6th ed. New York: McGraw-Hill, 2004:344.) emic response can be blocked by metabolic blockers of adenosine.12
 220
Endothelial Control of Coronary Vascular Tone abbreviation of diastole (increased heart rate), and increased intra-
ventricular diastolic pressure (e.g., valvular obstruction to flow).
The vascular endothelium, a single-cell tissue with an enormous
SECTION 2

Extravascular resistance may decrease coronary blood flow, pri-

surface area separating the blood from vascular smooth muscle of
marily during systole. This effect is much more pronounced in the
the artery wall, is capable of a broad range of metabolic functions.
left ventricle compared with the right ventricle. When the effect of
The endothelium functions as a protective surface for the artery wall,
increased contractility is separated from the effect of ventricular
and as long as it remains intact and functional, it promotes vascular
pressure, approximately 75% of extravascular resistance is accounted
smooth muscle relaxation and inhibits thrombogenesis and ath-
for by passive stretch in equilibrium with ventricular pressure
erosclerotic plaque formation; damaged endothelium reacts to
whereas only 25% results from active myocardial contraction.
numerous stimuli with vasoconstriction, thrombosis, and plaque
formation. The vascular endothelium of the coronary arteries syn-
Factors Intrinsic to the Vascular Bed
Cardiovascular Disorders

thesizes large molecules such as fibronectin, interleukin-1, tissue

plasminogen activator, and various growth factors. Small molecules Metabolic factors, myogenic responses, neural reflexes, and humoral
that are also produced include prostacyclin, platelet-activating fac- substances within the vascular bed of the coronary circulation
tor, endothelin-1, and endothelium-derived relaxing factor (EDRF) function in an orchestrated fashion to maintain relative consistency
that is now characterized as nitric oxide. EDRF is synthesized from in blood flow to the myocardium in the face of imposed changes in
1-arginine via nitric oxide synthase and released by shear force on the perfusion pressures. Autoregulation, mediated primarily through
endothelium, as well as through interaction with many biochemical the effects of myogenic responses and metabolic factors, is thought
stimuli such as acetylcholine, histamine, arginine, catecholamines, to be responsible for maintaining regional blood flow in a narrow
arachidonic acid, adenosine diphosphate, endothelin-1, bradykinin, range while systemic pressure varies over a range of approximately
serotonin, and thrombin.12 EDRF or nitric oxide then causes relax- 50 to 150 mm Hg.
ation of the underlying smooth muscle and may be thought of as a Myogenic control (also known as the Bayliss effect) of coronary
paracrine homeopathic defense mechanism against noxious stimuli. artery tone occurs when the vessel is stretched secondary to an
Denudation or loss of the vascular endothelium results in loss of increase in pressure and contracts to return blood flow to normal.
EDRF and this protective mechanism. Loss of the endothelial cell It is thought that the myogenic response to stretching in coronary
layer and function may occur secondary to physical disruption arteries is a modest one and that metabolic factors such as nitric
(percutaneous transluminal angioplasty [PTCA]), factors impinging oxide play a much larger role in autoregulation.
from the vascular side (cyanide from smoke), or disruption of the There are three well-studied metabolic factors that have the
intimal–medial layers (oxidized low-density lipoprotein). Impaired ability to modify coronary artery resistance and blood flow at the
endothelial function may be related to the development of prema- local level. Basal coronary blood flow meets oxygen demands of 8 to
ture atherosclerosis based on recent family studies.13 10 mL/min per 100 g of myocardium with essentially complete
extraction of oxygen from the blood. As cardiac output or mean
arterial blood pressure increases, the increased demand for oxygen
Factors Extrinsic to the Vascular Bed is met by increasing blood flow because little additional oxygen is
Blood flow to the coronary arteries arises from orifices located available from hemoglobin. Decreased oxygen availability causes
immediately distal to the aorta valve. Perfusion pressure is equal to vasodilation of vascular smooth muscle and relaxation of precapil-
the difference between the aortic pressure at an instantaneous point lary sphincters, which increase tissue oxygen and help maintain
in time minus the intramyocardial pressure. Coronary vascular blood flow on a regional basis.
resistance is influenced by phasic systolic compression of the vascu- At perfusion pressures below 60 mm Hg, as the coronary arteries
lar bed. Consequently, the driving force for perfusion is not con- are maximally dilated and the buffering effect of autoregulation has
stant throughout the cardiac cycle. Opening of the aortic valve may reached its capacity, further reduction in coronary blood flow will
also lead to a Venturi effect, which can slightly decrease perfusion decrease perfusion pressure and tissue oxygenation. It is thought that
pressure. If perfusion pressure is elevated for a period of time, autoregulation works more efficiently in the epicardial layers than in
coronary vascular resistance declines and blood flow increases; subendocardial layers, and this may contribute to coronary steal.
however, continued perfusion pressure increases lead, within limits, Neural components that participate in the regulation of coronary
to a return of coronary blood flow back toward baseline levels blood flow include the sympathetic nervous system, the parasympa-
through autoregulation. thetic nervous system, coronary reflexes, and possibly, central
Alterations in intramyocardial wall tension throughout the car- control of coronary blood flow. Within the sympathetic system,
diac cycle will also impose significant changes in coronary blood stimulation of the stellate ganglion elicits coronary vasodilation,
flow. Diastole is the period during which coronary artery filling can which is associated with tachycardia and enhanced contractility.
occur as a result of these pressure differences and little or no This indirect coronary vasodilation is secondary to increased MVO2
coronary blood flow occurs to the left ventricle during systole. The related to increased heart rate, contractility, and aortic pressure and
extent of pressure development in the ventricle and heart rate have occurs following stellate stimulation. The direct effect of the sympa-
a major effect on the development of wall tension, time for diastolic thetic system is α1-mediated vasoconstriction at rest and during
coronary artery filling, and myocardial oxygen demand. exercise. Other receptor types, α2 and β1, have little influence on
Under normal conditions, the average global distribution of blood tone, whereas β2 stimulation produces a modest vasodilatory effect.
flow between the epicardial and endocardial layer is about 1:1 at rest Although coronary atherosclerosis may decrease blood flow secon-
and remains approximately even during exercise secondary to auto- dary to obstruction, severe coronary atherosclerosis and obstruction
regulatory changes. Regional disparity of blood flow distribution may also increase the sensitivity of coronary arteries to the effects of
does exist normally, and these disparities are magnified in the α1 stimulation and vasoconstriction.
presence of diseased coronary arteries and with increased cardiac Vagal stimulation within the parasympathetic system produces a
work as the vasodilator reserve in the resistance vessels of the small to moderate increase in coronary blood flow, which involves
subendocardium layers is exhausted. Factors that favor a reduction the coronary efferent and afferent parasympathetic components
in subendocardial blood flow include decreased perfusion pressure (Bezold-Jarisch reflex). Indirectly, vasoconstriction may result, with
because of decreased diastolic blood pressure or coronary artery vagal stimulation as the result of bradycardia and decreased con-
obstruction by atherosclerotic plaques with or without vasomotion, tractility reducing myocardial oxygen demand.
 221
Coronary reflexes have an undetermined role in the regulation of Calcium accumulation and overload secondary to ischemia
coronary blood flow. Based on experimental data, coronary reflexes impairs ventricular relaxation as well as contraction. This is appar-

CHAPTER 17
that may be important include the baroreceptor, the chemorecep- ently a result of impaired calcium uptake after systole from the
tor, Bezold-Jarisch reflex, and the pulmonary inhalation reflex. myofilaments, leading to a less negative decline of the pressure in
the ventricle over time. Impaired relaxation is associated with
Factors Limiting Coronary Perfusion enhanced diastolic stiffness, decreased rate of wall thinning, and
slowed pressure decay, producing an upward shift in the ventricular
During exercise and pacing, as MVO2 increases, coronary vascular
pressure–volume relationship; put more simply, MVO2 is likely to
resistance can be reduced to approximately 25% of basal values,
be increased secondary to increased wall tension. Impairment of
which results in a four- to fivefold increase in coronary blood flow.
both diastolic and systolic function leads to elevation of the filling
The cross-sectional area can be reduced by approximately 80%

Ischemic Heart Disease

pressure of the left ventricle.
prior to any mechanical or biochemical changes in the myocardium,
reflecting a margin of safety for coronary blood flow. The extent of
cross-sectional obstruction, the length of the lesion, lesion compo-
CLINICAL PRESENTATION AND
sition, and the geometry of the obstructing lesion can each affect
DIAGNOSIS OF ANGINA
flow across coronary arteries with atherosclerosis. The Bernoulli General
theorem states that the pressure drop across a lesion is directly ■ Many episodes of ischemia do not cause symptoms of angina
related to the length of the lesion and inversely related to the radius (silent ischemia)
of the lesion to the fourth power; critical stenosis occurs when the
■ Patients often have a reproducible pattern of pain or other
obstructing lesion encroaches on the luminal diameter and exceeds
symptoms which appear after specific amount of exertion
70%. Lesions creating an obstruction of 50% to 70% may reduce
blood flow; however, these obstructions are not consistent and ■ Increased frequency, severity, duration, or symptoms at rest
vasospasm and thrombosis superimposed on a “noncritical” lesion suggest an unstable angina pattern and the patient should seek
may lead to clinical events such as myocardial infarction.14 If the help immediately
lesion enlarges from 80% to 90%, resistance in that vessel is tripled. Symptoms
Coronary reserve is diminished at approximately 85% obstruction
■  Sensation of pressure or burning over the sternum or near
owing to vasoconstriction. Exaggerated responsiveness can be seen it, often but not always radiating to the left jaw, shoulder and
when coronary stenosis reaches this critical level and the role of arm; also chest tightness, shortness of breath
vasoactive substances such as prostaglandins, thromboxanes, and
serotonin may play more of a role in the regulation of coronary ■ Pain usually lasts from 0.5 to 30 minutes, often with a visceral
vascular tone and thrombosis. quality (deep location)
Little reserve exists for coronary blood flow and a relatively small ■ Precipitating factors include exercise, cold environment, walk-
reduction of 10% to 20% results in decreased myocardial fiber ing after a meal, emotional upset, fright, anger, and coitus
shortening as the first evidence for abnormal function. The suben- ■ Relief occurs with rest and nitroglycerin
docardial layers are affected to a greater extent than the epicardium
Signs
by ischemia, considering changes in fiber shortening, arteriovenous
(AV) difference in oxygen saturation, and lactate production. A ■ Abnormal precordial (over the heart) systolic bulge
reduction of 80% gives rise to akinesis and a 95% reduction of ■ Abnormal heart sounds
coronary blood flow produces dyskinesis during contraction of the
Laboratory Tests
ventricles. Although these abnormalities of contraction are associ-
ated with transient impaired function, depletion of high-energy ■ Typically, no laboratory tests are abnormal; however, if the
phosphate compounds and ultrastructural changes may last for patient has intermediate to high-risk features for unstable
days, even after transient ischemia; this is referred to as “stunned angina, electrocardiographic changes and serum troponin, or
myocardium.” Chronic hypoperfusion may lead to “hibernation,” creatine kinase may become abnormal (Table 17–3)
in which ventricular function is impaired over longer time intervals. ■ Patients are likely to have laboratory test abnormalities for the
Hibernating myocardium can be differentiated from necrosis with risk factors for IHD such as elevated total and low-density
various techniques (see Chap. 13) and revascularization of hibernat- lipoprotein cholesterol, low high-density lipoprotein choles-
ing myocardium is useful in improving ventricular function. terol, impaired fasting glucose or elevated glucose, high blood
Regional loss of contractility may impose a burden on the remain- pressure, elevated C-reactive protein, and abnormal renal
ing myocardial tissue, resulting in heart failure, increased MVO2, function. Hemoglobin should be checked to make sure the
and rapid depletion of blood flow reserve. Consequently, zones of patient is not anemic.
tissue with marginal blood flow may develop in a lateral or trans- Other Diagnostic Tests (See Chap. 13)
mural fashion; such development puts this tissue at risk for more
■ A resting electrocardiogram followed by an exercise tolerance
severe damage if the ischemic episode persists or becomes more
test are usually the first tests done in stable patients. A chest
severe. Nonischemic areas of myocardium may compensate for the
radiograph should be done if the patient has heart failure
severely ischemic and border zones of ischemia by developing more
symptoms. Cardiac imaging using radioisotopes to detect
tension than usual in an attempt to maintain cardiac output. At the
ischemic myocardium and measure ventricular function are
cellular level, ischemia and the attendant acidosis are thought to
commonly done when revascularization is being considered.
alter calcium release from storage sites such as the sarcolemma and
Echocardiography may also be used to assess ventricular wall
the sarcoplasmic reticulum, as well as inhibiting the binding of
motion at rest or during stress. Cardiac catheterization and
calcium to troponin, thereby impairing the association of actin and
coronary arteriography are used to determine coronary artery
myosin. The clinical correlates of these cellular biochemical events
anatomy and if the patient would benefit from angioplasty,
leading to the development of left ventricle or right ventricle
coronary artery bypass surgery or other revascularization
dysfunction include an S3, dyspnea, orthopnea, tachycardia, fluctu-
procedures. Coronary artery calcium may be useful in detect-
ating blood pressure, transient murmurs, and mitral or tricuspid
ing early disease.
regurgitation.
 222

TABLE 17-3 Short-Term Risk of Death or Nonfatal Myocardial Infarction in Patients with Unstable Angina
SECTION 2

High Risk (At least 1 of the following Intermediate Risk (No high-risk feature Low Risk (No high- or intermediate-risk
Feature features must be present) but must have 1 of the following) feature but may have any of the following)
History Accelerating tempo of ischemic symptoms in Prior Ml, peripheral or cerebrovascular disease,
preceding 48 h or CABG, prior aspirin use
Character of pain Prolonged ongoing (>20 min), rest pain Prolonged (>20 min), rest angina, now resolved, New-onset CCS class III or IV angina in the past 2
with moderate or high likelihood of CAD weeks without prolonged (>20 min) rest pain but
with moderate or high likelihood of CAD
Clinical findings Pulmonary edema, most likely caused by
ischemia
Cardiovascular Disorders

New or worsening MR murmur

S3 or new/worsening rales
Hypotension, bradycardia, tachycardia
Age >75 y
ECG Angina at rest with transient ST-segment T-wave inversions >0.2 mV Normal or unchanged ECG during an episode of
changes >0.05 mV chest discomfort
Bundle-branch block, new or presumed new Pathologic Q waves
Cardiac markers Markedly elevated (e.g., TnT or TnI >0.1 ng/mL) Slightly elevated (e.g., TnT >0.01 but <0.1 ng/mL) Normal
CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; ECG, electrocardiogram; Ml, myocardial infarction; MR, mitral regurgitation; Tnl, troponin; TnT, troponin T.

asymptomatic ischemia is not more prevalent based on the Asymp-

CLINICAL PRESENTATION AND DIAGNOSIS tomatic Cardiac Ischemia Pilot (ACIP) study.17 Altered endorphin
release is a plausible explanation, but investigations with naloxone
Important aspects of the clinical history for chest pain for patients to block endorphins do not consistently show altered pain thresh-
with angina include the nature or quality of the pain, precipitating olds to various stimuli compared with patients with symptomatic
factors, duration, pain radiation, and the response to nitroglycerin or ischemia and patients with asymptomatic ischemia do not necessar-
rest. Because there can be considerable variation in the manifesta- ily have impaired somatic pain sensitivity.18 Alternatively, adenosine
tions of angina, it is more accurate to refer to these symptoms as an and substance P release during ischemia and mechanical stretch on
anginal syndrome. For some patients with significant coronary coronary arteries may play a role in the perception of pain.
disease, their presenting symptoms may differ from the classical Lastly, it should be recognized that the threshold for pain caused
symptoms, yet the symptoms are a result of ischemic pain, and these by exertion is fixed in some patients and variable in others and that
are often referred to as anginal equivalents. Obtaining an accurate the amount of exercise or stress necessary to provoke symptoms can
and detailed family history is useful in placing symptoms in perspec- change over time. A fixed threshold for the induction of pain or ECG
tive. Significant positive information includes premature coronary evidence of ischemia means these indicators of ischemia occur at the
heart disease (<55 years of age in men and <65 years of age in same, or nearly so, double rate–pressure product (systolic blood
women) as manifested as fatal and nonfatal myocardial infarction pressure × heart rate). This is apparently a consequence of at least
(MI), stroke, and peripheral vascular disease, as well as other risk two factors. Over long periods of time, atherosclerosis may progress,
factors such as hypertension, smoking, familial lipid disorders, and leading to more severe stenosis, reduced oxygen supply, and less of
diabetes mellitus. Typical pain radiation patterns include anterior an increase in demand to precipitate ischemic symptoms. Once
chest pain (96%), left upper arm pain (83.7%), left lower arm pain stenotic lesions reach a critical level of approximately 80% or greater,
(29.3%), and neck pain at some time (22%). Pain from other areas is vasomotion, vasospasm, and thrombotic occlusion become signifi-
less common. Ischemia detected by electrocardiogram (ECG) moni- cant factors impairing blood flow to the myocardium. Consequently,
toring is more likely to be detected in the morning hours (6 AM to 12 anatomic considerations and vasoactive substances may interact to
noon) than other periods throughout the day. Patients suffering provide an environment amenable to changing thresholds for the
from variant or Prinzmetal angina secondary to coronary spasm are production of angina.
more likely to experience pain at rest and in the early morning hours. There appears to be little relationship between the historical
Prinzmetal anginal pain is not usually brought on by exertion or features of angina and the severity or extent of coronary artery vessel
emotional stress, nor is it relieved by rest, and the ECG pattern is that involvement. Therefore, one may speculate that severe symptoms
of current injury with ST elevation rather than depression. might be associated with multivessel disease, but no predictive
It is also important to differentiate the pattern of pain for stable markers exist on a routine basis.
angina from that of unstable angina. Unstable angina may be Chest pain may resemble pain arising from a variety of noncardiac
stratified into categories of risk ranging from high to low (see Table sources and the differential diagnosis of anginal pain from other
17–3).15 Ischemia may also be painless or “silent” in 60% to 100% etiologies may be quite difficult based on history alone. Table 17–4
of patients, depending on the series cited and the patient popula- outlines other common problems that may present with episodic
tion.16 In patients with myocardial ischemia, approximately 70% of chest pain. Although much less common, nonatherosclerotic etiolo-
the episodes of documented ischemia are painless as determined by gies of coronary artery disease do exist and should be excluded with
ambulatory ECG monitoring, and the ST segment changes associ- appropriate tests. The clinical classification of chest pain encompasses
ated with these episodes can be ST elevation or depression. The typical angina including (a) substernal chest pain with a characteristic
mechanism of silent ischemia is unclear, but studies show that quality and duration that is (b) provoked by exertion or emotional
patients not experiencing pain have altered pain perception, with stress and (c) relieved by rest or nitroglycerin); atypical angina (meets
the threshold and tolerance for pain being higher than that of two of the characteristics for typical angina); and noncardiac chest
patients who have pain more frequently. Although patients with pain (meets ≤1 of the typical angina characteristics).2,3
diabetes tend to have more extensive coronary disease than those There are few signs apparent on physical examination to indicate
without diabetes and may suffer from autonomic neuropathy, the presence of coronary artery disease and usually only the cardio-
 223

TABLE 17-4 Differential Diagnosis of Episodic Chest Pain Resembling Angina Pectoris

CHAPTER 17
Duration Quality Provocation Relief Location Comment
Effort angina 5–15 min Visceral (pressure) During effort or emotion Rest, NTG Substernal, radiates First episode vivid
Rest angina 5–15 min Visceral (pressure) Spontaneous (? with exercise) NTG Substernal, radiates Often nocturnal
Mitral prolapse Min–hours Superficial (rarely vis- Spontaneous (no pattern) Time Left anterior No pattern, variable
ceral)
Esophageal 10 min–1 h Visceral Spontaneous, cold liquids, Foods, antacids, H2 Substernal, radiates Mimics angina
reflux exercise, lying down blockers, proton
pump inhibitors,
NTG

Ischemic Heart Disease

Peptic ulcer Hours Visceral, burning Lack of food, “acid” foods Foods, antacids, H2 Epigastric, substernal
blockers, proton
pump inhibitors
Biliary disease Hours Visceral (wax and Spontaneous, food Time, analgesia Epigastric, radiates Colic
wane)
Cervical disk Variable (gradually Superficial Head and neck, movement Time, analgesia Arm, neck Not relieved by rest
subsides) and palpation
Hyperventilation 2–3 min Visceral Emotion, tachypnea Stimulus removed Substernal Facial paraesthesia
Musculoskeletal Variable Superficial Movement, palpation Time, analgesia Multiple Tenderness
Pulmonary 30 min Visceral (pressure) Often spontaneous Rest, time Substernal Dyspneic
bronchodilator
NTG, nitroglycerin.

vascular system reveals any useful information. Elevated heart rate In addition to screening for CVD risk factors (see Table 23–7),
or blood pressure can yield an increased double product and may be other recommended tests include hemoglobin, fasting glucose,
associated with angina, and it would be important to correct fasting lipoprotein panel, resting ECG, and chest radiograph in
extreme tachycardia or hypertension if present. Other noncardiac patients with signs or symptoms of heart failure, valvular heart
physical findings that suggest that significant cardiovascular disease disease, pericardial disease, or aortic dissection/aneurysm.2 Hemo-
may be associated with angina include abdominal aortic aneurysms globin is assessed to insure adequate oxygen carrying capacity.
or peripheral vascular disease. Table 17–5 lists the cardiac examina- Fasting glucose determinations to exclude diabetes and glucose
tion findings in coronary artery disease. During an angina attack monitoring for concurrent diabetes should be performed routinely.
these findings may appear or become more prominent, making Lipids are assessed total-, low-density lipoprotein (LDL)- and high-
them more valuable if present. density lipoprotein (HDL)-cholesterol and triglycerides (see Chap.
23).19 Other risk factors that may be important for some patients
TABLE 17-5 Cardiac Findings in Patients with Coronary include C-reactive protein, homocysteine level, evidence of chla-
Artery Disease mydia infection, and elevations in lipoprotein(a), fibrinogen, and
plasminogen activator inhibitor.20,21 Cardiac enzymes should all be
Sign Clinical Significance Frequency
normal in stable angina. Troponin T or I, myoglobin, or creatinine
Abnormal precordial Left ventricular wall Not usually present unless phosphokinase-MB (myocardial band) isoform may be elevated in
systolic bulge motion abnormality patient has sustained a prior patients with unstable angina, and interventions such as anticoagu-
Ml (especially anterior wall)
lation or antiplatelet therapy reduce cardiac end points when these
or is experiencing angina at
markers for injury are elevated (see Table 17–3).22
time of examination
Decreased intensity Decrease in left ven- Difficult to evaluate in resting Patients presenting with chest pain are stratified into chronic stable
of S1 tricular contractility state, but can be commonly angina or having features of intermediate or high-risk unstable angina
demonstrated during angina (Fig. 17–2 and see Table 17–3). These features include rest pain
Paradoxical splitting Left ventricular wall Very uncommon but occasion- lasting longer than 20 minutes, age older than 65 years, ST- and T-
of S2 motion abnormality ally noted during angina wave changes and pulmonary edema. Patients with acute coronary
S3 (ventricular gallop) Increased left ventricu- Not usually present unless syndrome (unstable angina, non–ST-segment elevation acute myo-
lar diastolic pres- patient sustained extensive cardial infarction and ST-segment elevation acute myocardial infarc-
sure, with or without Ml; may occasionally be tion) are managed differently than chronic stable angina.
clinical CHF present during angina
S4 (atrial gallop) Reduced ventricular Common; very common in
compliance (“stiff patients who have sustained DIAGNOSTIC TESTS
heart”) a prior Ml as well as during
angina
See also Chap. 13.
Apical systolic murmur Papillary Not usually present unless
(in absence of rheu- muscle dysfunction patient has sustained prior Ml Electrocardiogram
matic mitral regurgi-
The ECG is normal in about one-half of patients with angina who
tation or Barlow
are not experiencing an acute attack. Typical ST-T–wave changes
syndrome)
Diastolic murmur (in Coronary artery Rare include depression, T-wave inversion, and ST-segment elevation.
absence of aortic stenosis Forms of ischemia other than exertional angina may have ECG
regurgitation) manifestations that are different; variant angina is associated with
ST-segment elevation, whereas silent ischemia may produce eleva-
CHF, congestive heart failure; MI, myocardial infarction; S1, first heart sound; S2, second heart sound;
S3, third heart sound; S4, fourth heart sound.
tion or depression. Significant ischemia is associated with ST-
From Cohn PF, ed. Diagnosis and Therapy of Coronary Artery Disease, 2d ed. Boston: Martinus segment depression of greater than 2 mm, exertional hypotension,
Nijhoff, 1985:101, with permission. and reduced exercise tolerance.
 224

Chest Pain
SECTION 2

History suggests Low probability of History and appropriate Reconsider probability

intermediate to high No coronary artery Yes diagnostic tests No of coronary artery
probability of coronary disease demonstrate noncardiac disease. Initiate
artery disease cause of chest pain? primary prevention.

*Features of "Intermediate- or No
high-risk" Unstable Angina:
Yes -Rest pain lasting >20 min
Cardiovascular Disorders

-Age >65 years Treat appropriately

-ST- and T-wave changes
-Pulmonary edema
See AHCPR Unstable
Intermediate or high-risk Yes Angina Guideline
unstable angina?*

No

See appropriate ACC-

Recent MI, PTCA, Yes AHA Guideline
CABG?

No

Condition present that

could cause angina? Angina resolves with treatment
Yes
e.g., severe anemia, of underlying conditions?
hyperthyroidism
No

No Enter Stress Testing

Angiography Algorithm

History &/or exam See ACC/AHA Valvular

suggests valvular, Severe primary valvular Heart Disease
Echocardiogram Yes Guideline Yes
pericardial disease or lesions?
ventricular dysfunction?

No

No LV Abnormality

Yes

High probability of coronary Empiric Enter Treatment

Indication for prognostic/risk
artery disease based on Yes No therapy Algorithm
assessment?**
history, exam, ECG

No
Yes
Enter Stress Testing/ **Factors necessary to determine the need
Angiography Algorithm for risk assessment:
-Comorbidity
-Patient preferences

FIGURE 17-2. Clinical assessment. (ACC/AHA, American College of Cardiologists/American Heart Association; AHCPR, Agency
for Health Care Policy and Research; CABG, coronary artery bypass graft; ECG, electrocardiogram; LV, left ventricular; MI,
myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty.)

Exercise Tolerance Testing23 ible and irreversible defects in blood flow to the myocardium
because it is more sensitive than ETT.
Exercise tolerance (stress) testing (ETT) is recommended for
patients with intermediate pretest probability of coronary artery
disease (CAD) based on age, gender, and symptoms, including those
Cardiac Imaging
with complete right bundle-branch block or <1 mm of rest ST Radionuclide angiocardiography (performed with technetium-
depression (Fig. 17–3). Although ETT is insensitive for predicting 99m, a radioisotope) is used to measure ejection fraction, regional
coronary artery anatomy, it does correlate well with outcome, such ventricular performance, cardiac output, ventricular volumes, val-
as the likelihood of progressing to angina, the occurrence of acute vular regurgitation, asynchrony or wall motion abnormalities, and
MI, and cardiovascular death. Ischemic ST depression that occurs intracardiac shunts.24 Technetium pyrophosphate scans are used
during ETT is an independent risk factor for cardiac events and routinely for detection and quantification of acute myocardial
cardiovascular mortality. Thallium (201Tl) myocardial perfusion infarction. Positron emission tomography is useful for quantifying
scintigraphy may be used in conjunction with ETT to detect revers- ischemia with metabolically important substrates such as oxygen,
 225

CHAPTER 17
For diagnosis (and risk stratification) in patients with chest pain and Need to guide
an intermediate probability of coronary disease No medical No
OR for risk stratification in patients with chest pain and management
a high probability of coronary artery disease

Yes

Contraindication to
Yes
stress testing?

Ischemic Heart Disease

No

Symptoms or clinical
findings warranting Yes Consider coronary
angiography? angiography

No Yes

Patient able to Pharmacologic

No
exercise? imaging study

Yes

Previous coronary
Yes
revascularization?

No

Resting ECG Exercise

No imaging study
interpretable?

Yes Test results suggest

Yes high risk?

Perform
exercise test No

Adequate information
on diagnosis and Yes
Test results suggest Consider coronary prognosis available?
Yes angiography/
high risk?
revascularization
No
No

Adequate information on
Consider imaging Consider coronary
diagnosis and prognosis Yes study/angiography angiography
available?

Yes Enter Treatment

Algorithm

FIGURE 17-3. Stress testing/angiography algorithm. (ECG, electrocardiogram.)

carbon, and nitrogen. Other metabolic probes use radiolabeled fatty stress echocardiography (dobutamine, dipyridamole, or adenosine)
acids and glucose to study metabolic processes that may be or pacing may be done to identify abnormalities during stress.
deranged during ischemia in animals and for investigative purposes
in man. Cardiac Catheterization and Coronary Arteriography
A new method using ultrarapid computerized tomography (spi-
Cardiac catheterization and angiography in patients with suspected
ral CT, ultrafast CT, electron-beam CT) minimizes artifact caused
coronary artery disease are used diagnostically to document the
by motion of the heart during contraction and relaxation and
presence and severity of disease, as well as for prognostic purposes.
provides a semiquantitative assessment of calcium content in coro-
High-risk features during ETT suggesting the need for coronary
nary arteries.25 Calcium scores >150 provide a sensitivity of 74%
angiography include early and significant (≥2 mm) changes on the
and specificity of 89%; consequently, this method may be cost-
ECG during ETT as well as multiple lead involvement, prolonged
effective compared with ETT.
recovery from ischemia, low workload performance, abnormal blood
pressure response (reduction in blood pressure), or ventricular
Echocardiography arrhythmias. Multiple defects with thallium scans as well as lung
Echocardiography is useful if patients have history or physical uptake during exercise or postexercise ventricular cavity dilation are
examination suggestive of valvular, pericardial disease or ventricu- also high-risk indications for catheterization. Interventional catheter-
lar dysfunction. For patients unable to exercise, pharmacologic ization is used for thrombolytic therapy in patients with acute myo-
 226
cardial infarction and for the management of patients with significant the deaths were attributable to CVD.4 Risk because of smoking is
coronary artery disease to relieve obstruction through PTCA, atherec- related to the number of cigarettes smoked per day and the duration
SECTION 2

tomy, laser treatment, or stent placement. Catheterization and angi- of smoking. Passive smoking in angina pectoris patients decreases
ography may be done after coronary artery bypass grafting (CABG) to exercise time.6 Pipe and cigar smokers are at increased risk compared
determine if the graft has closed or if coronary artery disease has with nonsmokers, but their risk is somewhat less than that of cigarette
progressed. Coronary artery intravascular ultrasound is useful for smokers.30 The direct effects of cigarette smoke that are detrimental to
directly imaging anatomy, calcified and fatty plaques, and thrombosis patients with angina include (a) elevated heart rate and blood pres-
superimposed on plaque as well as determining patency following sure from nicotine, which increases MVO2, and impaired myocardial
revascularization procedures. Intravascular ultrasound guidance of oxygen delivery due to carboxyhemoglobin generation from carbon
stent implantation may result in more effective stent expansion monoxide inhalation in smoke; (b) the negative inotropic effect of
Cardiovascular Disorders

compared with angiographic guidance alone.26 carboxyhemoglobin; (c) increased platelet adhesiveness and promo-
tion of aggregation resulting in thrombotic tendencies because of
nicotine and carboxyhemoglobin; (d) lowered threshold for ventric-
TREATMENT ular fibrillation during ischemia as a consequence of carboxyhemo-
globin; and (e) impaired endothelial function owing to smoking.31
Ischemic Heart Disease Similar changes have been noted for marihuana smoking as well.
Smoking also accelerates the risk for myocardial infarction, sudden
■ DESIRED OUTCOME death, cerebrovascular disease, peripheral vascular disease, and hyper-
tension, and it reduces high-density lipoprotein concentrations.
The short-term goals of therapy for ischemic heart disease are to
Clearly, primary prevention is needed for this risk factor and much of
reduce or prevent the symptoms of angina that limit exercise
the education effort to discourage initiation of smoking should be
capability and impair quality of life. Long-term goals of therapy are
targeted for teenagers. Techniques for cessation of smoking that may
to prevent CHD events such as myocardial infarction, arrhythmias,
be useful include aversive conditioning, group programs, self-help
and heart failure and to extend the patient’s life. Because there is
programs, hypnosis, “cold turkey,” and the use of nicotine substitutes
little evidence that revascularization procedures such as angioplasty
(lobeline) or other sources of nicotine replacement products for
and coronary artery bypass surgery extend life, the primary focus
short-term substitution during withdrawal syndrome. The antide-
should be on altering the underlying and ongoing process of
pressant sustained-release bupropion is more effective than placebo
atherosclerosis through risk factor modification while providing
and best used with smoking cessation counseling. Recently, vareni-
symptomatic relief through the use of nitrates, β-blockers, calcium
cline, a partial agonist selective for the α4β2 nicotinic acetylcholine
channel blockers, and ranolazine for anginal symptoms.
receptor subtype also was shown to improve cessation rates.32,33
Cessation of smoking reduces the incidence of coronary events to
Risk Factor Modification approximately 15% to 25% of that associated with continued smok-
 Primary prevention of ischemic heart disease through the identi- ing and these benefits are noted within 2 years of cessation.34
fication and modification of risk factors prior to the initial morbid Hypertension, whether labile or fixed, borderline or definite, casual
event would be the optimal management approach and should or basal, systolic or diastolic, at any age regardless of gender, is the
result in a significant impact on the prevalence of IHD. However, most common and a powerful contributor to atherosclerotic coro-
early recognition of some risk factors may not be possible in all nary vascular disease.35 Morbidity and mortality increase progres-
cases, and in others, the patient may not be willing to undertake sively with the degree of blood pressure elevation of either systolic or
intervention until overt evidence of coronary disease is apparent. diastolic pressure and pulse pressure, and no discernible critical value
Secondary intervention continues to be more commonly pursued exists (see Chap. 15). Numerous trials have documented the reduc-
by both healthcare professionals and patients, and it is important to tion in risk associated with blood pressure lowering; however, most of
recognize this type of intervention as effective in reducing subse- these studies show that mortality and morbidity reduction is a result
quent morbidity and mortality. The presence of risk factors in of fewer strokes and less renal failure and heart failure. The reduction
individual patients plays a major role in determining the occurrence in coronary heart disease end points is significant but not as dramatic.
and severity of IHD.19,27 Risk factors are additive in nature and can The reasons for this are unclear but perhaps relate to the multifacto-
be classified as alterable or unalterable (see Table 23–7). Unalterable rial etiology of IHD. Recent guideline changes from the AHA recom-
risk factors include gender; age; family history or genetic composi- mend goal blood pressure of <130/80 mm Hg for patients with stable
tion; environmental influences such as climate, air pollution, trace angina, unstable angina, non–ST-segment myocardial infarction, ST-
metal composition of drinking water; and to some extent, diabetes segment myocardial infarction and <120/80 mm Hg in patients with
mellitus. Improved glycemic control reduces the microvascular left ventricular dysfunction.36
complications of diabetes mellitus (see Chap. 77) and reduces Hypercholesterolemia is a significant cardiovascular risk factor,
coronary end points; however, based on the Diabetes Control and and risk is directly related to the degree of cholesterol elevation.19,27
Complications study, the reduction was impressive (40 vs. 23 major As with hypertension, there is no critical value that defines risk, but
events) but not significant because the trial was underpowered to rather, risk is incrementally related to the degree of elevation and the
detect these changes.28  Risk factors that can be altered include presence of other risk factors (see Chap. 23 for a detailed discussion).
smoking, hypertension, hyperlipidemia, obesity, sedentary lifestyle, A fasting lipoprotein panel should be obtained in all patients with
hyperuricemia, psychosocial factors such as stress and type A known CAD. Chapter 23 discusses the goals for total-, LDL-, and
behavior patterns, and the use of certain drugs that may be detri- HDL-cholesterol and triglycerides. All patients should undertake
mental, including progestins, corticosteroids, and cyclosporine. therapeutic lifestyle changes. Reductions in LDL-cholesterol for
Cigarette smoking is common. The Centers for Disease Control primary prevention and secondary intervention have been shown to
and Prevention estimates that 45.1 million people are current smok- reduce total and CAD mortality and stroke as well as the need for
ers (23.9% men; 18.1% women) in this country, and the risk for CHD interventions such as PTCA and CABG. Supplemental vitamin E or
is increased by about 1.8 in active smokers and by about 1.3 for other antioxidants reduce the susceptibility of LDL-cholesterol to
passive or environmental smoke exposure.29 From 1997 to 2001 oxidation, but clinical trial data fail to show any benefit with
437,902 Americans died from smoking-related illnesses and 34.7% of supplementation.37
 227
The prevalence of overweight and obesity, defined as a body mass 40% of all fatal automobile accidents and consumption of alcohol
index (weight in kilograms divided by height in meters squared) of predisposes to hepatic cirrhosis, the sixth to seventh most common

CHAPTER 17
≥25 kg/m2 and ≥30 kg/m,2 respectively, are estimated to occur in cause of death in middle age adults in the United States. With this
66.3% and 32.2% of the U.S. population. Body mass index is in mind, it seems illogical to suggest alcohol ingestion as a prophy-
associated with an increased mortality ratio compared with individ- lactic measure for coronary disease but rather to advise moderation
uals of normal body weight, and the objective for patients with IHD of alcohol consumption, if it is the preference of the individual.
is to maintain or reduce to a normal body weight.4 This may be Thiazide diuretics elevate serum cholesterol and triglyceride levels
accomplished through dietary modification, exercise, pharmacologic whereas β-blockers tend to lower HDL and raise LDL slightly;
therapy, or surgical therapy. Frequently associated with obesity is a however, a direct association between these drugs and cardiovascular
sedentary lifestyle, and inactivity may contribute to higher blood risk is tenuous and based on aggregating results rather than random-

Ischemic Heart Disease

pressure, elevated blood lipid levels, and insulin resistance associated ized clinical trials. Conjugated equine estrogen alone or in combina-
with glucose intolerance in diabetics (insulin resistance or metabolic tion with progestin lowers LDL and raises HDL based on the
syndrome). Exercise to the level of about 300 kcal three times a week Postmenopausal Estrogen/Progestin Interventions (PEPI) study.41
is useful in improving maximal oxygen uptake, improving cardiores- Unfortunately, the Heart and Estrogen/Progestin Replacement
piratory efficiency, promoting collateral artery formation, and pro- Study (HERS) trial showed no benefit of hormone replacement
moting potential alterations in the risk of ventricular fibrillation, therapy for secondary intervention and an increased risk for throm-
coronary thrombosis, and improved tolerance to stress. Epidemio- boembolism.42 In secondary intervention, hormone replacement
logic studies have found that mortality is directly related to resting therapy or estrogen alone in women after hysterectomy, HERS found
heart rate and a low heart rate difference between resting and that hormonal therapy health risks exceeded benefits as well.43
maximal exercise heart rate, and inversely related to exercise heart Unopposed estrogen is the optimal regimen for elevation of HDL,
rate. A regular exercise program has been shown to reduce all-cause but the high rate of endometrial hyperplasia restricts use to women
and cardiac mortality.38 without a uterus. In women with a uterus, estrogen with cyclic
Competitiveness, intense striving for achievement, easily pro- medroxyprogesterone has the most favorable effect on HDL and no
voked hostility, a sense of urgency about doing things quickly and excess risk of endometrial hyperplasia. Use of oral contraceptives in
being punctual, impatience, abrupt and rapid speech and gestures, women who smoke and are older than age 35 years increases the risk
and concentration on self-selected goals to the point of not perceiv- of MI, stroke, and venous thromboembolism by threefold or greater.
ing and attending to other aspects of the environment are traits that Alternative forms of contraception and cessation of smoking should
characterize the behavioral pattern known as the type A or coronary be promoted in these patients. The risk for nonsmoking oral contra-
prone personality. Although the issue is somewhat controversial, ceptive users younger than age 35 years is very small. The relative risk
type A individuals may have increased cardiovascular risk with risk of breast cancer is increased, but in the absence of risk factors for
ratios ranging from insignificant to three times that of a matched breast cancer, the relative risk is approximately 1.3 (30% increase).
population. Psychological stress and type D personality have been Coffee consumption is also linked to coronary heart disease and
associated with adverse cardiac prognosis, but little is known about caffeine does transiently elevate blood pressure; however, the overall
their relative effect on the pathogenesis of CHD. “Type D” refers to risk, if any, appears to be low and may be related to genetic
the tendency to experience negative emotions and to inhibit the makeup.44 Although thiazide diuretics and β-blockers (nonselective
expression of these emotions in social interactions. The mechanism without intrinsic sympathomimetic activity) may elevate both cho-
by which personality affects the cardiovascular system is not under- lesterol and triglycerides by some 10% to 20%, and these effects may
stood, but may reflect the activity of the sympathetic system and be detrimental, no objective evidence exists from prospective well-
enhanced responsiveness of other stress hormones when compared controlled studies to support avoiding these drugs at this time. This
with non-type A personalities. controversy is most pertinent in the treatment of mild hypertension
Alcohol ingestion in small to moderate amounts (<40 g/day of and it is discussed in greater detail in Chap. 15.
pure ethanol) reduces the risk of coronary heart disease; however,
consumption of large amounts (>50 g/day) or binge drinking of
alcohol is associated with increased mortality from stroke, cancer, TREATMENT
vehicular accidents, and cirrhosis.39,40 There appears to be a differ-
ential effect depending on race with an inverse relationship between
ethanol consumption in whites but a direct relationship in Blacks
Stable Exertional Angina Pectoris
between consumption and CAD risk. The mechanisms for the Table 17–6 lists the American College of Cardiology and American
presumed protective effects of alcohol are not known but the effects Heart Association’s evidence-grading recommendations.
may be related to increased high-density lipoprotein levels, The current national guidelines recommend that all patients be
impaired platelet function, or associations between the amount of given the following unless contraindications exist: (a) aspirin (Class I,
alcohol ingested and personality type. Whatever the relationship, it Level A); (b) β-blockers with prior MI (Class I, Level A); (c) angioten-
is well to remember that alcohol drinking is implicated in more than sin-converting enzyme inhibitor (ACEI) to patients with CAD and

TABLE 17-6 The American College of Cardiology and American Heart Association Evidence Grading System
Recommendation Class Level of Evidence
I Conditions for which there is evidence or general agreement that a given A Data derived from multiple randomized clinical trials with large numbers of
procedure or treatment is useful and effective patients
II Conditions for which there is conflicting evidence or a divergence of opinion about B Data derived from a limited number of randomized trials with small numbers of
the usefulness/efficacy of a given procedure or treatment is useful and effective patients, careful analyses of nonrandomized studies, or observational registries
IIa Weight of evidence/opinion is in favor or usefulness/efficacy C Expert consensus was the primary basis for the recommendation
IIb Usefulness/efficacy is less-well established by evidence/opinion
III Conditions for which there is evidence or general agreement that a given
procedure or treatment is not useful/effective and in some cases may be harmful
 228
diabetes or LV systolic dysfunction (Class I, Level A); (d) LDL-  Nitrate therapy should be the first step in managing acute
lowering therapy with CAD and LDL >130 mg/dL (Class I, Level A) attacks for patients with chronic stable angina if the attacks are
SECTION 2

(target LDL <100 mg/dL; <70 mg/dL in patients with CHD and infrequent (i.e., a few times per month) or for prophylaxis of
multiple risk factors is reasonable)27; (e) sublingual nitroglycerin or symptoms when undertaking activities known to precipitate attacks.
immediate relief of angina (Class I, Level B); (f) calcium antagonists or In general, if angina occurs no more often than once every few days,
long-acting nitrates for reduction of symptoms when β-blockers are then sublingual nitroglycerin tablets or spray or buccal products may
contraindicated (Class I, Level B); (g) calcium antagonists or long- be sufficient to allow the patient to maintain an adequate lifestyle. For
acting nitrates in combination with β-blockers when initial treat- episodes of “first-effort” angina occurring in a predictable fashion,
ment with β-blockers is unsuccessful (Class I, Level C); (h) calcium nitroglycerin may be used in a prophylactic manner with the patient
antagonists or long-acting nitrates are recommended as a substitute taking 0.3 to 0.4 mg sublingually about 5 minutes prior to the
for β-blockers if initial treatment with β-blockers leads to unaccept-
Cardiovascular Disorders

anticipated time of activity. Nitroglycerin spray may be useful when

able side effects (Class I, Level A). Clopidogrel may be substituted for inadequate saliva is produced to rapidly dissolve sublingual nitro-
when aspirin is absolutely contraindicated (Class IIa, Level B) and glycerin or if a patient has difficulty opening the container. Most
long-acting nondihydropyridine calcium antagonists used instead of patients have a response that lasts about 30 minutes or so, but this is
β-blockers as initial therapy (Class IIa, Level B). ACEIs are recom- subject to interindividual variability. When angina occurs more
mended in patients with CAD or other vascular disease (Class IIa, frequently than once a day, a chronic prophylactic regimen using β-
Level B). Angiotensin receptor antagonists are not mentioned in blockers as the first line of therapy should be considered (Fig. 17–4
these guidelines but substitution for ACEI intolerance is reasonable. illustrates the stable angina algorithm). Chronic prophylactic therapy
Low-intensity anticoagulation with warfarin, in addition to aspirin is with long-acting forms of nitroglycerin (oral or transdermal), isosor-
recommended, but bleeding would be increased (Class IIb, Level B).2 bide dinitrate, 5-mononitrate, and pentaerythritol trinitrate may be
Therapies to be avoided include dipyridamole (Class III, Level B) effective; however, the development of tolerance is a major limiting
and chelation therapy (Class III, Level B). Ranolazine is not step in their continued effectiveness. Because long-acting nitrates are
addressed in these guidelines because it was released after their not as effective as β-blockers and do not have beneficial effects,
publication. In the European Society of Cardiology guidelines, it has monotherapy with nitrates should not be first-line therapy unless β-
a Class IIb, Level B recommendation. blockers and calcium channel blockers are contraindicated or not
After assessing and manipulating the alterable risk factors as dis- tolerated. As described previously, providing a nitrate-free interval of
cussed previously, the next intervention that could be undertaken is 8 hours per day or longer appears to be the most promising approach
the institution of a regular exercise program. Training is possible in to maintaining the efficacy of chronic nitrate therapy. Recent investi-
many patients with angina and the observed benefits include gations into the mechanisms of nitrate tolerance have shown in
decreased heart rate and systolic blood pressure, as well as increased normal volunteers that treatment with isosorbide mononitrate for 7
ejection fraction and duration of exercise. Although the mechanism days resulted in tolerance as well as endothelial dysfunction, which is
of these effects has been debated, improved overall cardiovascular and thought to be a consequence of reactive oxygen species generated
muscular condition are probably most important. Improved produc- during bioactivation of high-potency nitrates.46,47 Oral administra-
tion of nitric oxide and coronary vasomotion may account partially tion of nitrates is susceptible to a saturable first-pass effect; conse-
for the beneficial effects of exercise. The intensity of exercise influ- quently, larger doses can produce a measurable hemodynamic effect
ences training and more vigorous programs provide better overall and dose titration should be based on these changes in the double
results.38 Obviously, an exercise program should be undertaken with product. There are few well-controlled studies that compare oral or
caution and in a graded fashion with adequate supervision. sublingual nitrate efficacy, and the choice among these products
 Chronic prophylactic therapy for patients with more than one should be based on familiarity with the preparation, cost, and patient
angina episode per day may also be instituted with β-adrenergic acceptance.
blocking agents, and in many instances β-blockers may be prefera-  Calcium channel antagonists have the potential advantage of
ble because of less-frequent dosing and other properties inherent in improving coronary blood flow through coronary artery vasodila-
β-blockade (e.g., potential cardioprotective effects, antiarrhythmic tion as well as decreasing MVO2 and may be used instead of β-
effects, lack of tolerance, and antihypertensive effects), as well as blockers for chronic prophylactic therapy; however, in chronic stable
their antianginal effects and documented protective effects in post- angina, comparative trials of long-acting calcium channel blockers
MI patients.2 Patients who continue to smoke have reduced anti- with β-blockers do not show significant differences in response.48,49
anginal efficacy of β-blockers. This may be a result of enhanced They are as effective as β-blockers and are most useful in patients
hepatic metabolism of drugs that are eliminated through this route who have a variable threshold for exertional angina. Calcium antag-
or related to the effects of smoking on MVO2 and oxygenation.45 onists may provide better skeletal muscle oxygenation, resulting in
The one characteristic that is relevant is the duration of effect on the decreased fatigue and better exercise tolerance. Additionally, if con-
double product. β-Blockers with longer half-lives (e.g., nadolol) are traindications exist to β-blocker therapy, calcium antagonists can be
more likely to affect the double product for a longer period of time safely used in many patients. The available calcium channel blockers
and require fewer doses per day. The choice of β-blocker for angina appear to have similar efficacy in the management of chronic stable
rests on choosing the appropriate dose to achieve the goals outlined angina. Differences in their electrophysiology, peripheral and central
for heart rate and double product, and choosing an agent that is well hemodynamic effects, and adverse-effect profiles are useful in select-
tolerated by individual patients and cost. Selective use may incorpo- ing the appropriate agent. Patients with conduction abnormalities
rate ancillary properties but these are secondary considerations in and moderate to severe LV dysfunction (ejection fraction <35%)
overall drug product selection. Patients most likely to respond well should not be treated with verapamil, whereas amlodipine may be
to β-blockade are those who have a high resting heart rate and those safely used in many of these patients. Diltiazem has significant effects
who have a relatively fixed anginal threshold. In other words, their on the AV node and can produce heart block in patients with
symptoms appear at the same level of exercise or workload on a preexisting conduction disease or when other drugs with effects on
consistent basis. Symptoms appearing with variable work loads conduction, such as digoxin or β-blockers, are used concurrently.
suggest fluctuations in myocardial oxygen supply, perhaps due to Nifedipine may cause excessive heart rate elevation, especially if the
coronary artery vasomotion, and these patients are more likely to patient is not receiving a β-blocker, and this may offset the beneficial
respond to calcium channel antagonists. effect it has on MVO2. Gingival hyperplasia has also been reported
 229

Chest Pain

CHAPTER 17
-Intermediate to high probability of coronary
Antianginal drug Education and risk
artery disease
treatment factor modification
-High risk CAD unlikely
-Risk stratification complete or not required
Initiate educational
program
Sublingual NTG

Serious
Aspirin 81 to 325 mg QD adverse effect or Clopidogrel
if no contraindication contraindication
History suggests Ca2+ channel blocker,
vasospastic angina? Yes

Ischemic Heart Disease

long-acting nitrate therapy Yes
(Prinzmetal)
No
Cigarette Smoking cessation
Yes
smoking? program
Medications or Treat Successful
conditions that provoke Yes Yes treatment?
appropriately
or exacerbate angina?* No

No
Yes See NCEP Guidelines
Cholesterol high?
β-blocker therapy if
no contraindication Successful
Yes
(Espec. if prior MI or treatment? No
Yes
other indication)

Serious contraindication Blood pressure

No Yes See JNC VII Guidelines
high?

Add or subsitute Ca2+ Successful

channel blocker if no Yes treatment?
contraindication Yes Routine Followup including (as
appropriate) diet, exercise program,
diabetes management
Serious contraindication No
Consider
revascularization
therapy**
No
Add long-acting Successful
nitrate therapy if no Yes
treatment?
contraindication
Yes

*Conditions that exacerbate or provoke angina **At any point in this process, based on coronary anatomy, severity of anginal
Medications: symptoms, and patient preferences, it is reasonable to consider evaluation for coronary
-Vasodilators revascularization. Unless a patient is documented to have left main, three-vessel, or
-Excessive thyroid replacement two-vessel coronary artery disease with significant stenosis of the proximal left anterior
-Vasoconstrictors descending coronary artery, there is no demonstrated survival advantage associated
with revascularization in low-risk patients with chronic stable angina; thus, medical
Other medical problems: therapy should be attempted in most patients before considering PTCA or CABG.
-Profound anemia
-Uncontrolled hypertension
-Hyperthyroidism
-Hypoxemia

Other cardiac problems:

-Tachyarrhythmias
-Bradyarrhythmias
-Valvular heart disease (espec. AS)
-Hypertrophic cardiomyopathy

FIGURE 17-4. Treatment algorithm. (AS, aortic stenosis; CABG, coronary artery bypass grafting; CAD, coronary artery disease; JNC VII, Seventh Report
of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; MI, myocardial infarction; NCEP, National
Cholesterol Education Program; NTG, nitroglycerin; PTCA, percutaneous transluminal coronary angioplasty; QD, every day.)

with nifedipine, and some dental authorities say this may be seen in Although revascularization (see below) would seem to provide
as many as 20% of patients on nifedipine. Case control studies with better symptomatic relief and improved survival rates, recent ran-
calcium blockers suggest an increased risk for MI and cancer.50,51 The domized trials have shown no advantage of angioplasty or surgery
relationship to cancer appears to be weak to nonexistent whereas the over medical therapy in patients with stable coronary artery dis-
risk for MI is probably real and related to the type of drug used and ease.53,54 In the Clinical Outcomes Utilizing Revascularization and
relationship to recent MI. Immediate-release formulations of cal- Aggressive Drug Evaluation (COURAGE) trial, the 4.6-year cumu-
cium blockers can activate the sympathetic nervous system and in lative primary event rates (death from any cause and nonfatal
patients with recent MI or significant coronary disease, may induce myocardial infarction) were 19.0% in the percutaneous coronary
ischemia. This effect has not been shown for longer-acting products. intervention (PCI) group and 18.5% in the medical therapy group
The hemodynamic effect of calcium antagonists is complementary to (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI],
β-blockade and, consequently, combination therapy is rational but 0.87 to 1.27; P = 0.62).53 The Medicine, Angioplasty, or Surgery
clinical trial data do not support the notion that combination Study (MASS II) found medical therapy was associated with an
therapy is always more effective.48,52 incidence of long-term events and rate of additional revasculariza-
 230
tion similar to those for PCI. CABG was superior to medical therapy balloon into the affected coronary artery and enlarging the lumen of
in terms of the primary end points, reaching a significant 44% the artery by stretching the vessel wall. This frequently causes ather-
SECTION 2

reduction in primary end points at the 5-year followup of patients oma plaque fracture by stretching inelastic components and denuda-
with stable multivessel coronary artery disease.54 tion of the endothelium resulting in loss of nitric oxide and other
vasodilators and exposure of plaque contents to the vascular com-
■ NONPHARMACOLOGIC THERAPY partment. Consequently, immediate vascular recoil, platelet adhesion
and aggregation, mural thrombus formation, and smooth muscle
Revascularization proliferation, and synthesis of extracellular matrix may give rise to
The decision to undertake PCI or CABG for revascularization is acute occlusion and early or late restenosis.62,63 The presence of
based on the extent of coronary disease (number of vessels and coronary artery spasm and intraluminal thrombus, common occur-
Cardiovascular Disorders

location/amount of stenosis) and ventricular function. Table 17–7 rences in unstable angina, increases the hazard of these complications.
outlines the recommended mode of coronary revascularization.15,55 The advent of combination therapy with acetylsalicylic acid, unfrac-
The largest randomized trial of PCI versus CABG is the Bypass tionated heparin or low-molecular-weight heparin, and glycoprotein
Angioplasty Revascularization Investigation (BARI) trial conducted IIb/IIIa receptor antagonists and coronary artery stents has dramati-
in 1,829 patients with two- or three-vessel disease; 64% of these cally reduced the occurrence of early reocclusion and late restenosis.64
patients had an admitting diagnosis of unstable angina and 19% were Patients best suited for PTCA are those with recent onset of worsen-
diabetic.56 The 10-year survival was 71.0% for PTCA and 73.5% for ing of angina without a long history of symptoms. Angiographic
CABG (P= 0.18). At 10 years, the PTCA group had substantially characteristics associated with these clinical findings that allow the
higher subsequent revascularization rates than the CABG group greatest probability of success for PTCA are severe, discrete, proximal
(76.8% vs. 20.3%, P<0.001), but angina rates for the two groups were lesions found in a large epicardial vessel subtending a moderate or
similar. In the subgroup of patients with no treated diabetes, survival large area of viable myocardium and have high-risk features. Patients
rates were nearly identical by randomization (PTCA 77.0% vs. CABG with focal saphenous vein graft lesions who are poor candidates for
77.3%, P = 0.59).57 Insulin-requiring diabetics seem to be at the reoperation have a class IIa recommendation for PCI. Class IIb
highest risk and CABG is the revascularization procedure of choice indications include patients with one or more lesions to be dilated in
for this population.58 In a large observational study by Hannan et al., vessels subtending a less-than-moderate area of viable myocardium
patients with proximal left anterior descending (LAD) lesions and and patients with multivessel disease and proximal LAD lesions,
multivessel disease had higher survival rates with CABG than with diabetes, or abnormal LV function.65 Candidates for PTCA must also
PTCA.59 High-risk patients who should be considered for CABG over be suited for CABG because a small percentage of procedures results
PCI are those with LV systolic dysfunction, patients with diabetes, in emergency CABG. Success of PCI may be defined as angiographic
and those with two-vessel disease with severe proximal LAD involve- success (Thrombolysis In Myocardial Infarction [TIMI] 3 flow and
ment or severe three-vessel or left main disease (see Table 17–7).15 <20% residual stenosis), procedural success (lack of in-hospital clini-
AWESOME (Angina With Extremely Serious Operative Mortality cal complications), and clinical success (anatomic and procedural
Evaluation) found that either bypass or percutaneous intervention success with relief of ischemic pain for at least 6 months). In trials of
effectively relieves medically refractory ischemia among high-risk invasive versus conservative strategies (medical management) using
unstable angina patients whose age was greater than 70 years.60 PCI, death or MI is less frequent in some, but not all, trials.66–69
PCI has been used successfully in the management of unstable Numerous studies support the use of glycoprotein IIb/IIIa receptor
angina.55,61 PTCA involves the insertion of a guidewire and inflatable antagonists in addition to acetylsalicylic acid and unfractionated
heparin or low-molecular-weight heparin, and as described previ-
ously, abciximab was superior to tirofiban in the only comparative
TABLE 17-7 Recommended Mode of Coronary Revascularization study available.15,65 The initial success rate for PTCA in unstable
angina is ~80% to 90%, but these patients are at risk for more
Class/Level
Extent of Disease Treatment of Evidence complications than are those with stable angina because of the
underlying pathophysiology.
Left main disease,a candidate for CABG CABG I/A In the event of prolonged chest pain and ischemic ECG changes
PCI III/C
unrelieved by nitrate therapy or calcium channel antagonists, one
Left main disease, not a candidate for CABG PCI IIb/C
Three-vessel disease with EF <0.50 CABG I/A
may assume total occlusion of a coronary vessel and steps should be
Multivessel disease including proximal CABG I/A taken to restore blood flow with either PCI or CABG.
LAD with EF
<0.50 or treated diabetes PCI IIb/B Coronary Artery Bypass Grafting70
Multivessel disease with EF >0.50 and PCI I/A
Following the introduction of saphenous vein graft replacement for
without diabetes
One- or two-vessel disease without proxi- CABG or PCI I/B
the severely occluded coronary arteries by Favorolo and Garrett in
mal LAD but with large areas of myocar- 1967, CABG became an accepted and commonly used approach for
dial ischemia or high-risk criteria on the management of IHD. The objectives in performing CABG are
noninvasive testing (see text) twofold: (a) to reduce the number of symptomatic anginal attacks
One-vessel disease with proximal LAD CBAG or PCI IIa/B not controlled with medical management or PCI and improve the
One- or two-vessel disease without proxi- CABG or PCI III/C lifestyle of the patient, and (b) to reduce the mortality associated
mal LAD with small area of ischemia or with coronary artery disease. Surgery is effective in providing pain
no ischemia on noninvasive testing relief in large numbers of patients, with approximately 70% to 95%
Insignificant coronary stenosis CABG or PCI III/C being pain-free at 1 year and 46% to 55% being pain-free at 5 years.
CABG, coronary artery bypass grafting; EF, ejection fraction; LAD, left anterior descending coronary This compares favorably with medical management, with which only
artery; PCI, percutaneous coronary intervention. approximately 30% are free of symptoms at 5 years. Mortality at 10
a
≥50% diameter stenosis. years from the largest published studies is 26.4% with CABG and
From Braunwald E, Antman EM, Beasley JW, et al. ACC /AHA guidelines for the management of patients
with unstable angina and non–ST-segment elevation myocardial infarction: A report of the American
30.5% with medical management (P = 0.03) but there are significant
College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the differences based on subgroup analysis (e.g., left main disease vs.
Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36:970–1062, with permission. one-vessel disease without a proximal LAD lesion).71 The second
 231
objective is met in certain patients and was addressed in three large, suggest that patients who have diabetes or peripheral vascular disease,
well-controlled trials of bypass surgery. These three studies, the who are African Americans, or who continue to smoke are at high risk

CHAPTER 17
Veterans Administration, European Cooperative Surgery Study, for CAD events, and diabetics, in particular, are more likely to have a
and the CASS, are not directly comparable because the inclusion better outcome with CABG than PTCA.56,73,74 The overall benefit
and exclusion criteria for entry into each study were different and noted after CABG is similar in men and women, and elderly patients
patients were followed for different periods of time. They have also appear to have outcomes similar to younger patients.
been criticized for not being representative of the population that Operative mortality is reported to range from 1% to 3% and is
may be candidates for surgery, lacking women or late-middle aged or related to the number of vessels involved and preoperative ventric-
elderly patients, and for crossover of medically managed patients to ular function. Patients in CASS with one-, two-, or three-vessel
the surgical group. A major change in medical practice that influ- disease had operative mortalities of 1.4%, 2.1%, and 2.8%, respec-

Ischemic Heart Disease

ences the interpretation of these older studies is the common tively. The relationship to left ventricular ejection fraction follows a
procedure of stent placement at the time of angioplasty.72 There are similar trend with ejection fractions of greater than 50%, 20% to
about 20 different types of stents available and their use is associated 40%, and less than 20% having operative mortality rates of 1.9%,
with greater luminal diameter after angioplasty, fewer acute reocclu- 4.4%, and 6.7%, respectively. Perioperative infarction averages 5%
sions and less restenosis after stent placement. Consequently, the depending on the sensitivity of the method for assessment, and the
validity of generalizing the results from these studies to routine occurrence of an infarct reduces long-term survival. Neurologic
practice has been questioned, but these studies are useful for provid- dysfunction is relatively common postoperatively in CABG patients
ing a basis for decisions concerning surgery. Current class I recom- (~6%), but many of the deficits are clinically insignificant and
mendations for CABG in asymptomatic or mild angina patient resolve with time. Fatal brain damage occurs in 0.3% to 0.7%, stroke
includes significant (>50%) left main coronary artery stenosis, left in approximately 5%, and ophthalmologic defects in 25%, but only
main equivalent (≥70% stenosis of the proximal LAD and proximal 3% have clinically apparent field defects. Peripheral nerve lesions
left circumflex artery), and three-vessel disease, especially in patients (12%) and brachial plexopathy (7%) are also reported to occur.
with a LV ejection fraction <0.50.71 Class IIa recommendations for Other complications include constrictive pericarditis (0.2%), cellu-
CABG are proximal LAD stenosis with one- or two-vessel disease litis at the site of vein graft, and mediastinal infections (1% to 4%).
and class IIb recommendations for one- or two-vessel disease not Graft patency influences the success for symptom control, and
involving the proximal LAD. In stable angina, class I recommenda- survival and the mechanism for early graft occlusion is probably
tions are the same as for mild angina with the following additions: different from that associated with late closure. Early occlusion is
one- or two-vessel disease without significant proximal LAD steno- related to platelet adhesion and aggregation whereas late occlusion
sis, but with a large area of viable myocardium and high-risk criteria may be related to endothelial proliferation and progression of athero-
in noninvasive testing; disabling angina despite maximal medical sclerosis. Patency of grafts early on after the CABG are reported to
therapy, when surgery can be performed with acceptable risk. Class range from 88% to 97% in at least one graft and 58% to 81% in all
IIb recommendations in stable angina include proximal LAD steno- grafts at 1 year. Long-term patency based on the CASS Montreal
sis with one-vessel disease and one- or two-vessel disease without Heart Institute experience suggests that 60% to 67% of all grafts
significant proximal LAD stenosis but with a moderate area of viable remain patent at 5 to 11 years. Antiplatelet therapy has been demon-
myocardium and ischemia on noninvasive testing. The indications strated to improve early and late patency rates and should probably
for CABG in unstable angina/non–ST-segment elevation myocardial be used in all patients who do not have any contraindications. Aspirin
infarction were described previously. In ST-segment MI, CABG is with or without other antiplatelet agents (clopidogrel) reduces the
indicated for ongoing ischemia/infarction not responsive to maximal late development of vein-graft occlusions. Late graft closure is related
medical therapy (class IIb). to elevated lipid levels and the progression of atherosclerosis in the
In patients with poor LV function CABG is indicated for the same grafted vessels as well as the native circulation. Elevation of very-low-
indications as in mild angina for class I. Class IIa recommendations density lipoprotein, LDL, and LDL apolipoprotein B is correlated to
include poor LV function with significant viable, noncontracting, disease progression and graft closure. Aggressive lipid lowering can
revascularizable myocardium without any of the aforementioned stabilize the progression of CAD and may induce regression in
anatomic patterns (e.g., left main disease). CABG is useful in patients selected coronary artery segments within a patient following CABG.
with life-threatening ventricular arrhythmia in the presence of left Cessation of smoking is an important preoperative and postoperative
main disease, three-vessel disease (class I) and in bypassable one- or objective as well as in the management of other coronary risk factors
two-vessel disease causing life-threatening ventricular arrhythmias (e.g., hypertension) and institution of a supervised, daily exercise
and proximal LAD disease with one- or two-vessel disease (class IIa). program is recommended. Internal mammary artery grafts should be
CABG may also be used for patients who have failed PTCA if there used for revascularizing the left anterior descending artery system
is ongoing ischemia or threatened occlusion with significant myocar- when possible owing to better graft survival and clinical outcomes.
dium at risk and in patients with hemodynamic compromise (class Valvular heart disease can coexist with coronary heart disease,
I). Class IIa recommendations for failed PTCA include a foreign although this is relatively uncommon with rheumatic valve disease,
body in a crucial anatomic position and hemodynamic compromise usually the mitral valve, and more common with aortic stenosis and
in patient with impairment of the coagulation system and without a regurgitation. Angina may occur in 35% to 65% of patients with
previous sternotomy. CABG may be repeated in patients with a aortic stenosis or regurgitation, and if severe, may be the cause of
previous CABG if disabling angina exists despite maximal noninva- angina in the absence of coronary artery disease. Patients being
sive therapy (class I) and if a large area of myocardium is threatened evaluated for possible CABG should also be evaluated for valvular
and is subtended by bypassable distal vessels (class IIa). disease to determine if valve replacement needs to be performed
The need for nitrates and β-blockers is clearly reduced by surgery, along with bypass grafting.
with only 30% of CABG patients requiring chronic medication,
whereas 70% of their medical counterparts received anginal drugs.
CASS showed that employment status after surgery was more depen-
Percutaneous Transluminal
dent on the pretreatment status than an effect induced by the Coronary Angioplasty55
treatment arm, and that approximately 70% of patients are employed Since the introduction into clinical cardiology of PTCA by Gruentzig
before and after surgery. Recent followup analyses of these studies in 1977, this procedure has gained rapid acceptance as a safe and
 232
effective means of managing coronary artery disease. It is estimated The overall complication rate ranges from 2% to 21%, depending
that more than 750,000 PCI procedures are done each year in this on the lesion type.77 Coronary occlusion, dissection, or spasm
SECTION 2

country and 525,000 of them are PTCA. The proposed mechanisms of occurs in 4% to 8% of patients, whereas ST-segment elevation MI
reduced stenosis with PTCA include (a) compression and redistribu- occurs in 1.6% to 4.8%.65 Prolonged angina and ventricular tachy-
tion of the atherosclerotic plaque; (b) embolization of plaque con- cardia or fibrillation occurs in 6.9% and 2.3%, respectively. In-
tents; (c) aneurysm formation; and (d) disruption of the plaque and hospital mortality ranges from 0.7% to 2.5% overall, and high-risk
arterial wall with distortion and tearing of the intima and media, events for mortality includes ventricular arrhythmias and myocar-
which leads to denudation of the endothelium, platelet adhesion and dial infarction. The frequency of urgent CABG because of compli-
aggregation, thrombus formation, and smooth muscle proliferation. cations ranges from 0.4% to 5.8%.65
Of these mechanisms, the last one is felt to be the most important, but Table 17–9 outlines current AHA/ACC recommendations for anti-
Cardiovascular Disorders

the others may contribute to opening of the lesions in some situations. thrombotic therapy in PCI.55,78 Antiplatelet therapy with acetylsali-

The indications for PTCA have been provided by the American cylic acid 80 to 325 mg/day given at least 2 hours prior to angioplasty
College of Cardiology/American Heart Association (ACC/AHA) is currently recommended. If patients are sensitive to acetylsalicylic
and now span single or multivessel disease, as well as asymptomatic acid, clopidogrel or ticlopidine are acceptable alternatives. Most
and symptomatic patients (Table 17–8).55 In addition to providing centers now use clopidogrel because of adverse effects (described in
recommendations for which type of patients are appropriate for Chap. 18) and prolonged time to onset for ticlopidine. In elective
PTCA, the guidelines also provide recommendations for the volume settings, clopidogrel should be started at least 72 hours in advance of
of procedures, the use of intravascular ultrasound, and surgery the procedure to allow for maximal antiplatelet effects. Alternatively,
backup when PTCA is being considered.  PTCA generally is not a loading dose of clopidogrel (300 to 600 mg) or ticlopidine (500 mg)
useful if only a small area of viable myocardium is at risk, or when may be given to achieve a more rapid antiplatelet effect.79 The
ischemia cannot be demonstrated, borderline (<50%) stenosis or combination of acetylsalicylic acid plus clopidogrel is currently rec-
lesions that are difficult to dilate are present, or the patient were at ommended for patients undergoing angioplasty and stenting, and this
high risk for morbidity or mortality or both (e.g., left main or combination is safer and superior to antiplatelet therapy plus antico-
equivalent disease or three-vessel disease). PTCA alone or when agulation with warfarin-like drugs.80 Followup for up to 4 years from
used in conjunction or sequentially with thrombolysis for acute the ISAR (Intracoronary Stenting and Antithrombotic Regimen) trial
myocardial infarction is discussed in Chap. 18. Stent placement shows that the benefit of combined antiplatelet therapy evident after
accompanies balloon angioplasty in approximately 80% of cases in 30 days is maintained after 4 years.81 Aspirin is an incomplete
the United States. Table 17–8 lists the current recommendations for inhibitor of platelet aggregation; combination therapy of acetylsali-
PCI based on class of angina. cylic acid plus a glycoprotein (GP) IIb/IIIa receptor antagonist for
Assessment of outcome with PCI can be based on several angio- PCI shows a relative risk reduction of 37.5% for death and nonfatal
graphic, procedural, and clinical outcomes, as discussed previously. MI at 30 days, favoring GP IIb/IIIa receptor antagonists over placebo
The success of PCI is dependent on the experience of the operator (absolute rates of 5.5% vs. 8.9% based on PCI trials. As discussed in
(high volume, better outcome), on complicating factors for the Chap. 18, high-risk patients and those having a stent placed are most
patient (including the number of vessels to be dilated), and on likely to benefit from GP IIb/IIIa receptor antagonist use. Patients
technical advances in the equipment used (e.g., steerable and low- presenting with elevated cardiac biomarkers are also more likely to
profile catheters). The acute success rate for opening of uncompli- receive benefit from GP IIb/IIIa receptor antagonists than patients
cated stenotic lesions ranges from 96% to 99% with the combined with normal levels of biomarkers.82 In the only comparative trial,
balloon/device/pharmacologic approach in experienced hands, and abciximab was superior to tirofiban.83
angina is decreased or eliminated in approximately 80% of cases. During PTCA patients are usually heparinized to prevent immedi-
The success rate totally occluded lesions is somewhat less (~65%). ate thrombus formation at the site of arterial injury and on coronary
Mortality at 1 year is 1% for single-vessel disease and 2.5% for guidewires and catheters; anticoagulation is continued for up to 24
multivessel involvement, reflecting the good prognosis associated hours. The intensity of anticoagulation is monitored using the acti-
with this degree of coronary artery disease. At 10 years, survival is vated clotting time and the targeted range for activated clotting time is
95% for single-vessel disease and 81% for multivessel disease.75 Most 250 to 300 seconds (HemoTec device) in the absence of GP IIb/IIIa
patients remain event-free (no death, MI, or CABG) for an extended receptor antagonist use.65 When GP IIb/IIIa receptor antagonists are
period. Symptomatic status, as measured by the New York Heart not used, unfractionated heparin is given as an IV bolus of 70 to 100
Association classification, is improved in many patients. Restenosis international units/kg to achieve a target activated clotting time of 200
is noted in 32% to 40% after balloon angioplasty at 6 months, and seconds. The loading dose is lowered to 50 to 70 international units/kg
half of these patients will have symptoms associated with resteno- when GP IIb/IIIa receptor antagonists are given. Target activated
sis.75 A few late restenotic events occur, but most restenosis occurs clotting time for eptifibatide and tirofiban is <300 seconds during
within the first 6 months. Anatomic factors that predict restenosis angioplasty; post-procedure unfractionated heparin infusions are not
include lesions >20 mm in length, excessive tortuosity of the recommended during GP IIb/IIIa receptor antagonist therapy. Mech-
proximal segment, extremely angulated segments (>90°), total anisms that result in restenosis include acute lumen loss owing to
occlusions >3 months old and and/or bridging collaterals, inability “recoil,” mural thrombosis formation, and smooth muscle cell prolif-
to protect major side branches, and degenerated vein grafts with eration with synthesis of extracellular matrix.84 Approaches to prevent
friable lesions. Clinical factors that predict worse outcome include restenosis may be aimed at altering the underlying mechanisms. Recoil
diabetes, advanced age, female gender, unstable angina, heart failure and loss of luminal diameter may be reduced by the use of stent
and multivessel disease. A four-variable scoring system that predicts placement; however, this beneficial effect is offset by an increased
cardiovascular collapse for failed PTCA includes percentage of number of vascular complications. Cracking of the plaque leads to
myocardium at risk (e.g., >50% viable myocardium at risk and LV severe damage to the arterial wall, exposure of collagen, and endothe-
ejection fraction <25%), preangioplasty percent diameter stenosis, lial dysfunction. These factors promote mural thrombi, and the pro-
multivessel CAD, and diffuse disease in the dilated segment or a high pensity for thrombus formation is related, in part, to the composition
myocardial jeopardy score.65 Strut thickness of the stent influences of the plaque as well as the depth of injury. Combination therapy with
restenosis as well and thicker struts are associated with angiographic acetylsalicylic acid, heparin and GP IIb/IIIa receptor antagonists is
and clinical restenosis.76 recommended to minimize acute occlusion and numerous clinical
 233

TABLE 17-8 Percutaneous Coronary Intervention Based on Angina Class

CHAPTER 17
Patients with Asymptomatic Ischemia or Canadian Cardiovascular Society (CCS) Class I or II Angina
Class I Class IIa
Patients who do not have treated diabetes with asymp- 1. PCI is reasonable in patients with asymptomatic Phrasing has been changed to reflect current terminol-
tomatic ischemia or mild angina with 1 or more ischemia or CCS class I or II angina and with 1 or more ogy. The recommendation and all of those that follow
significant lesions in 1 or 2 coronary arteries suitable significant lesions in 1 or 2 coronary arteries suitable in Section 5 have been reworded to be consistent with
for PCI with a high likelihood of success and low risk for PCI with a high likelihood of success and a low risk the CCS classification system of angina. This recom-
of morbidity and mortality. The vessels to be dilated of morbidity and mortality. The vessels to be dilated mendation has been changed to class IIa to reflect the
must subtend a large area of viable myocardium. must subtend a moderate to large area of viable published data and Writing Committee consensus that
(Level of Evidence: B) myocardium or be associated with a moderate to not all patients in this clinical category must have PCI
severe degree of ischemia on noninvasive testing. performed.

Ischemic Heart Disease

(Level of Evidence: B)
Class IIa
1. The same clinical and anatomic requirements as for This recommendation has been merged with other class
Class I, except the myocardial area at risk is of IIa recommendations of this section, and the phrasing
moderate size or the patient has treated diabetes. has been changed to reflect current terminology.
(Level of Evidence: B)
2. PCI is reasonable for patients with asymptomatic This is a new recommendation dealing with the manage-
ischemia or CCS class I or II angina, and recurrent ment of recurrent stenosis after PCI among patients
stenosis after PCI with a large area of viable myocar- with asymptomatic ischemia or class I or II angina.
dium or high-risk criteria on noninvasive testing.
(Level of Evidence: C)
3. Use of PCI is reasonable in patients with symptomatic This recommendation for PCI among patients who are
ischemia or CCS class I or II angina with significant left eligible for CABG who have significant left main
main CAD (greater than 50% diameter stenosis) who disease has been added to reflect the favorable results
are candidates for revascularization but are not eligible noted by several trials with PCI.
for CABG. (Level of Evidence: B)
Class IIb
Patients with asymptomatic ischemia or mild angina with This recommendation has been eliminated and replaced
greater than or equal to 3 coronary arteries suitable for by the following 2 recommendations. For each, the
PCI with a high likelihood of success and a low risk of phrasing has been constructed to reflect current termi-
morbidity and mortality. The vessels to be dilated must nology.
subtend at least a moderate area of viable myocar-
dium. In the physician's judgment, there should be
evidence of myocardial ischemia by ECG exercise
testing, stress nuclear imaging, stress echocardiogra-
phy or ambulatory ECG monitoring or intracoronary
physiologic measurements. (Level of Evidence: B)
Class IIb
1. The effectiveness of PCI for patients with asymptomatic Phrasing has been changed to reflect current terminology.
ischemia or CCS class I or II angina who have 2- or 3- Among patients who are eligible, CABG with 1 arterial
vessel disease with significant proximal LAD CAD who conduit is generally preferred for treatment of multives-
are otherwise eligible for CABG with 1 arterial conduit sel disease with significant proximal LAD obstruction in
and who have treated diabetes or abnormal LV function patients with treated diabetes and/or abnormal OV
is not well established. (Level of Evidence: B) function.
2. PCI might be considered for patients with asympto- Phrasing has been changed to reflect current terminol-
matic ischemia or CCS class I or II angina with ogy. PCI might be considered in this clinical setting.
nonproximal LAD CAD that subtends a moderate area
of viable myocardium and demonstrates ischemia on
noninvasive testing. (Level of Evidence: C)
Class III Class III
Patients with asymptomatic ischemia or mild angina who PCI is not recommended in patients with asymptomatic Phrasing has been changed to reflect current terminology.
do not meet the criteria as listed under Class I or Class ischemia or CCS class I or II angina who do not meet Recommendation has been reworded to be consistent
II and who have: the criteria as listed under the class II recommenda- with CCS classification system for angina.
a. Only a small area of viable myocardium at risk tions or who have 1 or more of the following: Level of evidence has been added for each subgroup.
b. No objective evidence of ischemia a. Only a small area of viable myocardium at risk (Level
c. Lesions that have a low likelihood of successful of Evidence: C)
dilation b. No objective evidence of ischemia (Level of Evidence: C)
d. Mild symptoms that are unlikely to be due to c. Lesions that have a low likelihood of successful
myocardial ischemia dilation (Level of Evidence: C)
e. Factors associated with increased risk of morbidity or d. Mild symptoms that are unlikely to be due to
mortality myocardial ischemia (Level of Evidence: C)
f. Left main disease e. Factors associated with increased risk of morbidity or
g. Insignificant disease less than 50% (Level of Evidence: mortality (Level of Evidence: C)
C) f. Left main disease and eligibility for CABG (Level of
Evidence: C)
g. Insignificant disease (less than 50% coronary stenosis)
(Level of Evidence: C)
(continued)
 234

TABLE 17-8 Percutaneous Coronary Intervention Based on Angina Class (continued)

SECTION 2

Patients with CCS Class III Angina

Class I Class IIa
Patient with 1 or more significant lesions in 1 or more 1. It is reasonable that PCI be performed in patients with Phrasing has been changed to reflect current terminol-
coronary arteries suitable for PCI with a high likelihood CCS class III angina and single-vessel or multivessel ogy. Recommendation has been reworded to be
of success and low risk of morbidity or mortality. The CAD who are undergoing medical therapy and who consistent with CCS classification system for angina.
vessel(s) to be dilated must subtend a moderate or have 1 or more significant lesions in 1 or more The recommendation class has been changed to IIa to
large area of viable myocardium and high risk. (Level coronary arteries suitable for PCI with a high likelihood reflect published data and Writing Committee consen-
of Evidence: B) of success and low risk of morbidity or mortality. sus. Criteria regarding viable and high-risk myocar-
(Level of Evidence: B) dium have been deleted from this commendation.
Cardiovascular Disorders

Class IIa
Patients with focal saphenous vein graft lesions or 2. It is reasonable that PCI be performed in patients with Phrasing has been changed to reflect current terminol-
multiple stenoses who are poor candidates for reoper- CCS class III angina with single-vessel or multivessel ogy.
ative surgery. (Level of Evidence: C) CAD who are undergoing medical therapy with focal
saphenous vein graft lesions or multiple stenoses who
are poor candidates for reoperative surgery. (Level of
Evidence: C)
3. Use of PCI is reasonable in patients with CCS class III This recommendation for PCI among patients with
angina with significant left main CAD (greater than significant left main disease who are not eligible for
50% diameter stenosis) who are candidates for revas- CABG has been added to reflect the favorable results
cularization but are not eligible for CABG. (Level of noted by several trials with PCI.
Evidence: B)
Class IIb Class IIb
Patient has 1 or more lesions to be dilated with reduced 1. PCI may be considered in patients with CCS class III Phrasing has been changed to reflect current terminol-
likelihood of success of the vessel(s) subtend a less angina with single-vessel or multivessel CAD who are ogy. The 2001 recommendation has been split into 2
than moderate area of viable myocardium. Patients undergoing medical therapy and who have 1 or more separate recommendations.
with 2- or 3-vessel disease, with significant proximal lesions to be dilated with a reduced likelihood of
LAD CAD and treated diabetes or abnormal LV func- success. (Level of Evidence: B)
tion. (Level of Evidence: B) 2. PCI may be considered in patients with CCS class III Phrasing has been changed to reflect current terminol-
angina and no evidence of ischemia on noninvasive ogy. The use of noninvasive testing to evaluate for
testing or who are undergoing medical therapy and evidence of ischemia has been added.
have 2- or 3-vessel CAD with significant proximal LAD
CAD and treated diabetes or abnormal LV function.
(Level of Evidence: B)
Class III Class III
Patient has no evidence of myocardial injury or ischemia PCI is not recommended for patients with CCS class III Phrasing has been changed to reflect current terminol-
on objective testing and has not had a trial of medical angina with single-vessel or multivessel CAD, no evi- ogy. Class II recommendations #2 and #3 from the
therapy, or has dence of myocardial injury or ischemia on objective 2001 guidelines have been merged into this recom-
a. Only a small area of myocardium at risk testing, and no trial of medical therapy, or who have 1 mendation.
b. All lesions or the culprit lesion to be dilated with of the following:
morphology with a low likelihood of success a. Only a small area of myocardium at risk (Level of
c. A high risk of procedure-related morbidity or mortality. Evidence: C)
(Level of Evidence: C) b. All lesions or the culprit lesion to be dilated with
morphology that conveys a low likelihood of success
(Level of Evidence: C)
c. A high risk of procedure-related morbidity or mortality
(Level of Evidence: C)
d. Insignificant disease (less than 50% coronary steno-
sis) (Level of Evidence: C)
e. Significant left main CAD and candidacy for CABG
(Level of Evidence: C)
2. Patients with insignificant coronary stenosis (e.g., less
than 50% diameter). (Level of Evidence: C)
3. Patients with significant left main CAD who are
candidates for CABG. (Level of Evidence: B)
CAEBG, coronary artery bypass graft; CAD, coronary artery disease; ECG, electrocardiograpy; LAD, left anterior descending; LV, left ventricle; OV, outflow volume; PCI, percutaneous coronary intervention.
From Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC /AHA/SCAI 2005 guideline update for percutaneous coronary intervention—Summary article: A report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (ACC /AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006;113:156–175.

trials document the efficacy of this combined approach.55,78 Bivaliru- Based on randomized trials, DCA produces greater initial luminal
din is a specific and reversible direct thrombin inhibitor that is diameter but results in a higher rate of post-procedure complica-
indicated for use as an anticoagulant in patients with unstable angina tions, such as non–Q-wave MI and death, and is more expensive.
undergoing PTCA. Bivalirudin is comparable to heparin in prevent- Consequently, PTCA is considered to be superior to DCA for most
ing thrombosis and may be associated with less bleeding.85–87 Chapter patients. Tissue debulking with DCA is useful for in-stent resteno-
18 has a more complete discussion of antithrombotic therapy. sis, particularly for diabetic patients.89 The use of abciximab may
Alternatives to PTCA include directional coronary atherectomy improve these results.90 Excimer laser angioplasty followed by
(DCA), excimer laser, rotational atherectomy (rotablator), and balloon angioplasty or rotational atherectomy provides no benefit
intracoronary stents, or some combination of these interventions.88 additional to balloon angioplasty alone.91
 235

TABLE 17-9 Pharmacologic Management of Percutaneous Coronary Intervention

CHAPTER 17
Antiplatelet and antithrombotic adjuctive therapies for PCI—oral antiplatelet therapy
Class I
1. Patients already taking daily chronic aspirin therapy should take 75 to 325 mg of A daily dose of 75 mg of aspirin has been shown to result in improved cardiovascular
aspirin before the PCI procedure is performed. (Level of Evidence: A) outcomes similar to daily doses of 325 mg but with fewer bleeding complications.
2. Patients not already taking daily chronic aspirin therapy should be given 300 to 325 Higher doses of aspirin are recommended for patients not already taking aspirin
mg of aspirin at least 2 hours and preferably 24 hours before the PCI procedure is therapy immediately before PCI procedures.
performed. (Level of Evidence: C)
3. After the PCI procedure, in patients with neither aspirin resistance, allergy, nor The doses and duration of aspirin therapy recommended herein and derived from those used
increased risk of bleeding, aspirin 325 mg daily should be given for at least 1 month for US Food and Drug Administration approval of the specific stent types noted in the

Ischemic Heart Disease

after bare-metal stent implantation, 3 months after sirolimus-eluting stent implanta- recommendation. Daily chronic aspirin therapy is based on recommendations in the ACC /
tion, and 6 months after paclitaxel-eluting stent implantation, after which daily AHA Guidelines for the Management of Patents with ST-Elevation Myocardial Infarction
chronic aspirin use should be continued indefinitely at a dose of 75 to 162 mg. (Level and evidence indicating that aspiring therapy in dosages as low as 75 mg per day yields
of Evidence: B) outcomes similar to those achieved with 325 mg per day but with fewer side effects.
4. A loading dose of clopidogrel should be administered before PCI is performed. Clopidogrel is an important adjunctive therapy for patients undergoing PCI with stent
(Level of Evidence: A) An oral loading dose of 300 mg, administered at least 6 hours placement. The best evidence of efficacy exists for 300 mg given at lest 6 hours
before the procedure, has the best established evidence of efficacy. (Level of before PCI is performed.
Evidence: B)
5. In patients who have undergone PCI, clopidogrel 75 mg daily should be given for at Clopidogrel therapy in the dosage of 75 mg daily should be given after stent placement
least 1 month after bare-metal stent implantation (unless the patient is at increased to all patients. The duration of therapy varies for each stent and is based on data from
risk for bleeding; then it should be given for a minimum of 2 weeks), 3 months after clinical trails used for U.S. Food and Drug Administration approval of that stent.
sirolimus stent implantation, and 6 months after paclitaxel stent implantation, and
ideally u to 12 months in patients who are not at high risk of bleeding. (Level of
Evidence: B)
Class IIa
1. If clopidogrel is given at the time of procedure, supplementation with GP IIb/IIIa When clopidogrel is given at the time of a PCI procedure, supplementation with
receptor antagonists can be beneficial to facilitate earlier platelet inhibition than with glycoprotein IIb/IIIa receptor antagonists can be beneficial, especially among high-risk
clopidogrel alone. (Level of Evidence: B) patients.
2. For patients with an absolute contraindication to aspirin, it is reasonable to give a A significant number of patients will have resistance to aspirin. The strongest evidence
300-mg loading dose of clopidogrel, administered at least 6 hours before PCI, and/ for clopidogrel benefit exists for doses of 300 mg given at least 6 hours before the
or GP IIb/IIIa antagonists, administered at the time of PCI. (Level of Evidence: C) procedure.
3. When a loading dose of clopidogrel is administered, a regimen of greater than 300 Many patients receive clopidogrel therapy at the time of PCI in dosages greater than
mg is reasonable to achieve higher levels of antiplatelet activity more rapidly, but the 600 mg. Although more pronounced inhibition of platelet function has been
efficacy and safety compared with a 300-mg loading dose are less established. (Level demonstrated for doses of clopidogrel greater than 300 mg, the safety of these
of Evidence: C) higher doses and their benefits on clinical outcome are not fully established.
4. It is reasonable that patients undergoing brachytherapy be given daily clopidogrel 75 Subacute or later thrombosis has been observed in patients undergoing brachytherapy,
mg indefinitely and daily aspirin 75 to 325 mg indefinitely unless there is significant and for this reason long-term antiplatelet therapy is recommended.
risk for bleeding. (Level of Evidence: C)
Class IIb
In patients in whom subacute thrombosis may be catastrophic or lethal (unprotected left Clopidogrel resistance is a significant problem, and owing to its contribution to
main, bifurcating left main, or last patent coronary vessel), platelet aggregation studies catastrophic clinical outcomes, the Writing Committee recommends studies be
may be considered and the dose of clopidogrel increased to 150 mg per day if less than performed with increases in clopidogrel dose being recommended for use in those
505 inhibition of platelet aggregation is demonstrated. (Level of Evidence: C) with higher-risk lesions.
Glycoprotein IIb/IIIa inhibitors
Class I
In patients with UA /NSTEMI undergoing PCI without clopidogrel administration, a C IIb/IIIa This recommendation and phrasing are compatible with the ACC /AHA 2002 Guideline
inhibitor (abciximab, eptifibatide, or tirofiban) should be administered. (Level of Update for the Management of Patients With Unstable Angina and Non–ST-Segment
Evidence: A) It is acceptable to administer the GP IIb/IIIa inhibitor before performance of Myocardial Infarction and current evidence from randomized clinical trials. The benefits
the diagnostic angiogram ("upstream treatment") or just before PCI ("in-lab treatment"). of GP IIb/IIa inhibition are especially efficacious when clopidogrel is not given.
Class IIa
1. In patients with UA/NSTEMI undergoing PCI with clopidogrel administration, it is
reasonable to administer a GP IIb/IIIa inhibitor (abciximab, eptifibatide, or tirofiban).
(Level of Evidence: B)
It is acceptable to administer the GP IIb/IIIa inhibitor before performance of the
diagnostic angiogram ("upstream treatment") or just before PCI ("in-lab treatment").
2. In patients with STEMI undergoing PCI, it is reasonable to administer abciximab as Recommendation has been added for consistency with the ACC /AHA Guidelines for
early as possible. (Level of Evidence: B) the Management of Patients With ST-Elevation Myocardial Infarction.
3. In patients undergoing elective PCI with stent placement, it is reasonable to administer a Phrasing has been changed to reflect current terminology, especially in a high-risk
GP IIb/IIIa inhibitor (abciximab, epitifibatide, or tirofiban). (Level of Evidence: B) patient.
Class IIb
In patients with STEMI undergoing PCI, treatment with eptifibatide or tirofiban may be Recommendation has been added for consistency with the ACC /AHA Guidelines for
considered. (Level of Evidence: C) the Management of Patients With ST-Elevation Myocardial Infarction.
Antithrombotic therapy
Unfractionated heparin, low-molecular-weight heparin, and bivalirudin
Class I
1. Unfractionated heparin should be administered to patients undergoing PCI. (Level of Phrasing has been changed to reflect current terminology.
Evidence: C)
2. For patients with heparin-induced thrombocytopenia, it is recommended that Bivalirudin and argatroban are established therapies in place of heparin among patients
bivalirudin or argatroban be used to replace heparin. (Level of Evidence: B) with heparin-induced thrombocytopenia.
(continued)
 236

TABLE 17-9 Pharmacologic Management of Percutaneous Coronary Intervention (continued)

SECTION 2

Class IIa
1. It is reasonable to use bivalirudin as an alternative to unfractionated heparin and New recommendation is based on data from a clinical trial (REPLACE-2) indicating
glycoprotein IIb/IIIa antagonists in low-risk patients undergoing elective PCI. (Level of bivalirudin is an acceptable alternative to heparin and GP IIb/IIIa antagonists in low-
Evidence: B) risk patients undergoing PCI.
2. Low-molecular-weight heparin is a reasonable alternative to unfractionated heparin Recommendation from the ACC /AHA 2002 Guideline Update for the Management of
in patients with UA/NSTEMI undergoing PCI. (Level of Evidence: B) Patients with Unstable Angina and Non–ST-Segment Myocardial Infarction has been
approved by this Writing Committee and included in these guidelines for consistency.
Class IIb
Low-molecular-weight heparin may be considered as an alternative to unfractionated Recommendation from the ACC /AHA Guidelines for the Management of Patients With
Cardiovascular Disorders

heparin in patients with STEMI undergoing PCI. (Level of Evidence: B) ST-Elevation Myocardial Infarction has been approved by this Writing Committee
and included in these guidelines for consistency.
GP, glycoprotein; NSTEMI, non–ST-segment elevation myocardial infarction; PCU, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.
From Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention—Summary article: A report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006;113:156–175.

When medical therapy, PTCA, and CABG have been compared, subjective, and their use as sole measures of efficacy should be
low-risk patients with single-vessel coronary artery disease and avoided. Objective assessment using ETT has shown that placebo
normal left ventricular function had greater alleviation of symptoms does not provide improvement in patients with exertional angina,
with PTCA than with medical treatment; mortality rates and rates of substantiating this as a valid means to assess efficacy.
myocardial infarction were unchanged. In high-risk patients (risk
was defined by severity of ischemia, number of diseased vessels, and β-Adrenergic–Blocking Agents97
presence of left ventricular dysfunction), improvement of survival
Decreased heart rate, decreased contractility, and a slight to moderate
was greater with CABG than with medical therapy. In moderate-risk
decrease in blood pressure with β-adrenergic receptor antagonism
patients with multivessel coronary artery disease (most had two-
reduce MVO2. The predominant receptor type in the heart is the β1-
vessel disease and normal left ventricular function), PTCA and
receptor, and competitive blockade minimizes the influence of endo-
CABG produced equivalent mortality rates and rates of myocardial
genous catecholamines on the chronotropic and inotropic state of the
infarction.
myocardium. These beneficial effects may be countered to some
The development of drug-eluting stents has changed the natural
degree with increased ventricular volume and ejection time seen with
course of stent thrombosis when compared to bare-metal stents that
β-blockade; however, the overall effect of β-blockers in patients with
have existed for a longer period of time. Currently there are two
effort-induced angina is a reduction in oxygen demand (Table 17–10).
types of drug-eluting stents available: (sirolimus (Cypher) and pacli-
The β-blockers do not improve oxygen supply, and in certain
taxel (Taxus). Soon after the introduction of bare-metal stents, it
instances, unopposed α-adrenergic stimulation following the use of
became apparent that early stent thrombosis (≤30 days) was an
β-blockers may lead to coronary vasoconstriction. For patients with
uncommon but serious complication of therapy.92–95 Stent thrombo-
chronic exertional stable angina, β-blockers improve symptoms
sis is an infrequent but severe complication of both bare-metal stents
approximately 80% of the time and objective measures of efficacy
and drug-eluting stents but there is no apparent difference in overall
demonstrate improved exercise duration and delay in the time at
stent thrombosis frequency at 4 years of followup, but the time
which ST-segment changes and initial or limiting symptoms occur. β-
course appears to be different. Although there is a relative numeric
Blockers do not alter the rate–pressure product (double product) for
excess of stent thrombosis late after drug-eluting stents implanta-
maximal exercise, therefore substantiating reduced demand rather
tion, no differences in death or death and infarction have been
than improved supply as the major consequence of their actions.
observed. Target lesion revascularization is needed less often with
Reflex tachycardia from nitrate therapy can be blunted with β-blocker
drug-eluting stents than with bare-metal stents. Implantation of
therapy, making this a common and useful combination. Although β-
drug-eluting stents outside of approved indications is probably
blockade may decrease exercise capacity in healthy individuals or in
related to the occurrence of late stent thrombosis. Longer-term
patients with hypertension, it may allow angina patients previously
followup with larger subsets of patients (i.e., lesion number, type and
limited by symptoms to perform more exercise and ultimately
location, and patient comorbidities) is needed to fully understand
improve overall cardiovascular performance through a training effect.
this issue and the evolution of newer platforms for drug delivery will
Ideal candidates for β-blockers include patients in whom physical
likely alter the natural history of drug-eluting stent thrombosis. A
very important consideration is the use of combination antiplatelet
therapy (aspirin + clopidogrel) for at least 1 year following implan- TABLE 17-10 Effect of Drug Therapy on Myocardial
tation.96 Patients who are hyporesponsive to clopidogrel may be Oxygen Demanda
treated with 150 mg/day rather than 75 mg/day.94
LV Wall Tension
■ PHARMACOLOGIC THERAPY Myocardial Systolic LV
Heart Rate Contractility Pressure Volume
Historically, approximately 30% of anginal syndrome symptoms have
Nitrates ⇓ 0 ⇓ ⇓⇓
responded regardless of which therapy was instituted. These observa-
β-Blockers ⇓⇓ ⇓ ⇓ ⇓
tions stem from two problems inherent in clinical trials undertaken
Nifedipine ⇓ 0 or ⇓ ⇓⇓ 0 or ⇓
to assess the efficacy of any therapy for angina: (a) adequate trial Verapamil ⇓ ⇓ ⇓ 0 or ⇓
design incorporating appropriate controls and washout periods, and Diltiazem ⇓⇓ 0 or ⇓ ⇓ 0 or ⇓
(b) assessment of treatment effects using objective measures of effi-
cacy, including improvement in exercise performance, resting and LV, left ventricular.
a
Calcium channel antagonists and nitrates also may increase myocardial oxygen supply through
ambulatory ECG improvement in ischemic changes, or other objective coronary vasodilation. Diastolic function also may be improved with verapamil, nifedipine, and
tests to address other aspects of myocardial function or metabolism. perhaps, diltiazem. These effects may vary from those indicated in the table depending on individual
The use of pain episode frequency and nitroglycerin consumption is patient baseline hemodynamics.
 237
activity figures prominently in their anginal attacks, those who have than 5%). Other drugs that depress conduction are additive to β-
coexistent hypertension, those with a history of supraventricular blockade, and intrinsic conduction system disease predisposes the

CHAPTER 17
arrhythmias or post-MI angina, and those who have a component of patient to conduction abnormalities. Altered glucose metabolism is
anxiety associated with angina.3 β-Blockers may also be safely used in most likely to be seen in insulin-dependent diabetics, and β-blockade
angina and heart failure as described in Chap. 16. obscures the symptoms of hypoglycemia except for sweating. β-
Pertinent pharmacokinetics for the β-blockers include half-life Blockers may also aggravate the lipid abnormalities seen in patients
and route elimination, which are reviewed in Chap. 15. Drugs with with diabetes; however, these changes are dose related, are more
longer half-lives need to be dosed less frequently than drugs with common with normal baseline lipids than dyslipidemia, and may be
shorter half-lives; however, disparity exists between half-life and of short-term significance only. One of the more common reasons
duration of action for several β-blockers (e.g., metoprolol), which for discontinuation of β-blocker therapy is related to central nervous

Ischemic Heart Disease

may reflect attenuation of the central nervous system-mediated system adverse effects of fatigue, malaise, and depression. Cognition
effects on the sympathetic system, as well as the direct effects of this changes seen with β-blockers are usually minimal and comparable to
category on heart rate and contractility. Renal and hepatic dysfunc- other categories of drugs based on studies done in hypertension.99,100
tion can affect the disposition of β-blockers, but these agents are Abrupt withdrawal of β-blocker therapy in patients with angina has
dosed to effect, either hemodynamic or symptomatic, and route of been associated with increased severity and number of pain episodes
elimination is not a major consideration in drug selection. and myocardial infarction. The mechanism of this effect is unknown
Guidelines for the use of β-blockers in treating angina include the but may be related to increased receptor sensitivity or disease
objective of lowering resting heart rate to 50 to 60 beats per minute progression during therapy, which becomes apparent following
and limiting maximal exercise heart rate to about 100 beats per discontinuation of β-blockade. In any event, tapering of β-blocker
minute or less. It has also been suggested that exercise heart rate therapy over about 2 days should minimize the risk of withdrawal
should be no more than about 20 beats per minute or a 10% reactions for those patients in whom therapy is being discontinued.
increment over resting heart rate with modest exercise. Because β- β-Adrenoreceptor blockade is effective in chronic exertional
blockade is competitive and circulating catecholamine concentrations angina as monotherapy and in combination with nitrates and/or
vary depending on the intensity of exercise and other factors, and calcium channel antagonists. β-Blockers should be the first-line
cholinergic tone may be important in controlling heart rate in some drug in chronic angina that requires daily maintenance therapy
patients, these guidelines are general in nature. These effects are because β-blockers are more effective in reducing episodes of silent
generally dose and plasma concentration related, and for propranolol, ischemia, reducing early morning peak of ischemic activity, and
plasma concentrations of 30 ng/mL are needed for a 25% reduction improving mortality after Q-wave MI than nitrates or calcium
of anginal frequency. Initial doses of β-blockers should be at the lower channel blockers (see Fig. 17–4).3 If β-blockers are ineffective or not
end of the usual dosing range and titrated to response as indicated tolerated, then monotherapy with a calcium channel blocker or
above. combination therapy if monotherapy is ineffective may be insti-
Although there is little evidence to suggest superiority of any β- tuted. Patients with severe angina, rest angina, or variant angina
blocker, the duration of β-blockade is dependent partially on the half- (i.e., a component of coronary artery spasm) may be better treated
life of the agent used, and agents with longer half-lives may be dosed with calcium channel blockers or long-acting nitrates.
less frequently. Of note, propranolol may be dosed twice a day in
most patients with angina and the efficacy is similar to that seen with Nitrates101,102
more frequent dosing. The ancillary property of membrane stabiliz-
Nitroglycerin has a well-documented role in the alleviation of acute
ing activity is irrelevant in the treatment of angina, and intrinsic
anginal attacks when used as rapidly absorbed and readily available
sympathomimetic activity appears to be detrimental in rest or severe
preparations by the oral and intravenous routes (Table 17–11; see
angina because the reduction in heart rate would be minimized,
also Fig. 17–4). Sublingual, buccal, or spray products are the prod-
therefore limiting a reduction in MVO2. Cardioselective β-blockers
ucts of choice for this indication. Prevention of symptoms may be
may be used in some patients to minimize adverse effects such as
accomplished by the prophylactic use of oral or transdermal prod-
bronchospasm in asthma, intermittent claudication, and sexual dys-
ucts; however, recent concern has been expressed over the long-term
function. A common misunderstanding is that β-blockers are not
efficacy of many of these preparations and the development of
well tolerated in peripheral arterial disease but, in fact, their use is
tolerance.46,47
associated with a reduction in death and improved quality of life.98 It
Nitrates have multiple potential mechanisms of action, and for a
should be remembered that cardioselectivity is a relative property and
given patient it is not always clear which of these is most important.
the use of larger doses (e.g., metoprolol 200 mg/day) is associated
In general, the major action appears to be indirectly mediated
with the loss of selectivity and with adverse effects. Post-acute-MI
patients with angina are particularly good candidates for β-blockade,
both because anginal symptoms may be treated and the risk of post- TABLE 17-11 Nitrate Products
MI reinfarction reduced, and because mortality has been demon- Product Onset (min) Duration Initial Dose
strated with timolol, propranolol, and metoprolol (see Chap. 15).
Nitroglycerin
Combined β- (nonselective) and α-blockade with labetalol may be
IV 1–2 3–5 min 5 mcg/min
useful in some patients with marginal LV reserve, and fewer deleteri- Sublingual/lingual 1–3 30–60 min 0.3 mg
ous effects on coronary blood flow are seen when compared with Oral 40 3–6 h 2.5–9 mg tid
other β-blockers. Ointment 20–60 2–8 h 0.5–1 in
Extension of pharmacologic effect is the underlying reason for Patch 40–60 >8 h 1 patch
many of the adverse effects seen with β-blockade. Hypotension, Erythritol tetranitrate 5–30 4–6 h 5–10 mg tid
decompensated heart failure, bradycardia and heart block, broncho- Pentaerythritol tetranitrate 30 4–8 h 10–20 mg tid
spasm, and altered glucose metabolism are directly related to β- Isosorbide dinitrate
adrenoreceptor antagonism. Patients with preexisting left ventricular Sublingual/chewable 2–5 1–2 h 2.5–5 mg tid
systolic decompensated and heart failure and the use of other Oral 20–40 4–6 h 5–20 mg tid
Isosorbide mononitrate 30–60 6–8 h 20 mg daily, bida
negative inotropic agents are most prone to developing overt heart
failure, and in the absence of these, heart failure is uncommon (less a
Product dependent.
 238
through a reduction of myocardial oxygen demand secondary to ment), vehicle used, the surface area and thickness of application, the
venodilation and arterial–arteriolar dilation, leading to a reduction site application, and other skin variables (temperature, moisture
SECTION 2

in wall stress from reduced ventricular volume and pressure (see content).
Table 17–10). Systemic venodilation also promotes increased flow to Nitroglycerin concentrations are affected by the route of adminis-
deep myocardial muscle by reducing the gradient between intraven- tration, with the highest concentrations usually obtained with intra-
tricular pressure and coronary arteriolar (R2) pressure. Direct venous administration, the lowest seen with lower oral doses. Peak
actions on the coronary circulation include dilation of large and concentrations with sublingual nitroglycerin appear within 2 to 4
small intramural coronary arteries, collateral dilation, coronary minutes, with the oral route producing peaks at about 15 to 30
artery stenosis dilation, abolition of normal tone in narrowed vessels, minutes and by the transdermal route at 1 to 2 hours. The half-life of
and relief of spasm; these actions occur even if the endothelium is nitroglycerin is 1 to 5 minutes regardless of route; hence the potential
Cardiovascular Disorders

denuded or dysfunctional. It is likely that depending on the underly- advantage of sustained-release and transdermal products. Transder-
ing pathophysiology, different mechanisms become operative. For mal nitroglycerin does produce sufficient concentrations for acute
example, in the presence of a 60% to 70% stenosis, venodilation with hemodynamic effects to occur and these concentrations are main-
MVO2 reduction is most important; however, with higher grade tained for long intervals; however, the hemodynamic and antianginal
lesions, direct effects on the coronary circulation and vessel tone are effects are minimal after 1 week or less with chronic, continuous (24
the predominant effects. Nitroglycerin and pentaerythritol tetrani- h/day) therapy.
trate in low doses are bioactivated by mitochondrial aldehyde dehy- ISDN is metabolized to isosorbide 2-mono- and 5-mononitrate
drogenase to nitrite or denitrated metabolites, which require further (ISMN). ISMN is well absorbed and has a half-life of about 5 hours
activation by cytochrome oxidase or acidic disproportionation in the and may be given once or twice daily depending on the product
inner membrane space, finally yielding nitric oxide. Nitric oxide chosen. Multiple, larger doses of ISDN lead to disproportionate
activates soluble guanylate cyclase to increase intracellular concen- increases in the area under the plasma time profile, suggesting that
trations of cyclic guanosine monophosphate (GMP) resulting in metabolic pathways are being saturated or that metabolite accumu-
vasorelaxation.47 In contrast, isosorbide dinitrate (ISDN) and isosor- lation may influence the disposition of ISDN. Little pharmacoki-
bide mononitrate (ISMN) are bioactivated via P450 enzymes to netic information is available for other nitrate compounds.
nitric oxide. At higher concentrations, nitroglycerin and pentaeryth- Nitrate therapy may be used to terminate an acute anginal attack,
ritol tetranitrate may also be bioactivated to nitric oxide via P450 to prevent effort or stress-induced attacks, or for long-term prophy-
enzymes. Increased cyclic GMP induces a sequence of protein laxis, usually in combination with β-blockers or calcium channel
phosphorylation associated with reduced intracellular calcium blockers. Sublingual nitroglycerin 0.3 to 0.4 mg will relieve pain in
release from the sarcoplasmic reticulum or reduced permeability to approximately 75% of patients within 3 minutes, with another 15%
extracellular calcium and, consequently, smooth muscle relaxation. becoming pain free in 5 to 15 minutes. Pain persisting beyond about
Oxidative stress within the mitochondria causes inactivation of 20 to 30 minutes following the use of two or three nitroglycerin
mitochondrial aldehyde dehydrogenase, leading to impaired bioacti- tablets is suggestive of acute coronary syndrome and the patient
vation of nitroglycerin during prolonged treatment.103,104 Thomas et should be instructed to seek emergency aid. Patients should be
al. performed a study in normal volunteers to evaluate the effect of instructed to keep nitroglycerin in the original, tightly closed glass
ISMN 120 mg/day given for 7 days on endothelial function. They container and to avoid mixing with other medication, because
found that ISMN impaired endothelial function suggesting a role for mixing may reduce nitroglycerin adsorption and vaporization. Addi-
oxygen free radicals and nitrate induced abnormalities in endothe- tional counseling should include the facts that nitroglycerin is not an
lial-dependent vasomotor responses that were reversed with a vita- analgesic but rather it partially corrects the underlying problem and
min C infusion of 24 mg/min given for 15 minutes.46 Furthermore, that repeated use is not harmful or addicting. Patients should also be
ISDN impairs flow-mediated dilation and carotid intimal-media aware that enhanced venous pooling in the sitting or standing
thickness after 3 months of treatment.105 These deleterious changes positions may improve the effect, as well as the symptoms of postural
in endothelial function, intima-media thickness and the occurrence hypotension, and that inadequate saliva may slow or prevent tablet
of tolerance suggest that the role of nitrates in IHD may be changing. disintegration and dissolution. An acceptable, albeit expensive, alter-
Pharmacokinetic characteristics common to the organic nitrates native is lingual spray, which may be more convenient and has a
used for angina include a large first-pass effect of hepatic metabo- shelf-life of 3 years, compared with 6 months or so for some forms
lism, short to very short half-lives (except for isosorbide mononi- of nitroglycerin tablets.
trate), large volumes of distribution, high clearance rates, and large Chewable, oral, and transdermal products are acceptable for the
interindividual variations in plasma or blood concentrations. Phar- long-term prophylaxis of angina; however, considerable controversy
macodynamic–pharmacokinetic relationships for the entire class surrounds their use and it appears that the development of tolerance
remain poorly defined, presumably because of methodologic diffi- or adaptive mechanisms limits the efficacy of all chronic nitrate
culty in characterizing the parent drug and metabolite concentra- therapies regardless of route. Dosing of the longer-acting prepara-
tions at or within vascular smooth muscle and secondary to tions should be adjusted to provide a hemodynamic response and, as
counterregulatory or adaptive mechanisms from the drug’s effects, as an example, may require doses of oral ISDN ranging from 10 to 60
well as the occurrence of tolerance. Nitroglycerin is extracted by a mg as often as every 3 to 4 hours owing to tolerance or first-pass
variety of tissues and metabolized locally; differential extraction and metabolism, and similar large doses are required for other products.
metabolite generation occur depending on the tissue site. There are Nitroglycerin ointment has a duration of up to 6 hours, but it is
also numerous technical problems limiting the generation of reliable difficult to apply in a cosmetically acceptable fashion over a consis-
pharmacokinetic parameter estimates including the following: assay tent surface area, and response varies depending on the epidermal
sensitivity; arterial–venous extraction gradients and therefore extra- thickness, vascularity, and amount of hair. Percutaneous adsorption
hepatic metabolism; in vitro degradation; drug adsorption to polyvi- of nitroglycerin ointment may occur unintentionally if someone
nyl chloride tubing and syringes; potentially saturable metabolism; other than the patient applies the ointment, and limiting exposure
accumulation of metabolites (some of which are active) with multi- through the use of gloves or some other means is advisable. Periph-
ple doses; postural and exercise-induced changes in pharmacokine- eral edema may also impair the response to nitroglycerin because
tics; a variety of variables associated with transdermal delivery venodilation cannot increase capacitance to a maximum and pooling
including the delivery system (matrix, membrane-limited, oint- may be reduced. Transdermal patch delivery systems were approved
 239
on the basis of sustained and equivalent plasma concentrations to nitrate preparations and dosing schedules demonstrate that this
other forms of therapy. Trials required by the Food and Drug approach is useful and the nitrate-free interval should be a minimum

CHAPTER 17
Administration using transdermal patches as a continuous 24-hour of 8 hours, and perhaps 12 hours for even better effects.97 Another
delivery system revealed a lack of efficacy for improved exercise concern for intermittent transdermal nitrate therapy is the occur-
tolerance. Subsequently, large, randomized, double-blind, placebo- rence of rebound ischemia during the nitrate-free interval. Freedman
controlled trials of intermittent (10 to 12 hours on; 12 to 14 hours et al.107 found more silent ischemia during the patch-free interval
off) transdermal nitroglycerin therapy in chronic stable angina during a randomized, double-blind, placebo-controlled trial than
demonstrated modest but significant improvement in exercise time during the placebo patch phase, although others have not noted this
after 4 weeks for the highest doses at 8 to 12 hours after patch effect. ISDN, for example, should not be used more often than three
placement.106 Subjective assessment methods for nitrate effects times per day if tolerance is to be avoided. Interestingly, hemody-

Ischemic Heart Disease

include reduction in the number of painful episodes and the amount namic tolerance does not always coincide with antianginal efficacy,
of nitroglycerin consumed. Objective assessment includes the resolu- but this is not well studied.
tion of ECG changes at rest, during exercise, or with ambulatory Nitrates may be combined with other drugs for anginal therapy
ECG monitoring. Because nitrates work primarily through a reduc- including β-adrenergic-blocking agents and calcium channel antago-
tion in MVO2, the double product can be used to optimize the dose nists. These combinations are usually instituted for chronic prophy-
of sublingual and oral nitrate products. It is important to realize that lactic therapy based on complementary or offsetting mechanisms of
reflex tachycardia may offset the beneficial reduction in systolic action (see Table 17–10). Combination therapy is generally used in
blood pressure and calculation of the observed changes is necessary. patients with more frequent symptoms or with symptoms that are not
The double product is best assessed in the sitting position and at responding to β-blockers alone (nitrates plus β-blockers or calcium
intervals of 5 to 10 minutes and 30 to 60 minutes following sublin- blockers), in patients intolerant of β-blockers or calcium channel
gual and oral therapy, respectively. Owing to the placebo effect, blockers, and in patients having an element of vasospasm leading to
unpredictable and variable course of angina, numerous pharmaco- decreased supply (nitrates plus calcium blockers).108 Modulation of
logic effects of nitroglycerin, diurnal variation in pain patterns, calcium entry into vascular smooth muscle and myocardium as well
stringent investigative protocols, and interindividual sensitivity to as a variety of other tissues is the principal action of the calcium
nitroglycerin, assessment with transdermal and sustained-release antagonists. The cellular mechanism of these drugs is incompletely
products is difficult. ETT provides valuable information concerning understood and it differs among the available classes of the phenyl-
efficacy and mechanism of action for nitrates but its use is usually alkylamines (verapamil-like), dihydropyridines (nifedipine-like),
reserved for clinical investigation rather than routine patient care. benzothiazepines (diltiazem-like), bepridil, and a recent class referred
Most ETT studies have shown nitrates to delay the onset of ischemia to as T-channel blockers. Receptor-operated channels stimulated by
(ST-segment changes or initial chest discomfort) at submaximal norepinephrine and other neurotransmitters, and potential-depen-
exercise but that the threshold for maximal exercise is unaltered, dent channels activated by membrane depolarization, control the
suggesting a reduction in oxygen demand rather than an improved entry of calcium, and, consequently, the cytosolic concentration of
oxygen supply. More sophisticated studies of myocardial function, calcium responsible for activation of actin–myosin complex leading
such as wall motion abnormalities and myocardial metabolism, to contraction of vascular smooth muscle and myocardium. In the
could be used to document efficacy; however, these studies are myocardium, calcium entry triggers the release of intracellular stores
generally only for investigative purposes. of calcium to increase cytosolic calcium, whereas in smooth muscle,
Adverse effects of nitrates are related most commonly to an calcium derived from the extracellular fluid may do this directly.
extension of their pharmacologic effects and include postural Binding proteins within the cell, calmodulin and troponin, after
hypotension with associated central nervous system symptoms, head- binding with calcium, participate in phosphorylation reactions lead-
aches and flushing secondary to vasodilation, and occasional nausea ing to contraction. Decreased calcium availability, through the
from smooth muscle relaxation. If hypotension is excessive, coronary actions of calcium antagonists, inhibits these reactions.
and cerebral filling may be compromised, leading to myocardial Direct actions of the calcium antagonists include vasodilation of
infarction and stroke. Although reflex tachycardia is most common, systemic arterioles and coronary arteries, leading to a reduction of
bradycardia with nitroglycerin has been reported. Other noncardio- arterial pressure and coronary vascular resistance, as well as depres-
vascular adverse effects include rash with all products, but particularly sion of the myocardial contractility and conduction velocity of the
with transdermal nitroglycerin, the production of methemoglobin- sinoatrial and atrioventricular nodes (see Chap. 19). Reflex β-adren-
emia with high doses given for extended periods, and measurable ergic stimulation overcomes much of the negative inotropic effect,
concentrations of ethanol (intoxication has been reported) and pro- and depression of contractility becomes clinically apparent only in the
pylene glycol (found in the diluent) with intravenous nitroglycerin. presence of LV dysfunction and when other negative inotropic drugs
Tolerance with nitrate therapy was first described in 1867 with the are used concurrently. Verapamil and diltiazem cause less peripheral
initial experience using amyl nitrate for angina and later widely recog- vasodilation than nifedipine, and, consequently, the risk of myocar-
nized in munitions workers who underwent withdrawal reactions dial depression is greater with these two agents. Conduction through
during periods of absence from exposure. Tolerance to nitrates is the AV node is predictably depressed with verapamil and diltiazem,
associated with a reduction in tissue cyclic GMP, which results from and they must be used cautiously in patients with preexisting conduc-
decreased production (guanylate cyclase) and increased breakdown via tion abnormalities or in the presence of other drugs with negative
cyclic GMP-phosphodiesterase and increased superoxide levels. One chronotropic properties. MVO2 is reduced with all of the calcium
proposed mechanism for the lack of cyclic GMP is lack of conversion channel antagonists because of reduced wall tension secondary to
of organic nitrates to nitric oxide as described previously.47,97 reduced arterial pressure and, to a minor extent, depressed contractil-
Most of the published information from controlled trials examin- ity (see Table 17–10). Heart rate changes are dependent on the drug
ing nitrate tolerance have been done with either ISDN or transdermal used and the state of the conduction system. Nifedipine generally
nitroglycerin, and these studies demonstrate the development of increases heart rate or causes no change, whereas either no change or
tolerance within as little as 24 hours of therapy. Although the onset of decreased heart rate is seen with verapamil and diltiazem because of
tolerance is rapid, the offset may be just as rapid, and one alternative- the interaction of these direct and indirect effects. In contrast to the
dosing strategy to circumvent or minimize tolerance is to provide a β-blockers, calcium channel antagonists have the potential to
daily nitrate-free interval of 6 to 8 hours. Studies with a variety of improve coronary blood flow through areas of fixed coronary
 240
obstruction and by inhibiting coronary artery vasomotion and vaso- three drugs. Although disease alterations in kinetics have been
spasm. Beneficial redistribution of blood flow from well-perfused described, the most important quantitative alteration is the influence
SECTION 2

myocardium to ischemic areas and from epicardium to endocardium of liver disease on bioavailability and elimination that reduce the
may also contribute to improvement in ischemic symptoms. Overall, clearance of verapamil and diltiazem, and dosing in this population
the benefit provided by calcium channel antagonists is related to should be done with caution. Altered protein binding because of renal
reduced MVO2 rather than improved oxygen supply, based on lack of disease, decreased protein concentration, or increased α1-acid glyco-
alteration in the rate pressure product at maximal exercise in most protein has been noted, but the clinical import of these changes is
studies performed to date. However, as coronary artery disease unknown.
progresses and vasospasm becomes superimposed on critical stenotic Good candidates for calcium channel blockers in angina include
lesions, improved oxygen supply through coronary vasodilation may patients with contraindications or intolerance of β-blockers, coex-
Cardiovascular Disorders

become more important. isting conduction system disease (except for verapamil and diltia-
Absorption of the calcium channel antagonists is characterized by zem), patients with Prinzmetal angina (vasospastic or variable
excellent absorption and large, variable, first-pass metabolism result- threshold angina), the presence of peripheral vascular disease,
ing in oral bioavailability ranging from approximately 20% to 50% or severe ventricular dysfunction (amlodipine is probably the calcium
greater for diltiazem, nicardipine, nifedipine, verapamil, felodipine, channel blocker of choice and others need to be used with caution
and isradipine. Amlodipine has a range of bioavailability of approxi- if the ejection fraction is <40%), and concurrent hypertension.
mately 60% to 80%. Saturation of this effect may occur with verapa- Ranolazine is a new drug for angina that has a unique mechanism
mil and diltiazem, resulting in greater amounts of drug being of action which is unlike that of any other drug used to alter the
absorbed with chronic dosing. Nifedipine may have slow or fast relationship between oxygen supply and demand. Ranolazine reduces
absorption patterns, and the ingestion of food delays and impairs its calcium overload in the ischemic myocyte through inhibition of the
absorption as well as potential enhanced absorption in elderly late sodium current (INa). Myocardial ischemia produces a cascade of
patients. This variability in absorption produces fluctuation in the complex ionic exchanges that can result in intracellular acidosis,
hemodynamic response with nifedipine. Sublingual nifedipine is excess cytosolic Ca2+, myocardial cellular dysfunction, and, if sus-
frequently used to provide a more rapid response; however, the tained, cell injury and death. Activation of the adenosine triphos-
rationale for this application is suspect because little nifedipine is phate-dependent K+ current during ischemia results in a strong efflux
absorbed from the buccal mucosa and the swallowed drug is respon- of K+ ions from myocytes. Sodium channels are activated on depolar-
sible for the observed plasma concentrations. Absorption of verapa- ization, leading to a rapid influx of sodium into the cells. The
mil in sustained-release products may be influenced by food, and inactivation of INa has a fast component that lasts a few milliseconds
when used in the fasted state, dose dumping may occur, resulting in and a slowly inactivating component that can last hundreds of milli-
high peak concentrations with some products. The approved sus- seconds.110 Ranolazine is a relatively selective inhibitor for late INa. In
tained-release products for nifedipine, verapamil, and diltiazem are isolated ventricular myocytes in which the late INa was pathologically
approved primarily for the treatment of hypertension (see Chap. 15). augmented, ranolazine prevented or reversed the induced mechanical
The presence of severe liver disease (e.g., alcoholic liver disease with dysfunction, as well as ameliorated abnormalities of ventricular repo-
cirrhosis) reduces the first-pass metabolism of verapamil, and this larization. Ranolazine does not affect heart rate, inotropic state, or
shunting of drug around the liver gives rise to higher plasma concen- hemodynamic state or increase coronary blood flow.
trations and lower dose requirements in these patients. Interestingly, Ranolazine is extensively metabolized via CYP450 3A and potent
this effect appears to be stereoselective for the more active isomer of inhibitors of 3A increase the plasma concentration by a factor of
verapamil. Verapamil may also reduce liver blood flow; however, about three. Ketoconazole, diltiazem and verapamil should not be
evidence for this reduction is based primarily on animal experiments. coadministered with ranolazine. Absorption from the gut is quite
Few data are available regarding the influence of liver disease on the variable and the apparent half-life is 7 hours. Steady state is reached
kinetics of calcium blockers; however, these drugs undergo extensive after 3 days of twice-daily dosing. Ranolazine is indicated for the
hepatic metabolism with little unchanged drug being renally excreted, treatment of chronic angina and because it prolongs the QT
and liver disease can be expected to alter the pharmacokinetics. interval, it should be reserved for patients who have not achieved an
Nifedipine has no active metabolites whereas norverapamil possesses adequate response with other antianginal agents. Contraindications
20% or less activity of the parent compound. Desacetyl-diltiazem has include preexisting QT interval prolongation, hepatic impairment,
not been studied in man, but canine studies suggest its potency ranges concurrent QT interval-prolonging drugs, and moderately potent to
from 100% to 40% of the parent compound for various cardiovascu- potent concurrent 3A inhibitors. QT prolongation occurs in a dose-
lar effects; the clinical importance of these observations remains to be dependent fashion with ranolazine with an average increase of 6
determined. With chronic dosing of verapamil and diltiazem, milliseconds but 5% of the population has QTc prolongation of 15
apparent saturation of metabolism occurs, producing higher plasma milliseconds. Baseline and followup ECGs should be obtained to
concentrations of each drug than those seen with single-dose admin- evaluate effects of the QT interval. In controlled trials, the most
istration. Consequently, the elimination half-life for verapamil is common adverse reactions are dizziness, headache, constipation
prolonged, and less-frequent dosing intervals may be used in some and nausea. Ranolazine should be started at 500 mg twice daily and
patients. The elimination half-life for diltiazem is also somewhat increased to 1,000 mg twice daily as needed based on symptoms.111
prolonged and the half-life of desacetyl-diltiazem is longer than that Based on randomized, placebo-controlled trials, the improve-
of the parent drug, but it is not clear if less-frequent dosing may be ment in exercise time is a modest increase of 15 to about 45 seconds
used. Bepridil also undergoes hepatic elimination and an active compared with placebo.112,113 In a large acute coronary syndrome
metabolite, 4-hydroxyphenyl bepridil, is produced; the parent com- trial, ranolazine reduced recurrent ischemia but did not improve
pound has a long half-life of 30 to 40 hours. Nifedipine does not the primary efficacy end point of the composite of cardiovascular
accumulate with chronic dosing; however, it is eliminated via oxida- death, MI, or recurrent ischemia.114
tive pathways that may be polymorphic, and slow and fast metaboliz-
ers have been described for nifedipine. Most of the calcium channel
blockers are eliminated via cytochrome (CYP) 3A4 and other CYP Investigational Agents
isoenzymes and many inhibit CYP3A4 activity as well.109 Renal Therapeutic angiogenesis aims to deliver an angiogenic growth factor
insufficiency has little or no effect on the pharmacokinetics of these or cytokine to the myocardium to stimulate collateral blood vessel
 241
growth throughout the ischemic tissue. The angiogenic factor may be patients respond rapidly to sublingual nitroglycerin or isosorbide
administered as a recombinant protein or as a transgene within a dinitrate; however, intravenous and intracoronary nitroglycerin

CHAPTER 17
plasmid or gene-transfer vector. An example of this approach is the may be very useful for patients who do not respond to sublingual
intracoronary administration of the adenoviral gene for fibroblast preparations. In particular, vasospasm provoked by ergonovine may
growth factor (Ad5FGF-4) to determine if therapeutic angiogenesis require intracoronary nitroglycerin. Although studies with nitrates
could improve myocardial perfusion compared with placebo.115 In generally show them to be efficacious, high does are often required
this study of 52 patients with stable angina and reversible ischemia, and it is unclear if they reduce mortality. Because calcium antago-
Ad5FGF-4 decreased ischemic defect by 21% (P <0.001) as deter- nists may be more effective, have few serious adverse effects in
mined by single-photon emission computed tomography imaging.115 effective doses, and can be given less frequently than nitrates, some
More trials are needed before angiogenesis becomes a standard consider them the agents of choice for variant angina.

Ischemic Heart Disease

therapy.116 Nifedipine, verapamil, and diltiazem are all equally effective as
single agents for the initial management of variant angina and
coronary artery spasm. Dose titration is important to maximize the
TREATMENT response with calcium antagonists. Comparative trials are few in
number and do not reveal significant differences among these three
Coronary Artery Spasm and drugs for variant angina. Patients unresponsive to calcium antago-
Variant Angina Pectoris nists alone, may have nitrates added. Combination therapy with
nifedipine–diltiazem or nifedipine–verapamil is reported to be
(Prinzmetal Angina)117 useful for patients who are unresponsive to single-drug regimens.
Although this is probably rational as at the cellular level the drugs
Prinzmetal, in his original description of variant angina pectoris, have different receptors, the combination of verapamil–diltiazem
noted the waxing and waning course of this syndrome associated should be used cautiously owing to their potential additive effects
with ST-segment elevation and that it most commonly resolves on contractility and conduction.
without progression to MI. Patients who develop variant angina are β-Adrenergic blockade has little or no role in the management of
usually younger, have fewer coronary risk factors but more com- variant angina according to most authorities.122 Although not all
monly smoke than patients with chronic stable angina. Hyperventi- studies report increased painful episodes of variant angina with the
lation, exercise, and exposure to cold may precipitate variant angina addition of β-blockers, they may induce coronary vasoconstriction
attacks, or there may be no apparent precipitating cause. The onset and prolong ischemia, as documented by continuous ECG monitor-
of chest discomfort is usually in the early morning hours. The exact ing. Other approaches to therapy attempting to modify sympathetic/
cause of variant angina is not well understood, but may be an parasympathetic tone include α-antagonists, anticholinergics, plex-
imbalance between endothelium-produced vasodilator factors ectomy, surgical interruption of the sympathetic innervation of the
(prostacyclin, nitric oxide) and vasoconstrictor factors (e.g., endo- heart, thromboxane receptor antagonism, prostacyclin, lipoxygenase
thelin, angiotensin II) as well as an imbalance of autonomic control inhibition, and ticlopidine but these drugs or procedures do not
characterized by parasympathetic dominance or inflammation may occupy a major place in therapy at the present time.
also play a role.118,119 More recently there have been a number
potential common adrenoreceptor polymorphisms that may predis-
pose patients to developing vasospasm.120,121 TREATMENT
The diagnosis of variant angina is based on ST-segment elevation
during transient chest discomfort (usually at rest) that resolves
when the chest discomfort diminishes in patients who have normal
Silent Ischemia16
or nonobstructive coronary lesions. In the absence of ST-segment The objective in the treatment of silent myocardial ischemia is to
elevation, provocative test using ergonovine, acetylcholine, or reduce the total number of ischemic episodes, both symptomatic and
methacholine may be used to precipitate coronary artery spasm, ST- asymptomatic, regardless of the direction of ST-segment shift. The
segment elevation and typical symptoms. Nitrates and calcium incidence of silent ischemia in the general, asymptomatic population
antagonists should be withdrawn prior to provocative testing. is unknown. Significant day-to-day variability in the number of
Provocative testing should not be used in patients with high-grade episodes, the duration of ischemia, and the amount of ST-segment
lesions. Hyperventilation may also be used to provoke spasm and deviation complicates both the understanding of this process and the
patients who positive a hyperventilation test are more likely to have utility of various therapeutic interventions. Silent ischemia in
higher frequency of attacks, multivessel disease, and a high degree of patients with known CAD is common (~80% of all ischemic epi-
AV block or ventricular tachycardia. sodes) and associated with the extent of disease as well as a high risk
Optimization of therapy includes dose titration using sufficiently for myocardial infarction and sudden death when compared with
high doses to obtain clinical efficacy without unacceptable adverse symptomatic episodes of ischemia. Although the underlying mecha-
effects in individual patients. All patients should be treated for acute nisms for silent ischemia are continuing to be defined, increased
attacks and maintained on prophylactic treatment for 6 to 12 physical activity, activation of the sympathetic nervous system,
months following the initial episode. The occurrence of serious increased cortisol secretion, increased coronary artery tone, and
arrhythmias during attacks is associated with a greater risk of sudden enhanced platelet aggregation as a result of endothelia dysfunction
death, and these patients should be treated more aggressively and for leading to intermittent coronary obstruction may be additive in
prolonged periods. Patients without arrhythmias who become lowering the threshold for ischemia. Platelet aggregability is
asymptomatic and remain so for several months after treatment has increased in the morning hours (7 AM to 11 AM), corresponding to
been instituted, withdrawal of therapy may be safe after first ascer- circadian rhythms noted for the peak frequency of ischemia, acute
taining that disease activity is quiescent. Aggravating factors such as myocardial infarction, and sudden death. Silent ischemia is associ-
alcohol or cocaine use or cigarette smoking should be eliminated ated with ST-segment elevation or depression and frequently occurs
when instituting treatment. without antecedent changes in heart rate or blood pressure, suggest-
Nitrates have been the mainstay of therapy for the acute attacks ing that this form of ischemia is a result of primary reduction in
of variant angina and coronary artery spasm for many years. Most oxygen supply. Silent ischemia is classified into class I, patients who
 242
do not experience angina at any time, and class II, patients who have because this is the only low-molecular-weight heparin proven to be
both asymptomatic and symptomatic ischemia. Patients with silent superior to unfractionated heparin. Several analyses show that,
SECTION 2

ischemia have a defective warning system for angina pain that may compared with unfractionated heparin plus aspirin, enoxaparin
encourage excessive myocardial demand. Regardless of the exact sodium provides cost savings both during hospitalization (30 days)
mechanism, there is increasing concern that painless ischemia carries and at 1-year followup. These cost savings are mainly attributable to
considerable risk for myocardial perfusion defects, detrimental fewer cardiac interventions, shorter hospital stays, and lower
hemodynamic changes, arrhythmogenesis, and sudden death. Silent administrative costs. Indeed, the clinical and economic advantages
ischemia is associated with reduced survival and increased need for of enoxaparin sodium have led to its recommendation in recent
PTCA and CABG, as well as increased risk of acute MI.123 Because it guidelines as the antithrombotic agent of choice for coronary artery
is apparently very common in some settings, major emphasis should disease. Most of the economic analyses of GP IIb/IIIa inhibitors
Cardiovascular Disorders

be placed on its management. Although a consensus has not been have been cost-effectiveness analyses.131 Such analyses indicate that
reached for the most appropriate method of detecting and quantify- the high acquisition costs of these drugs may be at least partially
ing the magnitude of silent ischemia, ambulatory electrocardiogram offset by reductions in other costs if a noninvasive approach to risk
monitoring is thought by many to be the most useful tool at the stratification is used. Furthermore, use of GP IIb/IIIa inhibitors
present time. appears to give favorable cost-effectiveness ratios compared with
The initial step in management is to modify the major risk factors other accepted therapies, such as fibrin-specific thrombolytic ther-
for IHD, hypertension, hypercholesterolemia, and smoking, and apy, in the cardiovascular field, particularly in high-risk patients and
data from the Multiple Risk Factor Intervention Trial (MRFIT) those undergoing percutaneous coronary intervention. However,
show these interventions to be useful in patients with silent more comprehensive economic data on the GP IIb/IIIa inhibitors are
ischemia. In a subset of the study population who had abnormal needed. Bivalirudin combined with provisional glycoprotein IIb/IIIa
baseline exercise ECG responses, the special intervention group had inhibitors appears to be an acceptable alternative to the standard of
a 57% reduction in coronary heart disease death (22.2/1,000 vs. care and is superior to unfractionated heparin alone in PCI and is
51.8/1,000) and a reduction in sudden death resulting from cessa- considered to be cost-effective.132
tion of smoking and lowering of blood pressure and cholesterol Atorvastatin when used in acute coronary syndrome reduces
when compared with the usual-care group. events, which offsets the upfront acquisition costs.131 The total
ACIP, a randomized trial of medical therapy versus revasculariza- expected cost was $1,573.83 per patient in the placebo cohort and
tion (PTCA or CABG), at the 2-year followup demonstrated that $1,709.39 per patient in the atorvastatin cohort, resulting in an
total mortality was 6.6% in the angina-guided strategy (i.e., therapy incremental cost of $135.56 per patient in the atorvastatin group.
based on symptoms), 4.4% in the ischemia-guided strategy (based The cost per event avoided was $3,536.95. A third of the cost of
on ECG changes), and 1.1% in the revascularization strategy (P atorvastatin treatment was offset within 16 weeks by the cost savings
<0.02). The rate of death or myocardial infarction was 12.1% in the resulting from the reduction in the number of events in the
angina-guided strategy, 8.8% in the ischemia-guided strategy, and atorvastatin cohort compared with the placebo cohort. Other anal-
4.7% in the revascularization strategy (P <0.04).124 The rate of death, yses of statins have found this class to be cost-effective, especially in
myocardial infarction, or recurrent cardiac hospitalization was patients who are at higher risk of an ischemic event.133
41.8% in the angina-guided strategy, 38.5% in the ischemia-guided Aspirin and clopidogrel have been evaluated for secondary pre-
strategy, and 23.1% in the revascularization strategy (P <0.001). vention of CHD, and although aspirin is very cost-effective, clopid-
Post-MI patients and those with a high level of sympathetic nervous ogrel is only cost-effective for patients who cannot take aspirin.134
system activity are perhaps the best candidates for β-blocker therapy.
Calcium channel antagonists alone and in combination are effec-
tive in reducing symptomatic and asymptomatic ischemia; however, CLINICAL CONTROVERSIES
they do not interrupt the diurnal surge in ischemia observed on
Once patients with angina develop symptoms sufficient for
ambulatory monitoring and, in general, are somewhat less effective
pharmacologic therapy on a daily basis, the initial prophylactic
than β-blockers for silent ischemia.125,126 Nifedipine in particular
therapy recommended is a β-blocker. There is a paucity of
seems to provide less protection and provides wide fluctuations in
comparative, long-term clinical trials of β-blockade versus cal-
response, with approximate reductions in the number of episodes
cium channel blockers to determine which is superior for sur-
ranging from 0% to 93% and in duration from 23% to 65% unless
vival benefit. β-Blockers are recommended first-line therapy
combined with β-blockers. Fewer studies are available with other
because of their efficacy in post-MI patients and favorable
calcium blockers and comparative trials are uncommon. Earlier
adverse effect profile.
studies showed that combination therapy with calcium and β-
blockers provides a better response than calcium blockers and Recent developments in the understanding of bioactivation of
nitrates or monotherapy.127,128 organic nitrates have given rise to concern over endothelial
Swiss Interventional Study on Silent Ischemia Type II (SWISSI dysfunction induced by nitrates when administered long-term.
II), a randomized, unblinded, controlled trial of PCI in patients Not all nitrate products are activated via the same mechanisms
with silent ischemia after acute MI, found that PCI, compared with and this may impact how effective individual drugs are in long-
antiischemic drug therapy, reduced the long-term risk of major term treatment.
cardiac events with better preservation of ventricular function than In stable CAD, medical management has been reported to
did medical therapy.129 produce outcomes similar to revascularization and these find-
ings may have a significant impact on how healthcare resources
are used in the future.
PHARMACOECONOMIC CONSIDERATIONS
Pharmacoeconomic studies have been performed primarily in EVALUATION OF THERAPEUTIC OUTCOMES
patients with acute coronary syndromes and only with low-molecu-
lar-weight heparins, GP IIb/IIIa receptor antagonists, and statins.130 Improved symptoms of angina, improved cardiac performance and
Most of the studies on low-molecular-weight heparins have been improvement in risk factors may all be used to assess the outcome
cost-minimization analyses that focused on enoxaparin sodium, of treatment of IHD and angina. Symptomatic improvement in
 243
exercise capacity (longer duration) or fewer symptoms at the same obtained through increase exercise duration on ETT and the
level of exercise is subjective evidence that therapy is working. Once absence of ischemic changes on ECG or deleterious hemodynamic

CHAPTER 17
patients have been optimized on medical therapy, symptoms should changes. Echocardiography and cardiac imaging may also be used,
improve over 2 to 4 weeks and remain stable until their disease however, due to their expense, they are only used if a patient is not
progresses. There are several instruments (e.g., Seattle angina ques- doing well to determine if revascularization or other measures
tionnaire, specific activity scale [see Table 17–1], Canadian classifi- should be undertaken. Coronary angiography may be used to assess
cation system [see Table 17–2]) that could be used improve the the extent of stenosis or re-stenosis after angioplasty or CABG.
reproducibility of symptom assessment.2 If the patient is doing well, Table 17–12 outlines the performance measurement set recom-
then no other assessment may be necessary. Objective assessment is mended by the ACC/AHA.

Ischemic Heart Disease

TABLE 17-12 American College of Cardiology, American Heart Association, and Physician Consortium for Performance Improvement Chronic
Stable Coronary Artery Disease Core Physician Performance Measurement Set a
Clinical Recommendations
Blood pressure measurement A blood pressure ready is recommended at every visit. Recommended blood pressure
management targets are ≤130 mm Hg systolic (Class I Recommendation, Level A
Evidence) and ≤85 mm Hg diastolic in patient with CAD coexisting condition (e.g.,
diabetes, heart failure, or renal failure) and <140/90 mm Hg in patient with CAD and no
coexisting condition.
Lipid profile A lipid profile is recommended and should include total cholesterol, high-density lipopro-
tein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides.
(Class I Recommendation, Level C Evidence)
Symptom and activity assessment Regular assessment of patients' anginal symptoms and levels of activity is recommended.
(Serves as a basis for treatment modification.)
Smoking cessation Smoking status should be determined and smoking cessation counseling and interventions
are recommended. (Class I Recommendation, Level B Evidence)
Antiplatelet therapy Routine use of aspirin is recommended in the absence of contraindications. If contraindica-
Denominator exclusion tions exist, other antiplatelet therapies may be substituted. (Class I Recommendation,
Documentation of medical reason(s)b for not prescribing antiplatelet ther- Level A Evidence)
apy; documentation of patient reason(s)c for not prescribing antiplatelet
therapy
Drug therapy for lowering LCL-cholesterol The LCL-C treatment goal is <100 mg/dL. Persons with established coronary heart disease
Denominator exclusion (CHD) who have a baseline LCL-C ≥130 mg/dL should be started on a cholesterol-
Documentation that a statin was not indicated;e documentation of medical lowering drug simultaneously with therapeutic lifestyle changes and control of nonlipid
reason(s)b for not prescribing a statin; documentation of patient rea- risk factors. (Class I Recommendation, Level A Evidence)
son(s)c for not prescribing statin
β-Blocker therapy—prior myocardial infarction (MI) β-Blocker therapy is recommended for all patients with prior MI in the absence of
Denominator inclusion contraindications. (Class I Recommendation, Level A Evidence)
Prior MI
Denominator exclusion
Documentation that a β-blocker was not indicated; documentation of
medical reason(s)b for not prescribing a β-blocker; documentation of
patient reason(s)c for not prescribing a β-blocker
ACE inhibitor therapy ACE inhibitor use is recommended in all patients with CAD who also have diabetes and/or
Denominator inclusion LVSD (Class I Recommendation, Level A Evidence)
Patient with CAD who also has diabetes and/or left ventricular systolic ACE inhibitor use is also recommended in patients with CAD or other vascular disease
dysfunction (LVSD) (left ventricular ejection fraction [LVEF] <40% or (Class IIa Recommendation, Level B Evidence)
moderately or severely depressed left ventricular systolic function)
Denominator exclusion
Documentation that ACE inhibitor was not indicated (e.g., patients on
angiotensin receptor blockers [ARB]); documentation of medical rea-
son(s)b for not prescribing ACE inhibitor; documentation of patient
reason(s)c for not prescribing ACE inhibitor
Screening for diabetes f Screening for diabetes is recommended in patients who are considered high risk (e.g., CAD)
Denominator exclusion (Class I Recommendation, Level A Evidence)
Patients with documented diabetes
ACE, angiotensin-converting enzyme; CAD, coronary artery disease; MI, myocardial infarction.
a
Refers to all patients diagnosed with CAD
b
Medical reasons for not prescribing antiplatelet therapy (aspirin, clopidogrel, or combination of aspirin and dipyridamole): active bleeding in the previous 6 months with required hospitalization and/or
transfusion(s), patient on other antiplately therapy, etc.
Medical reasons for not prescribing a statin: clinical judgement, documented LCL-C <130 mg/dL, etc.
Medical reasons for not prescribing a β-blocker: bradycardia (defined as heart rate <50 beats/min without β-blocker therapy), history of class IV (congestive) heart failure, history of second- or third-degree
atrioventricular block without permanent pacemaker, etc.
Medical reasons for not prescribing ACE inhibitor (ACEI): allergy, angioedema caused by ACEI, anuric rental failure caused by ACEI, pregnancy, moderate or severe aortic stenosis, etc.
c
Patient reasons for not prescribing antiplatelet therapy, statin, β-blocker, or ACEI: economic, social, and/or religious, etc.
d
Antiplatelet therapy may include aspirin, clopidogrel, or combination of aspirin and dipyridamole.
e
Not indicated for a stat refers to LCL-C <100 mg/dL.
f
Test measure.
g
Screening for diabetes is usually done by fasting blood glucose or 2-hour glucose tolerance testing. Clinical recommendations indicate screening should be considered at 3-year intervals.
 244
5. Sytkowski PA, D’Agostino RB, Belanger A, Kannel WB. Sex and time
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LV: left ventricle
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C HAP T E R

18 Acute Coronary Syndromes

SARAH A. SPINLER AND SIMON DE DENUS

protein IIb/IIIa receptor blocker. Intravenous β-blockers and ni-

KEY CONCEPTS troglycerin should be given to selected patients.

 The cause of an acute coronary syndrome (ACS) is erosion or

Following myocardial infarction, all patients, in the absence of
rupture of an atherosclerotic plaque with subsequent platelet ad- contraindications, should receive indefinite therapy with aspirin,
herence, activation, aggregation, and activation of the clotting cas- a β-blocker, and an angiotensin-converting enzyme inhibitor for
cade. Ultimately, a clot composed of fibrin and platelets forms. secondary prevention of death, stroke, and recurrent infarction.
Most patients are given a statin to reduce the low-density-lipo-
 The American Heart Association and the American College of protein cholesterol level to less than 70 to 100 mg/dL. Admin-
Cardiology recommend strategies or guidelines for the care of istration of clopidogrel should be considered for most patients,
patients with ST-segment elevation and non–ST-segment eleva- but the level of the recommendation and duration of therapy de-
tion ACS. pend on the diagnosis, the method of reperfusion used, and the
 Patients with ischemic chest discomfort and suspected ACS are risk of bleeding. Anticoagulation with warfarin should be consid-
risk stratified based on a 12-lead electrocardiogram, medical his- ered for patients at high risk for death, reinfarction, or stroke.
tory, signs and symptoms, and results of creatine kinase myocar-
dial band (CK MB) and troponin biochemical marker tests. Since the early 1900s, cardiovascular disease (CVD) has been the
 The diagnosis of myocardial infarction is confirmed based on leading cause of death in the United States. Acute coronary syn-
the results of the CK MB and troponin tests. dromes (ACSs), including unstable angina and myocardial infarction
(MI), are forms of coronary heart disease (CHD) that constitute the
 Early reperfusion therapy with either primary percutaneous most common cause of CVD death.1  The cause of an ACS is
coronary intervention or administration of a fibrinolytic agent erosion or rupture of an atherosclerotic plaque with subsequent
is the recommended therapy for patients presenting with ST- platelet adherence, activation, aggregation, and activation of the
segment elevation ACS. clotting cascade. Ultimately, a clot composed of fibrin and platelets
 In addition to reperfusion therapy, all patients with ST-segment forms. Correspondingly, pharmacotherapy of ACS has advanced to
elevation ACS and without contraindications should receive include combinations of fibrinolytics, antiplatelets, and anticoagu-
pharmacotherapy within the first day of hospitalization and pref- lants, with more traditional therapies such as nitrates and β-adrener-
erably in the emergency department, consisting of intranasal ox- gic blockers. Pharmacotherapy is integrated with reperfusion therapy
ygen (if oxygen saturation is low), aspirin, clopidogrel, sublingual and revascularization of the culprit coronary artery through interven-
nitroglycerin, oral β-blockers, and either unfractionated heparin tional means such as percutaneous coronary intervention (PCI) and
or enoxaparin. Intravenous β-blockers and nitroglycerin should coronary artery bypass graft (CABG) surgery.  The American Heart
be given to selected patients. Association (AHA) and the American College of Cardiology (ACC)
recommend strategies or guidelines for the care of patients with ST-
 High-risk patients with non–ST-segment elevation ACS should segment elevation (STE) and non–ST-segment elevation (NSTE)
undergo early coronary angiography and revascularization with ACS. These joint practice guidelines are based on a review of available
either percutaneous coronary intervention or coronary artery clinical evidence, have graded recommendations based on the weight
bypass graft surgery. and quality of evidence, and are updated periodically. The guidelines
In the absence of contraindications, all patients with non–ST- form the cornerstone for quality patient care of the ACS patient.2,3
segment elevation ACS should be treated in the emergency
department with intranasal oxygen (if oxygen saturation is low), EPIDEMIOLOGY
aspirin, sublingual nitroglycerin, oral β-blockers, and an antico-
agulant (unfractionated heparin, enoxaparin, fondaparinux, or Each year more than 1.5 million Americans will experience an ACS,
bivalirudin). Most patients should receive additional therapy and 220,000 will die of an MI.1 In the United States, more than 7.6
with clopidogrel. High-risk patients also should receive a glyco- million living persons have survived an MI.1 Chest discomfort is the
second most frequent reason for patient presentation to emergency
departments. Up to 5.6 million (~5.1%) emergency department
visits are linked to chest discomfort and possible ACS.2,4 CHD is the
Learning objectives, review questions, leading cause of premature chronic disability in the United States.
and other resources can be found at The cost of CHD is high, with direct and indirect costs estimated at
www.pharmacotherapyonline.com. $151.6 billion for 2007.1 The median length of hospital stay for MI
in 1999 was 4.3 days1 but decreased to a median of 3.3 days in 2006.5

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 250
Much of the epidemiologic data regarding ACS treatment and an imbalance between myocardial oxygen demand and supply.3 In
survival come from the National Registry of Myocardial Infarction contrast to stable angina, an ACS results primarily from diminished
SECTION 2

(NRMI), the Global Registry of Acute Coronary Events (GRACE), myocardial blood flow secondary to an occlusive or partially occlusive
and statistical summaries of U.S. hospital discharges prepared by the coronary artery thrombus. ACSs are classified according to electrocar-
AHA. In-hospital death rates are approximately 4.6% for patients diographic (ECG) changes into STE ACS, also called STEMI, and NSTE
with STE ACS but are lower (2.2%) for patients with NSTE ACS.6 ACS, which includes NSTE MI and unstable angina (Fig. 18–1).10
Patients with STEMI who are treated with reperfusion therapy, either Approximately 21% of patients presenting with ACS have STEMI.1
fibrinolytics or primary PCI, have lower mortality rates than patients NSTE MI differs from unstable angina in that ischemia is severe
treated without reperfusion. Reperfusion rates and mortality rates are enough to produce myocardial necrosis, resulting in the release of a
higher in the elderly and in women. For example, the mortality rate is detectable amount of biochemical markers, mainly troponin I or T,
Cardiovascular Disorders

19% in elderly patients who were eligible for reperfusion therapy but and creatine kinase myocardial band (CK MB) from the necrotic
did not receive it compared to 10.5% in patients who did.7 In women, myocytes into the bloodstream.3 The clinical significance of serum
the mortality rate is 18% for those eligible for reperfusion therapy but biochemical markers is discussed in greater detail in the Clinical
did not receive it compared to 9.3% for those who do not.7 In the first Presentation and Biochemical Markers sections of this chapter. Fol-
year after MI, 23% of women and 18% of men will die, most from lowing an STEMI, pathologic Q waves are seen frequently on the
recurrent infarction.1 At 1 year, rates of mortality and reinfarction ECG; such an ECG manifestation is seen less commonly in patients
between STE and NSTE MI are similar. with NSTE MI.7 The presence of Q waves usually indicates transmural
The rate of developing heart failure during hospitalization for ACS MI. Non–Q-wave MI, which is predominantly seen in NSTE MI, is
is declining rapidly. Compared to data from 1999, the incidence of in- limited to the subendocardial myocardium.2
hospital heart failure in patients with STEMI declined from 19.5% to
11% and that for patients with NSTE ACS declined from 13% to PLAQUE RUPTURE AND CLOT FORMATION
6.1%.6 In-hospital death rates for patients who present with or
develop heart failure are more than threefold higher than for those  The predominant cause of ACS in more than 90% of patients is
who do not.6 atheromatous plaque rupture, fissuring, or erosion of an unstable
Because reinfarction and death are major outcomes following ACS, atherosclerotic plaque. Plaques that encompass less than 50% of the
therapeutic strategies to reduce morbidity and mortality, particularly coronary lumen are more likely to rupture than those that occlude
use of coronary angiography, revascularization, and pharmacother- 70% to 90% of the coronary artery.3 Such stable 70% to 90% stenoses
apy, will have a significant impact on the social and economic burden of the coronary artery are characteristic of stable angina and tend to
of CHD in the United States. have a small lipid core, a thick fibrous cap, more calcification, and less
compensatory enlargement.8 Plaques that are more susceptible to
rupture are characterized by an eccentric shape, thin fibrous cap
ETIOLOGY (particularly in the shoulder region of the plaque), large fatty core,
high content in inflammatory cells such as macrophages and lympho-
This section discusses the formation of atherosclerotic plaques, the cytes, limited amounts of smooth muscle, and significant compensa-
underlying cause of coronary artery disease (CAD), and ACS in most tory enlargement. Compensatory enlargement is the growth of the
patients. The process of atherosclerosis starts early in life. Although lesion pushing the vessel outward rather than inward plaque growth.
atherosclerosis once was considered only a disease of cholesterol Therefore, compensatory enlargement may result in underestimation
excess, it now is clear that inflammation also plays a central role in the of the atherosclerotic stenosis as measured by coronary angiography.
genesis, progression, and complication of the disease.8 In the earliest Inflammatory cells promote thinning of the fibrous cap through the
stage of atherosclerosis—endothelial dysfunction—induction and/or release of proteolytic enzymes, particularly matrix metalloproteinases.8
repression of several genes occurs in response to sheer stress of the Following plaque rupture, a partially occlusive or completely occlu-
blood flowing over the atherosclerotic plaque on the endothelial sive thrombus—a clot—forms on top of the ruptured plaque. The
lining of the artery. In response to gene induction and repression, the thrombogenic contents of the plaque are exposed to blood elements.
endothelial cells decrease synthesis of nitric oxide, increase oxidation Exposure of collagen and tissue factor induces platelet adhesion and
of lipoproteins and facilitate their entry into the arterial wall, promote activation, which promote the release of platelet-derived vasoactive
the adherence of monocytes to the vessel wall and deposition of substances, including adenosine diphosphate (ADP) and thromboxane
extracellular matrix, cause smooth muscle cell proliferation, and A2.11 These substances produce vasoconstriction and potentiate platelet
release local vasoconstrictor and prothrombotic substances into the activation. Furthermore, during platelet activation, the conformation
blood; each action has a subsequent inflammatory response.9 Taken of the glycoprotein (GP) IIb/IIIa surface receptors of platelets changes
together, all these factors contribute to the evolution of endothelial such that platelets cross-link to each other via fibrinogen bridges. This
dysfunction to the formation of fatty streaks in the coronary arteries process is considered the final common pathway of platelet aggrega-
and eventually to atherosclerotic plaques. Therefore, the endothelium tion. Other substances known to promote platelet aggregation include
serves as an important autocrine and paracrine organ in the develop- serotonin, thrombin, and epinephrine.8 Inclusion of platelets gives the
ment of atherosclerosis. clot a white appearance. Simultaneously, the extrinsic coagulation
A number of factors are directly responsible for the development cascade pathway is activated as a result of exposure of blood compo-
and progression of endothelial dysfunction and atherosclerosis, nents to the thrombogenic lipid core and endothelium, which are rich
including hypertension, age, male gender, tobacco use, diabetes in tissue factor. This leads to the production of thrombin (factor IIa),
mellitus, obesity, and dyslipidemias.1 which converts fibrinogen to fibrin through enzymatic activity.11 Fibrin
stabilizes the clot and traps red blood cells, giving the clot a red
PATHOPHYSIOLOGY appearance. Therefore, the clot is composed of both cross-linked
platelets and fibrin strands.11 Although patients with an ACS more
SPECTRUM OF ACS commonly present with a single, ruptured atherosclerotic plaque in one
major coronary artery, they also may present with more than one
Acute coronary syndromes (ACSs) is a term that includes all clinical ruptured plaque and multiple active lesions in more than one coronary
syndromes compatible with acute myocardial ischemia resulting from artery, which predispose patients to a worse prognosis.8
 251

CHAPTER 18
Ischemic chest discomfort symptoms, lasting at least 20 min;
Suspect acute coronary syndrome

ST-segment Elevation Obtain and interpret a 12-lead ECG within 10 min No ST-segment Elevation

ST-segment depression T-wave inversion No ECG changes

Acute Coronary Syndromes

Initiate reperfusion therapy
in appropriate candidates
(fibrinolysis or primary PCI) Risk stratificationa; multilead continuous ST-segment monitoring; Obtain serial troponin and
CK MBb,c

Initiate pharmacotherapy for non-ST-segment

Obtain serial troponin and CK MB as elevation ACS based upon patient risk;
confirmatory; results not needed before evaluate moderate and high risk patients for
reperfusion therapy is initiated; multilead early angiography and revascularization
continuous ST-segment monitoring
Low-risk Moderate risk High risk

Initiate adjunctive ST-segment Stress test to evaluate likelihood of CAD

elevation ACS pharmacotherapy Angiography with
revascularization (PCI or
CABG)

Negative stress test

Positive stress test

Diagnosis of non-cardiac chest

pain syndrome

FIGURE 18-1. Evaluation of the acute coronary syndrome patient. (ACS, acute coronary syndrome; CABG, coronary artery bypass graft surgery; CAD,
coronary artery disease; CK MB, creatine kinase myocardial band; ECG, electrocardiogram; PCI, percutaneous coronary intervention.) aAs described in
Table 18–2. bPositive, above the myocardial infarction (MI) decision limit. c“Negative,” below the MI decision limit. (Reprinted with permission from
the American College of Clinical Pharmacy. Spinler SA. Acute coronary syndromes. In: Dunsworth TS, Richardson MM, Cheng JWM, et al., eds.
Pharmacotherapy Self-Assessment Program, 6th ed. Cardiology II module. Kansas City: American College of Clinical Pharmacy, 2007:69–70.)

A thrombus containing more platelets than fibrin, or a “white” matrix metalloproteinase activity and their inhibitors.13,14 This process
clot, generally produces an incomplete occlusion of the coronary affects both cardiomyocytes (cardiomyocyte hypertrophy, loss of cardi-
lumen and is more common in NSTE ACS. In patients presenting omyocytes) and the extracellular matrix (increased interstitial fibrosis),
with STE ACS, the vessel generally is completely occluded by a “red” thereby promoting both systolic and diastolic dysfunction.14
clot, which contains larger amounts of fibrin and red blood cells but Angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and
a smaller amount of platelets compared with a “white” clot.2 As aldosterone antagonists are agents that slow down or reverse ventricular
discussed later in Treatment of Acute Coronary Syndromes, the remodeling through neurohormonal blockage and/or through improve-
composition of the clot influences the selection of the combinations ment in hemodynamics (decreasing preload or afterload).12 These agents
of antithrombotic agents used for treatment of STE and NSTE ACS. also improve survival (discussed in more detail in the Secondary Preven-
Finally, myocardial ischemia can result from downstream emboliza- tion Following MI section of this chapter). This effect underlines the
tion of microthrombi and produce ischemia with eventual necrosis.2 importance of the remodeling process and the urgency of preventing,
halting, or reversing the process in patients who have experienced an MI.
VENTRICULAR REMODELING FOLLOWING
AN ACUTE MI COMPLICATIONS
Ventricular remodeling is a process that occurs in several cardiovas- This chapter focuses on management of the uncomplicated ACS
cular conditions, including heart failure, and following an MI. It is patient. However, it is important for clinicians to recognize complica-
characterized by changes in the size, shape, and function of the left tions of MI because they are associated with increased mortality. The
ventricle (LV) of both the infarcted area and the remaining ventricle, most serious complication is cardiogenic shock, which occurs in
ultimately leading to cardiac failure.12 Because heart failure is one of approximately 5% to 6% of patients presenting with STEMI and in
the principal causes of mortality and morbidity following an MI, less than 2% of those presenting with NSTE ACS.9,15 Mortality in
preventing ventricular remodeling is an important therapeutic goal.12 cardiogenic shock patients with MI is high, approaching 60%.16 Other
Many factors contribute to ventricular remodeling, including neuro- complications that may result from MI are heart failure, valvular
hormonal factors (e.g., activation of the renin-angiotensin-aldosterone dysfunction, ventricular and atrial tachyarrhythmias, bradycardia,
and sympathetic nervous systems), hemodynamic factors, mechanical heart block, pericarditis, stroke secondary to LV thrombus emboliza-
factors, changes in gene expression, and modifications in myocardial tion, venous thromboembolism, and LV free-wall rupture.17 More
 252
than 25% of MI patients die, presumably of ventricular fibrillation, department with symptoms of ischemic chest discomfort (or prefer-
prior to reaching the hospital.18 ably prehospital), a 12-lead ECG should be obtained and interpreted.
SECTION 2

If available, a previously recorded 12-lead ECG should be reviewed to

identify whether the findings on the current ECG are new or old, with
CLINICAL PRESENTATION new findings more indicative of an ACS. Key findings on review of a
12-lead ECG indicating myocardial ischemia or MI are ST-segment
The key points in the clinical presentation of patients with ACS are elevation, ST-segment depression, and T-wave inversion (see Fig. 18–1).
given in Table 18–1. ST-segment and/or T-wave changes in contiguous leads help to iden-
tify the location of the coronary artery that is the cause of the ischemia
SYMPTOMS AND PHYSICAL or infarction. In addition, the appearance of a new left bundle-branch
EXAMINATION FINDINGS
Cardiovascular Disorders

block accompanied by chest discomfort is highly specific for acute MI.

Approximately 65% of patients diagnosed with MI present with STE
The classic symptom of an ACS is midline anterior anginal chest
on ECG; the remainder have ST-segment depression, T-wave inver-
discomfort, most often at rest, severe new-onset angina, or increas-
sion, or, in some instances, no ECG changes.5 Some parts of the heart
ing angina at least 20 minutes in duration. The chest discomfort may
are more “electrically silent” than others, and myocardial ischemia
radiate to the shoulder, down the left arm, to the back, or to the jaw.
may not be detected on surface ECG. Therefore, it is important to
Associated symptoms that may accompany chest discomfort include
review findings from the ECG in conjunction with biochemical mark-
nausea, vomiting, diaphoresis, and shortness of breath. Typically,
ers of myocardial necrosis, such as troponin I or T levels, and other risk
patients with STE ACS present with unremitting chest discomfort.
factors for CHD to determine the patient’s risk for experiencing a new
Patients with NSTE ACS may present with (1) rest angina, (2) new-
MI or having other complications.
onset (<2 months) angina, or (3) angina that increases in frequency,
duration, or intensity. All healthcare professionals should review
these warning symptoms with patients at high risk for CHD. On BIOCHEMICAL MARKERS
physical examination, no specific features are indicative of ACS.  Biochemical markers of myocardial cell death are important for
confirming the diagnosis of MI. The ACC defines evolving MI as
TWELVE-LEAD ECG “typical rise and gradual fall (troponin) or more rapid rise and fall
(CK MB) of biochemical markers of myocardial necrosis.”19 Tropo-
 Key features of a 12-lead ECG identify and risk stratify patients with
nin and CK MB levels rise in the blood following the onset of
an ACS. Within 10 minutes of a patient presenting to an emergency
complete coronary artery occlusion subsequent to myocardial cell
death. Their time course is depicted in Fig. 18–2. Typically, blood is
TABLE 18-1 Presentation of Acute Coronary Syndromes obtained from the patient at least three times, once in the emergency
department and twice more over the next 12 to 24 hours, in order to
General
• The patient typically is in acute distress and may develop or present with measure troponin and CK MB levels. A single measurement of a
cardiogenic shock. biochemical marker is not adequate to exclude a diagnosis of MI
Symptoms because up to 15% of values that initially were below the level of
• The classic symptom of ACS is midline anterior chest discomfort. Accompanying detection (a negative test) are above the level of detection (a positive
symptoms may include arm, back or jaw pain, nausea, vomiting, or shortness of test) in the subsequent hours. An MI is identified if at least one
breath. troponin value is greater than the MI decision limit (set by the
• Patients less likely to present with classic symptoms include elderly patients, hospital laboratory) or two CK MB results are greater than the MI
diabetic patients, and women. decision limit (set by the hospital laboratory). These are termed
Signs positive biochemical markers for MI. Although troponins and CK MB
• No signs are classic for ACS.
appear in the blood within 6 hours of infarction, troponins stay
• However, patients with ACS may present with signs of acute heart failure,
including jugular venous distension, rales, and S3 sound on auscultation.
elevated in the blood for up to 10 days, whereas CK MB returns to
• Patients may present with arrhythmias and therefore may have tachycardia, normal values within 48 hours. Therefore, if a patient is admitted with
bradycardia, or heart block. elevated troponin and CK MB concentrations and several days later
Laboratory tests experiences recurrent chest discomfort, the troponin will be less
• Troponin I or T and creatine kinase MB are measured. sensitive for detecting new myocardial damage because the level still
• Blood chemistry tests are performed with particular attention to potassium and is elevated from the earlier event. If early reinfarction is suspected, CK
magnesium, which may affect heart rhythm, and glucose, which when elevated MB concentration determination is the preferred diagnostic test.19
places the patient at higher risk for morbidity and mortality. Biochemical markers, such as troponin measurements, that are below
• Serum creatinine level is measured to identify patients who may need dosing the detectable limit of hospital laboratories are termed negative, and
adjustments for some pharmacotherapy and patients who are at high risk for
the diagnosis of MI is excluded.
morbidity and mortality.
• Baseline complete blood count and coagulation tests (activated partial thrombo-
plastin time and international normalized ratio) should be obtained because most RISK STRATIFICATION
patients will receive antithrombotic therapy, which increases the risk for bleeding.
• Fasting lipid panel is obtained. Patient signs and symptoms, medical history, ECG, and troponin or
Other diagnostic tests CK MB determinations are used to stratify patients as having low,
• The 12-lead electrocardiogram is the first step in management. Patients are risk medium, or high risk of death or MI or likelihood of not responding
stratified into two groups: ST-segment elevation ACS and suspected non–ST- to pharmacotherapy and requiring urgent coronary angiography and
segment elevation ACS. PCI. Initial treatment according to risk stratification is depicted in
• During hospitalization, measurement of left ventricular function, such as an Fig. 18–1. Patients with STE ACS are at the highest risk of death.
echocardiogram, is performed to identify patients with low ejection fractions Initial treatment of STE ACS should proceed without evaluation of
(<40%) who are at high risk for death following hospital discharge. troponin or CK MB levels because these patients have a greater than
• Selected low-risk patients may undergo early stress testing.
97% chance of having an MI subsequently diagnosed with biochemi-
ACS, acute coronary syndrome. cal markers. The ACC/AHA defines a target time to initiate reperfu-
 253

60

CHAPTER 18
Diagnosis of MI confirmed (Troponin)
50

Multiples of the MI Cutoff Limit

20
Diagnosis of MI confirmed (CK MB)

Acute Coronary Syndromes

10
Indicates times that blood was
obtained for serial measurements of
5 biochemical marker

2
Diagnosis of MI excluded (Troponin or CK MB)
AMI decision limit 1

Upper reference limit

0
0 1 2 3 4 5 6 7 8

Days After Onset of AMI

FIGURE 18-2. Biochemical markers in suspected acute coronary syndrome. (AMI, acute myocardial infarction; CK MB, creatine kinase
myocardial band; MI, myocardial infarction.)

sion treatment for STEMI within 30 minutes of hospital presentation incorporated into routine patient care include C-reactive protein,27 a
for fibrinolytics and within no more than 90 minutes from presenta- maker of vascular inflammation; elevated serum creatinine or
tion for primary PCI.3 The sooner the infarct-related coronary artery reduced creatinine clearance,28 and brain (B-type) natriuretic peptide
is opened in these patients, the lower is their mortality and the greater (BNP),29 which is released predominately from ventricular myocytes
is the amount of preserved myocardium.20,21 While all patients should in response to cell stretch as the infarct remodels. Dialysis patients
be evaluated for reperfusion therapy, not all patients may be eligible. have a 1-year mortality rate of greater than 40% following a first MI.28
Indications and contraindications for fibrinolytic therapy as well as
eligibility criteria for primary PCI are described in the treatment
section of this chapter. In the United States in 2006, approximately
83% of eligible patients presenting to the hospital with STEMI
TREATMENT
underwent reperfusion therapy; 62% of the patients were treated with
primary PCI, 17% fibrinolysis alone, 1% fibrinolysis followed by Acute Coronary Syndromes
immediate PCI, and 2% immediate CABG surgery.5 However, more
■ DESIRED OUTCOMES
than 40% of patients with STEMI present too late for reperfusion
therapy (>12 hours since onset of symptoms).22,23 In addition, fewer The short-term goals of treatment for the ACS patient are as follows:
than 25% of hospitals in the United States are equipped to perform 1. Early restoration of blood flow to the infarct-related artery to
primary PCI,24 and approximately 5% to 6% of patients present with prevent infarct expansion (in the case of MI) or prevent com-
at least one contraindication to fibrinolysis.23,25 Unfortunately, 17% plete occlusion and MI (in unstable angina)
of patients eligible for reperfusion therapy consisting of either fibri-
nolysis or primary PCI do not receive it, suggesting a need for more 2. Prevention of death and other complications
thorough patient evaluation and treatment triage.5 3. Prevention of coronary artery reocclusion
If patients are not eligible for reperfusion therapy, additional 4. Relief of ischemic chest discomfort
pharmacotherapy for STE patients should be initiated in the emer-
5. Maintenance of normoglycemia
gency department, and patients should be transferred to the coro-
nary intensive care unit.
Risk stratification of the patient with NSTE ACS is more complex ■ GENERAL APPROACH TO TREATMENT
because in-hospital outcomes for this group of patients vary, with Selecting evidence-based therapies described in the ACC/AHA guide-
reported rates of death of 0% to 12%, reinfarction 0% to 3%, and lines for patients without contraindications results in lower mortal-
recurrent severe ischemia 5% to 20%.26 Not all patients who present ity.30,31 General treatment measures for all STE ACSs and high- and
with suspected NSTE ACS have CAD. Some eventually are diagnosed intermediate-risk NSTE ACS patients include admission to hospital,
with nonischemic chest discomfort. Additional information regard- oxygen administration (if oxygen saturation is low, i.e., <90%), contin-
ing risk stratification of NSTE ACS is presented in the General uous multilead ST-segment monitoring for arrhythmias and ischemia,
Approach to Treatment section. glycemic control, frequent measurement of vital signs, bedrest for 12
Newer markers that identify patients at high risk of mortality or hours in hemodynamically stable patients, avoidance of Valsalva
reinfarction that are under development but have not yet been maneuver (prescribe stool softeners routinely), and pain relief.
 254

TABLE 18-2 TIMI Risk Score for Non–ST-Segment Elevation Acute Coronary Syndromes
SECTION 2

Past Medical History Clinical Presentation

Age ≥65 years ST-segment depression (≥0.5 mm)
≥3 Risk factors for CAD ≥2 episodes of chest discomfort within the past 24 hours
Hypercholesterolemia Positive biochemical marker for infarctiona
HTN
TM
Smoking
Family history of premature CHDb
Known CAD (≥50% stenosis of coronary artery)
Cardiovascular Disorders

Use of aspirin within the past 7 days

Using the TIMI Risk Score
One point is assigned for each of the seven medical history and clinical presentation findings. The score (point) total is calculated, and the patient is assigned a risk for experiencing
the composite end point of death, myocardial infarction or urgent need for revascularization as follows:
High Risk Medium Risk Low Risk
TIMI risk score 5–7 points TIMI risk score 3–4 points TIMI risk score 0–2 points
Other Ways to Identify High-Risk Patients
Other findings that alone, or in combination, may identify high-risk patients:
• ST-segment depression
• Positive biochemical marker for infarction
• Deep symmetric T-wave inversions (≥2 mm)
• Acute heart failure
• DM
• Chronic kidney disease
• Refractory chest discomfort despite maximal pharmacotherapy for ACS
• Recent MI within the past 2 weeks
ACS, acute coronary syndromes; CAD, coronary artery disease; CHD, coronary heart disease; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction
a
A positive biochemical marker for infarction is a value of troponin I, troponin T, or creatinine kinase MB greater than the MI detection limit.
b
As defined in Chapter 23.
From Anderson et al.2 and Eagle et al.31

Because risk varies and resources are limited, triage and treatment STE ACS when the patient presents within 3 hours of symptom onset
of patients according to their risk category are important. Initial and both options are available at the institution. For primary PCI, the
approaches to treatment of STE and NSTE ACS patients are outlined patient is taken from the emergency department to the cardiac cathe-
in Fig. 18–1.2,3,10 Patients with STE ACS are at high risk of death, and terization laboratory and undergoes coronary angiography with either
efforts to reestablish coronary perfusion should be initiated immedi- balloon angioplasty or placement of a bare-metal or drug-eluting
ately. Reperfusion therapy should be considered immediately and intracoronary stent. Additional details regarding angioplasty and
adjunctive pharmacotherapy initiated.3 intracoronary stenting are provided in Chapter 17. Results from a
Features identifying low-, moderate-, and high-risk NSTE ACS meta-analysis of trials comparing fibrinolysis with primary PCI indi-
patients are listed in Table 18–2.2,30 Patients at low risk for death, MI, or cate a lower mortality rate with primary PCI.20 One reason for the
the need for urgent coronary artery revascularization typically are superiority of primary PCI compared with fibrinolysis is that more
evaluated in the emergency department, where serial biochemical than 90% of occluded infarct-related coronary arteries are opened
marker tests are obtained. If these test results are negative, the patient with primary PCI compared with less than 60% of coronary arteries
may be admitted to a general medical floor with ECG telemetry with currently available fibrinolytics.3,32 In addition, the intracranial
monitoring for ischemic changes and arrhythmias, undergo a noninva- hemorrhage (ICH) and major bleeding risks from primary PCI are
sive stress test, or be discharged from the emergency department. lower than following fibrinolysis. An invasive strategy of primary PCI
Moderate- and high-risk patients are admitted to a coronary intensive is generally preferred for patients presenting to institutions where
care unit, an intensive care step-down unit, or a general medical floor skilled interventional cardiologists and a catheterization laboratory are
in the hospital depending on the patient’s symptoms and perceived immediately available, patients with cardiogenic shock, patients with
level of risk. High-risk patients should undergo early coronary angiog- contraindications to fibrinolytics, and patients presenting with symp-
raphy (within 24–48 hours) and revascularization (with PCI or CABG) tom onset greater than 3 hours.3 A quality performance measure in the
if a significant coronary artery stenosis is found2 (see Fig. 18–1 and care of patients with STEMI is the time from hospital presentation to
Table 18–2). Moderate-risk patients with positive biochemical markers the time that the occluded artery is opened with PCI. This “door-to-
for infarction typically also undergo angiography and revascularization primary PCI time” should be 90 minutes or less (Table 18–3).3,10,33 In
during hospital admission. Moderate-risk patients with negative bio- 2006, the median time to primary PCI in the United States was 86
chemical markers for infarction also may undergo angiography and minutes, and only 55% of patients met the performance measure
revascularization or first undergo a noninvasive stress test; only selected target of 90 minutes or less, suggesting that slightly less than half of the
patients with a positive stress test proceed to angiography. Following primary PCIs occur more than 90 minutes after hospital presentation.5
risk stratification, pharmacotherapy for NSTE ACS is initiated. Unfortunately, most hospitals do not have interventional cardiology
services capable of performing primary PCI 24 hours per day.
■ NONPHARMACOLOGIC THERAPY PCI during hospitalization for STEMI also may be appropriate for
other patients following STEMI, such as those in whom fibrinolysis is
Primary PCI for STE ACS not successful (termed rescue PCI), those presenting later in cardio-
 Either fibrinolysis or immediate primary PCI is the treatment of genic shock, patients with life-threatening ventricular arrhythmias,
choice for reestablishing coronary artery blood flow in patients with and those with persistent rest ischemia or signs of ischemia on stress
 255

TABLE 18-3 2006 American College of Cardiology/American Heart Association ST-Segment Elevation and Non–ST-Segment Elevation Myocardial

CHAPTER 18
Infarction Performance Measures
Performance Measure Description
1. Aspirin upon arrival STEMI and NSTE MI patients without aspirin contraindications who received aspirin within 24 hours before or after hospital
arrival
2. Aspirin prescribed at hospital discharge STEMI and NSTE MI patients without aspirin contraindications who are prescribed aspirin at hospital discharge
3. β–Blocker upon hospital arrival β–Blocker STEMI and NSTE MI patients without β–blocker contraindications who received a β–blocker within 24 hours after
hospital arrival
4. β–Blocker prescribed at hospital discharge STEMI and NSTE MI patients without β–blocker contraindications who are prescribed a β–blocker at hospital discharge
5. LDL cholesterol assessment STEMI and NSTE MI patients with documentation of LDL cholesterol level in the hospital record or documentation that LDL

Acute Coronary Syndromes

cholesterol testing was done during the hospital stay or is planned for after hospital discharge
6. Lipid-lowering therapy at hospital discharge STEMI and NSTE MI patients with elevated LDL cholesterol (≥100 mg/dL or narrative equivalent a) who are prescribed lipid-
lowering medicine at hospital discharge
7. ACE inhibitor or ARB for LVSD at discharge STEMI and NSTE MI patients with LVSD and without ACE inhibitor and ARB contraindications who are prescribed an ACE
inhibitor or ARB at hospital discharge
8. Time to fibrinolytic therapy Median time from arrival to administration of fibrinolytic therapy in patients with STE or LBBB on the ECG performed closest
to hospital arrival time
STEMI or LBBB patients receiving fibrinolytic therapy during the hospital stay and having a time from hospital arrival to
fibrinolysis of 30 minutes or less
9. Time to PCI Median time from arrival to PCI in patients with STE or LBBB on the ECG performed closest to hospital arrival time
STEMI or LBBB patients receiving PCI during the hospital stay with a time from hospital arrival to PCI of 90 minutes or less
10. Reperfusion therapy STEMI patients with STE on the ECG performed closest to the arrival who receive fibrinolytic therapy or primary PCI
11. Adult smoking cessation advice counseling STEMI and NSTE MI patients with a history of smoking cigarettes who are given smoking cessation advice or counseling during
hospital stay
a
Mention in the patient’s medical record of elevated LDL cholesterol if not measured.
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ECG, electrocardiogram; LDL, low-density lipoprotein; LBBB, left bundle-branch block; LVSD, left ventricular systolic dysfunction;
cholesterol; MI, myocardial infarction; NSTE, non–ST-segment elevation; PCI, percutaneous coronary intervention; STE, ST-segment elevation.
Reproduced with permission ACC/AHA Clinical Performance Measures for Adults with ST-Elevation and Non-ST-Elevation Myocardial Infarction. ©2006, American Heart Association, Inc.

testing following MI.3,32 A randomized study established that rescue ventricular tachycardia more than 2 days following MI and those with
PCI was superior to repeated fibrinolytic administration or conserva- LVEF <30% measured at least 1 month following STEMI and 3
tive management and resulted in fewer cardiac and cerebrovascular months after coronary artery revascularization with either PCI or
events.34 The strategy of routine angiography and revascularization CABG benefit from placement of an implantable cardioverter-
performed in all STE patients later during hospitalization was contro- defibrillator (ICD).3 The Multicenter Automatic Defibrillator Implan-
versial for almost more than a decade, but data from the Occluded tation Trial II (MADIT II) demonstrated a 29% reduction in mortality
Artery Trial (OAT)35 demonstrated that routine angiography fol- in patients with a history of MI, low LVEF, and no history of
lowed by PCI in stable patients 3 to 28 days post-MI, without symptomatic ventricular arrhythmias who underwent prophylactic
recurrent unprovoked ischemia or ischemia induced by stress testing, placement of an ICD.38 Additional discussion of the role of ICDs in
was not beneficial in reducing mortality or heart failure and may the management of high-risk patients and those with ventricular
increase the risk of recurrent MI.35 Therefore, routine late restoration arrhythmias can be found in Chapter 19.
of antegrade coronary artery blood flow should not be performed. Predischarge stress testing (see Fig. 18–1) may be indicated for
moderate- or low-risk patients in order to determine which patients
PCI in NSTE ACS would benefit from coronary angiography to establish the diagnosis
 The most recent NSTE ACS ACC/AHA clinical practice guidelines of CAD and for patients following MI to predict intermediate- and
recommend early coronary angiography with either PCI or CABG long-term risk of recurrent MI and death.39 In most cases, patients
revascularization as an early treatment for high-risk NSTE ACS with a positive stress test indicating coronary ischemia then undergo
patients, and that such an approach be considered in patients at coronary angiography and subsequent revascularization of signifi-
moderate risk.2,32 Several clinical trials support an “early invasive cantly occluded coronary arteries. Exercise stress testing, most often
strategy” with PCI or CABG versus a “medical stabilization manage- with the addition of a radionuclide imaging agent, is preferred over
ment strategy” whereby coronary angiography with revascularization nonpharmacologic stress testing because it evaluates the workload
is reserved for patients with symptoms refractory to pharmacotherapy achieved with exercise as well as the occurrence of ischemia. If a
and patients with signs of ischemia on stress testing. An early invasive patient has a negative exercise stress test for ischemia, the patient is at
approach results in fewer MIs, hospital readmissions for recurrent low risk for subsequent CHD events. Therefore, exercise stress testing
ACS, and less need for additional revascularization procedures over has high negative predictive value. Additional discussion of the types
the next year following hospitalization.36 In addition, an early invasive of stress testing can be found in Chapter 13.
strategy is less costly than the conservative medical stabilization For patients admitted to the hospital for ACS, a fasting lipid panel
approach.37 should be drawn within the first 24 hours of hospitalization because,
after that period, values for cholesterol, an acute-phase reactant,
Additional Testing and Risk Stratification may be falsely low.33 Initiation of pharmacotherapy with a statin is
common for all ACS patients.
At some point during hospitalization but prior to discharge, patients
with MI should undergo evaluation of LV function for the purpose of
risk stratification.2,3,33 The most common form of LV function mea- ■ EARLY PHARMACOTHERAPY FOR STE ACS
surement is echocardiography to calculate the patient’s left ventricular Pharmacotherapy for early treatment of STE ACS is outlined in Fig.
ejection fraction (LVEF). LV function is the single best predictor of 18–3.2,3,10,40  According to the ACC/AHA STE ACS practice guide-
mortality following MI. Patients with LVEF less than 40% are at lines, early pharmacotherapy of STE ACS should include intranasal
highest risk of death. Patients with ventricular fibrillation or sustained oxygen (if oxygen saturation is <90%), sublingual (SL) nitroglycerin
 256

ST-segment Elevation ACS

SECTION 2

Oxygen (if O2 saturation < 90%)

SL NTG, Aspirin, Clopidogrel,
IV NTGb
Cardiovascular Disorders

Symptoms ≤ 12 hrs Symptoms > 12 hrs

PCI or CABG or fibrinolysis for selected

patients; For PCI during hospitalization,
administer abciximab or eptifibatide at
Reperfusion Therapy time of PCI and clopidogrel

Primary PCI Fibrinolysis

Unfractionated heparin (preferred) or IV UFH or IV and SC enoxaparinb (for

enoxaparina, Abciximab preferred (or eptifibatide) selected patients)

β-blocker (oral or IV), statin, ACE inhibitor (or ARB), eplerenone (or spironolactone)

FIGURE 18-3. Initial pharmacotherapy for ST-segment elevation acute coronary syndromes. (ACE, angiotensin-converting enzyme; ACS, acute coronary
syndrome; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft surgery; IV, intravenous; NTG, nitroglycerin; PCI, percutaneous coronary
intervention; SC, subcutaneous; SL, sublingual; UFH, unfractionated heparin.) aAlthough recommended by the 2004 American College of Cardiology and
American Heart Association practice guidelines, no dose recommendation is given. bSee Table 18–4 for dosing and specific types of patients who should
not receive enoxaparin or IV NTG.) (Reprinted with permission from the American College of Clinical Pharmacy. Spinler SA. Acute coronary syndromes.
In: Dunsworth TS, Richardson MM, Cheng JWM, et al., eds. Pharmacotherapy Self-Assessment Program, 6th ed. Cardiology II module. Kansas City:
American College of Clinical Pharmacy, 2007:69–70.)

(NTG), aspirin, a β-blocker, unfractionated heparin (UFH) or enox- of onset of chest discomfort and have persistent symptoms of
aparin, and fibrinolysis in eligible candidates. Morphine is adminis- ischemia and at least 1 mm of STE in two or more contiguous leads.
tered to patients with refractory angina as an analgesic and a The mortality benefit of fibrinolysis is highest with early administra-
venodilator that lowers preload. These agents should be administered tion and diminishes after 12 hours. Fibrinolytic therapy is preferred
early, while the patient is still in the emergency department. An ACE over primary PCI in patients who present within 3 hours of symptom
inhibitor should be started within 24 hours of presentation, particu- onset if primary PCI will be delayed, because a delay in access to a
larly in patients with LVEF ≤40%, signs of heart failure, or an anterior cardiac catheterization laboratory or a delay in obtaining patient
wall MI, in the absence of contraindications. Intravenous (IV) NTG vascular access would result in a “door-to-primary PCI” delay greater
and β-blockers should be administered to selected patients without than 90 minutes.3 Other indications and contraindications for fibri-
contraindications as described in Table 18–4. Dosing and contraindi- nolysis are listed in Table 18–5.3 It is not necessary to obtain the
cations for SL and IV NTG, aspirin, β-blockers, UFH, enoxaparin, results of biochemical markers before initiating fibrinolytic therapy.
ACE inhibitors, and fibrinolytics are listed in Table 18–4.2,3,10,32,40 Because administration of fibrinolytics results in clot lysis, patients at
high risk for major bleeding, including those with ICH, have either
relative or absolute contraindications. Patients presenting with an
Fibrinolytic Therapy absolute contraindication likely will not receive fibrinolytic therapy,
Administration of a fibrinolytic agent is indicated in patients with and primary PCI is preferred. Patients with a relative contraindication
STE ACS who present to the hospital within 12 hours of onset of chest can receive fibrinolytic therapy if the perceived risk of death from the
discomfort and have at least 1 mm of STE in two or more contiguous MI is higher than the risk of major hemorrhage. For every 1,000
ECG leads or a new left bundle-branch block.3 Fibrinolytic therapy patients with anterior wall MI, treatment with fibrinolysis saves 37
also should be considered in patients presenting within 12–24 hours lives compared with placebo. For patients with inferior wall MI, who
 257

TABLE 18-4 Evidence-Based Pharmacotherapy for ST-Segment Elevation and Non–ST-Segment Elevation Acute Coronary Syndrome

CHAPTER 18
Clinical Condition and ACC/AHA
Drug Guideline Recommendationa Contraindicationsb Dose and Duration of Therapy
Aspirin STEMI, class I recommendation for all Hypersensitivity 162–325 mg orally once on hospital day 1
patients Active bleeding 75–162 mg once daily orally starting hospital day 2 and continued indefinitely in
NSTE ACS, class I recommendation for Severe bleeding risk patients not receiving an intracoronary stent
all patients 162–325 mg once daily orally for a minimum of 30 days in patients undergoing
PCI receiving a bare metal stent, 3 months with a sirolimus-eluting stent and 6
months with a paclitaxel-eluting stent, followed by 75–162 mg once daily orally
thereafter

Acute Coronary Syndromes

Continue indefinitely
Clopidogrel STEMI, class I recommendation in Hypersensitivity 300 mg (class I recommendation) to 600 mg (class IIa recommendation in NSTE
patients allergic to aspirin Active bleeding ACS) loading dose on hospital day 1 followed by a maintenance dose of 75 mg
NSTE ACS, class I recommendation for all Severe bleeding risk po once daily starting on hospital day 2; consider omitting the loading dose in
hospitalized patients in whom a nonin- patients >75 years old when given with fibrinolytics
terventional approach is planned Administer indefinitely in patients with aspirin allergy (class I recommendation)
In PCI in STE and NSTE ACS, class I Administer at least 9 months in patients with NSTE ACS who are managed
recommendations medically (class I recommendation).
In STEMI with fibrinolytics, large ran- For post-PCI stented patients, administer at least 12 months (AHA Science
domized trial data published after Advisory)
2004 guidelines
Unfractionated STEMI, class I recommendation in Active bleeding For STEMI, administer 60 units/kg IV bolus (maximum 4000 units) followed by a
heparin (UFH) patients undergoing PCI, and for History of heparin-induced constant IV infusion at 12 units/kg/h (maximum 1000 units/h)
patients treated with alteplase, thrombocytopenia For NSTE ACS, administer 60–70 units/kg IV bolus (maximum 5000 units) followed
reteplase, or tenecteplase, class IIa Severe bleeding risk by a constant IV infusion at 12–15 units/kg/h (maximum 1000 units/h)
recommendation for patients not Recent stroke Titrated to maintain an aPTT of 1.5–2.5 times control for NSTE ACS and 50–70
treated with fibrinolytic therapy seconds for STEMI
NSTE ACS, class I recommendation in First aPTT should be measured at 4–6 hours for NSTE ACS and STE ACS in patients
combination with aspirin not treated with fibrinolytics
PCI, class I recommendation (NSTE First aPTT should be measured at 3 hours in patients with STE ACS who are treated
ACS and STEMI) with fibrinolytics
Continue for at least 48 hours or until the end of PCI
Low-molecular STEMI class IIb recommendation (and Active bleeding Enoxaparin 1 mg/kg SC every 12 hours for patients with NSTE ACS (CrCl
weight heparin a large randomized trial) for patients History of heparin-induced ≥30 mL/min)
treated with fibrinolytics and class IIa thrombocytopenia Enoxaparin 1 mg/kg SC every 24 hours (CrCl 15–29 mL/min) for NSTE ACS or
for patients not undergoing reperfu- Severe bleeding risk STEMI
sion therapy Recent stroke Dalteparin 120 IU/kg SC every 12 hours for patients with NSTE ACS (maximum
NSTE ACS, class I recommendation Avoid enoxaparin if CrCl single dose)
For PCI, class IIa recommendation as <15 mL/min For patients undergoing PCI following initiation of SC enoxaparin for NSTE ACS, a
an alternative to UFH in patients with Avoid dalteparin if CrCl supplemental 0.3 mg/kg IV dose of enoxaparin should be administered at the
NSTE ACS <30 mL/min time of PCI if the last dose of SC enoxaparin was given 8–12 hours prior
For primary PCI in STEMI, class IIb recom- Avoid if CABG surgery to PCI
mendation as an alternative to UFH For patients with STEMI receiving fibrinolytics:
Age <75 years: administer enoxaparin 30-mg IV bolus followed immediately by 1
mg/kg SC every 12 hours (first two doses administer maximum of 100 mg for
patients for weighing >100 kg)
For patients ≥75 yrs old with STEMI: administer enoxaparin 0.75 mg/kg SC every 12
hours (first two doses administer maximum of 75 mg for patients weighing
>75 kg)
Continue throughout hospitalization or up to 8 days for STEMI
Continue for hospital stay or until the end of PCI for NSTE ACS
Bivalirudin NSTE ACS class I recommendation for Active bleeding For NSTE ACS, administer 0.1 mg/kg IV bolus followed by 0.25 mg/kg/h
early invasive strategy infusion
Severe bleeding risk For PCI, administer a second bolus of 0.5 mg/kg IV and increase infusion rate to
1.75 mg/kg/h
Discontinue at end of PCI or continue for up to 4 hours
Fondaparinux NSTE ACS, class I recommendation Active bleeding For STEMI, 2.5-mg IV bolus followed by 2.5 mg SC once daily starting on hospital
Dosing information based on dose Severe bleeding risk day 2
administered in OASIS-5 and OASIS- SCr ≥3.0 mg/dL For NSTE ACS, 2.5 mg SC once daily
6 trials For PCI, administer UFH 50–60 units/kg UFH (strategy not rigorously tested in
clinical trials)
Continue until hospital discharge

(continued)
 258

TABLE 18-4 Evidence-Based Pharmacotherapy for ST-Segment Elevation and Non–ST-Segment Elevation Acute Coronary Syndrome (continued)
SECTION 2

Clinical Condition and ACC/AHA

Drug Guideline Recommendationa Contraindicationsb Dose and Duration of Therapy
Fibrinolytic STEMI, class I recommendation for Any prior intracranial Streptokinase: 1.5 million units IV over 60 minutes
therapy patients presenting within 12 hours hemorrhage Alteplase: 15-mg IV bolus followed by 0.75 mg/kg IV over 30 minutes (maximum
after onset of symptoms, class IIa in Known structural cere- 50 mg) followed by 0.5 mg/kg (maximum 35 mg) over 60 minutes (maximum
patients presenting between 12 and brovascular lesions dose 100 mg)
24 hours after the onset of symptoms such as arteriovenous Reteplase: 10 units IV × 2, 30 minutes apart
with continuing signs of ischemia malformation Tenecteplase:
NSTE ACS, class III recommendation Known intracranial malig- <60 kg = 30-mg IV bolus
Cardiovascular Disorders

nant neoplasm 60–69.9 kg = 35-mg IV bolus

Ischemic stroke within 3 70–79.9 kg = 40-mg IV bolus
months
Active bleeding (exclud-
ing menses)
Significant closed head or
facial trauma within 3
months
Glycoprotein IIb/ NSTE ACS, class IIa recommendation Active bleeding Dose for NSTE Dose adjustment
IIIa receptor for either tirofiban or eptifibatide for Thrombocytopenia ACS with/ for renal insuffi-
blockers patients with continuing ischemia, Prior stroke Drug Dose for PCI without PCI ciency
elevated troponin, or other high-risk Abciximab 0.25 mg/kg IV Not recom- None
features, class I recommendation for bolus followed mended
patients undergoing PCI, class IIb by 0.125 mcg/
recommendation for patients with- kg/min (maxi-
out high-risk features who are not mum 10 mcg/
undergoing PCI min) for 12
STEMI, class IIa for abciximab for pri- hours
mary PCI and class IIb for either Eptifibatide 180 mcg/kg IV 180 mcg/kg IV Reduce maintenance
tirofiban or eptifibatide for primary bolus × 2, 10 bolus followed infusion to 1 mcg/
PCI minutes apart by an infusion kg/min for patients
with an infu- of 2 mcg/kg/ with CrCl <50 mL/
sion of 2 mcg/ min for 18–24 min; not studied in
kg/min for hours patients with serum
18–24 hours creatinine >4.0 mg/
dL;
patients weighing
≥121 kg should
receive a maximum
infusion rate of 22.6
mg per bolus and a
maximum infusion
rate of 15 mg/h
Tirofiban Not FDA 0.4 mg/kg IV Reduce maintenance
approved bolus adminis- infusion to 0.05
tered over 30 mcg/kg/min for
minutes fol- patients with CrCl
lowed by an <30 mL/min
infusion of 0.1
mcg/kg/min for
18–24 hours
Nitroglycerin STEMI and NSTE ACS, class I indication SBP <90 mm Hg 0.4 mg SL, repeated every 5 minutes × 3 doses 5–10 mcg/min IV infusion titrated
in patients with persistent ischemia, HR <50 beats/min up to 200 mcg/min until relief of symptoms or limiting side-effects (headache)
symptoms of acute heart failure, or Right ventricular infarction with a SBP <90 mm Hg or >30% below starting mean arterial pressure levels if
signs of hypertension Sildenafil or vardenafil significant hypertension is present)
within 24 hours or Topical patches or oral nitrates and acceptable alternatives for patients without
tadalafil within 48 hours ongoing or refractory symptoms
Discontinue if SBP drops >30 mm Hg below baseline SBP
Continue IV infusion for 24–48 hours
β-Blockersc STEMI and NSTE ACS, oral β-blockers, PR ECG segment >0.24 Target resting HR of 50–60 beats/min
class I recommendation in all patients second Metoprolol 5 mg slow IV push (over 1–2 minutes), repeated every 5 minutes for a
without contraindications, class IIa rec- 2nd-degree or 3rd-degree total of 15 mg followed in 15–30 minutes by 25–50 mg by mouth every 6 hours;
ommendation for IV β-blockers for atrioventricular heart if a very conservative regimen is desired, initial doses can be reduced to 1–2 mg
patients with hypertension block Propranolol 0.5–1 mg IV dose followed in 1–2 hours by 40–80 mg by mouth every
HR <60 beats per min 6–8 hours
(continued)
 259

TABLE 18-4 Evidence-Based Pharmacotherapy for ST-Segment Elevation and Non–ST-Segment Elevation Acute Coronary Syndrome (continued)

CHAPTER 18
Clinical Condition and ACC/AHA
Drug Guideline Recommendationa Contraindicationsb Dose and Duration of Therapy
SBP <90 mm Hg Atenolol 5-mg IV dose followed in 5 minutes by a second 5-mg IV dose for a total
Shock of 10 mg followed in 1–2 hours by 50–100 mg by mouth once daily
Signs and symptoms of Initial IV therapy can be omitted and initial doses of oral therapy started
heart failure Continue oral β-blocker indefinitely
Severe reactive airway
disease
Calcium channel STEMI, class IIa recommendation and Pulmonary edema Diltiazem 120–360 mg sustained release orally once daily

Acute Coronary Syndromes

blockers NSTE ACS, class I recommendation Evidence of left ventricu- Verapamil 180–480 mg sustained release orally once daily
for patients with ongoing ischemia lar dysfunction Nifedipine 30–90 mg sustained release orally once daily
who are already taking adequate SBP <100 mm Hg Amlodipine 5–10 mg orally once daily
doses of nitrates and β-blockers PR ECG segment >0.24 Continue indefinitely if contraindication to oral β-blocker persists
For STEMI (diltiazem, verapamil, or second for verapamil
amlodipine) and diltiazem
For NSTE ACS, class I recommendation 2nd- or 3rd-degree atrio-
for diltiazem or verapamil for con- ventricular heart block
tinuing ischemia in patients with a for verapamil or
contraindication to a β-blocker; class diltiazem
IIa recommendation for patients with HR <60 beats/min for dil-
continuing ischemia who do not tiazem or verapamil
have a contraindication to a β-
blocker; class IIb recommendation
instead of a β-blocker
ACE inhibitors STEMI and NSTE ACS, class I recom- SBP <100 mm Hg Drug Initial Dose Target Dose
mendation within the first 24 hours History of intolerance to Captopril 6.25–12.5 mg 50 mg twice daily orally to
after hospital presentation for an ACE inhibitor 50 mg three times daily
patients with clinical signs of heart Bilateral renal artery Enalapril 2.5–5.0 mg 10 mg twice daily orally
failure or left ventricular EF <40% in stenosis Lisinopril 2.5–5.0 mg 10–20 mg once daily orally
the absence of contraindications Ramipril 1.25–2.5 mg 5 mg twice daily or 10 mg
class IIa recommendation for all once daily orally
other patients in the absence of con- Serum potassium >5.5 Trandolapril 1.0 4 mg once daily orally
traindications mEq/L Continue indefinitely
Acute renal failure
Pregnancy
STEMI and NSTE MI, class I recommen-
dation for late hospital care and post-
discharge care for patients with left
ventricular EF <40%, diabetes melli-
tus, or chronic kidney disease
Indicated indefinitely for all patients
with EF <40%, class I recommenda-
tion
Angiotensin STEMI and NSTE ACS, class I recom- SBP <100 mm Hg Drug Initial Dose Target Dose
receptor mendation in patients with an indica- Bilateral renal artery Candesartan 4–8 mg 32 mg once daily orally
blockers tion for an ACE inhibitor and a stenosis Valsartan 40 mg 160 mg twice daily orally
history of ACE inhibitor intolerance Serum potassium >5.5 Continue indefinitely
<40% mg/dL
STEMI and NSTE MI, class I recommen- Acute renal failure
dation for late hospital care and post- Pregnancy
discharge care for patients with a
history of ACE inhibitor intolerance
STEMI and NSTE MI, class IIa recom-
mendation as an alternative to an
ACE inhibitor in patients presenting
with signs of heart failure or left
ventricular EF <40%
STEMI and NSTE MI, class IIb recom-
mendation added to an ACE inhibitor
for long-term management of symp-
tomatic heart failure in patients with
left ventricular ejection fraction <40%
Aldosterone STEMI and NSTE MI, class I recommen- Hypotension Drug Initial Dose Maximum Dose
antagonists dation for patients with EF ≤40% Hyperkalemia, serum Eplerenone 25 mg 50 mg once daily orally
and either diabetes mellitus or heart potassium >5.0 mEq/L Spironolactone 12.5 mg 25–50 mg once daily orally
failure symptoms who are already SCr >2.5 mg/dL Continue indefinitely
receiving an ACE inhibitor
(continued)
 260

TABLE 18-4 Evidence-Based Pharmacotherapy for ST-segment Elevation and Non–ST-segment Elevation Acute Coronary Syndrome (continued)
SECTION 2

Clinical Condition and ACC/AHA

Drug Guideline Recommendationa Contraindicationsb Dose and Duration of Therapy
Morphine sulfate STE and NSTE ACS, class IIa recom- Hypotension 2–5 mg IV bolus dose
mendation for patients whose symp- Respiratory depression Can be repeated every 5–30 minutes as needed to relieve symptoms and maintain
toms are not relieved after three Confusion patient comfort
serial SL nitroglycerin tablets or Obtundation
whose symptoms recur with ade-
quate antiischemic therapy
a
Cardiovascular Disorders

Class I recommendations are conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective. Class II recommendations are those conditions for
which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure or treatment. For Class IIa recommendations, the weight of the evidence/opinion is in favor of
usefulness/efficacy. Class IIb recommendations are those for which usefulness/efficacy is less well established by evidence/opinion. Class III recommendations are those for which the procedure or treatment
is not useful and may be harmful.
b
Allergy or prior intolerance contraindication for all categories of drugs listed.
c
Choice of specific agent is not as important as ensuring that appropriate candidates receive this therapy. If there are concerns about patient intolerance due to existing pulmonary disease, especially asthma,
selection should favor a short-acting agent, such as propranolol or metoprolol or the ultrashort-acting agent esmolol. Mild wheezing or a history of chronic obstructive pulmonary disease should prompt a trial
of a short-acting agent at a reduced dose (e.g., 2.5-mg IV metoprolol, 12.5-mg oral metoprolol, or 25 mcg/kg/min esmolol as initial doses) rather than complete avoidance of β-blocker therapy.
ACC, American College of Cardiology; ACE, angiotensin-converting enzyme; AHA, American Heart Association; ACS, acute coronary syndrome; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy;
CABGF, coronary artery bypass graft; CrCl, creatinine clearance; ECG, electrocardiogram; EF, ejection fraction; HR, heart rate; IV, intravenous; MI, myocardial infarction; NSTE, non–ST-segment elevation; OASIS,
Organization to Assess Strategies in Acute Ischemic Syndromes; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; SC, subcutaneous; SCr, serum creatinine; SL, sublingual; STE, ST-segment elevation.
Data from references 2, 3, 10, 32, 55, and 108.

generally have smaller MIs and are at lower risk of death, treatment of absolute mortality reduction compared with placebo varies from
with fibrinolysis saves eight lives per 1,000 patients treated.20 approximately 1% to 9%, with some observational studies suggesting
Fibrinolytic therapy is controversial in patients older than 75 years. higher mortality in the very elderly treated with fibrinolysis compared
More than 60% of all MI deaths occur in this group. Benefit in terms with no fibrinolysis. Stroke rates also grow in number with increasing
patient age. The ICH rate is approximately 1% in younger patients
versus 2% to 3% in older patients. There is no excess risk of stroke in
TABLE 18-5 Indications and Contraindications to Fibrinolytic patients younger than 55 years, whereas patients older than 75 years
Therapy According to ACC/AHA Guidelines for experience more than eight strokes per 1,000 patients treated.20
Management of Patients with ST-Segment Elevation However, the ACC/AHA practice guidelines recommend use of
Myocardial Infarction fibrinolytics in this age group, provided the patient has no contrain-
Indications dications.3 A 1% absolute mortality benefit is believed to be clinically
1. Ischemic chest discomfort at least 20 minutes in duration but ≤12 hours since significant, and the benefit in terms of lives saved per 1,000 patients
symptom onset treated has been reported to range from 10 to 80 in patients older
and than 75 years.20 An AHA Scientific Statement concluded that a
ST-segment elevation of at least 1 mm in height in ≤2 contiguous leads or mortality benefit with fibrinolysis compared with no reperfusion was
New or presumed new left bundle-branch block
demonstrated in patients up to age 85 years and includes deaths
2. Ongoing ischemic chest discomfort at least 20 minutes in duration 12–24 hours
related to ICH, stroke, and shock, which all are higher in the elderly
since symptom onset
and
compared to younger patients.41 Careful attention to correct dosing
ST-segment elevation of at least 1 mm in height in ≥2 contiguous leads of UFH and enoxaparin can reduce ICH and bleeding rates.41 Because
Absolute contraindications older patients may have cognitive impairment, careful history taking
Active internal bleeding (not including menses) and assessment weighing the bleeding risk versus the benefit must be
Previous intracranial hemorrhage at any time; ischemic stroke within 3 months performed prior to administration of fibrinolysis.
Known intracranial neoplasm The comparative pharmacology of commonly prescribed fibrinolyt-
Known structural vascular lesion (e.g., arteriovenous malformation) ics is given in Table 18–6.42 According to the ACC/AHA STE ACS
Suspected aortic dissection practice guidelines, a more fibrin-specific agent, such as alteplase,
Significant closed head or facial trauma within 3 months reteplase, or tenecteplase, is preferred over a non–fibrin-specific agent,
Relative contraindications
such as streptokinase.3 Early administration of more fibrin-specific
Severe, uncontrolled hypertension on presentation (blood pressure >180/110 mm Hg)
fibrinolytics opens a greater percentage of infarct arteries. Because an
History of prior ischemic stroke >3 months, dementia, or known intracranial
pathology not covered above under absolute contraindications
early open artery results in smaller infarcts, administration of fibrin-
Current use of anticoagulants specific agents should result in lower mortality. This concept has been
Known bleeding diathesis termed the open-artery hypothesis. In a large clinical trial, administra-
Traumatic or prolonged (>10 minutes) CPR or major surgery (<3 weeks) tion of alteplase reduced mortality by 1% (absolute reduction) and
Noncompressible vascular puncture (e.g., a recent liver biopsy or carotid artery costs about $30,000 per year of life saved compared with streptoki-
puncture) nase.43 Two other trials that compared alteplase with reteplase and
Recent (within 2–4 weeks) internal bleeding alteplase with tenecteplase found similar mortality between agents.44,45
For streptokinase administration, previous streptokinase use (>5 days) or prior Therefore, alteplase, reteplase, or tenecteplase is acceptable as a first-line
allergic reactions agent. Most hospitals have at least two of these agents on their formu-
Pregnancy
lary. Most often, formulary decisions are based on the frequency of use
Active peptic ulcer
of fibrinolytics for other approved indications, such as ischemic stroke
History of severe, chronic poorly controlled hypertension
or pulmonary embolism, with alteplase having the most indications of
CPR, cardiopulmonary resuscitation. the fibrin-specific agents. Administration considerations also guide
Data from Antman EM, Anbe DT, Armstrong PW, Bates ER, et al. ACC/AHA guidelines for the
formulary decision making and choice for patient treatment, with
management of patients with ST-elevation myocardial infarction: Executive summary. A report of the
American College of Cardiology/American Heart Association Task Force on Practice Guidelines tenecteplase given as a single, weight-based dose and reteplase given as
(Committee to revise the 1999 Guidelines for the Management of Patients with Acute Myocardial two fixed doses without weight adjustment. Therefore, both tenec-
Infarction). Circulation 2004;110:588–636.. teplase and reteplase are easier to administer than alteplase.
 261

TABLE 18-6 Comparison Between Fibrinolytic Agents

CHAPTER 18
TIMI-3 Blood
Flow Complete Systemic Average
Fibrin Perfusion at 90 Bleeding Wholesale
Agent Specificity Minutes Risk/ ICH Risk Administration Price Other Approved Uses
Streptokinase + 35% +++/+ Infusion over 60 minutes $563 Pulmonary embolism, deep-vein thrombo-
(Streptase) sis, clearance of an occluded arteriove-
nous catheter, intrapleural administration
for clearance of pulmonary effusion
Alteplase (rt-PA) +++ 50%–60% ++/++ Bolus followed by infu- $3,826 Pulmonary embolism, acute ischemic

Acute Coronary Syndromes

(Activase) sions over 90 minutes, stroke, clearance of an occluded arterio-
weight-based dosing venous catheter
Reteplase (rPA) ++ 50%–60% ++/++ Two bolus doses, 30 min- $2,896
(Retavase) utes apart
Tenecteplase (TNK-tPA) ++++ 50%–60% +/++ Single bolus dose, weight- $2,918
(TNKase) based dosing
ICH, intracranial hemorrhage; TIMI, Thrombolysis in Myocardial Blood Flow (TIMI-3 blood flow indicates complete perfusion of the infarct artery).
Adapted from Spinler.10

ICH and major bleeding are the most serious side effects of achieve high blood concentrations and rapid platelet inhibition.2,3 The
fibrinolytic agents (see Table 18–6). The risk of ICH is higher with notion of chewing aspirin came from use of an enteric-coated formu-
fibrin-specific agents than with streptokinase. Models for use in lation of aspirin in the ISIS-2 trial in order to break the enteric coating
clinical practice are available to predict an individual patient’s risk to ensure more rapid effect.47 Current data suggest that although an
of ICH following administration of a fibrinolytic.3 The risk of initial dose of 160 to 325 mg is required, long-term therapy with doses
systemic bleeding other than ICH is higher with streptokinase than of 75 to 150 mg daily are as effective as higher doses and, therefore,48 a
with other, more fibrin-specific agents.43 daily maintenance dose of 75 to 160 mg is recommended in most
The percentage of eligible patients who receive reperfusion therapy patients to inhibit the 10% of the total platelet pool that is regenerated
is another quality performance measure of care in patients with daily.2,49 Whether these lower doses are as effective as a dose of 325 mg
STEMI (see Table 18–3).33 The “door-to-needle time,” which is the daily in patients undergoing intracoronary stent placement remains
time from hospital arrival to start of fibrinolytic therapy, is another uncertain. Current AHA/ACC guidelines recommend the use of 162–
quality performance measure (see Table 18–3).33 Although the ACC/ 325 mg daily for 1 month after placement of a bare-metal stent, 3
AHA guidelines recommend a door-to-needle time of less than 30 months after placement of a sirolimus-coated stent, and 6 months after
minutes, the median administration time in the United States in 2006 placement of a paclitaxel-coated stent, after which a daily aspirin dose
was 30 minutes, with only 50% of patients meeting the quality of 75 to 162 mg should be used indefinitely.40 Therefore, although the
performance measure target of less than 30 minutes.5 Therefore, risk of major bleeding, particularly gastrointestinal bleeding, appears to
healthcare professionals should work to shorten fibrinolytic adminis- be reduced by using lower doses of aspirin, low-dose aspirin, taken
tration times. chronically, is not free of adverse effects.49,50 Patients should be coun-
seled on the potential risk of bleeding.
Aspirin The ACC/AHA STE ACS guidelines specifically recommend that
Based on several randomized trials, aspirin has become the preferred ibuprofen not be administered on a regular basis for pain relief
antiplatelet agent for treatment of all ACSs.2,3 Early aspirin administra- concurrently with aspirin due to a reported drug interaction with
tion to all patients without contraindications within the first 24 hours aspirin whereby ibuprofen blocks aspirin’s antiplatelet effects.3 Theo-
of hospital admission is a quality care indicator (see Table 18–3).33 The retically, such a risk is also possible with other nonsteroidal antiinflam-
antiplatelet effects of aspirin are mediated by inhibition of thrombox- matory drugs (NSAIDs), although these theoretical drug interactions
ane A2 synthesis through irreversible inhibition of platelet cyclooxy- remain to be clearly established. Finally, although some concern has
genase-1 (COX-1).46 Following administration of a non–enteric-coated been voiced regarding the possible increased risk of hemorrhagic
formulation, aspirin rapidly (<10 minutes) inhibits thromboxane A2 stroke in patients taking aspirin, this risk appears to be very small and
production in the platelets. Aspirin also has antiinflammatory actions, is outweighed by the benefit in reducing the risk of ischemic stroke and
which decrease C-reactive protein and may contribute to its effective- other vascular events.48 The risk of hemorrhagic stroke appears to be
ness in ACS.46 In patients undergoing PCI, aspirin prevents acute minimal in patients with adequate blood pressure control,20 and there
thrombotic occlusion during the procedure. are no specific contraindications to antiplatelet therapy in hyperten-
The Second International Study of Infarct Survival (ISIS-2), which sive patients presenting with ACS.51 Aspirin therapy should be contin-
studied the impact of streptokinase and aspirin (162.5 mg/day) either ued indefinitely.3
alone or in combination, is a landmark clinical trial that convincingly
demonstrated the value of aspirin in patients with STE ACS.47 In this Thienopyridines
trial (n = 17,187), patients who received aspirin demonstrated a lower Although aspirin is effective in the setting of ACS, it is a relatively
risk of 35-day vascular mortality compared with placebo (9.4% vs weak platelet inhibitor that blocks platelet aggregation through only
11.8%; P <0.0001). Use of aspirin was not associated with an increase one pathway. The thienopyridines clopidogrel and ticlopidine are
in major bleeding, although the incidence of minor bleeding was antiplatelet agents that mediate their antiplatelet effects through a
increased. The combination of aspirin and streptokinase reduced blockade of ADP P2Y12 receptors on platelets.2 Because ticlopidine is
mortality compared with placebo as well as compared with either associated with the occurrence of neutropenia that requires frequent
agent alone, thereby highlighting the additive effects of combination monitoring of the complete blood count during the first 3 months of
antithrombotic therapy. use,52 clopidogrel is the preferred thienopyridine for ACS and PCI
In patients experiencing an ACS, an initial dose equal to greater than patients40 (see Table 18–4).
160 mg nonenteric aspirin is necessary to achieve rapid platelet inhibi- The AHA/ACC guidelines currently recommend clopidogrel as an
tion (see Table 18–4).46,47 This first dose can be chewed in order to alternative to aspirin in patients who have an allergy to aspirin.2,3 The
 262
updated recommendations from these professional associations, Some trials suggest that early administration of abciximab results
expected in 2007, are likely to extend the recommendation regarding in early opening of the coronary artery, making primary PCI easier
SECTION 2

the use of clopidogrel to include most patients with STE ACS. A trial for the interventional cardiologist. Clinical trials performed to date
of more than 45,000 patients with STE ACS showed that early suggest that the combination of early administration of a reduced
therapy with clopidogrel 75 mg once daily (started within 24 hours dose of a fibrinolytic agent in combination with abciximab does not
of hospital presentation), added to aspirin for the duration of reduce mortality and increases the risk of bleeding, including ICH, in
hospitalization (average 15 days) or up to 28 days, reduced mortality elderly patients with STE ACS.57–59 Additional clinical trials of
and reinfarction compared to placebo in patients treated with medi- combined antithrombotic therapy for STE PCI patients are ongoing.
cal therapy, including fibrinolytics, without increasing the risk of
major bleeding.53 Another smaller study showed that clopidogrel Anticoagulants
Cardiovascular Disorders

added to aspirin reduced the composite rate of 30-day death, MI, or

Options for anticoagulant therapy for patients with STE ACS are
stroke by 20% in patients ages 18 to 75 years with STE ACS treated
outlined in Fig. 18–3 and Table 18–4. UFH, administered as an IV
with fibrinolytics. Clopidogrel or placebo was administered as an
bolus followed by a continuous infusion, is a first-line anticoagulant
initial dose of 300 mg orally on day 1, followed by 75 mg daily.
for treatment of patients with STE ACS, both for medical therapy and
Angiography was encouraged as early as hospital day 2, and patients
for patients undergoing PCI.3,40 UFH binds to antithrombin and then
undergoing PCI at the time of angiography continued on open-label
inhibits the activity of clotting factors Xa and IIa (thrombin). Antico-
clopidogrel at a 300-mg loading dose followed by 75 mg once daily
agulant therapy should be initiated in the emergency department and
for the duration of the study. Patients who did not undergo revascu-
continued for at least 48 hours in selected patients who will be bridged
larization received clopidogrel up to the time of discharge or hospital
over to receive chronic warfarin anticoagulation following acute MI.3
day 8. At the time of angiography, more open infarct arteries were
If a patient undergoes PCI, UFH is discontinued immediately after
present in the clopidogrel-treated patients.54 Based on current data,
the procedure. UFH dosing is listed in Table 18–4. The dose of UFH
therefore, clopidogrel (either 75 mg or 300 mg on day 1 followed by
infusion is adjusted frequently to a target activated partial thrombo-
75 mg once daily) should be given for at least 14 to 28 days in
plastin time (aPTT; see Table 18–4). When coadministered with a
addition to aspirin in patients treated by fibrinolytics and in those
fibrinolytic, aPTTs above the target range are associated with an
receiving no revascularization therapy with either PCI or CABG
increased rate of bleeding, whereas aPTTs below the target range are
surgery. The safety of the 300-mg loading dose has not been evalu-
associated with increased mortality and reinfarction.61
ated in patients older than over 75 years receiving a fibrinolytic.
For more than 40 years UFH has been the traditional anticoagulant
Clopidogrel is recommended in addition to aspirin in patients
administered to patients with STE ACS for prevention of infarct
undergoing primary PCI. For primary PCI, clopidogrel is adminis-
artery reocclusion. Other beneficial effects of anticoagulation in
tered as a 300-mg loading dose, followed by 75 mg once daily, in
patients with ACS are prevention of cardioembolic stroke and venous
combination with aspirin 325 mg once daily, to prevent subacute stent
thromboembolism.3 When a fibrinolytic agent is administered, UFH
thrombosis and long-term events cardiovascular CV events.2,32,40
is given concomitantly with alteplase, reteplase, and tenecteplase.
Alternatively, an initial dose of 600 mg can be considered, although the
UFH is not administered to patients receiving the non–fibrin-selec-
clinical efficacy and safety of this dose is under investigation.40 The
tive agent streptokinase because no benefit of combined therapy has
duration of clopidogrel therapy depends on the type of stent imple-
been be demonstrated.62 Rates of reinfarction are higher if UFH is not
mented (either a bare-metal stent or a drug-eluting stent; see Table
given in combination with fibrin-selective agents.62 UFH currently is
18–4), the patient’s presentation (ACS vs stable angina), and the
the preferred anticoagulant in patients undergoing primary PCI.32,40
patient’s risk of bleeding.55,56
Besides bleeding, the most frequent adverse effect of UFH is the
The most frequent side effects of clopidogrel are nausea, vomiting,
immune-mediated clotting disorder heparin-induced thrombocyto-
and diarrhea, which occur in approximately 5% of patients. Rarely,
penia (see Chapter 21), which occurs in up to 5% of patients treated
thrombotic thrombocytopenic purpura has been reported with clo-
with UFH. Heparin-induced thrombocytopenia is less common in
pidogrel.52 The most serious side effect of clopidogrel is bleeding (see
patients receiving low-molecular-weight heparins (LMWHs).3,40
Early Pharmacotherapy for NSTE ACS below).
Because randomized controlled clinical trials comparing UFH to
placebo are lacking, no conclusive data support a benefit of UFH
GP IIb/IIIa Receptor Inhibitors over placebo in reducing mortality or reinfarction in STE ACS.63 On
Abciximab is a first-line GP IIb/IIIa receptor inhibitor for patients the contrary, the results of a meta-analysis of more than 7,500
undergoing primary PCI3,32,40,57 who have not received fibrinolytics. It patients suggests that LMWHs reduce both mortality and reinfarc-
should not be administered for medical management of patients with tion compared to placebo.63
STE ACS who will not be undergoing PCI. Abciximab is preferred over LMWHs, like UFH, bind to antithrombin and inhibit both factor
eptifibatide and tirofiban in this setting because abciximab is the most Xa and IIa. However, because their composition is mostly short
common GP IIb/IIIa receptor inhibitor studied in primary PCI tri- saccharide chain lengths, they preferentially inhibit factor Xa over
als.3,32,40,57 Abciximab, in combination with aspirin, a thienopyridine, factor IIa, which requires larger chain lengths for binding and
and UFH (administered as an infusion for the duration of the proce- inhibition. Although the possible superiority of LMWHs, particu-
dure) reduced mortality and reinfarction without increasing the risk of larly enoxaparin, has been suggested by many small trials,63 their
major bleeding in a meta-analysis of primary PCI clinical trials.57 relative benefits have been properly compared only recently in the
Dosing and contraindications for abciximab are listed in Table Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial
18–4. GP IIb/IIIa receptor inhibitors block the final common Infarction Treatment (ExTRACT)-Thrombolysis in Myocardial
pathway of platelet aggregation, namely, cross-linking of platelets by Infarction (TIMI) 25 trial.64 In this large trial, enoxaparin adminis-
fibrinogen bridges between the GP IIb/IIIa receptors on the platelet tered for a median of 7 days significantly reduced the risk of death or
surface. Abciximab typically is initiated at the time of PCI, and the nonfatal MI compared to UFH administered for a median of 2 days
infusion is continued for 12 hours. Administration of a GP IIb/IIIa (see Table 18–4). The benefit, although modest, was already appar-
receptor inhibitor may increase the risk of bleeding, especially if it is ent after 48 hours of treatment. Enoxaparin use was associated with
given in the setting of recent (<4 hours) administration of fibrino- a small (2.1% vs 1.4%) but significant increased risk of major
lytic therapy.57–59 An immune-mediated thrombocytopenia occurs bleeding. Whether the observed benefits and increase in bleeding
in approximately 5% of patients.60 observed in this trial can be solely attributed to the pharmacokinetic
 263
and pharmacodynamic differences between UFH and enoxaparin or addition, the reduction in heart rate increases diastolic time, thus
the longer duration of treatment in the enoxaparin group is uncer- improving ventricular filling and coronary artery perfusion.69 As a

CHAPTER 18
tain. Although the bleeding rates were increased in patients older result of these effects, β-blockers reduce the risk for recurrent
than 75 years compared to younger patients, the rates of major ischemic, infarct size, risk of reinfarction, and occurrence of ventric-
bleeding between enoxaparin and UFH use were similar in the older ular arrhythmias in the hours and days following MI.69
patient subgroup.65 Therefore, enoxaparin can be considered a Landmark clinical trials have established the role of early β-
valuable anticoagulant in the context of STEMI. Enoxaparin has not blocker therapy in reducing MI mortality. Most of these trials were
been studied in the setting of primary PCI. performed in the 1970s and 1980s before routine use of early
Fondaparinux is an indirect-acting specific inhibitor of factor Xa reperfusion therapy.70–73 However, data regarding the acute benefit
that has recently been studied in the setting of STE ACS. Unlike UFH of β-blockers in MI in the reperfusion era are derived mainly from

Acute Coronary Syndromes

and LMWHs, fondaparinux does not cause heparin-induced throm- a large clinical trial reported in 2005. The trial suggests that
bocytopenia. In the Sixth Organization for the Assessment of Strategies although initiating IV followed by oral β-blockers early in the
for Ischemic Syndromes (OASIS 6) trial, fondaparinux administered course of STEMI was associated with a lower risk of reinfarction or
for a median of 8 days had similar efficacy and safety as UFH ventricular fibrillation, there may be an early risk of cardiogenic
administered for a median of 2 days in patients receiving fibrinolytic shock, especially in patients presenting with pulmonary congestion
therapy with alteplase, reteplase, or tenecteplase (see Table 18–4 for or systolic blood pressure <120 mm Hg.74 Therefore, the use of β-
dosing).66 A small reduction in mortality was observed in patients blockers, particularly when administered IV, should be limited to
treated with fondaparinux versus placebo in patients treated with patients who are hemodynamically stable and who do not demon-
streptokinase or receiving no fibrinolytic therapy. No benefit of fonda- strate any signs or symptoms of decompensated heart failure.
parinux was observed in the subgroup of patients undergoing PCI Careful assessment for signs of hypotension and heart failure should
during hospitalization.66 Because of the lack of benefit of in the be performed following β-blocker initiation and prior to any dose
fondaparinux compared to UFH group as well as in the subgroup of titration. Early administration of β-blockers (to patients without
patients undergoing PCI, coupled with the relatively long duration of contraindications) within the first 24 hours of hospital admission is
administration, fondaparinux likely will not be used widely in practice a quality performance measure (see Table 18–3).3,33 The AHA and
for treatment of STEMI in the United States. ACC now are reevaluating this recommendation given the results of
the aforementioned trial. Current AHA guidelines for the manage-
ment of hypertension in the setting of ACS suggest that β-blockers
Nitrates
should be delayed in patients with hemodynamic instability or
Nitrates promote the release of nitric oxide from the endothelium, shock until resolution of heart failure symptoms and hypotension.51
which results in venous and arterial vasodilation at higher doses. The most serious side effects of β-blocker administration early in ACS
Venodilation lowers preload and myocardial oxygen demand. Arte- are hypotension, acute heart failure, bradycardia, and heart block.
rial vasodilation may lower blood pressure, thus reducing myocardial Although initial acute administration of β-blockers is not appropriate
oxygen demand. Arterial vasodilation relieves coronary artery vaso- for patients who present with decompensated heart failure, initiation of
spasm, dilating coronary arteries to improve myocardial blood flow β-blockers can be attempted before hospital discharge in most patients
and oxygenation. One SL NTG tablet (0.4 mg) should be adminis- following treatment of acute heart failure. It cannot be overemphasized
tered every 5 minutes for up to three doses to relieve myocardial that diabetes mellitus does not constitute a contraindication to β-
ischemia. If patients have previously been prescribed SL NTG and blockers. Although the use of β-blockers may mask symptoms of
ischemic chest discomfort persists for more than 5 minutes after the hypoglycemia, except sweating, diabetics greatly benefit from β-blocker
first dose, the patient should be instructed to contact emergency administration because they are at high risk for recurrent events.69 In
medical services before self-administering subsequent doses in order patients in whom a major concern exists regarding a possible intolerance
to activate emergency care sooner. IV NTG is indicated in patients to β-blockers, such as patients with bronchospastic pulmonary disease,
with ACS who do not have a contraindication and who have persis- a short-acting β-blocker, such as metoprolol or esmolol, initially should
tent ischemic symptoms, heart failure, or uncontrolled blood pres- be administered IV.69 β-Blockers are continued indefinitely.3
sure. It should be continued for approximately 24 hours after
ischemia is relieved (see Table 18–4).3 Importantly, other lifesaving
therapies, such as ACE inhibitors or β-blockers, should not be
Calcium Channel Blockers
withheld for nitrates use because the mortality benefit of nitrates is Administration of calcium channel blockers in the setting of STE
unproven. Nitrates play a limited role in the treatment of ACS ACS is reserved for patients who have contraindications to β-
patients, with two large, randomized clinical trials failing to show a blockers and is given for relief of ischemic symptoms.3 In patients
mortality benefit for IV followed by oral nitrate therapy in patients prescribed calcium channel blockers for treatment of hypertension
with acute MI.67,68 The most significant adverse effects of nitrates are who are not receiving β-blockers and who do not have a contraindi-
tachycardia, flushing, headache, and hypotension. Nitrate adminis- cation to β-blockers, the calcium channel blocker should be discon-
tration is contraindicated in patients who have received oral phos- tinued and a β-blocker initiated. Calcium channel blockers inhibit
phodiesterase-5 inhibitors, such as sildenafil and vardenafil, within calcium influx into myocardial and vascular smooth muscle cells,
the past 24 hours and tadalafil within the past 48 hours. causing vasodilation. Although all calcium channel blockers produce
coronary vasodilation and decrease blood pressure, other effects are
more heterogeneous between agents. Dihydropyridine calcium
β-Blockers channel blockers (e.g., amlodipine, felodipine, and nifedipine) pri-
A β-blocker should be administered early in the care of patients with marily produce their antiischemic effects through peripheral vasodi-
STE ACS and continued indefinitely. Early administration of a β- lation, with no clinical effects on atrioventricular nodal conduction
blocker within the first 24 hours of hospitalization in patients lacking and heart rate. Diltiazem and verapamil, on the other hand, have
a contraindication is a quality care indicator (see Table 18–3).33 In additional antiischemic effects by reducing contractility and atrio-
ACS, the benefit of β-blockers results mainly from the competitive ventricular nodal conduction and slowing heart rate.75
blockade of β1-adrenergic receptors located on the myocardium. β1- Current data suggest little benefit on clinical outcomes beyond
blockade produces a reduction in heart rate, myocardial contractil- symptom relief for calcium channel blockers in the setting of ACS.76,77
ity, and blood pressure, decreasing myocardial oxygen demand. In Moreover, the use of first-generation short-acting dihydropyridines,
 264
such as nifedipine, should be avoided because they appear to worsen inducing smooth muscle relaxation in the coronary arteries. In
outcomes through their negative inotropic effects, induction of reflex contrast, β-blockers generally should be avoided in these patients
SECTION 2

sympathetic activation, tachycardia, and increased myocardial unless they have uncontrolled sinus tachycardia (>100 beats/min)
ischemia.75 Therefore, the role of verapamil or diltiazem appears to be or severe uncontrolled hypertension following cocaine use because
limited to relief of ischemia-related symptoms or control of heart rate β-blockers actually may worsen vasospasm through an unopposed
in patients with supraventricular arrhythmias for whom β-blockers β2-blocking effect on the smooth muscle cells.2
are contraindicated or ineffective.2,3
Adverse effects and contraindications of calcium channel blockers are ■ EARLY PHARMACOTHERAPY FOR NSTE ACS
listed in Table 18–4. Verapamil, diltiazem, and first-generation dihydro-
pyridines also should be avoided in patients with decompensated heart In general, early pharmacotherapy for NSTE ACS (see Fig. 18–4) is
similar to that for STE ACS with three exceptions:
Cardiovascular Disorders

failure or LV dysfunction because these drugs can worsen heart failure

and potentially increase mortality secondary to their negative inotropic
effects. In patients with heart failure requiring treatment with a calcium 1. Fibrinolytic therapy is not administered.
channel blocker, amlodipine is the preferred agent.77,78 2. GP IIb/IIIa receptor blockers are administered to high-risk
Two groups of patients may benefit from calcium channel block- patients.
ers as opposed to β-blockers as initial therapy. Cocaine-induced 3. There are no standard quality performance measures for patients
ACS and variant (or Prinzmetal) angina are two conditions in which with NSTE ACS with unstable angina (not diagnosed with MI).
coronary vasospasm plays an important role.2,3,75 Calcium channel
blockers and/or NTG generally are considered the agents of choice According to the ACC/AHA NSTE ACS practice guidelines,
in these patients because they can reverse coronary spasm by early pharmacotherapy for NSTE ACS should include intranasal

Non-ST-segment Elevation ACS

Oxygen (if O2 saturation < 90%)

SL NTG, Aspirin
IV Nitroglycerina
Morphine sulfatea, Anticoagulant (either
IV UFH, SC enoxaparin, SC
fondaparinux or IV bivalirudin)b
Clopidogrelc

Early Invasive Strategy Early Conservative Strategy

Early PCI planned (≤12 hrs Delayed PCI planned No PCI planned
from hospital presentation), (>12 hrs from hospital (eg. low risk patient)
high risk patient presentation)

Abciximab or eptifibatide started at

time of PCI for patients receiving
UFH, enoxaparind or fondaparinuxe

β-blocker, statin, ACE inhibitor (or ARB)

β-blocker, statin, ACE inhibitor (or ARB)

β-blocker, statin, ACE inhibitor (or ARB);
discontinue NTG, anticoagulantg
High or moderate risk patient
Following PCI, continue abciximab for Recurrent ischemia
12 hrs, eptifibatide for at least 18–24 hrs;
discontinue NTG, anticoagulantg
Stress test
Initiate eptifibatide or tirofiban either
before before angiographyf/PCI or at Positive findings
time of PCI; discontinue NTG, IV UFH, for ischemia
enoxaparin, fondaparinux and bivalirudin
post-PCI Abciximab, eptifibatide
(with UFH or enoxaparin)
or bivalirudin at time of PCI

FIGURE 18-4. Initial pharmacotherapy for non–ST-segment elevation acute coronary syndrome. (ACE, angiotensin-converting enzyme; ARB,
angiotensin receptor blocker; ACS, acute coronary syndrome; CABG, coronary artery bypass graft surgery; IV, intravenous; NTG, nitroglycerin; PCI,
percutaneous coronary intervention; SC, subcutaneous; SL, sublingual; UFH, unfractionated heparin.) aFor selected patients, see Table 18–4. bEnoxaparin,
UFH, fondaparinux, or bivalirudin for early invasive strategy; enoxaparin or fondaparinux preferred if no angiography/PCI planned but UFH acceptable;
fondaparinux preferred if high risk for bleeding; UFH preferred anticoagulant for patients undergoing CABG. cIn patients unlikely to undergo CABG. dMay
require an IV supplemental dose; see Table 18–4. eRequires supplemental UFH bolus for PCI; see Table 18–4. f F or signs and symptoms of recurrent
ischemia. gSC enoxaparin or UFH can be continued at a lower dose for venous thromboembolism prophylaxis. (Adapted with permission from the
American College of Clinical Pharmacy. Spinler SA. Acute coronary syndromes. In: Dunsworth TS, Richardson MM, Cheng JWM, et al., eds.
Pharmacotherapy Self-Assessment Program, 6th ed. Cardiology II module. Kansas City: American College of Clinical Pharmacy, 2007: 69–70.)
 265
oxygen (if oxygen saturation is <90%), SL NTG, aspirin, an oral β- The major concern when combining two antiplatelet agents is the
blocker (IV β-blocker optional), and an anticoagulant (UFH, increased risk of bleeding. In CURE, the risk of major bleeding was

CHAPTER 18
LMWH [enoxaparin], fondaparinux, or bivalirudin). Morphine is increased in patients who received clopidogrel plus aspirin compared
also administered to patients with refractory angina, as described with aspirin alone (3.7% vs 2.7%; P = 0.001).79 A post hoc analysis of
previously in Early Pharmacotherapy for STE ACS. IV NTG should CURE revealed that the rate of major bleeding depended on the dose
be administered in selected patients without contraindications as of aspirin and showed that doses ≤100 mg daily reduced the risk of
described in Table 18–4. These agents should be administered early, bleeding with similar efficacy compared with higher doses.83 The
while the patient is still in the emergency department. Dosing and recommendation to use a lower dose of aspirin with clopidogrel is
contraindications for SL and IV NTG, aspirin, β-blockers, UFH, also supported by the results of a recent systematic review of clinical
and enoxaparin are listed in Table 18–4.2,3,10 trials that found no benefit to aspirin as a sole antiplatelet agent for

Acute Coronary Syndromes

chronic treatment in doses greater than 75 to 81 mg.48 However,
Fibrinolytic Therapy administration of a 325-mg dose of aspirin with clopidogrel is
recommended for patients with recent intracoronary stent place-
Fibrinolytic therapy is not indicated in any patient with NSTE ACS,
ment (see Early Pharmacotherapy for STE ACS) to prevent stent
even those who have positive biochemical markers (e.g., troponin)
thrombosis.40
that indicate infarction. Because the risk of death from MI is lower in
In patients undergoing CABG, major bleeding was increased in
patients with NSTE ACS whereas the risk for life-threatening adverse
those who underwent the procedure within 5 days of clopidogrel
effects, such as ICH, with fibrinolytics is similar between patients with
discontinuation (9.6% vs 6.3%; P = 0.06) but not in those in whom
STE and NSTE ACS, the risks of fibrinolytic therapy outweigh the
clopidogrel was discontinued more than 5 days before the proce-
benefit for NSTE ACS patients. In fact, increased mortality has been
dure.79 Aspirin was continued up to and after CABG. Therefore, in
reported with fibrinolytics compared with controls in clinical trials
patients scheduled for CABG, clopidogrel should be withheld at
where fibrinolytics have been administered to patients with NSTE
least 5 days and preferably 7 days before the procedure.2
ACS (patients with normal or ST-segment depression ECGs).20
The timing of initiation of clopidogrel in patients presenting with
NSTE ACS is controversial. Although clopidogrel should be initiated
Aspirin as soon as possible in patients being treated with a noninterventional
Aspirin reduces the risk of death or developing MI by about 50% strategy or in patients who have a contraindication to aspirin, the
(compared with no antiplatelet therapy) in patients with NSTE need to delay CABG for 5 to 7 days following clopidogrel has led
ACS.49 Therefore, aspirin remains the cornerstone of early treat- many to suggest that clopidogrel administration should be delayed
ment for all ACSs. Dosing of aspirin for NSTE ACS is the same as until coronary angiography is performed and the need for CABG is
that for STE ACS (see Table 18–4). Aspirin is continued indefinitely. excluded. This is particularly relevant in centers where the waiting
time for CABG is less than 5 days. However, existing data also
Thienopyridines suggest that early treatment with clopidogrel before angiography is
performed reduces the number of cardiovascular events following
For patients with NSTE ACS, the addition of clopidogrel started on
the procedure.81 Therefore, others have advocated the expanded use
the first day of hospitalization as a 300- to 600-mg loading dose
of early clopidogrel in all patients experiencing a NSTE ACS.
followed the next day by 75 mg/day orally is recommended for most
patients.2 Although the use of aspirin in ACS is the mainstay of
antiplatelet therapy, morbidity and mortality following an ACS GP IIb/IIIa Receptor Inhibitors
remain high. Researchers explored whether combining two oral Administration of tirofiban or eptifibatide is recommended for
antiplatelet agents with different mechanisms of action, aspirin and high-risk NSTE ACS patients as medical therapy without planned
clopidogrel, would result in additional clinical benefit over using revascularization, and administration of either abciximab or eptifib-
aspirin alone. Efficacy and safety of this dual antiplatelet therapy atide is recommended for NSTE ACS patients undergoing PCI.
were demonstrated in the Clopidogrel in Unstable Angina to Pre- Administration of tirofiban or eptifibatide is also indicated in
vent Recurrent Events (CURE) trial.79,80 In CURE, 12,562 patients patients with continued or recurrent ischemia despite treatment
with unstable angina or an NSTE MI and new ECG changes with aspirin, clopidogrel, and an anticoagulant.2 The pharmacologic
consistent with ischemia or positive cardiac markers were random- similarities and differences between GP IIb/IIIa receptor inhibitors
ized to a loading dose of clopidogrel 300 mg, followed by a daily are reviewed in Chapter 17. As discussed in Chapter 17, the benefits
dose of 75 mg or placebo in addition to aspirin for a mean duration of GP IIb/IIIa receptor inhibitors in PCI is well established, and they
of 9 months. Clopidogrel reduced the combined risk of death from are considered first-line agents for reducing the risk of reinfarction
cardiovascular causes, nonfatal MI, or stroke from 11.4% to 9.4% and the need for repeat PCI.2,32,40
compared with placebo, mainly through a reduction in the risk of Two large clinical trials highlight the role of GP IIb/IIIa receptor
MI. Cardiovascular mortality was similar between groups. Results inhibitors in the setting of NSTE ACS and PCI. In the Platelet
from a second trial in PCI patients, the Clopidogrel for the Reduc- Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression
tion of Events During Observation (CREDO) trial,81 in which Using Integrilin Therapy (PURSUIT) trial (n = 10,948), eptifibatide
patients were treated with long-term clopidogrel (1 year), demon- added to aspirin and UFH and continued for 48 to 96 hours reduced
strated a lower risk of death, MI, or stroke compared with patients the combined end point of death or MI at 30 days (14.2% vs 15.7%)
who received only 28 days of clopidogrel (8.5% vs 11.5%; P = 0.02). compared with aspirin and UFH alone.84 In the Platelet Receptor
However, the interpretation of this study is limited in that the Inhibition in Ischemic Syndrome Management in Patients Limited
control group did not receive a loading dose of clopidogrel on the by Unstable Signs and Symptoms (PRISM-PLUS) study (n = 1,915),
first day. According to the ACC/AHA 2007 guidelines, clopidogrel tirofiban added to aspirin and UFH and continued for up to 72
is indicated for up to 12 months in NSTE ACS patients, with a hours reduced the rate of death, MI, or refractory ischemia at 7 days
minimum duration of treatment of 1 month after placement of a compared with aspirin and UFH alone.85 However, in these and
bare-metal stent and 12 months after placement of a sirolimus or other trials of GP IIb/IIIa inhibitors for NSTE ACS, the benefit was
paclitaxel coated stent.2,55 Whether or not treatment with clopido- mostly limited to patients undergoing PCI and not those treated
grel should be extended to more than 1 year is questionable based without interventional therapy.86 Therefore, medical therapy with
on recent a large, randomized trial.82 GP IIb/IIIa receptor inhibitors is reserved for higher-risk patients,
 266
such as those with positive troponin or ST-segment depression, and
patients who have continued or recurrent ischemia despite other CLINICAL CONTROVERSIES
SECTION 2

antithrombotic therapy.2,32,40 Patients undergoing PCI in these trials

A recent noninferiority study comparing early “upstream” admin-
received several hours to days of pretreatment with the GP IIb/IIIa istration of a GP IIb/IIIa inhibitor versus delayed selective therapy
receptor inhibitor before proceeding to PCI. at the time of PCI in patients with NSTE ACS showed no statistical
The role of GP IIb/IIIa receptor antagonists in patients with NSTE difference in ischemic events but more bleeding events when a GP
ACS undergoing PCI also was evaluated in two large clinical trials that IIb/IIIa inhibitor (with either UFH or enoxaparin) was adminis-
used GP IIb/IIIa receptor inhibitors initiated at the time of PCI. In the tered prior to angiography.95 Ninety-eight percent of patients in
Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin
the upstream arm received a GP IIb/IIIa inhibitor, but only 56% of
Therapy (ESPRIT) trial (n = 1,024), eptifibatide in combination with
patients received one in the selective arm, mostly because no PCI
Cardiovascular Disorders

aspirin and UFH reduced the rate of death or MI up to 1 year in

was performed and therefore a GP IIb/IIIa inhibitor was no longer
patients undergoing PCI.87 The benefits of treatment in the ACS
indicated. The median duration of administration of a GP IIb/IIIa
subgroup were more pronounced compared with the stable angina inhibitor prior to PCI in the upstream arm was short, only 4 hours,
subgroup, thereby establishing a role for eptifibatide in ACS PCI as were the overall median durations of administration in both
patients. groups, 18 hours in the upstream arm and 13 hours in the selective
Only one trial has compared two GP IIb/IIIa receptor inhibitors arm, indicating that statistical power may not have been sufficient.
with each other. In the Do Tirofiban and ReoPro Give Similar Efficacy Because the difference in duration of administration between the
Outcomes Trial (TARGET), tirofiban, at a different dose from that two groups was small, some question whether this study was a true
used in the PRISM-PLUS study, was compared with abciximab in comparison of early versus deferred treatment. Therefore,
patients undergoing PCI.88,89 In the subgroup of patients with ACS, although a GP IIb/IIIa inhibitor may be used in patients with NSTE
there was a statistically significant reduction in the composite end ACS the timing of administration, whether given early or deferred
point of death, nonfatal MI, or need for repeat PCI at 30 days in and used selectively at the time of angiography is controversial.
patients randomized to receive abciximab compared with tirofiban
(6.3% vs 9.3%).89 Although the numerical benefit of a 3% absolute risk
reduction was maintained at 6 months, it approached but was no Anticoagulants
longer statistically significant (hazard ratio 1.19, abciximab better than The recommendations for anticoagulants in the 2007 NSTE ACS
tirofiban, 95% confidence internal 0.99–1.42).89 Following TARGET, ACC/AHA guidelines are guided by the results of recent clinical
the dose of tirofiban that was used in that trial has been shown to be trials.2 For patients undergoing planned early angiography and
ineffective at inhibiting platelet aggregation during the PCI proce- revascularization with PCI, UFH, LMWH, fondaparinux, or bivaliru-
dure.90 Therefore, tirofiban cannot be recommended for PCI unless din should be administered to patients with NSTE ACS.2 Because
the patient has been treated with tirofiban for several hours to days more data support the use of enoxaparin,2 it is the preferred LMWH
prior to PCI and adequate inhibition of platelet aggregation can be for ACS. Therapy should be continued for up at least 48 hours for
ensured. If a GP IIb/IIIa receptor inhibitor is initiated while the patient UFH, until the patient is discharged from the hospital for either
is undergoing the procedure, abciximab or eptifibatide should be used. enoxaparin or fondaparinux or a maxiumum of 8 days, and until the
Importantly, in patients with NSTE ACS undergoing PCI, use of end of PCI or angiography procedure (or up to 42 hours following
clopidogrel does not obviate the need for a GP IIb/IIIa inhibitor.91 PCI) for bivalirudin.2 UFH is the preferred anticoagulant following
As emphasized in the ACC/AHA guidelines,2 the benefits of GP angiography in patients subsequently undergoing CABG during the
IIb/IIIa inhibitors are greater in patients undergoing PCI. A meta- same hospitalization.2 In patients in whom an initial conservative
analysis estimated that 30 adverse outcomes (either death or MI) are strategy is planned (i.e., are not anticipated to receive angiography
prevented for every 1,000 patients treated with a GP IIb/IIIa and revascularization), enoxaparin, UFH, or fondaparinux is recom-
inhibitor before PCI, whereas only four events are prevented for mended.2 For patients presenting with NSTE ACS in whom cardiolo-
medical management of patients with NSTE ACS using GP IIb/IIIa gists suspect a high risk for bleeding while receiving an anticoagulant,
inhibitors without PCI.92 This translates into a number needed to fondaparinux is the preferred anticoagulant recommended by the
treat (NNT) of 32 patients to prevent one event if a GP IIb/IIIa ACC/AHA NSTA ACS guidelines.2 In patients initiating warfarin
inhibitor is administered before PCI and 250 patients to prevent one therapy, UFH or LMWHs should be continued until the international
event if it is administered as medical therapy without PCI.92 normalized ratio (INR) with warfarin is in the therapeutic range.
Doses and contraindications to GP IIb/IIIa receptor blockers are Data supporting the addition of UFH to aspirin stems from a meta-
listed in Table 18–4, and common adverse effects are described in the analysis of six randomized trials demonstrating a 33% reduction in
preceding section. Administration of IV GP IIb/IIIa receptor inhibi- the risk of death or MI at 6 weeks with UFH plus aspirin compared
tor in combination with aspirin and either UFH or enoxaparin results with aspirin alone.96 One trial compared the LMWH dalteparin plus
in major bleeding rates of 0.4% to 10.6% 84,85 but no increased risk of aspirin with aspirin alone and found a 60% reduction in death or MI
ICH in the absence of concomitant fibrinolytic treatment. Some at 6 days.97 Three clinical trials have compared UFH with LMWHs for
studies suggest that although the risk of minor bleeding is higher, the medical management of NSTE ACS.98–100 Two trials with a total of
risk of major bleeding with a GP IIb/IIIa inhibitor is similar to approximately 7,000 patients demonstrated a 15% reduction in the
placebo in patients treated with UFH who undergo PCI.85,91 Risk composite end point of death, MI, or recurrent ischemia with enox-
factors that increase the chance of bleeding with a GP IIb/IIIa aparin compared with UFH.98,99 One trial of dalteparin in approxi-
inhibitor include female gender, older age, and reduced renal func- mately 1,400 patients demonstrated similar outcomes between
tion.93 Older patients, especially women, are more likely to receive an dalteparin and UFH.100 The results from these trials also showed no
excessive dose of a GP IIb/IIIa inhibitor, which can result in bleed- increased risk of major bleeding with LMWHs compared with
ing.94 Because both eptifibatide and tirofiban require dose reductions UFH.98–100 Minor bleeding, mostly injection-site hematomas, was
for patients with renal insufficiency (see Table 18–4), careful attention increased because the LMWHs are given by subcutaneous injection,
to calculating creatinine clearance and dose adjustment is required for whereas UFH was administered by continuous infusion.98–100 Because
these agents. The risk of thrombocytopenia with tirofiban and eptifib- of a reduction in event rates compared with UFH, enoxaparin was
atide appears to be lower than that with abciximab. Bleeding risks mentioned as “preferred” over UFH in the ACC/AHA clinical prac-
appear similar among agents. tice guidelines.2
 267
Previously, lack of data with LMWHs in NSTE ACS patients with a GP IIb/IIIa inhibitor in patients with NSTE ACS. Potential
undergoing PCI has limited their use in this setting. Traditionally, advantages of direct thrombin inhibitors over UFH are that they bind

CHAPTER 18
interventional cardiologists monitor the degree of anticoagulation of to and inhibit clot-bound thrombin in addition to circulating throm-
UFH using the activated clotting time (ACT) in the cardiac catheter- bin, and they have no significant binding to plasma proteins so they
ization laboratory. Because LMWHs have only a small effect on have a more predictable anticoagulant response. In addition, because
increasing the ACT owing to their preferential effect on activated thrombin is a potent stimulus for platelet aggregation, direct thrombin
factor X inhibition, the ACT cannot be used to monitor LMWH inhibitors have antiplatelet as well as anticoagulant activity. Like
efficacy or toxicity. One large clinical trial of enoxaparin compared lepirudin, bivalirudin exhibits bivalent binding to thrombin, that is, it
with UFH in this setting found similar efficacy with a higher risk of binds to both the active site and exosite-1, although argatroban binds
major bleeding with enoxaparin (9.1% vs 7.6%; P = 0.008).101 The to only to the active site. Unlike lepirudin, both argatroban and

Acute Coronary Syndromes

authors concluded that use of enoxaparin resulted in a similar bivalirudin exhibit reversible binding to thrombin, whereas lepirudin
reduction in death or MI compared to UFH. This trial was con- binds irreversibly. After bivalirudin binds to thrombin, thrombin
founded by a large number of patients who received both UFH and cleaves a bivalirudin Arg3–Pro4 bond, reexposing the thrombin cata-
enoxaparin either prior to randomization or during PCI. A subgroup lytic site.104 Thus, bivalirudin provides consistent anticoagulation
analysis of patients receiving only consistent therapy with either when administered as an IV bolus and infusion, but its activity is short
enoxaparin or UFH throughout the study demonstrated an 18% lived when the drug is discontinued. These potential advantages
reduction in 30-day death or MI with enoxaparin (P = 0.004), but suggest that bivalirudin may have similar or superior efficacy and
still with an increased risk of bleeding with enoxaparin compared to fewer bleeding complications compared to traditional anticoagulants.
UFH.102 Switching between UFH and enoxaparin should be avoided. In the Acute Catheterization and Urgent Intervention Triage
The risk of major bleeding with UFH or LMWHs is higher in Strategy (ACUITY) trial, 13,819 patients with NSTE ACS at moder-
patients undergoing angiography because of an associated risk of ate to high risk of death or MI (expected to undergo coronary
hematoma at the femoral access site. The risk of heparin-induced angiography within the first 48–72 hours of hospital admission)
thrombocytopenia is lower in some, but not all, clinical trials with were randomized to one of three antithrombotic treatment strate-
LMWHs compared with UFH. gies: (1) heparin (UFH or enoxaparin) plus a GP IIb/IIIa inhibitor,
Because LMWHs are eliminated renally and patients with renal (2) bivalirudin plus GP IIb/IIIa inhibitor, or (3) bivalirudin alone in
insufficiency generally are excluded from clinical trials, some prac- a noninferiority trial (see Table 18–4 for dosing).104 The primary end
tice protocols recommend UFH for patients with creatinine clear- point was “net clinical outcome” at 30 days, which was a quadruple
ance rates less than 30 mL/min. (Creatinine clearance is calculated end point consisting of the composite ischemic end point (death, MI,
based on total patient body weight.) However, although recommen- or unplanned revascularization for ischemia) plus non-CABG major
dations for dosing adjustment of enoxaparin in patients with creati- bleeding. The results of the quadruple end point were that bivaliru-
nine clearances between 10 and 30 mL/min are listed in the product din alone was noninferior to bivalirudin plus a GP IIb/IIIa inhibitor
manufacturer’s label, the safety and efficacy of LMWH in this patient and superior to heparin plus a GP IIb/IIIa inhibitor. The benefit of
population remain vastly understudied (see Table 18–4). Adminis- bivalirudin alone was that it reduced the rate of major bleeding by
tration of LMWHs should be avoided in dialysis patients with ACS. 47% compared to heparin plus a GP IIb/IIIa receptor inhibitor.
UFH is monitored and the dose adjusted to a target aPTT, whereas Although numerically higher in the bivalirudin group, the ischemic
LMWHs are administered by a fixed, weight-based dose. Other end points were not statistically different between the groups.105
dosing information and contraindications are listed in Table 18–4. With similar efficacy and a lower bleeding rate, on the surface
In OASIS-5, the largest NSTE ACS trial performed to date (N = bivalirudin alone appears the preferred therapy. However, several
20,078), a low dose of fondaparinux, 2.5 mg administered once daily issues surround the study design and application to practice. The
subcutaneously, was compared to the usual NSTE ACS dose of main issue surrounds the noninferiority margin of 25% used in the
enoxaparin, 1 mg/kg administered every 12 hours.103 Fondaparinux trial. This means that bivalirudin could be 25% “worse” than heparin
was found to be noninferior to enoxaparin with respect to the plus GP IIb/IIIa inhibitor treatment and still be called “noninferior.”
clinical end point of 9-day death, MI, or refractory ischemia (5.8% vs In fact, the upper boundary of the 95% confidence interval for the
5.7%, hazard ratio 1.01, 95% confidence interval 0.90–1.13). Fonda- ischemic composite end point comparing bivalirudin alone with
parinux also reduced the rate of major bleeding compared to heparin plus a GP IIb/IIIa inhibitor was 1.24.105 Other contemporary
enoxaparin (2.2% vs 4.1%, P <0.001). At 30 days, mortality was NSTE ACS trials, such as SYNERGY (Superior Yield of the New
lower in fondaparinux-treated patients (8.0 vs 8.6%, hazard ratio Strategy of Enoxaparin, Revascularization, and Glycoprotein Inhibi-
0.83, 95% confidence interval 0.71–0.97), and the investigators tors), have used lower margins. More than 60% of patients received
suggested that the excess mortality observed in enoxaparin-treated on average more than 14 hours of prerandomized treatment prior to
patients was related to bleeding events. The major limitation of study enrollment and were “crossed over” to study medications.105
OASIS-5 is that only 30% of patients underwent PCI. In addition, Study medications were administered for a median duration of less
the duration of study drug administration (median ≈5 days) was than 6 hours before coronary angiography and PCI, and the overall
longer than usual in the United States, which may have increased duration of study drug administration was less than 18 hours
bleeding events. Supplemental doses of UFH were administered to because most study drugs were discontinued after angiography. 105
patients randomized to enoxaparin who underwent PCI. For Therefore, although patients were randomized, there was potential
patients randomized to fondaparinux who underwent PCI, the for the prerandomization therapy to impact study outcomes. Some
protocol was changed. The original protocol specified that IV fonda- have questioned whether the short duration of treatment was long
parinux be administered to patients undergoing PCI. When this enough to impact outcomes. Therefore, although bivalirudin is a
practice was associated with catheter thrombosis, the protocol was choice for higher-risk patients anticipated to undergo angiography
changed to recommend administration of supplemental UFH (see and PCI, it was not given a “preferred” recommendation in the 2007
Table 18–4 for recommendations) to fondaparinux-treated patients NSTE ACS guidelines.
undergoing PCI. As a result, interventional cardiologists may be Because a variety of anticoagulants are recommended by the guide-
reluctant to use low-dose fondaparinux in patients undergoing PCI. lines, practitioners should be familiar with the study designs, patient
Bivalirudin is an IV direct thrombin inhibitor that has been com- demographics, and results for recent NSTE ACS studies and develop
pared to the combination of a heparin, either UFH or enoxaparin, protocols for dosing each agent that is on the hospital formulary.
 268

Nitrates 3. Prevent recurrent MI and stroke

In patients with ischemic chest discomfort, SL NTG 0.4 mg every 5 4. Prevent death, including sudden cardiac death
SECTION 2

minutes for a total of three doses should be administered. IV NTG

Pharmacotherapy that has been proven to decrease mortality,
should be administered to all patients with NSTE ACS who have heart failure, reinfarction, or stroke should be initiated prior to hospital
persistent ischemia, heart failure symptoms, or hypertension in the discharge for secondary prevention. Guidelines from the ACC/AHA
absence of contraindications (see Table 18–4).2 The mechanism of suggest that following MI from either STE or NSTE ACS, patients
action, dosing, contraindications, and adverse effects are the same as should receive indefinite treatment with aspirin, a β-blocker, and an
described in the section on Early Pharmacotherapy for STE ACS ACE inhibitor.2,3,108 All patients should receive SL NTG or lingual spray
above. IV NTG typically is continued for approximately 24 hours and instructions for use in case of recurrent ischemic chest discomfort.2
following ischemia relief. The mechanism of action, dosing, contra- Clopidogrel should be considered for most patients, but the duration of
Cardiovascular Disorders

indications, and adverse effects are the same as described in the therapy is individualized according to the type of ACS and whether the
section on Early Pharmacotherapy for STE ACS above. patient is treated medically or undergoes intracoronary stent implan-
tation.2 All patients should receive annual influenza vaccina-
β-Blockers tion.108,109 Selected patients (described below in Anticoagulation)
Oral β-blockers should be administered to all patients with NSTE also should be treated with long-term warfarin anticoagulation.
ACS in the absence of contraindications.2 IV β-blockers should be Newer therapies include eplerenone, an aldosterone antagonist for
considered in hemodynamically stable patients who present with heart failure. For all ACS patients, treatment and control of modifiable
persistent ischemia, hypertension, or tachycardia. The mechanism risk factors, such as hypertension, dyslipidemia, and diabetes mellitus,
of action, dosing, contraindications, and adverse effects are the are essential. Most patients with CHD will require drug therapy for
same as described in the section on Early Pharmacotherapy for STE dyslipidemia, usually with a statin (hydroxymethylglutaryl coenzyme A
ACS above. β-Blockers are continued indefinitely. reductase inhibitor). Benefits and adverse effects of long-term treat-
ment with these medications are discussed in more detail below.
Calcium Channel Blockers
Calcium channel blockers should not be administered to most Aspirin
patients with ACS.2 Their role is a second-line treatment for patients Aspirin decreases the risk of death, recurrent MI, and stroke following
with certain contraindications to β-blockers (as described in Table MI. An aspirin prescription at hospital discharge is a quality care
18–4) and those with continued ischemia despite β-blocker and indicator in MI patients (see Table 18–3).33 The clinical value of
nitrate therapy. They are a first-line therapy for patients with aspirin in secondary prevention of ACS and other vascular diseases
Prinzmetal vasospastic angina and those with cocaine-associated was demonstrated in a large number of clinical trials. Following an
ACS. Administration of amlodipine, diltiazem, or verapamil is MI, aspirin is expected to prevent 36 vascular events per 1,000
preferred.2 Agent selection based on heart rate and LV dysfunction patients treated for 2 years.46 Because the benefit of antiplatelet agents
(diltiazem and verapamil contraindicated in patients with bradycar- appears to be sustained for at least 2 years following an MI,49 aspirin
dia, heart block, or systolic heart failure) is described in more detail should be given indefinitely to all patients, or clopidogrel to patients
in the section on Early Pharmacotherapy for STE ACS above. with a contraindication to aspirin.2,3
Dosing and contraindications are described in Table 18–4. The risk of major bleeding from chronic aspirin therapy is approx-
imately 2% and is dose related. Although high doses of aspirin (>325
Glycemic Control mg daily) are well established to have a higher risk of bleeding
Numerous guidelines and standards address the management of compared to lower doses, whether dose of 75 to 100 mg daily have a
diabetes mellitus in the outpatient setting, but only recently has lower bleeding risk than doses >100 to 325 mg daily remains contro-
sufficient evidence warranted the development of standards of care to versial.48,50 After an initial dose of 325 mg, chronic therapy with
optimize inpatient glycemic control for hospitalized individuals with aspirin should be 75 to 81 mg once daily. The exception is patients in
diabetes or illness-induced hyperglycemia. A joint practice guideline the setting of recent intracoronary stent placement for whom the
from the American Diabetes Association and the American College of AHA/ACC recommend 162–325 mg of aspirin once daily for at least
Endocrinology recommends that the blood glucose level in critically 30 days following placement of a bare-metal stent, 3 months after a
ill patients, such as those with ACS, be kept as close as possible to 110 sirolimus-coated stent, and 6 months after a paclitaxel-coated, fol-
mg/dL (6.1 mmol/L).106 This is supported by the 2004 ACC/AHA lowed thereafter by a daily dose of 75 to 162 mg.40
STEMI guidelines that recommend normalization of blood glucose In order to minimize the risk of bleeding, use of aspirin with
during the first 24 to 48 hours of care.3 Elevated blood glucose levels other agents that can induce bleeding, including clopidogrel and
are associated with higher mortality rates and larger infarct size in warfarin, should be avoided, unless the combination is clinically
patients with acute MI.106 Beneficial outcomes associated with “tight” indicated and the increased risk of bleeding has been considered in
glucose control include reductions in the development of renal evaluating the potential benefit of using such a combination.
dysfunction, infections, and length of mechanical ventilation.3,106 A Other gastrointestinal disturbances, including dyspepsia and
meta-analysis of 35 clinical trials found a 15% reduction in mortal- nausea, are infrequent when low-dose aspirin is used.46
ity.107 IV insulin infusions are commonly administered to critically ill
patients hospitalized in the intensive care unit to maintain euglyce- Thienopyridines
mia.3 Additional information on management of hyperglycemia in For patients with NSTE ACS, clopidogrel decreases the risk of develop-
the hospitalized patient can be found in Chapter 77. ing death, MI, or stroke. The benefit derives primarily from reducing
the rate of MI.79 Most patients with NSTE ACS should receive
■ SECONDARY PREVENTION FOLLOWING MI clopidogrel, in addition to aspirin, for up to 12 months.2,108 For
patients with an STEMI treated medically without revascularization
The long-term goals following MI are as follow:
including PCI or CABG, clopidogrel can be given for 14 to 28 days.53,54
1. Control modifiable CHD risk factors In patients in whom an intracoronary stent has been implanted,
2. Prevent development of systolic heart failure clopidogrel can be continued for up to 12 months in patients at low
 269
risk for bleeding, with a minimum duration of treatment contingent currently is not recommended as a preferred regimen by any profes-
upon the type of stent placed.2,48 sional association practice guidelines in the absence of the conditions

CHAPTER 18
The most common adverse effects in patients receiving clopido- for selected patients outlined previously.
grel are rash (5%) and gastrointestinal upset (3%).79

Anticoagulation CLINICAL CONTROVERSIES

Warfarin should be considered in selected patients following an No prospective, randomized trials have evaluated whether the
ACS, including patients with an LV thrombus, patients demonstrat- addition of warfarin to aspirin plus clopidogrel therapy is safe or
ing extensive ventricular wall-motion abnormalities on cardiac effective. However, the combination is used in select patients in
echocardiogram, and patients with a history of thromboembolic practice. Clinical situations in which aspirin, clopidogrel, and

Acute Coronary Syndromes

disease or chronic atrial fibrillation.3 A more detailed discussion warfarin can be used together include placement of an intracor-
regarding the use of warfarin is given in Chapter 21. onary stent (where aspirin and clopidogrel are indicated) in
Because of the importance of thrombus formation in the patho- patients with an indication for anticoagulant therapy including
physiology of ACS and the findings from several studies suggesting atrial fibrillation, acute deep vein thrombosis, presence of a
residual thrombus at the site of plaque rupture even months mechanical heart valve, and MI with a low EF. In such cases, the
following an MI, anticoagulants, primarily warfarin, have been the duration of use of this triple antithrombotic drug combination
subject of many clinical trials of patients after an ACS. These trials should be minimized and the INR monitored closely. The most
have produced varying and inconsistent results. Because the inten- recent guidelines from the ACC/AHA recommend a lower target
sity of anticoagulation varied among these trials, it is important to INR of 2.0 to 2.5 in patients receiving this combination, but no
take into consideration the intensity of the anticoagulation when prospective randomized trials have been reported.2
interpreting the results of these trials.
Data from two large, randomized trials demonstrate that use of
low, fixed-dose warfarin (mean INR 1.4) combined with aspirin110
β-Blockers, Nitrates, and Calcium
or of low-intensity anticoagulation (mean INR 1.8) monotherapy111 Channel Blockers
provided no significant clinical benefit compared with aspirin Current treatment guidelines recommend that, following an ACS,
monotherapy but significantly increased the risk of major bleeding. patients should receive a β-blocker indefinitely,2,3,107 whether or not
Therefore, warfarin therapy targeted to INR <2 cannot be recom- they have residual symptoms of angina.116 β-Blocker prescription at
mended for secondary prevention of CHD events following MI. hospital discharge in the absence of contraindications is a quality
Subsequently, in two other large, randomized trials, a strategy of performance measure (see Table 18–3).33 Overwhelming data support
combining intermediate-intensity anticoagulation (target INR 2–2.5) the use of β-blockers in patients with a previous MI. Data from a
with low-dose aspirin reduced the combined end point of death, MI, or systematic review of long-term trials of patients with recent MI demon-
stroke in patients following MI compared with aspirin alone. The strate that the NNT for 1 year with a β-blocker to prevent one death is
Antithrombotics in Secondary Prevention of Events in Coronary only 84 patients.116 Because the benefit from β-blockers appears to be
Thrombosis-2 (ASPECT-2)112 and the Warfarin-Aspirin Re-Infarction maintained for at least 6 years following an MI,117 it is recommended
Study (WARIS II)113 reported that warfarin alone targeted to a high- that all patients receive β-blockers indefinitely in the absence of contra-
intensity INR and medium-intensity warfarin plus low-dose aspirin indications or intolerance.2,3 Currently, no data support the superiority
were superior to aspirin alone in preventing the combined end point of of one β-blocker over another. Although β-blockers with intrinsic
death, MI, or stroke. The target INR in the high-intensity warfarin sympathomimetic actvity are generally not recommended, one study of
monotherapy group was 3 to 4111 and 2.8 to 4.2,113 respectively. The modest size showed that acebutolol, a β-blocker with intrinsic sym-
target INR in the more effective medium-intensity warfarin and low- pathomimetic activity, was beneficial following MI.118
dose aspirin group was 2 to 2.5 in both trials. No significant differences Although β-blockers should be avoided in patients with decom-
in efficacy were observed between the combination of medium-inten- pensated heart failure from LV systolic dysfunction complicating an
sity anticoagulation and low-dose aspirin and monotherapy with high- MI, clinical trial data suggest that initiation of β-blockers prior to
intensity anticoagulation. A meta-analysis of 14 clinical trials in more hospital discharge is safe in these patients once heart failure symp-
than 25,000 patients following either STE or NSTE MI found that the toms have resolved.119 These patients actually may benefit more
addition of warfarin (target INR of 2 to 3) to aspirin reduced the risk of than those without LV dysfunction.120
death, MI or stroke, whereas the addition of warfarin with a target INR Despite the overwhelming benefit demonstrated in clinical trials,
outside this target was of no benefit.114 Nonetheless, this benefit was β-blockers are still widely underused, perhaps because clinicians fear
obtained at the cost of doubling the risk of major bleeding.114 that patients will experience adverse reactions, including depression,
Many consider this net benefit to be small in comparison with the fatigue, and sexual dysfunction. A systematic review of 15 trials that
large management issues related to warfarin therapy, such as INR included more than 35,000 patients demonstrated that withholding
monitoring and drug interactions. In the meta-analysis described β-blocker therapy in such a group was unfounded because β-blockers
above,114 the NNT to prevent one event was 33, whereas the number do not significantly increase the risk of depression and only modestly
needed to harm (NNH) was 100. In addition, WARIS II and ASPECT- increase the risk of fatigue and sexual dysfunction.121
2 were conducted in the Netherlands and in Norway, two countries In patients who cannot tolerate or have a contraindication to a β-
renowned for the quality of their anticoagulation programs and blocker, a calcium channel blocker can be used to prevent anginal
clinics, thereby limiting generalization of the findings. Furthermore, a symptoms but should not be used routinely in the absence of such
large proportion of ACS patients in North America undergo coronary symptoms.2,3,122 Finally, all patients should be prescribed short-acting
revascularization with subsequent intracoronary stent implementa- SL NTG or lingual NTG spray to relieve any anginal symptoms when
tion for which patients require a combination of aspirin and clopido- necessary and should be instructed on its use.2,3 Chronic long-acting
grel to prevent stent thrombosis, a platelet-dependent phenomenon nitrate therapy has not been shown to reduce CHD events following
that warfarin does not effectively prevent.115 Therefore, because of the MI. Therefore, IV NTG is not followed routinely by chronic, long-
complexity of managing current anticoagulants, use of warfarin is acting oral nitrate therapy in ACS patients who have undergone
unlikely to gain wide acceptance (see Clinical Controversies). Despite revascularization unless they have chronic stable angina or significant
the superiority of warfarin plus aspirin over aspirin alone, warfarin coronary stenoses that were not revascularized.122
 270

ACE Inhibitors and Angiotensin (ARBs) candesartan and valsartan improve clinical outcomes in
Receptor Blockers patients with heart failure.130,131 Therefore, either an ACE inhibitor or
SECTION 2

candesartan or valsartan is an acceptable choice for chronic therapy

ACE inhibitors should be initiated in all patients following MI to reduce for patients with a low EF and heart failure following MI. Because
mortality, decrease reinfarction, and prevent development of heart fail- more than five different ACE inhibitors have proven benefits in MI
ure.2,3,108 Dosing and contraindications are described in Table 18–4. The but only two ARBs have been studied, the benefits of ACE inhibitors
benefit of ACE inhibitors in patients with MI most likely derives from are generally considered a class effect while the benefits of ARBs are
their ability to prevent cardiac remodeling. Other proposed mechanisms still under study. ACE inhibitor prescription (or alternatively an
include improvement in endothelial function, reduction in atrial and ARB) at hospital discharge following MI, in the absence of contrain-
ventricular arrhythmias, and promotion of angiogenesis, leading to a dications, to patients with depressed LV function (EF <40%) cur-
reduction in ischemic events. The largest reduction in mortality is
Cardiovascular Disorders

rently is a quality performance measure,33 and plans are being made

observed for patients with LV dysfunction (low LVEF) or heart failure to make administration of an ACE inhibitor in all patients without
symptoms. Use of ACE inhibitors in relatively unselected patients with- contraindications a quality care measure.
out a contraindication to ACE inhibitors can be expected to save five lives Besides hypotension, the most frequent adverse reaction to an ACE
per 1,000 patients treated for 30 days.123 Long-term studies in patients inhibitor is cough, which may occur in up to 30% of patients. Patients
with LV systolic dysfunction with or without heart failure symptoms with ACE inhibitor cough and either clinical signs of heart failure or
demonstrate greater benefit because mortality reductions are larger LVEF <40% can be prescribed an ARB.3 Other less common but
(23.4% vs 29.1%; P <0.0001) such that only 17 patients need treatment more serious adverse effects of ACE inhibitors and ARBs include
to prevent one death, with 57 lives saved for every 1,000 patients acute renal failure and hyperkalemia. Although the incidence of
treated.124 ACE inhibitor prescription at hospital discharge following MI, angioedema appears higher in patients receiving ACE inhibitors
in the absence of contraindications, to patients with depressed LV (0.1%–1.0% with ACE inhibitor), ARBs also have been associated
function (EF <40%) currently is a quality care indicator, and plans are with angioedema, including recurrent angioedema in patients with a
being made to make administration of an ACE inhibitor in all patients history of angioedema while receiving an ACE inhibitor.132 Therefore,
without contraindications a quality care indicator (see Table 18–3).33 although ARBs are not contraindicated, the severity of angioedema
Early initiation (within 24 hours) of an oral ACE inhibitor while receiving an ACE inhibitor (e.g., tongue or laryngeal edema
appears to be crucial during an acute MI because 40% of the 30-day necessitating intubation and mechanical ventilation) should be con-
survival benefit is observed during the first day, 45% from days 2 to sidered before starting an ARB in a patient with prior ACE inhibitor-
7, and approximately only 15% from days 8 to 30.123 However, associated angioedema.
current data do not support the early administration of IV ACE Although some data have suggested that aspirin use may decrease
inhibitors in patients experiencing an MI because mortality may be the benefits of ACE inhibitor treatment, a systematic review of more
increased.125 Hypotension should be avoided because coronary than 20,000 patients demonstrated that ACE inhibitors improve
artery filling may be compromised. Because the benefits of ACE outcome irrespective of treatment with aspirin.133
inhibitor administration have been documented for up to 12 years
following therapy for 2 to 4 years post- MI in patients with LV
dysfunction,124,126 administration should continue indefinitely. Aldosterone Antagonists
Additional data suggest that most patients with CAD, not just ACS Administration of an aldosterone antagonist, either eplerenone or
or heart failure, benefit from an ACE inhibitor. In the Heart Outcome spironolactone, should be considered within the first 2 weeks
Prevention Evaluation (HOPE) trial, ramipril significantly reduced the following MI in all patients already receiving an ACE inhibitor who
risk of death, MI, or stroke in high-risk patients aged 55 years or older have EF ≤40% and either heart failure symptoms or a diagnosis of
with chronic CAD or with diabetes and one cardiovascular risk diabetes mellitus to reduce mortality.3,108 Aldosterone plays an
factor.127 The European Trial on Reduction of Cardiac Events with important role in heart failure and MI because it promotes vascular
Perindopril in Stable Coronary Artery Disease (EUROPA) extended and myocardial fibrosis, endothelial dysfunction, hypertension, LV
the benefit of chronic therapy with ACE inhibitors, in this case hypertrophy, sodium retention, potassium and magnesium loss,
perindopril, to patients with stable CAD at moderate risk for cardio- and arrhythmias. Experimental and human studies have shown that
vascular events.128 However, a trial of low-risk patients with stable aldosterone blockers attenuate these adverse effects.134 As discussed
CAD and normal LV function has suggested that the benefit of ACE in Chapter 16, the benefit of aldosterone blockade in patients with
inhibitors may not extend to these populations.129 Importantly, in this stable, severe heart failure was highlighted in the Randomized
trial, patients were treated more aggressively with both medical ther- Aldactone Evaluation Study (RALES), in which spironolactone
apy and revascularization than in HOPE and EUROPA, and risk decreased the risk of all-cause mortality.135
factors were more optimally managed. Recent AHA/ACC guidelines Eplerenone, like spironolactone, is an aldosterone blocker that
on secondary prevention of coronary and other vascular diseases have blocks the mineralocorticoid receptor. In contrast to spironolactone,
highlighted that although an ACE inhibitor should be started and eplerenone has no effect on the progesterone or androgen receptor,
continued indefinitely in all patients with LVEF ≤40% and in those thereby minimizing the risk of gynecomastia, sexual dysfunction, and
with hypertension, diabetes, or chronic kidney disease, unless contra- menstrual irregularities.134 The Eplerenone Post-Acute Myocardial
indicated, and that these agents should be considered for all other Infarction Heart Failure Efficacy and Survival Study (EPHESUS)
patients, use of ACE inhibitors may be considered optional in low-risk evaluated the effect of aldosterone antagonism in patients with an MI
patients with normal LVEF in whom cardiovascular risk factors are complicated by heart failure or LV dysfunction. Patients (n = 6,642)
well controlled and revascularization has been performed.108 There- were randomized 3 to 14 days following the MI to eplerenone or
fore, although all patients with an ACS initially should be treated with placebo.136 Eplerenone significantly reduced the risk of mortality
an ACE inhibitor, it may be appropriate to reevaluate their long-term (14.4% vs 16.7%; P = 0.008). Data from EPHESUS suggest that
use in selected low-risk individuals who may want to limit the number eplerenone reduced mortality from sudden death, heart failure, and
of medications they receive. MI. Eplerenone also reduced the risk of hospitalizations for heart
Many patients cannot tolerate chronic ACE inhibitor therapy failure. Most patients in EPHESUS also were being treated with
secondary to adverse effects outlined in the next paragraph. How- aspirin, a β-blocker, and an ACE inhibitor. Approximately half the
ever, trials have documented that the angiotensin receptor blockers patients were also receiving a statin. Therefore, the mortality reduc-
 271
tion observed was in addition to that resulting from standard therapy Additional discussion, dosing, monitoring, and adverse effects of
for secondary CHD prevention. These benefits were obtained at the using lipid-lowering drugs for secondary prevention can be found

CHAPTER 18
expense of an increased risk of severe hyperkalemia (5.5% vs 3.9%; P in Chapter 23.
= 0.002), defined as a potassium concentration ≥6 mEq/L. Patients
with serum creatinine concentration >2.5 mg/dL or serum potassium
concentration >5 mEq/L at baseline were excluded. The risk of
Fish Oils (Marine-Derived ω-3 Fatty Acids)
hyperkalemia was particularly alarming in patients with creatinine Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are
clearance <50 mL/min. This highlights the importance of close ω-3 polyunsaturated fatty acids that are most abundant in fatty fish
monitoring of potassium levels and renal function in patients being such as sardines, salmon, and mackerel. Epidemiologic and random-
treated with eplerenone. No increase in gynecomastia, breast pain, or ized trials have demonstrated that a diet high in EPA plus DHA or
supplementation with these fish oils reduces the risk of cardiovascular

Acute Coronary Syndromes

impotence was noted.
The results from EPHESUS have raised the question of which mortality, reinfarction, and stroke in patients who have experienced
aldosterone blocker, spironolactone or eplerenone, should be used an MI.145 Although the exact mechanism responsible for the benefi-
preferentially. Currently, no data support that the more selective but cial effects of ω-3 fatty acids has not been clearly elucidated, potential
more expensive eplerenone is superior to, or should be preferred to, the mechanisms include triglyceride-lowering effects, antithrombotic
less expensive generic spironolactone unless a patient has experienced effects, retardation in the progression of atherosclerosis, endothelial
gynecomastia, breast pain, or impotence while receiving spironolac- relaxation, mild antihypertensive effects, and reduction in ventricular
tone. Finally, it should be noted that hyperkalemia is just as likely to arrhythmias.145
appear with both these agents. The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto
(GISSI)-Prevenzione trial, the largest randomized trial of fish oils
Lipid-Lowering Agents published to date, evaluated the effects of open-label EPA plus DHA
(Lovaza) in 11,324 patients with recent MI who were randomized to
Overwhelming data now support the benefits of statins in patients receive 850 to 882 mg/day of n-3 polyunsaturated fatty acid (EPA plus
with CAD for the prevention of total mortality, cardiovascular DHA) at an EPA/DHA ratio of 1.2:1, 300 mg of vitamin E, both, or
mortality, and stroke. According to the National Cholesterol Educa- neither.146,147 Use of EPA plus DHA reduced the risk of death,
tion Program (NCEP) Adult Treatment Panel recommendations, all nonfatal acute MI, or nonfatal stroke, whereas use of vitamin E had
patients with CAD should receive dietary counseling and pharma- no significant impact on this combined clinical end point. Therefore,
cologic therapy in order to reach a low-density lipoprotein (LDL) based on current data, the AHA recommends that CHD patients
cholesterol concentration <100 mg/dL, with statins the preferred consume approximately 1 g EPA plus DHA per day, preferably from
agents for lowering LDL cholesterol.108,137,138 Although the primary oily fish.108,145 Because oil content in fish varies, the number of 6-oz
effect of statins is to decrease LDL cholesterol, statins are believed to servings of fish that would need to be consumed to provide 7 g EPA
produce many non–lipid-lowering or “pleiotropic” effects. These plus DHA per week varies from approximately four to more than 14
effects, which include improvement in endothelial dysfunction, for secondary prevention. The average diet only contains one tenth to
antiinflammatory and antithrombotic properties, and decreased one fifth the recommended amount.145 Supplements could be consid-
matrix metalloproteinase activity, may be relevant in patients expe- ered in selected patients who do not eat fish, have limited access to
riencing an ACS and result in short-term (<1 year) benefit. In a fish, or who cannot afford to purchase fish. Approximately three 1-g
meta-analysis of randomized, controlled clinical trials of almost fish oil capsules per day should be consumed to provide 1 g of ω-3
18,000 patients with recent ACS (<14 days), statin therapy reduced fatty acids, depending on the brand of supplement.145 Alternatively,
mortality by 19%, with benefits observed after approximately 4 the prescription drug Lovaza can be used at a dose of 1 g/day. Finally,
months of treatment.139 current guidelines suggest that higher doses of EPA plus DHA (2–4 g/
Newer recommendations from the NCEP give an optional goal of day) can be considered for the management of hypertriglyceride-
LDL cholesterol <70 mg/dL for secondary prevention.2,138 This recom- mia.2,108,145 Adverse effects from fish oils include fishy aftertaste,
mendation is based upon a large clinical trial evaluating recurrence of nausea, and diarrhea.145
major cardiovascular events in patients with a history of an ACS
occurring within the past 10 days. This trial documented the benefit of
lowering LDL cholesterol to, on average, 62 mg/dL, with 80 mg of Other Modifiable Risk Factors
atorvastatin compared to 95 mg/dL in patients treated with pravastatin Smoking cessation, control of hypertension, weight loss, and tight
40 mg daily.140 Whether a statin should be used routinely in all patients glucose control for patients with diabetes mellitus, in addition to
irrespective of their baseline LDL cholesterol level is currently being treatment of dyslipidemia, are important treatments for secondary
investigated, but preliminary data from the Heart Protection Study prevention of CHD events.3,108 All patients with CAD should receive
suggest that patients benefit from statin therapy irrespective of their annual influenza vaccination.108,109 Influenza-related deaths are high-
baseline LDL cholesterol level.141 The 2007 ACC/AHA NSTE ACS est among patients with CVD compared to patients with other
guidelines recommend statin therapy, in addition to diet, for all ACS medical conditions.109 Randomized controlled clinical trials have
patients, regardless of LDL cholesterol level, although the exact target shown that annual influenza vaccination reduces cardiovascular mor-
LDL, if the patient’s LDL cholesterol at hospital presentation is already tality and MI.109 Smoking cessation is accompanied by a significant
<70 mg/dL is not stated.2 reduction in all-cause mortality in patients with CAD.148 Smoking
A fibrate or niacin should be considered in selective patients with a cessation counseling at the time of discharge following MI is a quality
low high-density lipoprotein (HDL) cholesterol concentration (<40 care indicator (see Table 18–3). 33 Use of nicotine patches or gum or
mg/dL) and/or a high triglyceride level (>200 mg/dL).2,108,137 In a of bupropion alone or in combination with nicotine patches should
large, randomized trial of men with established CAD and low levels of be considered in appropriate patients.3 Following MI, hypertension
HDL cholesterol, use of gemfibrozil (600 mg twice daily) significantly should be strictly controlled to a target blood pressure <130/80 and
decreased the risk of nonfatal MI or death from coronary causes.142 even lower, and to <120/80 in patients with LV dysfunction according
No such benefit was observed with fenofibrate in a large multicenter to recently published guidelines from AHA.51 Patients who are over-
primary and secondary prevention study in patients with diabetes weight should be educated on the importance of regular exercise,
mellitus.143 Due to the increased risk of myopathy, gemfibrozil is not healthy eating habits, and of reaching and maintaining an ideal
recommended in patients receiving a statin.144 weight.149 Finally, because diabetics have up to a fourfold increased
 272
risk of mortality compared with nondiabetics, the importance of tight ■ ADHERENCE TO THERAPY
glucose control, as well as other CHD risk factor modification, cannot
SECTION 2

be understated.150 Medication noncompliance poses a problem in patients following

ACS. Medication discontinuation has been associated with an
Therapies Not Useful and Potentially increased risk of cardiovascular events and mortality in patients with
various types of CVD.158–160 In clinical trials, poor adherence is
Harmful following MI associated with poor outcome, regardless of treatment assignment,160
Administration of hormone-replacement therapy to all women fol- highlighting that this behavior may be related with other health-
lowing MI does not prevent recurrent CHD events and may be related behaviors in patients. Increased adherence to statins and β-
harmful.151,152 According to the NSTE and NSTE ACS guidelines, blockers has been associated with lower long-term mortality.161
postmenopausal women already taking estrogen plus progestin should The discontinuation of clopidogrel may be particularly problem-
Cardiovascular Disorders

not continue, especially while at bedrest in hospital, because of an atic in patients treated with a drug-eluting stent,162 because this action
increased risk of venous thromboembolism.2,3 The U.S. Preventative places the patient at increased risk for stent thrombosis.55 Current
Services Task Force as well as the ACC/AHA have concluded that the data suggest that long-term adherence and persistence to statins in
administration of vitamins A, C, or E, multivitamins with vitamins B6, patients with an ACS and in patients with chronic CAD is variable.163–166
B12, folic acid, or a combination of antioxidants for secondary preven- Early initiation of statins in patients with ACS appears to increase
tion are ineffective following MI.2,146,153–157 Furthermore, they caution long-term adherence with statin therapy, which should result in
against the use of β-carotene supplementation, particularly in heavy clinical benefit.139 Therefore, statin therapy initiation should not be
smokers, because of an apparent increased risk of lung cancer.154 A delayed in patients with an ACS, and statins should be prescribed at
stepped-care approach using acetaminophen, small doses of narcotics, or prior to discharge in most patients.
and nonacetylated salicylates are preferable to COX-2–selective Several clinical trials have documented the value of a pharmacist in
NSAIDs for treatment of chronic musculoskeletal pain. Use of the the management of improving adherence and persistence to medica-
nonselective NSAID naproxen is recommended over more COX-2– tion, which in turn can significantly improve the treatment of risk
selective agents, which have been associated with risks for MI.2 factors such as hypertension, heart failure, and dyslipidemia.167,168

TABLE 18-7 Therapeutic Drug Monitoring for Adverse Effects of Pharmacotherapy for Acute Coronary Syndromes
Drug Adverse Effects Monitoring
Aspirin Dyspepsia, bleeding, gastritis Clinical signs of bleeding,a gastrointestinal upset; baseline CBC and platelet count; CBC
platelet count every 6 months
Clopidogrel Bleeding, TTP (rare), diarrhea, rash Clinical signs of bleeding a; baseline CBC and platelet count; CBC and platelet count every
6 months following hospital discharge
Unfractionated heparin Bleeding, heparin-induced thrombocytope- Clinical signs of bleeding a; baseline CBC, platelet count, aPTT and INR; aPTT every 6 hours
nia until target then every 24 hours; daily CBC; platelet count every 2 days (minimum,
preferably every day)
Low-molecular-weight heparins Bleeding, heparin-induced thrombocytope- Clinical signs of bleeding a; baseline CBC, platelet count, SCr, aPTT and INR; daily CBC,
(enoxaparin and dalteparin) nia platelet count every 2–3 days (minimum, preferably every day); SCr daily
Fondaparinux Bleeding Clinical signs of bleeding,a baseline CBC, platelet count, INR, SCr, and aPTT; daily CBC and SCr
Bivalirudin Bleeding Clinical signs of bleeding,a baseline CBC, platelet count, INR, SCr, and aPTT; daily CBC and SCr
Fibrinolytics Bleeding, especially intracranial Clinical signs of bleeding,a baseline CBC, platelet count, INR, and aPTT; mental status every
hemorrhage 2 hours for signs of intracranial hemorrhage; daily CBC
Glycoprotein IIb/IIIa receptor Bleeding, acute profound thrombocytopenia Clinical signs of bleeding,a baseline CBC and platelet count; daily CBC; platelet count at 4
blockers hours after initiation then daily
Intravenous nitrates Hypotension, flushing, headache, tachycardia BP and HR every 2 hours
β-Blockers Hypotension, bradycardia, heart block, bron- BP, RR, HR, 12-lead ECG, and clinical signs of heart failure every 5 minutes during bolus intravenous
chospasm, heart failure, fatigue, depression, dosing; BP, RR, HR, and clinical signs of heart failure every shift during oral administration during
sexual dysfunction, nightmares, masking hospitalization, then BP and HR every 6 months following hospital discharge
hypoglycemia symptoms in diabetic patients
Diltiazem or verapamil Hypotension, bradycardia, heart block, BP and HR and signs of clinical heart failure every shift during oral administration during
heart failure, gingival hyperplasia, hospitalization, then every 6 months following hospital discharge; dental examination and
constipation teeth cleaning every 6 months
Amlodipine Hypotension, dependent peripheral BP every shift during hospitalization, then every 6 months following hospital discharge;
edema, gingival hyperplasia dental examination and teeth cleaning every 6 months
Angiotensin-converting enzyme Hypotension, cough (with ACE inhibitors), BP every 2 hours × 3 for first dose, then shift during oral administration during
(ACE) inhibitors and angiotensin hyperkalemia, prerenal azotemia, hospitalization, then once every 6 months following hospital discharge; baseline SCr and
receptor blockers (ARBs) angioedema (ACE inhibitors >ARBs) potassium; daily SCr and potassium while hospitalized, then every 6 months (or 1–2
weeks after each outpatient dose titration); closer monitoring required in selected patients
(e.g., those taking spironolactone or eplerenone or with renal insufficiency); counsel
patient on throat, tongue, and facial swelling
Aldosterone antagonists Hypotension, hyperkalemia, prerenal BP and HR every shift during oral administration during hospitalization, then once every 6
azotemia months; baseline SCr and serum potassium concentration; SCr and potassium at 48
hours, monthly for 3 months then every 3 months thereafter
Statins Myalgia, myopathy, elevated LFTs, rhabdo- Baseline LFTs, then repeat LFTs at 6 weeks and when patient titrated to target maintenance dose;
myolysis, teratogenic in first trimester if LFTs >3 times upper limit of normal, decrease dose or discontinue; if myalgia and/or brown
urine, monitor creatine kinase for rhabdomyolysis
Morphine sulfate Hypotension, respiratory depression BP and RR 5 minutes after each bolus dose
a
Clinical signs of bleeding include bloody stools, melena, hematuria, hematemesis, and bruising and oozing from arterial or venous puncture sites.
aPTT, activated partial thromboplastin time; BP, blood pressure; CBC, complete blood count; ECG, electrocardiogram; HR, heart rate; INR, international normalized ratio; LFT, liver function test; RR, respiratory
rate; SCr, serum creatinine, TTP, thrombotic thrombocytopenic purpura.
 273
(hypotension and bradycardia) rather than immediate therapy
PHARMACOECONOMIC CONSIDERATIONS with intravenous beta-blocker (Class I recommendation).

CHAPTER 18
The risks of CHD events, such as death, recurrent MI, and stroke, are 2. Reinforcement of a short time to reperfusion (Class I recom-
higher for patients with established CHD and a history of MI than for mendations)
patients with no known CHD. Because the costs for chronic preventa- a. If a patient arrives at a hospital capable of performing
tive pharmacotherapy are the same for primary and secondary preven- primary PCI, the hospital arrival-to-balloon time for PCI
tion while the risk of events is higher with secondary prevention, should be within 90 minutes.
secondary prevention is more cost effective than primary prevention of
b. If a patient arrives at a hospital that is not capable of
CHD.169 Pharmacotherapy, which has demonstrated cost effectiveness
performing primary PCI, the door-to-needle time for initia-
in preventing death in ACS and post-MI patient, includes fibrinolytics

Acute Coronary Syndromes

tion of fibrinolytic therapy should be within 30 minutes.
($2,000–$33,000 cost per year of life saved),169,170 aspirin,171 GP IIb/IIIa
receptor blockers ($13,700–$16,500 per year of life added),172 β-block- c. If a patient arrives at a hospital that is not capable of
ers (<$5,000–$15,000 cost per year of life saved),173 ACE inhibitors performing primary PCI, the patient can be transferred to a
($3,000–$5,000 cost per year of life saved),174,175 eplerenone ($15,300– hospital that can perform primary PCI if there is a contrain-
$32,400 per life year gained),176 statins ($4,500– $9,500 per year of life dication to fibrinolysis and PCI can be initiated at the
saved),177 gemfibrozil ($17,000 per year of life saved),178 and fish oil.179 receiving hospital within 90 minutes of arrival at the first
Because cost-effectiveness ratios less than $50,000 per added life-year hospital or if fibrinolysis was administered but was not
are considered economically attractive from a societal perspective,169 successful at opening the coronary artery.
pharmacotherapy for ACS and secondary prevention are standards of 3. A PCI performed after successful fibrinolysis therapy (i.e. facili-
care because of their efficacy and cost attractiveness to payors. tated PCI) is associated with excess bleeding, stroke, and mortal-
ity risk, and is not recommended (Class III recommendation).
EVALUATION OF THERAPEUTIC OUTCOMES 4. Either enoxaparin, UFH, or fondaparinux may be administered in
combination with a fibrinolytic agent (Grade I recommendation).
The monitoring parameters for efficacy of nonpharmacologic and 5. For patients undergoing PCI, either UFH, enoxaparin, or fonda-
pharmacotherapy for both STE and NSTE ACS are similar: parinux in combination with UFH may be administered (Class I
• Relief of ischemic discomfort recommendations) as fondaparinux alone is associated with
• Return of ECG changes to baseline PCI-related catheter thrombosis (Class III recommendation).

• Absence or resolution of heart failure signs 6. Clopidogrel 75 mg daily (Class I recommendation) should be
administered to all patients regardless of whether or not they
Monitoring parameters for recognition and prevention of adverse undergo reperfusion therapy and should be continued for at
effects from ACS pharmacotherapy are given in Table 18–7. In least 14 days (Class I recommendation) and up to one year
general, the most common adverse reactions to ACS therapies are (Class IIa recommendation).
hypotension and bleeding. Treatment for bleeding and hypotension
7. A loading dose of clopidogrel of 300 mg may be administered
involves discontinuation of the offending agent(s) until symptoms
as the initial dose (Class IIa recommendation).
resolve. Severe bleeding resulting in hypotension secondary to
hypovolemia may require blood transfusion. 8. In patients who do not undergo reperfusion therapy, it is reason-
able to administer anticoagulant therapy for the duration of
hospitalization, up to 8 days (Class IIa recommendation).
CONCLUSIONS
9. In patients requiring warfarin for clinical indications such as
The AHA and ACC published evidence-based practice guidelines for atrial fibrillation, atrial flutter, or presence of LV thrombus
the treatment of patients with STE and NSTE ACS. Mainstays of who also receive clopidogrel and aspirin, it is recommended
therapy include risk stratification, primary PCI for STE ACS, and early that the INR be maintained at 2.0 to 2.5 and that a lower dose
angiography and revascularization with either PCI or CABG for of aspirin be used, 75 mg to 81 mg (Class I recommendation).
patients with NSTE ACS at high risk for MI and death. Pharmacother- 10. Nonselective nonsteroidal antiinflammatory agents (except
apy for acute treatment includes SL NTG, antiplatelets, anticoagulants, aspirin) as well as COX-2 selecting antiinflammatory agents
and β-blockers. Insulin infusions can be administered to maintain should be discontinued at the time of STE MI secondary to
euglycemia in patients with diabetes mellitus. Pharmacotherapy for increased risk of mortality, reinfarction, heart failure, and
secondary prevention of recurrent ACS, MI, and CHD death includes myocardial rupture (Class III recommendation).
aspirin, clopidogrel, lipid-lowering therapy (statin preferred), β-block-
ers and either an ACE inhibitor or an ARB. Ensuring selection of
evidence-based therapies in all patients without contraindications ABBREVIATIONS
results in lower mortality. Pharmacists have an important role in
encouraging patient adherence and persistence to pharmacotherapy. ACC: American College of Cardiology
In January 2008, the AHA/ACC published an update to the 2004
ACE: angiotensin-converting enzyme
STE MI guidelines. (Antman EM, Hand M, Armstrong PW, et al.
2007 focused update of the ACC/AHA 2004 guidelines for the ACS: acute coronary syndrome
management of patients with ST-elevation myocardial infarction: A ACT: activated clotting time
report of the American College of Cardiology/American Heart ACUITY: Acute Catheterization and Urgent Intervention Triage
Association Task Force on Practice Guidelines. Circulation 2008 Jan Strategy
15;117(2):296-329.) The most significant changes in this guideline
compared to the 2004 guidelines are: ADP: adenosine diphosphate
1. Emphasis on oral beta-blocker therapy administered within the AHA: American Heart Association
first 24 hours with monitoring for hemodynamic instability aPTT: activated partial thromboplastin time
 274
ARB: angiotensin receptor blocker STE: ST-segment elevation
ASPECT: Antithrombotics in Secondary Prevention of Events in TARGET: Do Tirofiban and ReoPro Give Similar Efficacy Out-
SECTION 2

Coronary Thrombosis comes Trial

BNP: brain (B-type) natriuretic peptide TIMI: Thrombolysis in Myocardial Infarction
CABG: coronary artery bypass graft UFH: unfractionated heparin
CHD: coronary heart disease WARIS: Warfarin Re-Infarction Study
CK: creatine kinase
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infarction: Systematic review and meta regression analysis. Br Med J infarction. N Engl J Med 2003;348:1309–1321.
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139. Hulten E, Jackson JL, Douglas K, et al. The effect of early, intensive 160. Granger BB, Swedberg K, Ekman I, et al. Adherence to candesartan
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Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 161. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to
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141. Anonymous. MRC/BHF Heart Protection Study of cholesterol lower- 162. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and
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142 Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary try. Circulation 2006;113:2803–2809.
prevention of coronary heart disease in men with low levels of high-density 163. Muhlestein JB, Horne BD, Bair TL, et al. Usefulness of in-hospital
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143. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy tality. Am J Cardiol 2001;87:257–261.
on cardiovascular events in 9795 people with type 2 diabetes mellitus (the 164. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in
FIELD study): Randomised controlled trial. Lancet 2005;366:1849–1861. elderly patients with and without acute coronary syndromes. JAMA
144. Mcpherson R, Frohlich J, Fodor G, et al. Canadian Cardiovascular 2002;288:462–467.
Society position statement—Recommendations for the diagnosis and 165. Lachaine J, Rinfret S, Merikle EP, Terride JE. Persistence and adher-
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Can J Cardiol 2006;22:913–927. ance Maladie du Quebec data. Am Heart J 2006;152:164–169.
145. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, 166. Kulkarni SP, Alexander KP, Lytle B, et al. Long-term adherence with
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146. Gruppo Italiano per lo Studio della Sopravvivenza nell’infarcto mio- improve medication adherence in heart failure: A randomized trial.
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1999;354:447–455. medication adherence and persistence, blood pressure, and low-den-
147. Bays H. Fish oil composition of Omacor and the GISSI trial. Am J sity lipoprotein cholesterol: A randomized controlled trial. JAMA
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148. Critchley JA, Capewell S. Mortality risk reduction associated with 169. Mark DB. Medical economics in cardiovascular medicine. In: Topol EJ,
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149. Thompson PD, Bucner D, Pina IL, et al. Exercise and physical activity in 170. Hlatky MA, Califf RM, Naylor CD, et al. Cost effectiveness of thrombolytic
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Diabetes (EASD). Eur Heart J 2007;28:88–136. 173. Phillips KA, Shlipak MG, Coxson P, et al. Health and economic
151. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus benefits of increased beta-blocker use following myocardial infarction.
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155. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the sec-
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and meta-analysis on the hazards of discontinuing or not adhering to arcto (GISSI)-Prevenzione Trial. Pharmacoeconomics 2001:19:411–420.
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C HAP T E R

19 The Arrhythmias

CYNTHIA A. SANOSKI, MARIEKE DEKKER SCHOEN, AND JERRY L. BAUMAN

different strategies: orthodromic reentry (adenosine), antidro-

KEY CONCEPTS mic reentry (adenosine or procainamide), and AF (procain-
amide or amiodarone). Atrioventricular nodal-blocking drugs
 The use of antiarrhythmic drugs in the United States has de- are contraindicated in patients with WPW and AF.
clined because of major trials that show increased mortality with
their use in several clinical situations, the realization of proar-  Because of the results of the Cardiac Arrhythmia Suppression
rhythmia as a significant side effect and the advancing technolo- Trial (CAST) and other trials, antiarrhythmic drugs (with the ex-
gy of nondrug therapies such as ablation and the implantable ception of β-blockers) should not be routinely used in patients
cardioverter-defibrillator (ICD). with prior myocardial infarction (MI) or left ventricular (LV) dys-
function and minor ventricular rhythm disturbances (e.g., pre-
 Antiarrhythmic drugs frequently cause side effects and are com- mature ventricular complexes [PVCs]).
plex in their pharmacokinetic characteristics. The therapeutic range
of these agents provide only a rough guide to modifying treat- Patients with hemodynamically significant ventricular tachycardia
ment; it is preferable to attempt to define an individual’s effective (VT) or ventricular fibrillation (VF) not associated with an acute MI
(or target) concentration and match that during long-term therapy. who are successfully resuscitated (electrical cardioversion, vaso-
pressors, amiodarone) are at high risk for sudden cardiac death
 The most commonly prescribed antiarrhythmic drug is now (SCD) and should receive an ICD (“secondary prevention”).
amiodarone. This agent is effective in terminating and prevent-
ing a wide variety of symptomatic supraventricular and ventric-
Implantation of an ICD should be considered for the primary
ular tachycardias. However, because this antiarrhythmic drug is prevention of SCD in certain high-risk patient populations.
plagued by frequent side effects, it requires close monitoring. High-risk patients include those with a history of MI and LV dys-
The most concerning toxicity is pulmonary fibrosis; side-effect function (regardless of whether they have inducible sustained
profiles of the intravenous (IV) (acute, short-term) and oral ventricular arrhythmias), as well as those with New York Heart
(chronic, long-term) forms differ substantially. Association (NYHA) class II or III heart failure (HF) as a result
of either ischemic or nonischemic causes.
 In patients with atrial fibrillation (AF), therapy is traditionally
aimed at controlling ventricular response (digoxin, nondihydro-  Life-threatening ventricular proarrhythmia generally takes two
pyridine calcium channel blockers [CCBs], β-blockers), prevent- forms: sinusoidal or incessant monomorphic VT (type Ic antiar-
ing thromboembolic complications (warfarin, aspirin), and rhythmic drugs) and torsade de pointes (TdP) (type Ia or III an-
restoring and maintaining sinus rhythm (antiarrhythmic drugs, tiarrhythmic drugs and many other noncardiac drugs).
direct-current cardioversion [DCC]). Studies show there is no
need to aggressively pursue strategies to maintain sinus
rhythm (i.e., long-term antiarrhythmic drugs); rate control alone The heart has two basic properties, namely an electrical property and
(leaving the patient in AF) is often sufficient in patients who a mechanical property. The synchronous interaction between these
can tolerate it. Nonetheless, it is not uncommon for patients to two properties is complex, precise, and relatively enduring. The
have remaining troublesome symptoms with the rate-control study of the electrical properties of the heart has grown at a steady
strategy alone, necessitating oral antiarrhythmic drug therapy. rate, interrupted by periodic salvos of scientific breakthroughs.
Einthoven’s pioneering work allowed graphic electrical tracings of
 Paroxysmal supraventricular tachycardia (PSVT) is usually a re-
cardiac rhythm and probably represents the first of these break-
sult of reentry in or proximal to the atrioventricular (AV) node
throughs. This discovery (of the surface electrocardiogram [ECG])
or AV reentry incorporating an extranodal pathway; common
has remained the cornerstone of diagnostic tools for cardiac rhythm
tachycardias can be terminated acutely with AV nodal-blocking
disturbances. Since then, intracardiac recordings and programmed
agents such as adenosine, and recurrences can be prevented
cardiac stimulation have advanced our understanding of arrhyth-
by ablation with radiofrequency current.
mias, and microelectrode, voltage-clamping, and patch-clamping
 Patients with Wolff-Parkinson-White (WPW) Syndrome may techniques have allowed considerable insight into the electrophysio-
have several different tachycardias that are acutely treated by logic actions and mechanisms of antiarrhythmic drugs. Certainly,
the new era of molecular biology and mapping of the human genome
promises even greater insights into mechanisms (and potential
Learning objectives, review questions, therapies) of arrhythmias. Noteworthy in this regard is the discovery
and other resources can be found at of genetic abnormalities in the ion channels that control electrical
www.pharmacotherapyonline.com. repolarization (heritable long QT syndrome) or depolarization (Bru-
gada syndrome).

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 280
The clinical use of drug therapy started with the use of digitalis are referred to as the junctional areas. Again, this area of tissue
and then quinidine, followed somewhat later by a surge of new (junction) is largely influenced by autonomic input, and possesses a
SECTION 2

agents in the 1980s. A theme of drug discovery during this decade relatively high degree of inherent automaticity (about 40 beats/min,
was initially to find orally absorbed lidocaine-congeners (such as less than that of the SA node). From the bundle of His, the cardiac
mexiletine and tocainide); later, the emphasis was on drugs with conduction system bifurcates into several (usually three) bundle
extremely potent effects on conduction (i.e., flecainide-like agents). branches: one right bundle and two left bundles. These bundle
The most recent focus of investigational antiarrhythmic drugs are branches further arborize into a conduction network referred to as
the potassium channel blockers, with dofetilide being the most the Purkinje system. The conduction system as a whole innervates
recently approved in the United States. Previously, there was some the mechanical myocardium and serves to initiate excitation–con-
expectation that advances in antiarrhythmic drug discovery would traction coupling and the contractile process. After a cell or group
Cardiovascular Disorders

lead to a highly effective and nontoxic agent that would be effective of cells within the heart is electrically stimulated, a brief period of
for a majority of patients (i.e., the so-called magic bullet). Instead, time follows in which those cells cannot again be excited. This time
significant problems with drug toxicity and proarrhythmia have period is referred to as the refractory period. As the electrical
resulted in a decline in the overall volume of antiarrhythmic drug wavefront moves down the conduction system, the impulse eventu-
usage in the United States since 1989.  The other phenomenon, ally encounters tissue refractory to stimulation (recently excited)
which has significantly contributed to the decline in antiarrhythmic and subsequently dies out. The SA node subsequently recovers, fires
drug usage, is the development of extremely effective nondrug spontaneously, and begins the process again.
therapies. Technical advances have made it possible to permanently Prior to cellular excitation, an electrical gradient exists between
interrupt reentry circuits with radiofrequency ablation, which ren- the inside and the outside of the cell membrane. At this time the cell
ders long-term antiarrhythmic drug use unnecessary in certain is polarized. In atrial and ventricular conducting tissue, the intracel-
arrhythmias. Furthermore, the impressive survival data associated lular space is approximately 80 to 90 mV negative with respect to
with the use of ICDs for the primary and secondary prevention of the extracellular environment. The electrical gradient just prior to
SCD has led most clinicians to choose “device” therapy as the first- excitation is referred to as resting membrane potential (RMP) and
line treatment for patients who are at high-risk for life-threatening is the result of differences in ion concentrations between the inside
ventricular arrhythmias. Both of these nondrug therapies have and the outside of the cell. At RMP, the cell is polarized primarily by
become increasingly popular for the management of arrhythmias so the action of active membrane ion pumps, the most notable of these
that the potential proarrhythmic effects and organ toxicities associ- being the sodium-potassium pump. For example, this specific
ated with antiarrhythmic drugs can be avoided. What does the pump (in addition to other systems) attempts to maintain the
future hold for the use of antiarrhythmic drugs? Certainly new intracellular sodium concentration at 5 to 15 mEq/L and the
knowledge and technologic advances have forced investigators and extracellular sodium concentration at 135 to 142 mEq/L; the intra-
clinicians to rethink the concept of traditional membrane-active cellular potassium concentration at 135 to 140 mEq/L and the
drugs. Although some degree of enthusiasm exists for some of the extracellular potassium concentration at 3 to 5 mEq/L. The RMP
newer or investigational agents, the overall impact of these drugs can be calculated by using the Nernst equation:
has yet to be determined.
This chapter reviews the principles involved in both normal and +
[ K ] outside
abnormal cardiac conduction and addresses the pathophysiology
and treatment of the more commonly encountered arrhythmias.
RMP = 61.5 log ⎛
( ⎞
⎝ [ K + ] inside ⎠
(
Certainly, many volumes of complete text could be (and have been)
devoted to basic and clinical electrophysiology. Consequently, this
Electrical stimulation (or depolarization) of the cell will result in
chapter briefly addresses those principles necessary for clinicians.
changes in membrane potential over time or a characteristic action
potential curve (Fig. 19–1). The action potential curve results from
ARRHYTHMOGENESIS the transmembrane movement of specific ions and is divided into
different phases. Phase 0 or initial, rapid depolarization of atrial and
NORMAL CONDUCTION ventricular tissues is caused by an abrupt increase in the permeability
of the membrane to sodium influx. This rapid depolarization more
Electrical activity is initiated by the sinoatrial (SA) node and moves than equilibrates (overshoots) the electrical potential, resulting in a
through cardiac tissue by a tree-like conduction network. The SA brief initial repolarization or phase 1. Phase 1 (initial depolarization)
node initiates cardiac rhythm under normal circumstances because is caused by a transient and active potassium efflux (i.e., the IKto
this tissue possesses the highest degree of automaticity or rate of current). Calcium begins to move into the intracellular space at about
spontaneous impulse generation. The degree of automaticity of the –60 mV (during phase 0) causing a slower depolarization. Calcium
SA node is largely influenced by the autonomic nervous system in influx continues throughout phase 2 of the action potential (plateau
that both cholinergic and sympathetic innervations control sinus phase) and is balanced to some degree by potassium efflux. Calcium
rate. Most tissues within the conduction system also possess varying entrance (only through L channels in myocardial tissue) distinguishes
degrees of inherent automatic properties. However, the rates of cardiac conducting cells from nerve tissue, and provides the critical
spontaneous impulse generation of these tissues are less than that of ionic link to excitation-contraction coupling and the mechanical
the SA node. Thus these latent automatic pacemakers are continu- properties of the heart as a pump (see Chap. 16). The membrane
ously overdriven by impulses arising from the SA node (primary remains permeable to potassium efflux during phase 3, resulting in
pacemaker) and do not become clinically apparent. cellular repolarization. Phase 4 of the action potential is the gradual
From the SA node, electrical activity moves in a wave front depolarization of the cell and is related to a constant sodium leak into
through an atrial specialized conducting system and eventually the intracellular space balanced by a decreasing (over time) efflux of
gains entrance to the ventricle via the atrioventricular (AV) node potassium. The slope of phase 4 depolarization determines, in large
and a large bundle of conducting tissue referred to as the bundle of part, the automatic properties of the cell. As the cell is slowly
His. Aside from this AV nodal–Hisian pathway, a fibrous AV ring depolarized during phase 4, an abrupt increase in sodium permeabil-
that will not permit electrical stimulation separates the atria and ity occurs, allowing the rapid cellular depolarization of phase 0. The
ventricles. The conducting tissues bridging the atria and ventricles juncture of phase 4 and phase 0 where rapid sodium influx is initiated
 281

1 2

CHAPTER 19
Ca2+ Ca2+ Ca2+
Ca2+
+20
K+ K+ K+ K+
0
Na+
Membrane potential (mV)

3
Ca2+ K+
FIGURE 19-1. Purkinje fiber action poten-
Na+

The Arrhythmias
tial showing specific ion flux responsible for
0 the change in membrane potential. Ions
K+
Na+ outside of the line (e.g., sodium) move
from the extracellular space to the intracel-
Na+ lular space and ions on the inside of the
4 line (e.g., potassium) move from the inside
Na+
–70 K+ of the cell to the outside. Below the line is
Na+ the corresponding ventricular excitation and
K+
–90 K+ recovery from the surface ECG. One can
K+ see that excessive sodium channel block
from drugs may lead to QRS prolongation
Time and excessive potassium channel block
from drugs may lead to QT prolongation.

is referred to the threshold potential of the cell. The level of threshold organized and disorganized lipids and phospholipids in a dynamic sol-
potential also regulates the degree of cellular automaticity. gel matrix. During ion flux and electrical excitation, changes in this
Not all cells in the cardiac conduction system rely on sodium sol-gel equilibrium occur and permit the formation of activated ion
influx for initial depolarization. Some tissues depolarize in response channels. Besides channel formation and membrane composition,
to a slower inward ionic current caused by calcium influx. These intrachannel proteins or phospholipids, referred to as gates also regu-
“calcium-dependent” tissues are found primarily in the SA and AV late the transmembrane movement of ions. These gates are thought to
nodes (both L and T channels) and possess distinct conduction be positioned strategically within the channel to modulate ion flow
properties in comparison to “sodium-dependent” fibers. Calcium- (Fig. 19–2). Each ion channel conceptually has two types of gates: an
dependent cells generally have a less-negative RMP (–40 to –60 mV) activation gate and an inactivation gate. The activation gate opens
and a slower conduction velocity. Furthermore, in calcium-depen- during depolarization to allow the ion current to enter or exit from the
dent tissues, recovery of excitability outlasts full repolarization, cell, and the inactivation gate later closes to stop ion movement. When
whereas in sodium-dependent tissue, recovery is prompt after the cell is in a rested state, the activation gates are closed and the
repolarization. These two types of electrical fibers also differ dra- inactivation gates are open. The activation gates then open to allow ion
matically in how drugs modify their conduction properties. movement through the channel, and the inactivation gates later close
Ion conductance across the lipid bilayer of the cell membrane occurs to stop ion conductance. Thus, the cell cycles between three states:
via the formation of membrane pores or “channels” (Fig. 19–2). resting, activated or open, and inactivated or closed. Activation of SA
Selective ion channels probably form in response to specific electrical and AV nodal tissue is dependent on a slow depolarizing current
potential differences between the inside and the outside of the cell through calcium channels and gates, whereas the activation of atrial
(voltage dependence). The membrane itself is composed of both and ventricular tissue is dependent on a rapid depolarizing current
through sodium channels and gates.
Na+
Activation gates ABNORMAL CONDUCTION
The mechanisms of tachyarrhythmias have been classically divided into
A+ two general categories: those resulting from an abnormality in impulse
generation or “automatic” tachycardias and those resulting from an
abnormality in impulse conduction or “reentrant” tachycardias.
A Automatic tachycardias depend upon spontaneous impulse gen-
eration in latent pacemakers and may be a result of several different
mechanisms. Experimentally, chemicals, such as digitalis glycosides
or catecholamines, and conditions, such as hypoxemia, electrolyte
+
abnormalities (e.g., hypokalemia), and fiber stretch (cardiac dila-
Inactivation A
gates tion), may lead to an increased slope of phase 4 depolarization in
cardiac tissues other than the SA node. These factors, which experi-
FIGURE 19-2. Lipid bilayer, sodium channel, and possible sites of action mentally lead to abnormal automaticity, are also known to be
of the type I agents (A). Type I antiarrhythmic drugs may theoretically arrhythmogenic in clinical situations. The increased slope of phase
inhibit sodium influx at an extracellular, intramembrane, or intracellular
4 causes heightened automaticity of these tissues and competition
receptor site. However, all approved agents appear to block sodium
conductance at a single receptor site by gaining entrance to the interior
with the SA node for dominance of cardiac rhythm. If the rate of
of the channel from an intracellular route. Active ionized drugs block the spontaneous impulse generation of the abnormally automatic tissue
channel predominantly during the activated or inactivated state and bind exceeds that of the SA node, then an automatic tachycardia may
and unbind with specific time constants (described as fast on-off, slow result. Automatic tachycardias have the following characteristics:
on-off, and intermediate). (a) the onset of the tachycardia is unrelated to an initiating event
 282
such as a premature beat; (b) the initiating beat is usually identical relatively shorter refractory period. The impulse may then proceed
to subsequent beats of the tachycardia; (c) the tachycardia cannot be through a loop of tissue and “reenter” the area of unidirectional block
SECTION 2

initiated by programmed cardiac stimulation; (d) the onset of the in a backward direction (retrograde). Because the antegrade pathway
tachycardia is usually preceded by a gradual acceleration in rate and has slow conduction characteristics, the area of unidirectional block
termination is usually preceded by a gradual deceleration in rate. has time to recover its excitability. The impulse can proceed retrograde
Clinical tachycardias resulting from the classic forms of enhanced through this (previously refractory) tissue and continue around the
automaticity described above are not as common as once thought. loop of tissue in a circular fashion. Thus, the key to the formation of a
Examples are sinus tachycardia and junctional tachycardia. reentrant focus is crucial conduction discrepancies in the electrophys-
Triggered automaticity is also a possible mechanism for abnormal iologic characteristics of the two pathways. The reentrant focus may
impulse generation. Briefly, triggered automaticity refers to transient excite surrounding tissue at a rate greater than that of the SA node and
Cardiovascular Disorders

membrane depolarizations that occur during repolarization (early a clinical tachycardia results. The above model is anatomically deter-
after-depolarizations [EADs]) or after repolarization (late after- mined in that there is only one pathway for impulse conduction with
depolarizations [LADs]) but prior to phase 4 of the action potential. a fixed circuit length. Another model of reentry, referred to as a
After-depolarizations may be related to abnormal calcium and functional reentrant loop or leading circle model, may also occur (Fig.
sodium influx during or just after full cellular repolarization. Exper- 19–4).1 In a functional reentrant focus, the length of the circuit may
imentally, EADs may be precipitated by hypokalemia, type Ia antiar- vary depending on the conduction velocity and recovery characteris-
rhythmic drugs, or slow stimulation rates—any factor that blocks the tics of the impulse. The area in the middle of the loop is continually
ion channels (e.g., potassium) responsible for cellular repolarization. kept refractory by the inwardly moving impulse. The length of the
Early after-depolarizations provoked by drugs that block potassium circuit is not fixed, but is the smallest circle possible, such that the
conductance and delay repolarization are the underlying cause of leading edge of the wavefront is continuously exciting tissue just as it
TdP. Late after-depolarizations may be precipitated by digitalis or recovers; that is, the head of the impulse nearly catches its tail. It differs
catecholamines and suppressed by CCBs, and have been suggested as from the anatomic model in that the leading edge of the impulse is not
the mechanism for multifocal atrial tachycardia, digitalis-induced preceded by an excitable gap of tissue, and it does not have an obstacle
tachycardias and exercise-provoked VT. Triggered automatic in the middle or a fixed anatomic circuit. Clinically, many reentrant
rhythms possess some of the characteristics of automatic tachycar- foci probably have both anatomic and functional characteristics. In the
dias and some of the characteristics of reentrant tachycardias figure 8 model, a zone of unidirectional block is present; allowing for
(described below). two impulse loops that join and reenter the area of block in a
As previously mentioned, the impulse originating from the SA node retrograde fashion to form a pretzel-shaped reentrant circuit. This
in an individual with sinus rhythm eventually meets previously excited model combines functional characteristics with an excitable gap. All of
and thus refractory tissue. Reentry is a concept that involves indefinite these theoretical models require a critical balance of refractoriness and
propagation of the impulse and continued activation of previously conduction velocity within the circuit and as such have helped to
refractory tissue. There are three conduction requirements for the explain the effects of drugs on terminating, modifying, and causing
formation of a viable reentrant focus: two pathways for impulse cardiac rhythm disturbances.
conduction; an area of unidirectional block (prolonged refractoriness) What causes reentry to become clinically manifest? Reentrant foci
in one of these pathways; and slow conduction in the other pathway may occur at any level of the conduction system: within the branches
(Fig. 19–3). Usually a critically timed premature beat initiates reentry. of the specialized atrial conduction system, the Purkinje network, and
This premature impulse enters both conduction pathways but even within portions of the SA and AV nodes. The anatomy of the
encounters refractory tissue in one of the pathways at the area of Purkinje system appears to provide a suitable substrate for the
unidirectional block. The impulse dies out because it is still refractory formation of microreentrant loops and is often used as a model to
from the previous (sinus) impulse. Although it fails to propagate in facilitate the understanding of reentry concepts (see Fig. 19–4). Of
one pathway, the impulse may still proceed in a forward direction course, because reentry does not usually occur in normal, healthy
(antegrade) through the other pathway because of this pathway’s conduction tissue, various forms of heart disease or conduction
abnormalities must usually be present before reentry becomes mani-
fest. In other words, the various forms of heart disease (e.g., ischemic
heart disease, LV dysfunction) can result in changes in conduction in
Sinoatrial
node the pathways of a suitable reentrant substrate. An often-used example
is reentry occurring as a consequence of ischemic or hypoxic damage:
with inadequate cellular oxygen, cardiac tissue resorts to anaerobic
glycolysis for adenosine triphosphate production. As high-energy
phosphate concentration diminishes, the activity of the transmem-
Atrioventricular
node brane ion pumps declines and RMP rises. This rise in RMP causes
inactivation in the voltage-dependent sodium channel and the tissue
Bundle begins to assume slow conduction characteristics. If changes in
of His Purkinje fibers
conduction parameters occur in a discordant manner due to varying
FIGURE 19-3. Conduction system of the heart. The magnified portion degrees of ischemia or hypoxia, then a reentry circuit may become
shows a bifurcation of a Purkinje fiber traditionally explained as the manifest. Furthermore, an ischemic, dying cell liberates intracellular
etiology of reentrant ventricular tachycardia. A premature impulse travels potassium, which also causes a rise in RMP. In other cases, reentry
to the fiber, damaged by heart disease or ischemia. It encounters a zone may occur as a consequence of anatomic or functional variants in the
of prolonged refractoriness (area of unidirectional block; cross-hatched
normal conduction system. For instance, patients may possess two
area) but fails to propagate because it remains refractory to stimulation
from the previous impulse. However, the impulse may slowly travel
(instead of one) conduction pathways near or within the AV node, or
(squiggly line) through the other portion of the Purkinje twig and will have an anomalous extranodal AV pathway that possesses different
“reenter” the cross-hatched area if the refractory period is concluded and electrophysiologic characteristics from the normal AV nodal path-
it is now excitable. Thus, the premature impulse never meets refractory way. Reentry in these cases may occur within the AV node or
tissue; circus movement ensues. If this site stimulates the surrounding encompass both atrial and ventricular tissue. Reentrant tachycardias
ventricle repetitively, clinical reentrant ventricular tachycardia results. have the following characteristics: (a) the onset of the tachycardia is
 283

A
ANTIARRHYTHMIC DRUGS

CHAPTER 19
1a 1b In a theoretical sense, drugs may have antiarrhythmic activity by
directly altering conduction in several ways. First, a drug may depress
the automatic properties of abnormal pacemaker cells. An agent may
do this by decreasing the slope of phase 4 depolarization and/or by
elevating threshold potential. If the rate of spontaneous impulse
generation of the abnormally automatic foci becomes less than that of
2a 2b
the SA node, normal cardiac rhythm can be restored. Second, drugs
may alter the conduction characteristics of the pathways of a reen-

The Arrhythmias
trant loop.1,2 An agent may facilitate conduction (shorten refractori-
ness) in the area of unidirectional block, allowing antegrade
conduction to proceed. On the other hand, an antiarrhythmic may
further depress conduction (prolong refractoriness) in either the area
of unidirectional block or in the pathway with slowed conduction and
B a relatively shorter refractory period. If refractoriness is prolonged in
the area of unidirectional block, retrograde propagation of the
impulse is not permitted, causing a “bidirectional” block. In the
a anatomic model, if refractoriness is prolonged in the pathway with
slow conduction, antegrade conduction of the impulse is not permit-
ted through this route. In either case, drugs that reduce the discor-
b dance and cause uniformity in conduction properties of the two
pathways may suppress the reentrant substrate. In the functionally
determined model, if refractoriness is prolonged without significantly
slowing conduction velocity, the tachycardia may terminate or slow
in rate as a consequence of a greater circuit length (see Fig. 19–4).
c
There are other theoretical ways to stop reentry: a drug may eliminate
the critically timed premature impulse that triggers reentry; a drug
may slow conduction velocity to such an extent that conduction is
extinguished; or a drug may reverse the underlying form of heart
FIGURE 19-4. A. Possible mechanism of proarrhythmia in the anatomic disease that was responsible for the conduction abnormalities that led
model of reentry. (1a) Nonviable reentrant loop due to bidirectional block to the arrhythmia (i.e., “reverse remodeling”).
(shaded area). (1b) Instance where a drug slows conduction velocity Antiarrhythmic drugs have specific electrophysiologic actions that
without significantly prolonging the refractory period. The impulse is now alter cardiac conduction in patients with or without heart disease.
able to reenter the area of unidirectional block (shaded area) because These actions form the basis of grouping antiarrhythmics into specific
slowed conduction through the contralateral limb allows recovery of the
categories based upon their electrophysiologic actions in vitro.
block. A new reentrant tachycardia may result. (2a) Nonviable reentrant
loop due to a lack of a unidirectional block. (2b) Instance where a drug
Vaughan Williams proposed the most frequently used classification
prolongs the refractory period without significantly slowing conduction system (Table 19–1).2 This classification has been criticized because
velocity. The impulse moving antegrade meets refractory tissue (shaded (a) it is incomplete and does not allow for the classification of agents
area) allowing for unidirectional block. A new reentrant tachycardia may such as digoxin or adenosine; (b) it is not pure and many agents have
result. B. Mechanism of reentry and proarrhythmia. (a) Functionally properties of more than one class of drugs; (c) it does not incorpo-
determined (leading circle) reentrant circuit. This model should be rate drug characteristics such as mechanisms of tachycardia termina-
contrasted with anatomic reentry; here the circuit is not fixed (it does not tion/prevention, clinical indications, or side effects; and (d) agents
necessarily move around an anatomic obstacle) and there is no excitable become “labeled” within a class although they may be distinct in
gap. All tissue inside is held continuously refractory. (b) Instance where a many regards.3 These criticisms formed the basis for an attempt to
drug prolongs the refractory period without significantly slowing conduc-
reclassify antiarrhythmic agents based upon a variety of basic and
tion velocity. The tachycardia may terminate or slow in rate as shown as
a consequence of a greater circuit length. The dashed lines represent the
clinical characteristics (called the Sicilian Gambit3). Nonetheless, the
original reentrant circuit prior to drug treatment. (c) Instance where a drug Vaughan Williams classification remains the most frequently used
slows conduction velocity without significantly prolonging the refractory despite many proposed modifications and alternative systems.
period (i.e., type Ic agents) and accelerates the tachycardia. The The type Ia antiarrhythmic drugs—quinidine, procainamide, and
tachycardia rate may increase (proarrhythmia) as shown as a conse- disopyramide—slow conduction velocity, prolong refractoriness,
quence of a shorter circuit length. The dashed lines represent the original and decrease the automatic properties of sodium-dependent (nor-
reentrant circuit prior to drug treatment. (From McCollam PL, Parker RB, mal and diseased) conduction tissue. Although type Ia agents are
Beckman KJ, et al. Proarrhythmia: A paradoxic response to antiarrhyth- primarily considered sodium channel blockers, their electrophysio-
mic agents. Pharmacotherapy 1989;9:146, with permission.) logic actions can also be attributed to blockade of potassium
channels. In reentrant tachycardias, these drugs generally depress
conduction and prolong refractoriness, theoretically transforming
usually related to an initiating event (i.e., premature beat), (b) the the area of unidirectional block into a bidirectional block. Clinically,
initiating beat is usually different in morphology from subsequent type Ia drugs are broad-spectrum antiarrhythmics that are effective
beats of the tachycardia, (c) the initiation of the tachycardia is usually for both supraventricular and ventricular arrhythmias.
possible with programmed cardiac stimulation, and (d) the initiation The type Ib antiarrhythmic drugs—lidocaine and phenytoin—
and termination of the tachycardia is usually abrupt without an were historically categorized separately from quinidine-like drugs.
acceleration or deceleration phase. There are many examples of This was a result of early work demonstrating that lidocaine had
reentrant tachycardias including AF, atrial flutter, AV nodal or AV distinctly different electrophysiologic actions. In normal tissue mod-
reentrant tachycardia, and recurrent VT. els, lidocaine generally facilitates actions on cardiac conduction by
 284

TABLE 19-1 Classification of Antiarrhythmic Drugs

SECTION 2

Conduction Refractory
Type Drug Velocitya Period Automaticity Ion Block
Ia Quinidine ↓ ↑ ↓ Sodium (intermediate)
Procainamide Potassium
Disopyramide
Ib Lidocaine 0/↓ ↓ ↓ Sodium (fast on-off)
Mexiletine
Ic Flecainide ↓↓ 0 ↓ Sodium (slow on-off)
Propafenoneb Potassiumd
Cardiovascular Disorders

Moricizinec
IIe β-blockers ↓ ↑ ↓ Calcium (indirect)
III Amiodaronef 0 ↑↑ 0 Potassium
Dofetilide
Sotalolb
Ibutilide
IVe Verapamil ↓ ↑ ↓ Calcium
Diltiazem
AV, atrioventricular; SA, sinoatrial.
a
Variables for normal tissue models in ventricular tissue.
b
Also has type II, β-blocking actions.
c
Classification controversial.
d
Not clinically manifest.
e
Variables for SA and AV nodal tissue only.
f
Also has sodium, calcium, and β-blocking actions; see Table 19–2.

shortening refractoriness and having little effect on conduction veloc- tion). For example, lidocaine and flecainide block sodium
ity. Thus, it was postulated that these agents could improve antegrade current primarily when the cell is in the inactivated state,
conduction, eliminating the area of unidirectional block. Of course, whereas quinidine is predominantly an open (or activated)-
arrhythmias do not usually arise from normal tissue, leading investi- channel blocker.
gators to study the actions of lidocaine and phenytoin in ischemic and 2. Type I antiarrhythmics have specific binding and unbinding
hypoxic tissue models. Interestingly, studies have shown these drugs characteristics to the receptor. For example, lidocaine binds to
to possess type Ia quinidine-like properties in diseased tissues. There- and dissociates from the channel receptor quickly (termed
fore, it is probable that lidocaine acts in clinical tachycardias in a “fast on-off”) but flecainide has very “slow on-off” properties.
similar fashion to the type Ia drugs (i.e., prolong refractoriness in This explains why flecainide has such potent effects on slowing
diseased ischemic tissues leading to bidirectional block in a reentrant ventricular conduction whereas lidocaine has little effect on
circuit). Lidocaine and similar agents have accentuated effects in normal tissue (at normal heart rates). In general the type Ic
ischemic tissue caused by the local acidosis and potassium shifts that antiarrhythmics are slow on-off, the type Ib antiarrhythmics
occur during cellular hypoxia. Changes in pH alter the time that local are fast on-off, and the type Ia antiarrhythmics are intermedi-
anesthetics occupy the sodium channel receptor, thereby affecting the ate in their binding kinetics.
agent’s electrophysiologic actions. In addition, the intracellular acido-
3. Type I antiarrhythmics possess rate dependence (i.e., sodium
sis that ensues as a consequence of ischemia could cause lidocaine to
channel blockade and slowed conduction are greatest at fast
become “trapped” within the cell, allowing increased access to the
heart rates and least during bradycardia). For slow on-off
receptor. The type Ib agents are considerably more effective in
drugs, sodium channel blockade is evident at normal rates (60
ventricular arrhythmias than supraventricular arrhythmias. As a
to 100 beats/min) but for fast on-off agents, slowed conduction
group these drugs are relatively weak sodium channel antagonists (at
is only apparent at rapid rates of stimulation.
normal stimulation rates).
The type Ic antiarrhythmic drugs include propafenone, flecain- 4. Type I antiarrhythmics (except phenytoin) are weak bases with
ide, and moricizine. These agents are extremely potent sodium a pKa >7.0 and block the sodium channel in their ionized form.
blockers, profoundly slowing conduction velocity while leaving Consequently, pH will alter these actions: acidosis accentuates
refractoriness relatively unaltered. The type Ic drugs theoretically and alkalosis diminishes sodium channel blockade.
eliminate reentry by slowing conduction to a point where the 5. Type I antiarrhythmics appear to share a single receptor site in
impulse is extinguished and cannot propagate further. Although the the sodium channel. It should be noted, however, that a number
type Ic drugs are effective for both ventricular and supraventricular of type I antiarrhythmics have other electrophysiologic proper-
arrhythmias, their use for ventricular arrhythmias has been limited ties. For instance, quinidine has potent potassium channel
by the risk of proarrhythmia. blocking activity (manifest predominantly at low concentra-
Type I agents are grouped together because of their common tions) as does N-acetylprocainamide (manifest predominantly
action in blocking sodium conductance. The receptor site for these at high concentrations), the primary metabolite of procain-
antiarrhythmics is probably inside the sodium channel so that, in amide. Additionally propafenone has β-blocking actions.
effect, the drug plugs the pore. The agent may gain access to the
receptor either via the intracellular space through the membrane These principles are important in understanding additive drug
lipid bilayer or directly through the channel. Several principles are combinations (e.g., quinidine and mexiletine), antagonistic combi-
inherent in antiarrhythmic sodium channel receptor theories4: nations (e.g., flecainide and lidocaine), and potential antidotes to
excess sodium channel blockade (sodium bicarbonate or propran-
1. Type I antiarrhythmics have predominant affinity for a partic- olol). They also explain a number of clinical observations, such as
ular state of the channel (e.g., during activation or inactiva- why lidocaine-like drugs are relatively ineffective for supraventricu-
 285
lar tachycardia. The type Ib antiarrhythmics are fast on-off, inacti- blocks potassium channels and also has a small degree of calcium
vated sodium blockers; atrial cells, however, have a very brief antagonist activity (Table 19–2). At normal heart rates and with

CHAPTER 19
inactivated phase relative to ventricular tissue. chronic use, its predominant effect is to prolong repolarization. Upon
The β-blockers are classified as type II antiarrhythmic drugs. For the IV administration, its onset is relatively quick (unlike the oral form)
most part, the clinically relevant acute antiarrhythmic mechanisms of and β-blockade predominates initially. Theoretically, amiodarone,
the β-blockers result from their antiadrenergic actions. Because the SA like type I agents, may interrupt the reentrant substrate by transform-
and AV nodes are heavily influenced by adrenergic innervation, β- ing an area of unidirectional block into an area of bidirectional block.
blockers would be most useful in tachycardias in which these nodal However, electrophysiologic studies using programmed cardiac stim-
tissues are abnormally automatic or are a portion of a reentrant loop. ulation imply that amiodarone may leave the reentrant loop intact. In
These agents are also helpful in slowing ventricular response in atrial addition, the potent β-blocking properties of amiodarone may con-

The Arrhythmias
tachycardias (e.g., AF) by their effects on the AV node. Furthermore, tribute significantly to both its acute and chronic efficacy. The
some tachycardias are exercise-related or precipitated by states of high impressive effectiveness of amiodarone coupled with its low proar-
sympathetic tone (perhaps through triggered activity), and β-blockers rhythmic potential has challenged the notion that selective ion chan-
may be useful in these instances. β-adrenergic stimulation results in nel blockade by antiarrhythmic agents is preferable. Sotalol is a potent
increased conduction velocity, shortened refractoriness, and increased inhibitor of outward potassium movement during repolarization and
automaticity of the nodal tissues; β-blockers will antagonize these also possesses nonselective β-blocking actions. Unlike amiodarone
effects. Propranolol is often noted to have “local anesthetic” or quini- and sotalol, ibutilide and dofetilide are only used for the treatment of
dine-like activity; however, suprapharmacologic concentrations are supraventricular arrhythmias. Both ibutilide (only available IV) and
usually required to elicit this action. In the nodal tissues, β-blockers dofetilide (only available orally) can be used for the acute conversion
interfere with calcium entry into the cell by altering catecholamine- of AF or atrial flutter to sinus rhythm. Dofetilide can also be used to
dependent channel integrity and gating kinetics. In sodium-dependent maintain sinus rhythm in patients with AF or atrial flutter of longer
atrial and ventricular tissue, β-blockers shorten repolarization some- than 1 week’s duration who have been converted to sinus rhythm.
what, but otherwise have little direct effect. The antiarrhythmic prop- Both of these agents are structurally similar to sotalol and exert their
erties of β-blockers observed with long-term, chronic therapy in electrophysiologic effects by blocking the rapid component of the
patients with heart disease are less well understood. Although it is clear delayed potassium rectifier current (IKr).
that β-blockers decrease the likelihood of SCD (presumably arrhyth- There are a number of different potassium channels which func-
mic death) after myocardial infarction (MI), the mechanism for this tion during normal conduction; all approved type III antiarrhythmic
benefit remains unclear but may relate to the complex interplay of drugs inhibit the delayed rectifier current (IK) responsible for phases
changes in sympathetic tone, damaged myocardium, and ventricular 2 and 3 repolarization. Subcurrents make up IK; an ultrarapid compo-
conduction. In patients with HF, drugs such as β-blockers, angioten- nent (IKur), a rapid component (IKr), and the slow component (IKs).
sin-converting enzyme inhibitors, and angiotensin II receptor blockers N-acetylprocainamide, sotalol, ibutilide, and dofetilide selectively
may prevent arrhythmias such as AF by attenuating the structural block IKr, whereas amiodarone and azimilide (investigational) block
remodeling process in the myocardium and subsequently improving both IKr and IKs. New drugs that selectively block IKur (found predom-
ventricular performance over time.5,6 inantly in the atrium but not ventricle) are being investigated for
The type III antiarrhythmic drugs include those agents that supraventricular arrhythmias. The clinical relevance of selectively
specifically prolong refractoriness in atrial and ventricular tissue. blocking components of the delayed rectifier current remains to be
This class includes very different drugs: bretylium, amiodarone, determined. Potassium current blockers (particularly those with
sotalol, ibutilide, and dofetilide; they share the common effect of selective IKr blocking properties) display “reverse use dependence”
delaying repolarization by blocking potassium channels. While (i.e., their effects on repolarization are greatest at low heart rates).
rarely used, bretylium has complex pharmacology: in addition to Sotalol and drugs like it also appear to be much more effective in
blocking potassium channels and delaying repolarization, it first preventing VF (in dog models) than the traditional sodium channel
releases then depletes catecholamines. Bretylium increases the VF blockers. They also decrease defibrillation threshold in contrast to
threshold and seems to have selective antifibrillatory but not anti- type I agents, which tend to increase this parameter. This could be
tachycardic effects. In other words, bretylium can be effective in VF, important in patients with ICDs, as concurrent therapy with type I
whereas it is often ineffective in VT. drugs may require more energy for successful cardioversion or may
In contrast, amiodarone and sotalol are effective in most supraven- render the ICD ineffective in terminating the ventricular tachyar-
tricular and ventricular tachycardias. Amiodarone displays electro- rhythmia. The Achilles’ heel of all type III agents is an extension of
physiologic characteristics of all the classes within the Vaughan their underlying ionic mechanism (i.e., by blocking potassium chan-
Williams scheme; it is a sodium channel blocker with relatively fast nels and delaying repolarization, they may also cause proarrhythmia
on-off kinetics, has noncompetitive, nonselective β-blocking actions, in the form of TdP by provoking EADs).

TABLE 19-2 Time Course and Electrophysiologic Effects of Amiodarone

IV Oral
Class Mechanism EP ECG Min-Hrs Hrs-Days Days-Wks Wks-Mos
Type I +
Na block ↑ HV ↑ QRS 0 + + ++
Type II β-block ↑ AH ↑ PR ++ ++ ++ ++
↓ HR
Type III K+ block ↑ VERP ↑ QT 0 + ++ ++++
↑ AERP
Type IV Ca2+ blocka ↑ AH ↑ PR + + + +
a
Rate-dependent.
AERP, atrial effective refractory period; AH, atria-His interval; ECG, electrocardiographic effects; EP, electrophysiologic actions; HR, heart rate; HV, His-
ventricle interval; VERP, ventricular effective refractory period.
 286
The nondihydropyridine CCBs—verapamil and diltiazem—com- TABLE 19-3 Side Effects of Antiarrhythmic Drugs
prise the type IV antiarrhythmic category. At least two types of calcium
SECTION 2

Quinidine Cinchonism, diarrhea, abdominal cramps, nausea, vomiting,

channels are operative in SA and AV nodal tissues: an L-type channel
hypotension, TdP, aggravation of underlying HF, conduction
and a T-type channel. Both L-channel blockers (verapamil and diltia-
disturbances or ventricular arrhythmias, fever, hepatitis,
zem) and selective T-channel blockers (mibefradil—previously thrombocytopenia, hemolytic anemia
approved but withdrawn from the market) will slow conduction, Procainamide Systemic lupus erythematosus, diarrhea, nausea, vomiting, TdP,
prolong refractoriness, and decrease automaticity (e.g., due to EADs aggravation of underlying HF, conduction disturbances or
or LADs) of the calcium-dependent tissue in the SA and AV nodes. ventricular arrhythmias, agranulocytosis
Therefore, these agents are effective in automatic or reentrant tachy- Disopyramide Anticholinergic symptoms (dry mouth, urinary retention, consti-
cardias, which arise from or use the SA or AV nodes. In supraventric- pation, blurred vision), nausea, anorexia, TdP, HF, aggravation
Cardiovascular Disorders

ular arrhythmias (e.g., AF), these drugs can slow ventricular response of underlying conduction disturbances and/or ventricular
by slowing AV nodal conduction. Furthermore, because calcium entry arrhythmias
seems to be integral to exercise-related tachycardias and/or tachycar- Lidocaine Dizziness, sedation, slurred speech, blurred vision, paresthesia,
muscle twitching, confusion, nausea, vomiting, seizures, psy-
dias caused by some forms of triggered automaticity, these agents may
chosis, sinus arrest, aggravation of underlying conduction
be effective in the treatment of these types of arrhythmias. In all disturbances
likelihood, verapamil and diltiazem work at different receptor sites Mexiletine Dizziness, sedation, anxiety, confusion, paresthesia, tremor, ataxia,
because of their dissimilar chemical structures and pharmacologic blurred vision, nausea, vomiting, anorexia, aggravation of
actions. Calcium channel blockers can slightly shorten repolarization underlying conduction disturbances or ventricular arrhythmias
in normal sodium-dependent tissue, but otherwise have little effect. Moricizine Dizziness, headache, fatigue, insomnia, nausea, diarrhea,
The dihydropyridine CCBs (e.g., nifedipine) do not have significant blurred vision, aggravation of underlying conduction distur-
antiarrhythmic activity because a reflex increase in sympathetic tone bances or ventricular arrhythmias
caused by vasodilation counteracts their direct negative dromotropic Flecainide Blurred vision, dizziness, dyspnea, headache, tremor, nausea,
action. aggravation of underlying HF, conduction disturbances or
ventricular arrhythmias
All antiarrhythmic agents currently available have an impressive
Propafenone Dizziness, fatigue, bronchospasm, headache, taste disturbances,
side-effect profile (Table 19–3). A considerable percentage of patients
nausea, vomiting, bradycardia or AV block, aggravation of under-
cannot tolerate long-term therapy with these drugs and chances are lying HF, conduction disturbances or ventricular arrhythmias
good that an agent will have to be discontinued because of side effects. Amiodarone Tremor, ataxia, paresthesia, insomnia, corneal microdeposits,
 In one trial,7 more than 50% of patients had to discontinue long- optic neuropathy/neuritis, nausea, vomiting, anorexia, consti-
term procainamide (mostly because of a lupus-like syndrome) after pation, TdP (<1%), bradycardia or AV block (IV and oral use),
MI. In another study,8 disopyramide caused anticholinergic side pulmonary fibrosis, liver function test abnormalities, hepatitis,
effects in approximately 70% of patients. Flecainide, propafenone, hypothyroidism, hyperthyroidism, photosensitivity, blue-gray
and disopyramide may precipitate congestive HF in a significant skin discoloration, hypotension (IV use), phlebitis (IV use)
number of patients with underlying LV systolic dysfunction; conse- Dofetilide Headache, dizziness, TdP
Ibutilide Headache, TdP, hypotension
quently, these drugs should be avoided in this patient population.9
Sotalol Dizziness, weakness, fatigue, nausea, vomiting, diarrhea, brady-
The type Ib agents, such as tocainide and mexiletine, cause neurologic
cardia, TdP, bronchospasm, aggravation of underlying HF
and/or gastrointestinal toxicity in a high percentage of patients.
Tocainide, specifically, has been reported to cause both pulmonary AV, atrioventricular; HF, heart failure; IV, intravenous; TdP, torsades de pointes.
fibrosis and leukopenia, the significance of which came to light after
its approval by the Food and Drug Administration; it has now been
cause corneal microdeposits (which usually do not affect vision) in
withdrawn from the market and is currently unavailable. One of the
virtually every patient, it has also been associated with the develop-
most frightening adverse effects related to antiarrhythmic drugs is the
ment of optic neuropathy/neuritis, which can lead to blindness. All of
aggravation of underlying ventricular arrhythmias or the precipita-
these side effects mandate close and continued monitoring (liver
tion of new (and life-threatening) ventricular arrhythmias.10
enzymes, thyroid function tests, eye exams, chest radiographs, pul-
Amiodarone has assumed a prominent place in the treatment of
monary function tests) and have led to a proliferation of “amiodarone
both chronic and acute supraventricular and ventricular arrhythmias
clinics” designed just for patients receiving this agent on a chronic
and is now the most commonly prescribed antiarrhythmic drug.11
basis (Table 19–4). 14
Once considered a drug of last resort, it is now the first drug
Table 19–5 summarizes the pharmacokinetics of the antiarrhyth-
considered in many symptomatic tachycardias. Yet amiodarone is a
mic agents and Table 19–6 lists recommended dosages of the oral
peculiar and complex drug, displaying unusual pharmacologic effects,
dosage forms. Table 19–7 lists the dosing recommendations for the
pharmacokinetics, dosing schemes, and multiorgan side effects. Ami-
corresponding IV forms.
odarone has an extremely long elimination half-life and large volume
of distribution; consequently, its onset of action with the oral form is
delayed (days to weeks) despite a loading regimen and its effects SUPRAVENTRICULAR ARRHYTHMIAS
persist long (months) after discontinuation. Amiodarone inhibits P-
glycoprotein and most cytochrome P450 (CYP) enzymes, resulting in The common supraventricular tachycardias that often require drug
the potential for numerous drug interactions (e.g., it will cause treatment are (a) AF or atrial flutter, (b) PSVT, and (c) automatic
digoxin levels to approximately double and one must reduce the atrial tachycardias. Other common supraventricular arrhythmias that
maintenance dose of warfarin by one-third to one-half). Acute usually do not require drug therapy include premature atrial com-
administration of amiodarone is usually well-tolerated by patients, plexes, wandering atrial pacemaker, sinus arrhythmia, and sinus tachy-
but severe organ toxicities may result with chronic use. Severe cardia. As an example, premature atrial complexes rarely cause
bradycardia (sometimes requiring pacing to allow the patient to symptoms, never cause hemodynamic compromise, and therefore
remain on amiodarone), hyper- and hypothyroidism, photosensitiv- drug therapy is usually not indicated. Likewise, sinus tachycardia is
ity, and a blue-gray skin discoloration on exposed areas are common. usually the result of underlying metabolic or hemodynamic disorders
Fulminant hepatitis (uncommon) and pulmonary fibrosis (5% to (e.g., infection, dehydration, hypotension) and therapy should be
10% of patients) have caused death.12,13 Although amiodarone can directed at the underlying cause, not the tachycardia per se. Of course,
 287

TABLE 19-4 Amiodarone Monitoring

CHAPTER 19
Side Effect Monitoring Recommendations Management of Side Effect
Pulmonary fibrosis Chest radiograph (baseline, then every 12 months) Discontinue amiodarone immediately; initiate corticosteroid therapy
Pulmonary function tests (if symptomatic)
Hypothyroidism Thyroid function tests (baseline, then every 6 months) Thyroid hormone supplementation (e.g., levothyroxine)
Hyperthyroidism Thyroid function tests (baseline, then every 6 months) Antithyroid drugs
Optic neuritis/neuropathy Ophthalmologic examination (baseline, then every 12 Discontinue amiodarone immediately
months)
Corneal microdeposits Slit-lamp examination (routine monitoring not necessary) No treatment necessary
Increased LFTs LFTs (baseline, then every 6 months) Consider lowering the dose or discontinuing amiodarone if LFTs

The Arrhythmias
>3× normal
Bradycardia/heart block ECG (baseline, then every 3–6 months) Lower the dose, if possible, or discontinue amiodarone if severe
Tremors, ataxia, peripheral neuropathy History/physical examination (each office visit) Lower the dose, if possible, or discontinue amiodarone if severe
Photosensitivity/blue-gray skin discoloration History/physical examination (each office visit) Advise patients to wear sunblock while outdoors
ECG, electrocardiogram; LFTs, liver function tests.

TABLE 19-5 Pharmacokinetics of Antiarrhythmic Drugss

Bioavailability Primary Route of Protein Therapeutic
Drug (%) Eliminationa Substrateb Inhibitorb VD ss (L/kg) Binding (%) t1/2c Range (mg/L)
Quinidine 70–80 H CYP3A4 (M) CYP2D6 (S) 2.0–3.5 80–90 5–9 h 2–6
CYP2C9 CYP3A4 (S)
CYP2C9
P-GP
Procainamide 75–95 H/R NAT — 1.5–3.0 10–20 5–6 h (SAs) 4–15
CYP2D6 (M) 2–3 h (FAs)
Disopyramide 70–95 H/R CYP3A4 (M) — 0.8–2.0 50–80 4–8 h 2–6
Lidocaine — H CYP3A4 (M) CYP1A2 (S) 1–2 65–75 1–3 h 1.5–5.0
CYP2D6 (M) CYP2D6
CYP1A2 CYP3A4
CYP2C9
Mexiletine 80–95 H CYP2D6 (M) CYP1A2 (S) 5–12 60–75 12–20 h (PMs) 0.8–2.0
CYP1A2 (M) 7–11 h (EMs)
Moricizine 34–38 H CYP3A4 (M) — 6–11 92–95 2–4 h —
Flecainide 90-95 H/R CYP2D6 (M) CYP2D6 8–10 35–45 14–20 h (PMs) 0.2–1.0
CYP1A2 10–14 h (EMs)
Propafenone d 11–39 H CYP2D6 (M) CYP1A2 2.5–4.0 85–95 10–25 h (PMs) —
CYP1A2 CYP2D6 3–7 h (EMs)
CYP2D6
Amiodarone 22–88 H CYP3A4 (M) CYP2C9 70–150 95–99 15–100 d 1.0–2.5
CYP1A2 CYP2D6
CYP2C19 CYP3A4
CYP2D6 CYP1A2
CYP2C19
P-GP
Sotalol 90–95 R — — 1.2–2.4 30–40 10–20 h —
Dofetilide 85–95 R/H CYP3A4 — 2.5–3.5 60–70 6–10 h —
Ibutilide — H — — 6–12 40–50 3–6 h —
Verapamil 20–40 H CYP3A4 (M) CYP3A4 1.5–5.0 95–99 4–12 h —
CYP1A2 CYP1A2
CYP2C9 CYP2C9
CYP2D6
P-GP
Diltiazem 35–50 H CYP3A4 (M) CYP3A4 3–5 70–85 4–10 h —
CYP2C9 CYP2C9
CYP2D6 CYP2D6
P-GP
a
H, hepatic; R, renal.
b
CYP, cytochrome P450 isoenzyme; M, major; NAT, N-acetyltransferase; P-GP, P-glycoprotein; S, strong.
c
EMs, extensive metabolizers; FAs, fast acetylators; PMs, poor metabolizers; SAs, slow acetylators.
d
Variables for parent compound (not 5-OH-propafenone).
 288

TABLE 19-6 Typical Maintenance Doses of Oral Paroxysmal Supraventricular Tachycardia caused by Reentry
Antiarrhythmic Drugs
SECTION 2

General
Drug Dose Dose Adjusted ■ These rhythms can be transient, resulting in little, if any,
Quinidine 200–300 mg sulfate salt q 6 h HEP, age >60 yr symptoms.
324–648 gluconate salt q 8–12 h
Symptoms
Procainamide 500–1,000 mg q 6 h (Pronestyl SR) HEP, RENa
1,000–2,000 mg q 12 h (Procanbid) ■ Patients frequently complain of intermittent episodes of rapid
Disopyramide 100–150 mg q 6 h HEP, REN heart rate/palpitations that abruptly start and stop, usually
200–300 mg q 12 h (SR form) without provocation (but occasionally as a result of exercise).
Mexiletine 200–300 mg q 8 h HEP Severe symptoms include syncope. Often (in particular, those
Cardiovascular Disorders

Flecainide 50–150 mg q 8 h HEP, REN with AV nodal reentry), patients complain of a chest pressure
Propafenone 150–300 mg q 8 h HEP or neck sensation. This is caused by simultaneous AV contrac-
Moricizine 200 mg q 8 h HEP, REN tion with the right atrium contracting against a closed tricuspid
Sotalol 80–160 mg q 12 h RENb
valve. Life-threatening symptoms (syncope, hemodynamic col-
Dofetilide 500 mcg q 12 h RENc
lapse) are associated with an extremely rapid heart rate (e.g.,
Amiodarone 400 mg two to three times daily until 10 g
total, then 200–400 mg daily d >200 beats/min) and AF associated with an accessory AV
pathway.
HEP, hepatic disease; REN, renal dysfunction; SR, sustained release.
a
Accumulation of parent compound or metabolite (e.g., NAPA) may occur. Diagnostic Tests/Signs (ECG; See Text for Details)
b
Should not be used for atrial fibrillation when creatinine clearance <40 mL/min. ■ Most commonly, PSVT is a rapid, narrow QRS tachycardia
c
Dose should be based upon creatinine clearance; should not be used when creatinine clearance <20
(regular in rhythm) that starts and stops abruptly. Atrial
mL/min.
d
Usual maintenance dose for atrial fibrillation is 200 mg/day (may further decrease dose to activity, although present, is difficult to ascertain on surface
100 mg/day with long-term use if patient clinically stable in order to decrease risk of toxicity); usual ECG because P waves are “buried” on the QRS or T wave.
maintenance dose for ventricular arrhythmias is 300–400 mg/day.

ATRIAL FIBRILLATION AND ATRIAL FLUTTER

there are exceptions to these suggestions. For example, sinus tachycar-
Mechanisms and Background
dia may be deleterious in patients after cardiac surgery or MI. In
another unusual tachycardia termed nonparoxysmal sinus tachycardia, Atrial fibrillation and atrial flutter are common supraventricular
chronically elevated heart rates may cause alterations in LV function. tachycardias. These tachycardias occur more often in men and the
In both of these instances, antiarrhythmic drugs, such as β-blockers,
may be indicated. Stated in another way, although many arrhythmias
generally do not require therapy, clinical judgment and patient- TABLE 19-7 Intravenous Antiarrhythmic Dosing
specific variables play an important role in this decision. Nevertheless, Drug Clinical Situation Dose
for the purpose of this discussion, only the tachycardias usually
Amiodarone Pulseless VT/VF 300 mg IV/IO push (can give additional
requiring antiarrhythmic drug therapy, as listed above, are addressed. 150 mg IV/IO push if persistent VT/
VF), followed by infusion of 1 mg/min
CLINICAL PRESENTATION: for 6 h, then 0.5 mg/min
SUPRAVENTRICULAR TACHYCARDIA Stable VT (with a 150 mg IV over 10 min, followed by
pulse) infusion of 1 mg/min for 6 h, then 0.5
Atrial Fibrillation/Flutter mg/min
General AF (termination) 5 mg/kg IV over 30 min, followed by
■ These rhythms are usually not directly life-threatening nor do infusion of 1 mg/min for 6 h, then 0.5
mg/min
they generally cause hemodynamic collapse or syncope; 1:1
Diltiazem PSVT; AF (rate control) 0.25 mg/kg IV over 2 min (may repeat
atrial flutter (ventricular response ~300 beats/min) is an
with 0.35 mg/kg IV over 2 min), fol-
exception. Also, patients with underlying forms of heart lowed by infusion of 5–15 mg/h
disease that are heavily reliant on atrial contraction to main- Ibutilide AF (termination) 1 mg IV over 10 min (may repeat if
tain adequate cardiac output (e.g., mitral stenosis, obstructive needed)
cardiomyopathy) display more severe symptoms of AF or Lidocaine Pulseless VT/VF 1–1.5 mg/kg IV/IO push (can give addi-
atrial flutter. tional 0.5–0.75 mg/kg IV/IO push every
5–10 min if persistent VT/VF [maxi-
Symptoms
mum cumulative dose = 3 mg/kg]),
■ Most often, patients complain of rapid heart rate/palpitations followed by infusion of 1–4 mg/min
and/or worsening symptoms of HF (shortness of breath, (1–2 mg/min if liver disease or HF)
fatigue). Medical emergencies are severe HF (i.e., pulmonary Stable VT (with a 1–1.5 mg/kg IV push (can give addi-
edema, hypotension) or AF occurring in the setting of acute MI. pulse) tional 0.5–0.75 mg/kg IV push every
5–10 min if persistent VT [maximum
Diagnostic Tests/Signs (ECG; See Text for Details)
cumulative dose = 3 mg/kg]), fol-
■ Atrial fibrillation is an irregularly, irregular supraventricular lowed by infusion of 1–4 mg/min (1–
rhythm with no discernible, consistent atrial activity (P waves). 2 mg/min if liver disease or HF)
Ventricular response is usually 120 to 180 beats/min and the Procainamide AF (termination); sta- 15–18 mg/kg IV over 60 min, followed
pulse is irregular. Atrial flutter is (usually) a regular supraven- ble VT (with a pulse) by infusion of 1–4 mg/min
tricular rhythm with characteristic flutter waves (or sawtooth Verapamil PSVT; AF (rate control) 2.5–5 mg IV over 2 min (may repeat up to
pattern) reflecting more organized atrial activity. Commonly, maximum cumulative dose of 20 mg);
can follow with infusion of 2.5–10 mg/h
the ventricular rate is in factors of 300 beats/min (e.g., 150, 100,
or 75 beats/min). AF, atrial fibrillation; IO, intraosseous; IV, intravenous; PSVT, paroxysmal supraventricular tachycardia;
VF, ventricular fibrillation; VT, ventricular tachycardia.
 289
elderly. In the general population, the overall prevalence of AF is Patients with AF or artrial flutter may experience the entire range
0.4% to 1% and this increases with age (e.g., approximately an 8% of symptoms associated with other supraventricular tachycardias,

CHAPTER 19
prevalence in patients >80 years old).15 The prevalence of AF also although syncope as a presenting symptom is uncommon. Because
appears to increase as patients develop more severe HF, increasing atrial kick is lost with the onset of AF, patients with LV systolic or
from 4% in asymptomatic NYHA functional class I patients to 50% diastolic dysfunction may develop worsening signs and symptoms of
in patients with NYHA functional class IV HF.15 HF as they often depend on the contribution of their atrial kick to
Atrial flutter and AF may present as a chronic, established tachy- maintain an adequate cardiac output. Thromboembolic events,
cardia, an acute tachycardia, or a self-terminating, paroxysmal form. resulting from atrial stasis and poorly adherent mural thrombi, are
The following semantics and definitions are sometimes used specifi- an additional complication of AF. Of course, the most devastating
cally for AF:15,16 acute AF (onset within 48 hours); paroxysmal AF complication in this regard is the occurrence of an embolic stroke.

The Arrhythmias
(terminates spontaneously in <7 days); recurrent AF (two or more Approximately 15% of all strokes in the United States can be
episodes); persistent AF (duration >7 days and does not terminate attributed to AF.17 The average rate of ischemic stroke in patients
spontaneously); and permanent AF (does not terminate with with AF who are not receiving antithrombotic therapy is approxi-
attempts at pharmacologic or electrical cardioversion). Atrial fibril- mately 5% per year.17,18 Stroke can precede the onset of documented
lation is characterized as an extremely rapid (atrial rate of 400 to 600 AF, probably as a result of undetected paroxysms prior to the onset
beats/min) and disorganized atrial activation. With this disorganized of established AF. The risk of stroke significantly increases with age,
atrial activity, there is a loss of the contribution of synchronized atrial with the annual attributable risk increasing from 1.5% in individuals
contraction (atrial kick) to forward cardiac output. Supraventricular ages 50 to 59 years to almost 24% in those ages 80 to 89 years of age.17
impulses penetrate the AV conduction system in variable degrees Patients with concomitant AF and rheumatic heart disease are at
resulting in an irregular activation of the ventricles and an irregularly, particularly high risk for stroke, with their risk being increased 17-
irregular pulse. The AV junction will not conduct most of the fold compared to patients in sinus rhythm.17 Other risk factors for
supraventricular impulses causing ventricular response to be consid- stroke identified from recent trials are previous ischemic stroke,
erably slower (120 to 180 beats/min) than the atrial rate. It is transient ischemic attack, or other systemic embolic event; moderate
sometimes stated that “AF begets AF”; that is, the arrhythmia tends or severe LV systolic dysfunction and/or congestive HF; hyperten-
to perpetuate itself. Long episodes are more difficult to terminate sion; and diabetes.17 Younger patients (age <65 years) with AF in
perhaps because of tachycardia-induced changes in atrial function whom precipitating factors cannot be identified (i.e., lone AF) are
(mechanical and/or electrical “remodeling”). considered to be at low risk for stroke.17 The risk of stroke in patients
Atrial flutter occurs less frequently than AF, but is similar in its with only atrial flutter has been traditionally believed to be low,
precipitating factors, consequences, and drug therapy approach. This prompting some to recommend only aspirin for prevention of
arrhythmia is characterized by rapid (270 to 330 atrial beats/min) thromboembolism in this particular patient population. However,
but regular atrial activation. The slower and regular electrical activity because patients with atrial flutter may also intermittently have
results in a regular ventricular response that is in approximate factors episodes of AF, this patient population also may be at risk for a
of 300 beats/min (i.e., 1:1 AV conduction = ventricular rate of 300 thromboembolic event. Although the role of antithrombotic therapy
beats/min; 2:1 AV conduction = ventricular rate of 150 beats/min; in patients with atrial flutter has not been adequately studied in
3:1 AV conduction = ventricular rate of 100 beats/min). Atrial flutter clinical trials, the most recent guidelines suggest that the same risk
may occur in two distinct forms (type I and type II). Type I flutter is stratification scheme and antithrombotic recommendations used in
the more common classic form with atrial rates of approximately 300 patients with AF also be applied to those with atrial flutter.17
beats/min and the typical “sawtooth” pattern of atrial activation as
shown by the surface ECG. Type II flutter tends to be faster, being Management
somewhat of a hybrid between classic atrial flutter and AF. Although
The traditional approach to the treatment of AF can be organized into
the ventricular response usually has a regular pattern, atrial flutter
several sequential goals: (a) First, evaluate the need for acute treat-
with varying degrees of AV block or that occur with episodes of AF
ment (usually the administration of drugs that slow ventricular rate).
(“fib-flutter”) can cause an irregular ventricular rate.
(b) Next, contemplate methods to restore sinus rhythm taking into
It is generally accepted that the predominant mechanism of AF
consideration the risks (e.g., thromboembolism). (c) Last, consider
and atrial flutter is reentry. Atrial fibrillation appears to result from
ways to prevent the long-term complications of AF such as arrhyth-
multiple atrial reentrant loops (or wavelets) while atrial flutter is
mia recurrences and thromboembolism.  One of the biggest con-
caused by a single, dominant, reentrant substrate (counterclockwise
troversies in the management of AF is whether or not the restoration
circus movement in the right atrium around the tricuspid annulus).
and maintenance of sinus rhythm is a desirable goal for all patients
Atrial fibrillation or flutter usually occurs in association with vari-
with AF. A review of the management of AF/atrial flutter, including a
ous forms of structural heart disease that cause atrial distension,
discussion of this controversy follows, organized according to the
including myocardial ischemia or infarction, hypertensive heart
goals outlined above. Figure 19–5 shows an algorithm for the man-
disease, valvular disorders such as mitral stenosis or mitral insuffi-
agement of AF and atrial flutter. In addition, Table 19–8 summarizes
ciency, congenital abnormalities such as septal defects, dilated or
the recommendations for pharmacologically controlling ventricular
hypertrophic cardiomyopathy, and obesity. Disorders that cause
rate and restoring and maintaining sinus rhythm from the most
right atrial stretch and are associated with AF or atrial flutter include
recent AF guidelines developed by the American College of Cardiol-
acute pulmonary embolus and chronic lung disease resulting in
ogy (ACC)/American Heart Association (AHA)/European Society of
pulmonary hypertension and cor pulmonale. Atrial fibrillation may
Cardiology (ESC).15
also occur in association with states of high adrenergic tone such as
thyrotoxicosis, surgery, alcohol withdrawal, sepsis, and excessive Acute Treatment First, consider the patient with new-onset,
physical exertion. Atrial fibrillation that develops in the absence of symptomatic AF or atrial flutter. Although uncommon, patients
clinical, electrocardiographic, radiographic, and echocardiographic may present with signs and/or symptoms of hemodynamic instabil-
evidence of structural heart disease is defined as lone AF. Other ity (e.g., severe hypotension, angina, or pulmonary edema), which
states in which patients are predisposed to episodes of AF are the qualifies as a medical emergency. In these situations, DCC is
presence of an anomalous AV pathway (i.e., Kent bundle) and sinus indicated as first-line therapy in an attempt to immediately restore
node dysfunction (i.e., tachy-brady or sick sinus syndrome). sinus rhythm (without regard to the risk of thromboembolism).
 290

Atrial Fibrillation/Flutter
SECTION 2

Severe symptoms Minimal or moderate symptoms

Slow ventricular rate

DCC
(BB, CCB, or digoxin)
Cardiovascular Disorders

Rhythm control
If atrial flutter Rate control
only (restore sinus
(leave in AF)
rhythm)

Consider Warfarin ≥3 Chronic

ablation weeks or TEE antithrombotic
to exclude therapy (see
thrombusa Figure 19–6)

Elective Consider
cardioversion adding AAD if
(electrical or patient remains
pharmacologic) symptomatic
despite
adequate
ventricular rate
Long-term control
AADs?

Isolated Episode Recurrent Episodes

FIGURE 19-5. Algorithm for the treatment

of atrial fibrillation and atrial flutter. aIf AF <48
May consider AAD (especially if patient
hours, anticoagulation prior to cardioversion
remains symptomatic despite adequate
is unnecessary; may consider TEE if patient No AADs
ventricular rate control)b (see Table 19–9)
has risk factors for stroke. bAblation may be
considered for patients who fail or do not May also consider leaving in AF (and
tolerate ≥1 AAD. c Chronic antithrombotic providing rate control and anticoagulation)
therapy should be considered in all patients
with AF and risk factors for stroke regardless
of whether or not they remain in sinus
rhythm. (AAD, antiarrhythmic drug; AF, atrial
fibrillation; BB, β-blocker; CCB, calcium chan- Consider chronic antithrombotic therapy
for patients with risk factors for strokec
nel blocker [i.e., verapamil or diltiazem]; DCC, (see Figure 19–6)
direct-current cardioversion; TEE, transesoph-
ageal echocardiogram.)

Atrial flutter often requires relatively low energy levels of counter- heart rate during exercise. Although an initial decrease in the ventric-
shock (i.e., 50 joules), whereas AF often requires higher energy ular rate can sometimes be observed within 1 hour of IV administra-
levels (i.e., greater than 200 joules). tion, full control (heart rate <80 beats/min at rest and <100 beats/min
If patients are hemodynamically stable, there is no emergent need during exercise) is usually not achieved for 24 to 48 hours. In
to restore sinus rhythm. Instead, the focus should be directed toward addition, digoxin tends to be ineffective for controlling ventricular
controlling the patient’s ventricular rate. Achieving adequate ventric- rate under conditions of increased sympathetic tone (i.e., surgery,
ular rate control should be a treatment goal for all patients with AF. thyrotoxicosis) because it slows AV nodal conduction primarily
To achieve this goal, drugs that slow conduction and increase refrac- through vagotonic mechanisms. In contrast, IV β-blockers and non-
toriness in the AV node (e.g., β-blockers, nondihydropyridine CCBs, dihydropyridine CCBs have a relatively quick onset and can effec-
or digoxin) should be used as initial therapy. Although loading tively control the ventricular rate at rest and during exercise. β-
dosages of digoxin have been historically recommended as first-line blockers are also effective for controlling ventricular rate under
treatment to slow ventricular rate, use of this drug for achieving conditions of increased sympathetic tone.
ventricular rate control, especially in patients with normal LV systolic Based on the most recent guidelines for the treatment of AF, the
function (left ventricular ejection fraction [LVEF] >40%) has selection of a drug to control ventricular rate in the acute setting
declined.11 In this patient population, IV β-blockers (propranolol, should be primarily based on the patient’s LV function.15 In patients
metoprolol, esmolol), diltiazem, or verapamil is preferred. A few of with normal LV function (LVEF >40%), IV β-blockers, diltiazem, or
the potential reasons for the declining use of digoxin in this patient verapamil is recommended as first-line therapy to control ventricular
population are its relatively slow onset and its inability to control the rate.15 All of these agents have proven efficacy in controlling the
 291

TABLE 19-8 Evidence-Based Pharmacologic Treatment Recommendations for Controlling Ventricular Rate, Restoring Sinus Rhythm, and Maintaining

CHAPTER 19
Sinus Rhythm in Patients with Atrial Fibrillation
ACC/AHA/ESC Guideline
Treatment Recommendations Recommendation
Ventricular rate control (acute setting)
In the absence of an accessory pathway, IV β-blockers, or IV nondihydropyridine CCBs are recommended for patients without hypotension or HF. Class I
In the absence of an accessory pathway, IV digoxin or IV amiodarone is recommended for patients with HF. Class I
IV amiodarone can be used to control the ventricular rate in patients who are refractory to or have contraindications to IV β-blockers, Class IIa
nondihydropyridine CCBs, or digoxin.
IV procainamide or ibutilide is a reasonable alternative in patients with an accessory pathway when DCC is not necessary. Class IIa

The Arrhythmias
IV procainamide, ibutilide, or amiodarone may be considered for hemodynamically stable patients with an accessory pathway. Class IIb
IV nondihydropyridine CCBs are not recommended in patients with decompensated HF. Class III
Ventricular rate control (chronic setting)
Oral digoxin is effective for controlling the ventricular rate at rest in patients with HF or LV dysfunction, and in those who are sedentary. Class I
Combination therapy with oral digoxin and either an oral β-blocker or nondihydropyridine CCB is reasonable to control the ventricular rate both at rest Class IIa
and during exercise.
Oral amiodarone can be used when the ventricular rate cannot be adequately controlled at rest and during exercise with an oral β-blocker, Class IIb
nondihydropyridine CCB, and/or digoxin.
Digoxin should not be used as the only agent for controlling the ventricular rate in patients with paroxysmal AF. Class III
Restoration of sinus rhythm
Flecainide, dofetilide, propafenone, or ibutilide is recommended for pharmacologic cardioversion of AF. Class I
Amiodarone is a reasonable option for pharmacologic cardioversion of AF. Class IIa
The “pill-in-the-pocket” approach (see text) can be used to terminate persistent AF on an outpatient basis once the treatment has been used Class IIa
safely in the hospital, in patients without sinus or AV node dysfunction, bundle-branch block, QT interval prolongation, Brugada syndrome, or
structural heart disease (Note: AV node must be adequately blocked before initiating this therapy.)
Amiodarone can be used on an outpatient basis in patients with paroxysmal or persistent AF when rapid restoration of sinus rhythm is not necessary. Class IIa
Quinidine or procainamide might be considered for pharmacologic cardioversion of AF, but their efficacy is not well established. Class IIb
Digoxin and sotalol should not be used for pharmacologic cardioversion of AF (may be harmful). Class III
Quinidine, procainamide, disopyramide, and dofetilide should not be initiated on an outpatient basis Class III
Maintenance of sinus rhythm
Antiarrhythmic therapy can be useful for maintaining sinus rhythm and preventing tachycardia-induced cardiomyopathy. Class IIa
Outpatient initiation of antiarrhythmic therapy is reasonable in patients without structural heart disease. Class IIa
Propafenone or flecainide may be initiated on an outpatient basis in patients with paroxysmal AF who have no structural heart disease and Class IIa
are in sinus rhythm at the time therapy is initiated.
Sotalol may be initiated on an outpatient basis in patients without structural heart disease, QT interval prolongation, electrolyte abnormalities, Class IIa
or other risk factors for proarrhythmia.
An antiarrhythmic drug should not be used when patients have risk factors for proarrhythmia with that particular agent. Class III
Antiarrhythmic therapy is not recommended in patients with sinus or AV node dysfunction unless a pacemaker is present. Class III
ACC, American College of Cardiology; AF, atrial fibrillation; AHA, American Heart Association; AV, atrioventricular; CCB, calcium channel blocker; DCC, direct-current cardioversion; ESC, European Society of
Cardiology; HF, heart failure; IV, intravenous; LV, left ventricular.
Adapted from reference 15.

ventricular rate in patients with AF. Propranolol and metoprolol can Patients may present with a slow ventricular response (in the
be administered as intermittent IV boluses, whereas esmolol (because absence of AV nodal-blocking drugs) and thus, do not require
of its very short half-life of 5 to 10 minutes) must be administered as therapy with β-blockers, nondihydropyridine CCBs, or digoxin.
a series of loading doses followed by a continuous infusion. Likewise, This type of presentation should alert the clinician to the possibility
because control of ventricular rate can be transient with a single of preexisting SA or AV nodal conduction disease such as sick sinus
bolus, verapamil or diltiazem can be given as an initial IV bolus syndrome. In these patients, DCC should not be attempted without
followed by a continuous infusion.19 These continuous infusions can a temporary pacemaker in place.
be adjusted in monitored settings to the desired ventricular response
(e.g., acutely <100 beats/min). In situations where AF or atrial flutter Restoration of Sinus Rhythm? After treatment with AV nodal-
is precipitated by states of increased adrenergic tone, IV β-blockers blocking agents and a subsequent decrease in the ventricular rate, the
can be highly effective and should be considered first. patient should be evaluated for the possibility of restoring sinus
In patients with LV dysfunction (LVEF ≤40%), IV diltiazem or rhythm if AF persists. Within the context of this evaluation, several
verapamil should be avoided because of their potent negative inotro- factors should be considered. First, many patients spontaneously
pic effects. Intravenous β-blockers should be used with caution in this convert to sinus rhythm without intervention, obviating therapy
patient population and should be avoided if patients are in the midst needed to achieve this goal. For instance, AF occurs frequently as a
of an episode of decompensated HF. In those patients who are having complication of cardiac surgery and often spontaneously reverts to
an exacerbation of HF symptoms, IV administration of either digoxin sinus rhythm without therapy. Second, restoring sinus rhythm is not
or amiodarone should be used as first-line therapy to achieve ventric- a necessary or realistic goal in some patients. To date, a total of five
ular rate control.15 Intravenous amiodarone can also be used in clinical trials (Pharmacological Intervention in Atrial Fibrillation
patients who are refractory to or have contraindications to β-block- [PIAF], Rate Control versus Electrical Cardioversion for Persistent
ers, nondihydropyridine CCBs, and digoxin.15 However, clinicians Atrial Fibrillation [RACE], Atrial Fibrillation Follow-up Investigation
should be aware that the use of amiodarone for controlling ventricu- of Rhythm Management [AFFIRM], Strategies of Treatment of Atrial
lar rate may also stimulate the conversion of AF to sinus rhythm, and Fibrillation [STAF], and How to Treat Chronic Atrial Fibrillation
place the patient at risk for a thromboembolic event, especially if the [HOT-CAFE]), have been published that have shed some light on this
AF is at least 48 hours or of unknown duration. particular issue.20–24 Of these, the AFFIRM is the largest study to
 292
compare the effects of a rate-control (controlling ventricular rate; situation, if the decision is made to allow a patient to remain in AF,
patient remains in AF) and rhythm-control (restoring and maintain- consideration must be given to selecting the most appropriate anti-
SECTION 2

ing sinus rhythm) strategy in patients with AF.22 In the AFFIRM trial, thrombotic therapy for these patients as they continue to be at risk for
patients with AF and at least one risk factor for stroke were random- thromboembolic complications (see below).
ized to either a rate-control or rhythm-control group. Rate-control Because a rate-control strategy is now considered a reasonable
treatment involved AV nodal-blocking drugs (digoxin, β-blockers, approach for the chronic management of AF, the question that
and/or CCBs) first, then nondrug treatment (AV nodal ablation with remains to be answered is, “In which patients should restoration of
pacemaker implantation), if necessary. All patients in this group were sinus rhythm be considered?” Given the results of the AFFIRM trial,
anticoagulated with warfarin to achieve an international normalized this decision should be left to clinical judgment but one could imagine
ratio (INR) of 2.0 to 3.0. In the rhythm-control group, type I or type that several groups of patients should undergo electrical or pharmaco-
Cardiovascular Disorders

III antiarrhythmic drugs were used to maintain sinus rhythm. The logic cardioversion. They include those patients who are judged to
choice of antiarrhythmic therapy was left up to each patient’s physi- have a relatively low chance of recurrence (e.g., first episode of lone AF
cian; however, by the end of the trial, more than 60% of patients had in young individuals, transient states of high sympathetic tone) and
received at least one trial of amiodarone and approximately 40% of those with troublesome symptoms despite adequate ventricular rate
patients had received at least one trial of sotalol. In this group, control. In the former patient population, chronic antiarrhythmic
anticoagulation was encouraged but could be discontinued if sinus therapy is usually not needed since the AF is often self-limiting.
rhythm had been maintained for at least 4 weeks. After a mean In those patients in whom it is decided to restore sinus rhythm, one
follow-up period of 3.5 years, overall mortality was not statistically must consider that this very act (regardless of whether an electrical or
different between the two strategies but tended (P = 0.08) to be higher pharmacologic method is chosen) places the patient at risk for a
in the rhythm-control group. The results of the PIAF, RACE, STAF, thromboembolic event. The reason for this is that the return of sinus
and HOT-CAFE trials were consistent with those of the AFFIRM rhythm restores effective contraction in the atria, which may dislodge
trial.20,21,23,24 In addition, a recently published meta-analysis of the poorly adherent thrombi. Administering antithrombotic therapy
data from all of these trials demonstrated no significant difference in prior to cardioversion not only prevents clot growth and the forma-
overall mortality between rate-control and rhythm-control strategies, tion of new thrombi but also allows existing thrombi to become
which persisted even when the results from the AFFIRM trial were organized and well-adherent to the atrial wall. It is a generally
excluded from this analysis.25 Overall, the results of these trials accepted principle that patients become at increased risk of thrombus
collectively demonstrate that a rate-control strategy is a viable alterna- formation and a subsequent embolic event if the duration of the AF
tive to a rhythm-control strategy in patients with persistent AF. exceeds 48 hours. Therefore, it is vital for clinicians to estimate the
Clearly, these important findings temper the old approach of duration of the patient’s AF, so that appropriate antithrombotic
aggressively attempting to maintain sinus rhythm. Because a rhythm- therapy can be administered prior to cardioversion, if needed.
control strategy does not confer any advantage over a rate-control According to the most recent guidelines derived from the Seventh
strategy in the management of AF, it now remains acceptable to allow American College of Chest Physicians Consensus Conference on
patients to remain in AF, while being chronically treated with AV Antithrombotic Therapy, patients with AF for longer than 48 hours
nodal-blocking agents to achieve adequate ventricular rate control or an unknown duration should receive warfarin treatment (target
(e.g., heart rate <80 beats/min at rest and <100 beats/min during INR 2.5; range: 2.0 to 3.0) for at least 3 weeks prior to cardioversion.17
exercise).  Overall, the selection of an AV nodal-blocking agent to The common clinical scenario is to discharge the patient from the
control ventricular rate in the chronic setting should be primarily hospital, monitor them on an ambulatory basis, and readmit for
based on the patient’s LV function.15 In patients with normal LV elective cardioversion after this time period. After restoration of sinus
function (LVEF >40%), oral β-blockers, diltiazem, or verapamil are rhythm, full atrial contraction does not occur immediately. Rather, it
preferred over digoxin because of their relatively quick onset and returns gradually to a maximum contractile force over a 3- to 4-week
maintained efficacy during exercise. When adequate ventricular rate period. Consequently, warfarin should be continued for at least 4
control cannot be achieved with one of these agents, the addition of weeks after effective cardioversion and return of sinus rhythm. To
digoxin may provide an additive lowering of the heart rate. If shorten the time to cardioversion, these patients may alternatively
adequate ventricular rate control during rest and exercise cannot be undergo transesophageal echocardiography (TEE) to provide guid-
achieved with β-blockers, nondihydropyridine CCBs, and/or digoxin, ance regarding the need for antithrombotic therapy prior to cardio-
oral amiodarone can be used as alternative therapy to control the version. If no thrombus is noted on TEE, then these patients can be
heart rate.15 Verapamil and diltiazem should not be used in patients cardioverted without the mandatory 3 weeks of warfarin pretreat-
with LV dysfunction (LVEF ≤40%). Instead, β-blockers (i.e., meto- ment. However, IV unfractionated heparin should still be adminis-
prolol, carvedilol, or bisoprolol) and digoxin are preferred in these tered during the TEE and cardioversion procedures to prevent the
patients, as these agents are also concomitantly used to treat chronic formation of thrombi during the pericardioversion and postcardio-
HF; if possible, β-blockers should be considered over digoxin in this version periods. After effective cardioversion and return of sinus
situation because of their survival benefits in patients with LV systolic rhythm, these patients should receive 4 weeks of warfarin therapy, as
dysfunction. If patients are having an episode of decompensated HF, their atria may still be mechanically stunned during this period. If the
digoxin is preferred as first-line therapy to achieve ventricular rate TEE performed prior to cardioversion reveals thrombus, patients
control. Occasionally, patients may be encountered who are highly should then be anticoagulated indefinitely, and cardioversion should
refractory to AV nodal-blocking agents (including combination drug not be attempted until there is absence of thrombus on repeat TEE.
therapy) and continue to have a rapid ventricular rate. In this Overall, the use of TEE in this manner has been compared to the
situation, aggressive attempts to lower the heart rate are necessary as conventional 3 weeks of anticoagulation before cardioversion in
chronic tachycardia can result in a progressive decline in LV function patients with AF.27 In this large, multicenter, randomized trial, the
causing so-called tachycardia-induced cardiomyopathy. Hence, in incidence of thromboembolic events was not different between the
drug-refractory patients, ablation or modification of the AV node by two strategies, but bleeding episodes were higher in the “3 weeks of
a transvenous catheter delivering radiofrequency current is indi- warfarin” group. Patients in the TEE strategy group had a higher
cated.15,26 This procedure often completely blocks conduction from success rate of achieving sinus rhythm, probably because it’s more
the atrium to the ventricle, requiring the concurrent implantation of difficult to terminate AF the longer a patient remains in it (i.e., “AF
a permanent pacemaker with a ventricular lead. Regardless of the begets AF”).
 293
In patients with AF that is less than 48 hours in duration, anticoag- Although amiodarone can be administered safely on an outpatient
ulation prior to cardioversion is unnecessary because there has not basis because of its low proarrhythmic potential, dofetilide can only

CHAPTER 19
been sufficient time to form atrial thrombi.17 However, it is recom- be initiated in the hospital. Additionally, it should be remembered
mended that these patients should receive either IV unfractionated that a patient’s ventricular rate should be adequately controlled with
heparin or a low-molecular-weight heparin (subcutaneously at treat- AV nodal-blocking drugs prior to administering a type Ic (or Ia)
ment doses) at presentation prior to cardioversion. If these patients antiarrhythmic for cardioversion. The types Ia and Ic agents may
have risk factors for stroke, a TEE could alternatively be performed paradoxically increase ventricular response. Traditionally, this obser-
prior to cardioversion to exclude the presence of thrombus. Patients vation has been attributed to the vagolytic action of these drugs
with AF that is less than 48 hours in duration do not require the 4 despite the fact that only disopyramide displays significant anticho-
weeks of postcardioversion anticoagulation therapy unless they have linergic side effects. Therefore, a more likely alternative explanation

The Arrhythmias
risk factors for stroke or if the AF recurs. exists: all of these agents slow atrial conduction, decreasing the
After prior anticoagulation or TEE, the methods available to number of impulses reaching the AV node; as a result, the AV node
restore sinus rhythm can be considered. There are two methods of paradoxically allows more impulses to gain entrance to the ventricu-
restoring sinus rhythm in patients with AF or atrial flutter: pharma- lar conduction system (increasing ventricular rate).
cologic cardioversion and DCC. Which of these is the method of
choice is generally a matter of clinical preference. The disadvantages Long-Term Complications There are two forms of therapy that
of pharmacologic cardioversion are the risk of significant side the clinician must consider in each patient: long-term antithrombotic
effects (e.g., drug-induced TdP),28 the inconvenience of drug–drug therapy to prevent stroke, and long-term antiarrhythmic drugs to
interactions (e.g., digoxin–amiodarone), and the fact that drugs are prevent recurrences of AF. Consider the issue of antithrombotic
generally less effective when compared to DCC. The advantages of therapy first. In the past, patients with AF were not routinely antico-
DCC are that it is quick and more often successful (80% to 90% agulated (unless there was a history of stroke or concurrent mitral
success rate). The disadvantages of DCC are the need for prior valve disease) because it was believed that the risk of warfarin
sedation/anesthesia and a risk (albeit small) of serious complica- exceeded its potential (though unknown) benefit. In the past several
tions such as sinus arrest or ventricular arrhythmias. Contrary to years, a large number of randomized, placebo-controlled trials
past beliefs, DCC carries very little risk in patients who are receiving designed to evaluate this issue have been published. All possess
digoxin and have no evidence of digitalis toxicity. relatively similar findings and many were terminated prematurely
Nonetheless, despite the relatively high success rate associated with because of a significant effect in the treatment group (warfarin). In all,
DCC, some clinicians elect to use antiarrhythmic drugs first, then these studies culminated in the following recommendations from the
resort to DCC in the event that these agents fail. Pharmacologic Seventh American College of Chest Physicians Consensus Conference
cardioversion appears to be most effective when initiated within 7 on Antithrombotic Therapy for patients with paroxysmal, persistent,
days after the onset of AF.15 According to the most recent treatment or permanent AF17: warfarin (target INR: 2.5; range: 2.0 to 3.0)
guidelines for AF, there is relatively strong evidence for efficacy of the should be prescribed to all patients who are at high risk for stroke
type III pure IK blockers (ibutilide and dofetilide), the type Ic antiar- (rheumatic mitral valve disease; previous ischemic stroke, transient
rhythmics (e.g., flecainide and propafenone), and amiodarone (oral ischemic attack, or other systemic embolic event; age >75 years;
or IV).15 Type Ia antiarrhythmics have limited efficacy in this setting. moderate or severe LV systolic dysfunction and/or congestive HF;
Sotalol is not effective for cardioversion of paroxysmal or persistent hypertension; or prosthetic heart valve); those at intermediate risk
AF. Single, oral loading doses of propafenone (600 mg) and flecainide (age 65 to 75 years with none of the above high-risk factors) should
(300 mg) are effective compared to placebo for conversion of recent- receive either warfarin (target INR: 2.5; range: 2.0 to 3.0) or aspirin
onset AF and provide a simple regimen.29 A method called the “pill- 325 mg/day; and those at low risk (age <65 years with none of the
in-the-pocket” approach was recently endorsed by the treatment above high-risk factors) should receive aspirin 325 mg/day. In the
guidelines.15 With this method, outpatient, patient-controlled self- intermediate-risk group, the decision of whether to use warfarin or
administration of a single, oral loading dose of either flecainide or aspirin should be based on such factors as the patient’s risk for
propafenone can be a relatively safe and effective approach for the bleeding, patient preference, potential drug interactions with war-
termination of recent-onset AF in a selected patient population that farin, and the availability of an appropriate monitoring system for
does not have sinus or AV node dysfunction, bundle-branch block, warfarin therapy. Although it was previously an acceptable practice to
QT interval prolongation, Brugada syndrome, or structural heart continue antithrombotic therapy for only 4 weeks after successful
disease.30 In addition, this treatment regimen should only be consid- cardioversion (with the belief that a patient’s risk for thromboembo-
ered in patients who have been successfully cardioverted with these lism had abated since they were in sinus rhythm), recent data from
drugs on an inpatient basis. In patients with AF that is longer than 7 the PIAF, RACE, AFFIRM, STAF, and HOT-CAFE trials strongly
days in duration, only dofetilide, amiodarone, and ibutilide have suggest that patients with AF and other risk factors for stroke
proven efficacy for cardioversion.15 The types Ia and Ic antiarrhyth- continue to be at risk for stroke even when maintained in sinus
mics have limited efficacy in this setting. rhythm.20–24 It is possible that these patients may be having undetec-
Overall, when considering pharmacologic cardioversion, the selec- ted episodes of paroxysmal AF, placing them at risk for stroke.
tion of an antiarrhythmic drug should be based on whether the Consequently, the updated treatment guidelines for AF recommend
patient has structural heart disease (e.g., LV dysfunction, coronary that chronic antithrombotic therapy be considered for all patients
artery disease, valvular heart disease, LV hypertrophy).15 In the with AF and risk factors for stroke regardless of whether or not they
absence of any type of structural heart disease, the use of a single, oral remain in sinus rhythm.15 Figure 19–6 is an algorithm for preventing
loading dose of flecainide or propafenone is a reasonable approach thromboembolism in patients with AF.
for cardioversion; the “pill-in-the-pocket” approach should only be The second form of chronic therapy to be considered is antiar-
used in select patients (see above). Ibutilide can also be used as an rhythmic drugs to prevent recurrences of AF. With some exceptions
alternative agent in this patient population; however, this agent can (e.g., postoperative situations or transient states of high sympathetic
only be administered in the hospital because it is only available in IV tone), AF often recurs after initial cardioversion because most
form. In patients with underlying structural heart disease, these patients have irreversible, underlying heart or lung disease. Large
antiarrhythmics should be avoided because of the increased risk of atrial size, poor LV function, and the presence of long-standing AF
proarrhythmia, and amiodarone or dofetilide should be used instead. are factors that make the restoration and maintenance of sinus
 294

Paroxysmal, Persistent, or Permanent AF

SECTION 2

Low-Risk Patient Moderate-Risk Patient

(with the low-risk factor (with the moderate-risk High-Risk Patient
below, but no high-risk factor below, but no (≥1 high-risk factor)
Cardiovascular Disorders

factors) high-risk factors)

Warfarin
(target INR 2.5; Warfarin
Aspirin 325 mg/day range = 2.0–3.0) (target INR 2.5;
or range = 2.0–3.0)a
Aspirin 325 mg/day

High-risk factors
Prior stroke, transient ischemic attack, or systemic embolism
Hypertension
Diabetes mellitus
Moderate or severely impaired left ventricular systolic function or congestive heart faliure
Age >75 years
Rheumatic mitral valve stenosis
FIGURE 19-6. Algorithm for the pre- Prosthetic heart valve
vention of thromboembolism in parox-
Moderate-risk factors
ysmal, persistent, or permanent atrial
Age = 65–75 years
fibrillation. aThe target INR for patients
with prosthetic heart valves should be Low-risk factors
based upon the type of valve that is Age <65 years
present. (AF, atrial fibrillation; INR, inter-
national normalized ratio.)

rhythm difficult if not impossible. Nevertheless, historically, many deemphasized throughout these updated guidelines as they are consid-
clinicians have aggressively attempted to maintain sinus rhythm by ered less effective or incompletely studied compared to the type Ic and
prescribing oral antiarrhythmic drugs (usually quinidine) to prevent type III agents. Realistically, however, these agents can still be consid-
these recurrences despite the fact that only small studies with conflict- ered as last-line therapy in patients without structural heart disease
ing results existed evaluating this approach. To evaluate the efficacy of and in patients with hypertension (without significant LV hypertro-
quinidine in preventing AF, a well-known meta-analysis of the exist- phy) or coronary artery disease (with normal LV systolic function).
ing literature was completed.31 This meta-analysis demonstrated that
indeed more patients remain in sinus rhythm with quinidine therapy
(compared to placebo); however, approximately 50% have recur- TABLE 19-9 Guidelines for Selecting Antiarrhythmic Drug
rences of AF within a year despite quinidine. However, this reported Therapy for Maintenance of Sinus Rhythm in Patients
effectiveness was at the cost of an associated increase in mortality with Recurrent Paroxysmal or Recurrent Persistent
(presumably due, in part, to proarrhythmia) in the quinidine-treated Atrial Fibrillation
patients. These disturbing results (published soon after the CAST32) No structural heart disease a
became widely quoted and highly visible, making clinicians question First line: flecainide, propafenone, or sotalol
the wisdom of long-term prevention of recurrences of AF with Second line: amiodarone or dofetilide (catheter ablation could also be consid-
antiarrhythmic drugs. Although the results were questioned because ered as an alternative to antiarrhythmic therapy)
some of the reported causes of death in the treated patients could not Heart failure a
be directly attributed to quinidine, subsequent studies33 tended to First line: amiodarone or dofetilide
support the findings of the meta-analysis. Second line: catheter ablation
These results coupled with the recent findings of the PIAF, RACE, Coronary artery disease a
First line: sotalol (to be used only if patients have normal LV systolic function)
AFFIRM, STAF, and HOT-CAFE trials question the need to use
Second line: amiodarone or dofetilide (catheter ablation could also be consid-
antiarrhythmic drugs to prevent recurrences of AF.20–24 Perhaps this
ered as an alternative to antiarrhythmic therapy)
practice should now be totally abandoned, allowing patients to remain Hypertension a
in AF once recurrences happen and only using strategies to control rate Presence of significant LVH
and prevent thromboembolism. Although it is true that these data have First line: amiodarone
certainly led to a less-aggressive approach, patients with paroxysmal AF Second line: catheter ablation
who continue to have intolerable symptoms during recurrences do Absence of significant LVH:
require antiarrhythmic drugs to prevent these symptomatic attacks. First line: flecainide, propafenone, or sotalol
According to the recent treatment guidelines for AF, the type Ic or Second line: amiodarone or dofetilide (catheter ablation could also be
type III antiarrhythmic drugs are reasonable to consider to maintain considered as an alternative to antiarrhythmic therapy)
patients in sinus rhythm (Table 19–9).15 The role of the type Ia LV, left ventricular; LVH, left ventricular hypertrophy.
antiarrhythmic drugs for maintenance of sinus rhythm has been a
Drugs are listed alphabetically and not in order of suggested use.
 295
The type Ic antiarrhythmics, flecainide and propafenone, are with concurrent AF) type I atrial flutter, ablation of the reentrant
effective for maintaining sinus rhythm. However, because of the substrate with radiofrequency current is highly effective (~80%)42

CHAPTER 19
increased risk for proarrhythmia, these drugs should be avoided in and can be considered first-line treatment of atrial flutter to prevent
patients with structural heart disease. recurrences.43 For patients with AF, an innovative surgical procedure,
Although all of the oral type III antiarrhythmic drugs have demon- referred to as the “maze” operation, has been used for more than a
strated efficacy in preventing recurrences of AF, amiodarone is clearly decade.44 Because of its highly complex and invasive nature, the maze
the most effective agent and is now the most frequently chosen procedure is often reserved for highly drug-refractory patients. Over
despite its impressive organ toxicity.11 Since 2000, the superiority of the past several years, most of the emerging data in the literature
amiodarone over other antiarrhythmics for maintaining patients in regarding nondrug treatment of AF have primarily focused on the
sinus rhythm has been demonstrated in a number of clinical trials. In safety and efficacy of catheter ablation techniques. Patients with AF

The Arrhythmias
the Canadian Trial of Atrial Fibrillation, amiodarone was significantly have been found to have arrhythmogenic foci that occur in atrial
more effective than sotalol or propafenone in maintaining sinus tissue near and within the pulmonary veins. During the ablation
rhythm in patients with persistent or paroxysmal AF.34 Furthermore, procedure, radiofrequency energy can be delivered to these areas in
in a substudy of the AFFIRM trial, amiodarone appeared to be the an attempt to abolish the foci. Historically, this procedure was often
most effective antiarrhythmic agent of those used in the study.35 In considered last-line therapy for patients who had failed all antiar-
the more recently published Sotalol Amiodarone Atrial Fibrillation rhythmic drugs, including amiodarone. However, in some of the
Efficacy Trial, amiodarone and sotalol were equally effective at con- recent trials, the use of catheter ablation in patients with AF has been
verting AF to sinus rhythm.36 However, amiodarone was significantly associated with a significant reduction in recurrent episodes of AF
more effective than sotalol at maintaining sinus rhythm in all patient and an improvement in quality of life when compared with antiar-
subgroups, except for those with ischemic heart disease where the rhythmic drug therapy.45,46 There is even some evidence47 to suggest
efficacy of these two drugs was comparable. that this procedure may be superior to antiarrhythmic drugs as first-
Although sotalol is not effective for conversion of AF, it is an line therapy of symptomatic AF; however, these results will have to be
effective agent for maintaining sinus rhythm. Sotalol has been shown validated in larger trials. Based on this recent data, the guidelines now
to be at least as effective as quinidine or propafenone in preventing recommend that catheter ablation be considered as a reasonable
recurrences of AF.34,37 However, treatment with either quinidine or treatment alternative for patients with symptomatic episodes of
sotalol is associated with a similar incidence of TdP. Because this form recurrent AF who fail or do not tolerate at least one antiarrhythmic
of proarrhythmia primarily occurs with higher doses of sotalol (quin- drug.15 This procedure is not without its risks, as major complica-
idine usually causes TdP at low or therapeutic concentrations), it may tions, such as pulmonary vein stenosis, thromboembolic events,
be more easily predicted and therefore avoided. Nonetheless, sotalol cardiac tamponade, and new atrial flutter, have been reported in up
may increase mortality in patients with AF similar to quinidine; to 6% of patients.48
however, this requires further study.38
Dofetilide is effective in preventing recurrences of AF39 but has
not been directly compared with either amiodarone or sotalol. In a PAROXYSMAL SUPRAVENTRICULAR
large, multicenter trial,40 dofetilide (dose adjusted for renal function TACHYCARDIA CAUSED BY REENTRY
and QT interval) was more effective than placebo in maintaining
Paroxysmal supraventricular tachycardia arising by reentrant mech-
sinus rhythm (approximately 35% to 50% at 1 year). The efficacy of
anisms includes those arrhythmias caused by AV nodal reentry, AV
dofetilide for the maintenance of sinus rhythm has also specifically
reentry incorporating an anomalous AV pathway, SA nodal reentry,
been demonstrated in patients with LV dysfunction.41 Like sotalol
and intraatrial reentry. Atrioventricular nodal reentry and AV
and quinidine, dofetilide also has significant potential to cause TdP
reentry are by far the most common of these tachycardias. 
(in a dose-related fashion).
Overall, the use of antiarrhythmic drug therapy to maintain sinus
Mechanisms
rhythm is reasonable to consider in patients with recurrent paroxys-
mal or persistent AF who develop intolerable symptoms during The underlying substrate of AV nodal reentry is the functional
episodes of AF. As with cardioversion, the selection of an antiarrhyth- division of the AV node into two (or more) longitudinal conduction
mic drug for maintaining sinus rhythm should be based on whether pathways or “dual” AV nodal pathways.49 Most clinicians now believe
the patient has structural heart disease.15 For those patients with no that there are not two distinct anatomic pathways inside the AV node
underlying structural heart disease, flecainide, propafenone, or sotalol itself; rather, it is likely that a fan-like network of perinodal fibers
should be considered initially because they have the most optimal inserts into the AV node and represents the second pathway. The two
long-term safety profile. However, amiodarone or dofetilide could be pathways possess key differences in conduction characteristics: one is
used as alternative therapy if the patient fails or does not tolerate one a fast conducting pathway with a relatively long refractory period (fast
of these initial antiarrhythmic drugs. In the presence of structural pathway), and the other is a slower conducting pathway with a
heart disease, flecainide and propafenone, should be avoided because shorter refractory period (slow pathway). The presence of dual
of the risk of proarrhythmia. If LV dysfunction is present (LVEF pathways does not necessarily imply that the patient will have clinical
≤40%), amiodarone should be considered the antiarrhythmic of PSVT. In fact, it is estimated that between 10% and 50% of patients
choice. Dofetilide can be used as an alternative if patients develop have discernible dual pathways but the incidence of PSVT is consid-
intolerable side effects with amiodarone. In patients with coronary erably lower.49 Sustenance of the tachycardia depends on the critical
artery disease, sotalol can be used initially, provided that the patient’s electrophysiologic discrepancies and the ability of one pathway (usu-
LV function is normal. Amiodarone or dofetilide could be used as an ally the slow) to allow repetitive antegrade conduction, and the ability
alternative therapy if the patient fails or does not tolerate sotalol. The of the other pathway (usually the fast) to allow repetitive retrograde
presence of LV hypertrophy may predispose the myocardium to conduction. During sinus rhythm, a patient with dual pathways
proarrhythmic events. Because of its low proarrhythmic potential, conducts supraventricular impulses antegrade through both path-
amiodarone should be considered first-line therapy in these patients. ways. Electrical activity reaches the distal common pathway at the
Nondrug forms of therapy, designed to maintain sinus rhythm are level of or above the His bundle and continues to depolarize the
becoming increasingly popular treatment options for patients with ventricles in an antegrade direction. Conduction proceeds via the two
AF or atrial flutter. For patients who have “pure” (i.e., not associated pathways but reaches the distal common pathway first through the
 296

A A
Sinus SA node
SECTION 2

impulse
Atrium
AV node
AV ring
F
His
Node AV bypass
pathway
S
RB LB
Cardiovascular Disorders

His

B
B
Premature SA node
Premature impulse
*
impulse
Atrium
* AV node
F AV ring
His
AV bypass
Node
pathway
S
RB LB

His FIGURE 19-8. Reentry mechanism for AV accessory pathway PSVT in

Wolff-Parkinson-White syndrome. A. Sinus rhythm: The impulse travels
from the atrium to the ventricle by two pathways—the AV node and an
FIGURE 19-7. Reentry mechanism of dual AV nodal pathway PSVT. A. accessory bypass pathway. B. AV reentry: A critically timed premature
Sinus rhythm: The impulse travels from the atrium through the fast impulse (*) is stopped in the Kent bundle (because of prolonged
pathway (F) and then to the His-Purkinje system (His). The impulse also refractoriness) but travels antegrade through the AV node and retrograde
travels through the slow pathway (S) but is stopped when refractory through the Kent bundle. (AV, atrioventricular; His, His-Purkinje system;
tissue is encountered. B. Dual AV nodal reentry: A critically timed LB, left bundle-branch; RB, right bundle-branch; SA, sinoatrial.)
premature impulse (*) is stopped in the fast pathway (because of
prolonged refractoriness) but is able to travel antegrade down the slow
pathway and retrograde through the fast pathway. accessory pathways are often incapable of antegrade conduction and
can only accept electrical stimulation in a retrograde fashion. The
fast AV nodal route (Fig. 19–7). For this reason, a short PR interval is electrocardiographic expression of preexcitation (delta wave) depends
sometimes observed during sinus rhythm. on the location of the accessory pathway, the distance from the
Paroxysmal supraventricular tachycardia caused by AV nodal wavefront of sinus activation and the conduction characteristics of the
reentry may occur by the following sequence of events. The occur- various structures involved. It should be noted that (similar to patients
rence of an appropriately timed premature impulse penetrates the with dual AV nodal pathways) not all patients with preexcitation with
AV node, but is blocked in the fast pathway that is still refractory an accessory AV pathway are capable of having clinical PSVT.
from the previous beat. However, the slow pathway, which has a Patients with an accessory AV pathway may have three forms of
shorter refractory period, permits antegrade conduction of the pre- supraventricular tachycardia: orthodromic reentry, antidromic reen-
mature impulse. By the time the impulse has reached the distal try, and/or AF or atrial flutter. Atrioventricular reentrant PSVT
common pathway, the fast pathway has recovered its excitability and usually occurs by the following sequence of events. Analogous to AV
now will permit retrograde conduction. The impulse reaches the nodal reentry, two pathways (the normal AV nodal pathway and the
common proximal pathway, preceded by an excitable gap of tissue, accessory AV pathway) exist that have different electrophysiologic
and reenters the slow pathway. A reentrant circuit that does not characteristics. The AV nodal pathway usually has a relatively slower
require atrial or ventricular tissue is completed within (or nearly so) conduction velocity and shorter refractory period, and the accessory
the AV node, and a tachycardia is thereby initiated (see Fig. 19–7). pathway has a faster conduction velocity and a longer refractory
The common form of this tachycardia uses the slow pathway for period. A critically timed premature impulse may be blocked in the
antegrade conduction and the fast pathway for retrograde conduc- accessory pathway because this area is still refractory from the previ-
tion; an uncommon form exists in which the reentrant impulse ous sinus beat. However, the AV nodal pathway, with a relatively
travels in the opposite direction. shorter refractory period, may accept antegrade conduction of the
Atrioventricular reentrant tachycardia depends upon the presence premature impulse. Meanwhile, the accessory pathway may recover
of an anomalous, or accessory, extranodal pathway that bypasses the its excitability and now allow retrograde conduction. A macroreen-
normal AV conduction pathway. Several different types of accessory trant tachycardia is thereby initiated in which the antegrade pathway
pathways have been described, depending on the specific anatomic is the AV nodal pathway; the distal common pathway is the ventricle;
areas they connect (e.g., AV bundles or nodoventricular tracts); some the retrograde pathway the accessory pathway; and the proximal
are also referred to as eponyms, such as the Kent bundle. A Kent common pathway is the atrium (see Fig. 19–8). This sequence of
bundle is an extranodal AV connection that is associated with WPW events (down the node, up the Kent bundle), termed orthodromic
syndrome. During sinus rhythm (Fig. 19–8), patients with WPW PSVT, is the common variety of reentry in patients with an accessory
syndrome depolarize the ventricles simultaneously through both AV AV pathway, resulting in a narrow QRS tachycardia. In the uncom-
pathways (AV nodal pathway and the Kent bundle), creating a fusion mon variety, conduction proceeds in the opposite direction (down
pattern on the early portion of the QRS complex (delta wave). The the Kent bundle, up the node), resulting in a wide QRS tachycardia,
degree of ventricular “preexcitation” depends on the contribution of which is termed antidromic PSVT. Patients with WPW syndrome can
antegrade ventricular activation through the accessory pathway. have a third type of tachycardia, namely AF. The occurrence of AF in
Patients may have an accessory pathway that is not evident on ECG, the setting of an accessory AV pathway (i.e., WPW syndrome) can be
which is referred to as a “concealed” Kent bundle. These concealed extremely serious and has been documented. As AF is an extremely
 297
rapid atrial tachycardia, conduction can proceed down the accessory increase refractoriness primarily in the slow antegrade pathway of the
AV pathway, resulting in a very fast ventricular response or even VF. reentrant loop. In PSVT caused by AV reentry incorporating an

CHAPTER 19
Unlike the AV nodal pathway, the refractory period of the accessory extranodal pathway, type I drugs increase refractoriness in the fast
bundle shortens in response to rapid stimulation rates. accessory pathway or within the His-Purkinje system. β-blockers,
Sinus node reentry and intraatrial reentry occur less commonly digoxin, adenosine, and verapamil all act by their effects on the AV
and are not as well-described as AV nodal reentry and AV reentry. nodal (antegrade, slow) portion of the reentrant circuit. Regardless of
Aside from a characteristic abrupt onset and termination, coupled the mechanism, treatment measures are directed at first terminating
with subtle changes in P-wave morphology, these tachycardias can an acute episode of PSVT and then preventing symptomatic recur-
be difficult to diagnose. Electrophysiologic studies may be necessary rences of the arrhythmia.
to determine the ultimate mechanism of the PSVT. For those patients with PSVT who present with severe symptoms

The Arrhythmias
(syncope, near syncope, angina, or severe HF), synchronized DCC is
the treatment of choice. Even at low energy levels (such as 25 joules),
Management DCC is almost always effective in quickly restoring sinus rhythm and
Both pharmacologic and nonpharmacologic methods have been used correcting symptomatic hypotension. Patients with only mild to
to treat patients with PSVT. Drugs used in the treatment of PSVT can moderate symptoms usually do not require DCC and nondrug
be divided into three broad categories: (a) those that directly or measures that increase vagal tone to the AV node can be used initially.
indirectly increase vagal tone to the AV node (e.g., digoxin); (b) those Unilateral carotid sinus massage, Valsalva maneuver, ice water facial
that depress conduction through slow, calcium-dependent tissue immersion, induced retching, and other more elaborate vagomimetic
(e.g., adenosine, β-blockers, and CCBs); and (c) those that depress measures are often successful in terminating PSVT, although carotid
conduction through fast, sodium-dependent tissue (e.g., quinidine, massage and Valsalva maneuver are the simplest, least obtrusive, and
procainamide, disopyramide, and flecainide). Drugs within these most frequently used of these techniques.
categories alter the electrophysiologic characteristics of the reentrant In the event that vagal maneuvers fail (approximately 80% of acute
substrate so that PSVT cannot be sustained.50,51 In PSVT caused by episodes) in those patients with tolerable symptoms, drug therapy is
AV nodal reentry, type I antiarrhythmic drugs, such as procainamide, the next option. Figure 19–9 shows a therapeutic approach to the
act primarily on the retrograde fast pathway. Digoxin and β-blockers acute treatment of the different forms of reentrant PSVT.  This
may work on either the retrograde fast or the antegrade slow limb. approach is based on analysis of the electrocardiographic characteris-
Verapamil, diltiazem, and adenosine prolong conduction time and tics of the rhythm because PSVT is not always discernible from other

Symptoms

Severe Mild

Narrow QRS, regular Wide QRS, regular Wide QRS, irregular

AVNRT or othrodromic VT or antidromic AF with AP?

AVRT? AVRT? Acute
termination

DCC Adenosine, verapamil or Procainamide or

Adenosine or
diltiazem procainamide amiodarone

AVNRT or AVRT

Definitive diagnosis
(ECG, EPS)

Mild and infrequent Severe or frequent

episodes episodes
Chronic
No therapy prevention
PRN ADD AVN modification or AP
ablation

FIGURE 19-9. Algorithm for the treatment of acute (top portion) paroxysmal supraventricular tachycardia and chronic prevention of recurrences
(bottom portion). Note: For empiric bridge therapy prior to radiofrequency ablation procedures, calcium channel blockers (or other AV nodal blockers)
should not be used if the patient has AV reentry with an accessory pathway. (AAD, antiarrhythmic drugs; AF, atrial fibrillation; AP, accessory pathway;
AV, atrioventricular; AVN, atrioventricular nodal; AVNRT, atrioventricular nodal reentrant tachycardia; AVRT, atrioventricular reentrant tachycardia; DCC,
direct current cardioversion; ECG, electrocardiographic monitoring; EPS, electrophysiologic studies; PRN, as needed; VT, ventricular tachycardia.)
 298
arrhythmias, and some forms of PSVT require different treatment. In response in patients with PSVT; in other words, the tachycardia
patients with a narrow QRS, regular arrhythmia (AV nodal reentry or behaves as if it has a “weak link.” Patients who respond to agents that
SECTION 2

orthodromic AV reentry), IV verapamil (5 to 10 mg), IV diltiazem act on one limb of the reentrant loop are less likely to respond to
(15 to 25 mg), or adenosine (6 to 12 mg) are all equally efficacious. drugs that block conduction on the other limb. For instance, in a
Approximately 80% to 90% of PSVT episodes will revert to sinus patient with AV nodal reentry, one may first choose a nondihydro-
rhythm within 5 minutes of IV verapamil, diltiazem, or adenosine pyridine CCB or β-blocker (to affect the antegrade, slow pathway). If
therapy.52 Both verapamil and diltiazem have the advantage in terms symptomatic recurrences are subsequently documented, it may be
of cost, being available in generic formulations; whereas adenosine prudent to switch to a type Ic agent (to affect the retrograde, fast
(although it has a higher frequency of side effects) may be safer pathway) in an attempt to find the weak link or susceptible pathway.
because of its ultrashort duration of action. Adenosine should not be Patients with evidence of preexcitation (delta waves during sinus
Cardiovascular Disorders

used in patients with severe asthma because of the potential risk of rhythm) should not be treated with only AV nodal-blocking agents.
bronchospasm. The most recent guidelines for cardiopulmonary If AF were to occur, these agents would facilitate rapid conduction
resuscitation (CPR) and emergency cardiovascular care from the over the accessory pathway. The trial-and-error method for deter-
AHA,53 and practice guidelines from the ACC/AHA/ESC,43 promote mining drug effectiveness in this setting has inherent shortcomings.
adenosine as the drug of first choice in patients with PSVT.  These If the PSVT episodes are infrequent, a considerable time period may
recommendations are particularly important when treating a patient be consumed before an effective regimen is realized, or if the patient
who presents with a wide QRS, regular tachycardia that may be VT or has moderate to severe symptoms associated with PSVT, he/she may
PSVT (antidromic AV reentry or as a result of aberrancy). Because of experience several troublesome episodes before the correct agent is
its short duration of action (seconds), adenosine will not cause the identified. Consequently, a method of serial testing of antiarrhyth-
severe and prolonged hemodynamic compromise seen in patients mic agents by invasive electrophysiologic techniques has been used
with VT who were mistakenly treated with verapamil and suffer from to determine effective long-term therapy in those patients with
its negative inotropic effects and vasodilator properties.54 If, in fact, sporadic and/or symptomatic PSVT and this method represents
the arrhythmia is PSVT, adenosine will likely terminate it. An alterna- another strategy to find an effective antiarrhythmic regimen. Using
tive treatment for this type of patient is IV procainamide, which this method, the patient’s clinical tachycardia is replicated in the
works on the fast, sodium-dependent extranodal pathway, and is also laboratory by inserting appropriately timed, premature extra stim-
effective for VT. Likewise, IV procainamide, or perhaps amiodarone uli via a transvenous right-heart catheter. The patient is first studied
(particularly in patients with LV dysfunction), should be used for the off of antiarrhythmic therapy; induction of the tachycardia by
patient who presents with a wide QRS, irregular arrhythmia that is premature stimuli by programmed stimulation serves as a control
hemodynamically stable.53 This rhythm could represent AF with study. Then, over a period of several days, specific drugs are
rapid ventricular activation occurring primarily through an extrano- administered in a serial fashion and tested for efficacy in preventing
dal pathway. Administration of IV verapamil, diltiazem, digoxin, or the induction of PSVT.50 The goal is to find an effective drug
adenosine to these patients could result in a paradoxical increase in regimen in a short period of time, obviating the recurrence of highly
ventricular response, causing severe symptoms requiring cardiover- symptomatic or rare episodes that may occur in the trial-and-error
sion. Consequently, these agents are considered contraindicated in method. Occasionally, one encounters a patient with uncommon
this specific setting. and very-well-tolerated recurrences of PSVT. Similar to those with
Once the acute episode of PSVT is terminated, a decision on paroxysmal AF, self-administered, single-dose oral therapy (i.e., the
long-term preventive therapy must follow. Most patients require “pill-in-the-pocket” strategy) has been shown effective. Specifically,
long-term therapy; preventive treatment is indicated if: (a) frequent 120 mg of oral diltiazem coupled with 80 mg of oral propranolol has
episodes occur that necessitate therapeutic intervention (i.e., been shown to be superior to single-dose flecainide in terminating
emergency room visits or interference with the patient’s lifestyle), PSVT, decreasing the need to visit the emergency department for
or (b) infrequent but severely symptomatic symptoms occur. For treatment.55 Nonetheless, all forms of drug treatment designed to
those patients in whom a preventive treatment is deemed necessary, prevent or terminate the arrhythmia by self-administered therapy
two methods of management have been used: preventive drug therapy should probably be avoided in most patients because of the superior
and ablation. efficacy of nondrug treatment strategies.
Antiarrhythmic drugs are no longer the treatment of choice to Transcutaneous catheter ablation using radiofrequency current
prevent recurrences of reentrant PSVT for the following reasons: on the PSVT substrate has dramatically altered the traditional
(a) life-long treatment is necessary in these generally young, but treatment of these patients (Fig. 19–10).  Radiofrequency energy
otherwise healthy, individuals; (b) there are few, if any, large con- delivered through a transvenous or arterial catheter causes small,
trolled or comparative trials to assist the clinician in rationally discrete lesions through thermal energy. During invasive electro-
choosing effective agents, and most importantly; (c) other nondrug physiologic studies, portions of the reentrant circuit can be located
treatments are clearly more effective. Nevertheless, occasionally one (or “mapped”) by the use of a number of catheters. Once this is
must resort to the use of drug therapy in these patients. A trial-and- completed, radiofrequency energy is applied, creating thermal
error approach on an ambulatory basis may be considered for those injury in the tissue necessary for reentry. In this way, the substrate
patients with frequently recurrent, mildly symptomatic PSVT. for reentry is destroyed, “curing” the patient of recurrent episodes
Ambulatory electrocardiographic recordings (Holter) or telephonic of PSVT and obviating the need for chronic drug therapy. Histori-
transmissions of cardiac rhythm (event monitors) can be used to cally, ablation procedures were reserved for drug-refractory patients
objectively document the efficacy or failure of drug therapy. Drugs because they necessitated open-heart surgery. However, break-
known to be effective in preventing recurrences of PSVT are the AV throughs in technology initially included transvenous catheter
nodal-blocking agents (digoxin, β-blockers, nondihydropyridine approaches, followed by the use of radiofrequency (rather than
CCBs, and combinations of these agents) and the type Ic antiar- direct current) energy. Complications, although unusual, include
rhythmic drugs (flecainide, propafenone). Agents such as quinidine, tamponade, pericarditis, valvular insufficiency, and AV block.
disopyramide, amiodarone, and dofetilide, although effective in Radiofrequency ablation is highly effective, preventing the recur-
some patients, should be discouraged because of the risk of toxicity rences of PSVT in 85% to 98% of patients.56,57 The procedure was
with long-term treatment. One concept that can serve as an aid to originally used in patients with WPW syndrome.56 In these patients,
arriving at an effective regimen is that there are patterns of drug the extranodal pathway is most often located at the left lateral free
 299
words, it should be considered in any patient who would previously
Left atrial wall
be considered for chronic antiarrhythmic drug treatment. Radiofre-

CHAPTER 19
quency ablation is also a cost-effective approach (in the long-term)
Atrioventricular sulcus
because, if effective, the costs of drugs and repeated hospital visits
Accessory are avoided. In one cost-effectiveness analysis, radiofrequency abla-
pathway Epicardium tion improved quality of life and reduced lifetime medical expendi-
tures by nearly $30,000 compared to chronic drug treatment.59
Coronary sinus

Ablation
AUTOMATIC ATRIAL TACHYCARDIAS
Mitral annulus
catheter

The Arrhythmias
Automatic atrial tachycardias, such as multifocal atrial tachycardia,
Left circumflex
coronary artery appear to arise from supraventricular foci that have enhanced
automatic properties.60 It is presumed that multifocal atrial tachy-
Left ventricular wall
cardia is the result of multiple ectopic atrial pacemakers, which
account for the variable and differing P-wave morphology. In
Mitral valve
unifocal atrial tachycardia (more often referred to as ectopic atrial
tachycardia), a single P-wave morphology, different from that of
sinus rhythm, is recorded. In either case, the underlying, precipitat-
ing disorder present in the majority (60% to 80%) of these patients
is severe pulmonary disease. Other disease states associated with
these arrhythmias include acute infection (pneumonia and sepsis)
Transseptal and dilated congestive cardiomyopathy. It should be noted that
sheath
young patients without associated precipitating factors might rarely
present with rapid atrial tachycardias from unknown etiologies. In
these cases, long-standing tachycardias cause the cardiomyopathic
state. Effective treatment of the tachycardia may result in reversal of
Left
atrium the LV dysfunction. Traditionally, many factors (i.e., electrolyte
disturbances, hypoxia, catecholamines, and tissue stretch) may
cause an elevated slope of phase 4 depolarization and theoretically
result in abnormal heightened automaticity. Noteworthy is that
many of these factors are often clinically present in patients with
concurrent pulmonary disease and automatic atrial tachycardia.
However, it appears that triggered activity (i.e., LADs) is a more
likely mechanism in the genesis of these tachycardias. Atrial tachy-
cardias with AV block or a slow ventricular response should alert
the clinician to the possibility of digitalis toxicity.
The first step in the treatment of automatic atrial tachycardia is to
correct the underlying, precipitating factors.60 One should ensure
proper oxygenation and ventilation and correct acid–base or elec-
trolyte disturbances. These measures alone may result in the return
of sinus rhythm, but in some cases, the tachycardia will persist.
Patients with an asymptomatic atrial tachycardia and a relatively
slow ventricular rate usually require no drug therapy. In sympto-
Right ventricle Left ventricle
matic patients, medical therapy can be tailored to either control
FIGURE 19-10. Drawing showing catheter placement for radiofrequency ventricular rate or to restore sinus rhythm. Type I antiarrhythmic
ablation of a left lateral free wall accessory pathway. Here, a venous drugs, such as procainamide and quinidine, are only occasionally
(atrial) transseptal puncture to gain access to the Kent bundle is shown; effective in restoring sinus rhythm, and are usually not considered
a retrograde arterial approach has also been used. (From Lerman BB, first-line therapy. Direct-current cardioversion is ineffective in
Basson CT. High risk patients with ventricular preexcitation: A pendulum restoring sinus rhythm, and the use of programmed stimulation will
in motion. N Engl J Med 2003;349:1787–1789, with permission.) not replicate the clinical tachycardia; consequently, serial drug
testing is of no value. The use of IV β-blockers to slow ventricular
wall of the left ventricle (Fig. 19–10). After the pathway is located, rate is usually contraindicated because of the frequent coexistence of
the catheter is put as close to the site as possible and radiofrequency bronchospastic pulmonary disease or decompensated HF. Digoxin
current is applied to make small burns in the tissue. Ablation of the has been used but is controversial because of its ability to increase
extranodal connection occurs promptly and evidence of preexcita- the automatic properties of atrial tissue and the high sympathetic
tion (delta waves) disappears. Thereafter, a similar approach was state of these patients frequently overrides the vagotonic effects of
developed for patients with AV nodal reentry, placing the catheter digoxin, rendering it ineffective. Nondihydropyridine CCBs, such as
in the coronary sinus, proximal to the AV node.57 The preferred verapamil, are most effective and are now considered first-line drug
method in these individuals is to apply small amounts of radiofre- therapy.61 Interestingly, verapamil seems to decrease ventricular
quency current to the slow pathway of the reentrant circuit in order rate by altering atrial automaticity, not by slowing AV nodal
to modify its properties enough so that PSVT can not recur. conduction.61 Intravenous magnesium (independent of serum mag-
It has been suggested that all patients with symptomatic PSVT nesium) can also be effective, but high doses are required and its
undergo radiofrequency catheter ablation.58 This is because it is effects are transient, rendering it impractical.60 Both verapamil and
highly effective and curative, rarely results in complications, and parenteral magnesium probably act by suppressing calcium-medi-
obviates the need for chronic antiarrhythmic drug therapy. In other ated LADs.
 300
mias” and included frequent ventricular ectopy (more than 5 beats/
CLINICAL PRESENTATION:
min), multiform configuration (different morphology), couplets
VENTRICULAR ARRHYTHMIAS
SECTION 2

(two in a row), and R-on-T phenomenon (PVCs occurring during

Premature Ventricular Contractions the repolarization phase of the preceding sinus beat in the vulnerable
■ Premature ventricular contractions are non-life-threatening period of ventricular recovery). However, as a result of using contin-
and usually asymptomatic. Occasionally, patients will complain uous electrocardiographic monitoring techniques, it has become
of palpitations or uncomfortable heart beats. Since the PVC, by apparent that almost all patients have warning arrhythmias in the
definition, occurs early and the ventricle contracts when it is acute infarct setting. In those patients who experience VF, warning
incompletely filled, patients do not feel the PVC. Rather, the arrhythmias are no more common than in those without VF. Conse-
next beat (after the PVC and a compensatory pause) is usually quently, warning arrhythmias observed during acute MI are neither
Cardiovascular Disorders

responsible for the patient’s symptoms. sensitive nor specific for determining which patients will have VF.
Thus, there is little need to direct drug therapy specifically at PVC
Ventricular Tachycardia
suppression in these particular patients. Studies show that effective
■ The symptoms of VT (monomorphic VT or TdP), if prolonged prevention of VF in the acute infarct setting may be achieved without
(i.e., sustained), can vary from nearly completely asymptomatic the abolition of PVCs.
to pulseless, hemodynamic collapse. Fast heart rates and under- Conversely, data strongly imply that PVCs documented in the
lying poor LV function will result in more severe symptoms. convalescence period of MI do carry important long-term prognostic
Symptoms of nonsustained, self-terminating VT also correlate significance.63 Premature ventricular complexes occurring after a MI
with duration of episodes (e.g., patients with 15-second episodes seem to be a risk factor for patient death that is independent of the
will be more symptomatic than those with 3-beat episodes). degree of LV dysfunction or the extent of coronary atherosclerosis.
Ventricular Fibrillation Ruberman et al.63 employed a simple classification of PVCs: simple or
■ By definition, VF results in hemodynamic collapse, syncope, benign (infrequent and monomorphic) versus “complex” (≥5 PVCs/
and cardiac arrest. Cardiac output and blood pressure are not min, couplets, R-on-T beats, and multiform). These investigators
recordable. found that the presence of complex (but not simple) ventricular
ectopy in the setting of ischemic heart disease was associated with a
higher incidence of overall mortality and cardiac death. One can see
VENTRICULAR ARRHYTHMIAS that within the controversy of the significance of PVCs is a basic
question: Are complex forms of PVCs simply an unimportant marker
The common ventricular arrhythmias include: (a) PVCs, (b) VT, of underlying structural heart disease or are PVCs an important
and (c) VF. These arrhythmias may result in a wide variety of electrical disorder that should be addressed independently?
symptoms. Premature ventricular complexes often cause no symp- Because PVCs without associated structural heart disease, in
toms or only mild palpitations. Ventricular tachycardia may be a apparently healthy individuals, carry little or no risk, drug therapy
life-threatening situation associated with hemodynamic collapse or is unnecessary. However, because of the prognostic significance of
may be totally asymptomatic. Ventricular fibrillation, by definition, complex PVCs in patients with structural heart disease, the use of
is an acute medical emergency necessitating CPR. antiarrhythmic drug therapy to suppress them has been controver-
sial. Historically, many supported the aggressive use of antiarrhyth-
PREMATURE VENTRICULAR COMPLEXES AND mic drug therapy designed to suppress a high percentage of PVCs,
PREVENTION OF SUDDEN CARDIAC DEATH based on the underlying premise of eliminating a risk factor for SCD
in patients with coronary disease (namely the presence of complex
Premature ventricular complexes are very common ventricular PVCs). However, others favored a more conservative approach and
rhythm disturbances that occur in patients with or without struc- disregarded drug therapy in the absence of significant symptoms.
tural heart disease. Experimental models show that premature An important study, the CAST,32 abruptly put an end to this debate
ventricular depolarizations may be elicited by abnormal automatic- in noteworthy fashion and its results are reviewed below because of
ity, triggered activity, or by reentrant mechanisms. It is well known its great historical significance and lingering impact.
that PVCs are commonly observed in apparently healthy individu-
als; in these patients, the PVCs seem to have little if any prognostic The Cardiac Arrhythmia Suppression Trial
significance. Premature ventricular contractions occur more fre-
The CAST32,64 was initiated by the National Institutes of Health in
quently and in more complex forms in patients with structural heart
1987 to determine if suppression of ventricular ectopy with encainide,
disease than in healthy individuals. The prognostic meaning of
flecainide, or moricizine could decrease the incidence of death from
PVCs has been well studied in patients with MI (acute or remote)
arrhythmia in patients who had suffered a MI.  Entrance criteria
with several consistent themes. Patients with some forms of PVCs
included documented MI between 6 days and 2 years prior to enroll-
are at higher risk for “sudden death” than if they did not have these
ment, and ≥6 PVCs per hour (associated with no or minimal symp-
minor rhythm disturbances. Sudden cardiac death can be defined as
toms) without runs of VT greater than 15 beats in length. Also,
unexpected death occurring in a patient within 1 hour of experienc-
patients were required to have a LVEF ≤55% if recruited within 90
ing symptoms. Studies of patients who experienced SCD (and
days of MI or ≤40% if recruited 90 days or more after infarction.
happened to be wearing an electrocardiographic monitor at the
Patients with a LVEF <30% were randomized only to encainide or
time) often demonstrate the cause to be VF preceded by a short run
moricizine. Patients were randomized to receive drug therapy or
of VT and frequent PVCs.62 Therein lies the basis of the so-called
placebo after demonstrating PVC suppression with one of the agents.
“PVC hypothesis” (i.e., preventing more minor arrhythmias, such
The drug and dose were determined during an open-label, dose-
as PVCs, may prevent the occurrence of SCD).
titration phase that preceded randomization.
In April 1989, a routine, preliminary review of the study by the
Significance Safety and Monitoring Board revealed alarming results and the
Historically, investigators promoted the concept that patients in the study was interrupted. The results showed that compared to pla-
acute phase of MI may have types of PVCs that are predictive of VF cebo, treatment with encainide or flecainide was associated with a
and SCD. These types of PVCs were referred to as “warning arrhyth- significantly higher rate of total mortality and death due to arrhyth-
 301
100 shown not to increase mortality with long-term use: amiodarone and
dofetilide. A number of trials66,67 have shown amiodarone to decrease

CHAPTER 19
the incidence of sudden (or arrhythmic) death, but not total mortality,
95 in post-MI patients with complex ventricular ectopy. A meta-analysis
of all trials (6,553 combined patients) demonstrated a reduction in
total mortality (by 13%) with long-term amiodarone therapy.68 It is
Survival (%)

90
unclear if these findings can be attributed to one property (e.g., β-
blocking) or a combination of amiodarone’s complex pharmacologic
Placebo (n = 725) effects on conduction. Noteworthy is that in two major studies,
Encainide or flecainide (n = 730) patients treated with amiodarone and a β-blocker generally did better
85
than when no β-blocker was used.66,67 Clearly, because of its impres-

The Arrhythmias
P = .0006
sive adverse effect profile and its inability to improve survival, amio-
darone cannot routinely be recommended in patients with heart
0 50 100 150 200 250 300 350 400 450 500 disease such as remote MI and complex PVCs. Two randomized,
Days after randomization controlled trials69,70 showed that chronic therapy with dofetilide has
no effect on overall mortality in patients who have suffered MI with
FIGURE 19-11. Life table curves from the Cardiac Arrhythmia Suppres- LV dysfunction. Dofetilide (not approved for prevention of sudden
sion Trial (CAST), specifically for patients receiving encainide or flecainide
death) caused TdP in approximately 5% of patients, necessitating a
(lighter line) and matching placebo (darker line). Note the divergent
slopes of each line, implying a sustained risk of death (presumed
protocol amendment with dosage adjustments during both trials
proarrhythmia). (From The CAST Investigators. Preliminary report: Effect (particularly in those with renal disease because its primary route of
of encainide and flecainide on mortality in a randomized trial of elimination is through the kidney).
arrhythmia suppression after myocardial infarction. N Engl J Med How should the clinician approach the patient with documented
1989;321:406–412, with permission.) asymptomatic PVCs? Clearly, attempts to suppress asymptomatic
PVCs should not be made with any antiarrhythmic drug. Indeed,
those patients who are at risk for arrhythmic death (recent MI, LV
mia, presumably caused by proarrhythmia (Fig. 19–11). Analysis of
dysfunction, complex PVCs) should not be routinely given any type
the moricizine arm indicated neither harm nor benefit from this
I or III antiarrhythmic agent.71 If these patients have symptomatic
therapy; therefore, only this portion of the study was allowed to
continue as CAST II.64 However, in July 1991, CAST II was also PVCs, chronic drug therapy should be limited to the use of β-
blockers. The use of β-blockers in post-MI patients is associated
prematurely stopped because there was a trend toward an increase
in mortality in moricizine-treated patients. This increase in mortal- with a decrease in the incidence of total mortality and SCD,
ity was primarily observed during the initiation of moricizine especially in the presence of LV dysfunction. These agents can also
therapy (dose-titration phase) but not during the chronic treatment be used in patients without underlying structural heart disease to
phase. The overall results of the two CASTs conclusively prove that suppress symptomatic PVCs. 
that the use of antiarrhythmic drug therapy (beyond the general use
of β-blocking agents) to suppress PVCs in patients after a MI does VENTRICULAR TACHYCARDIA
not improve survival and is most likely detrimental. These studies
Mechanisms and Types of VT
also put into perspective the risk associated with the use of antiar-
rhythmic therapy and the need to carefully select only those patients Ventricular tachycardia is a wide QRS tachycardia that may acutely
with a defined therapeutic benefit. occur as a result of metabolic abnormalities, ischemia, or drug
Even though the CAST was conducted nearly 2 decades ago, it is toxicity, or chronically recur as a paroxysmal form. On electrocardio-
considered one of the most important trials ever undertaken and has graphic inspection, VT may appear as either repetitive monomorphic
had a tremendous influence on the overall approach to the treatment or polymorphic ventricular complexes. The definition of VT is three
of arrhythmias, as well as a far-reaching impact on new drug develop- or more consecutive PVCs occurring at a rate greater than 100 beats/
ment. The results of the CAST have clearly had a negative influence min. An acute episode of VT may be precipitated by severe electrolyte
on the long-term use of all antiarrhythmics, causing a broad skepti- abnormalities (hypokalemia), hypoxemia, or digitalis toxicity, or
cism in the risk-versus-benefit analysis of this class of drugs. Conse- (most commonly) may occur during an acute MI or ischemia com-
quently, pharmaceutical companies have shifted their drug discovery plicated by HF. In these cases, correction of the underlying precipitat-
and investigative efforts away from potent sodium channel blockers. ing factors will usually prevent further recurrences of VT. As an
As immediate fallout, encainide was withdrawn from the market, and example, if VT occurs during the first 24 hours of an acute MI, it will
another type Ic agent, indecainide, was not even brought to market probably not reappear on a chronic basis after the infarcted area has
despite approval by the Food and Drug Administration. The findings been reperfused or healed with scar formation. This form of acute VT
of the CAST also provided additional fuel for the pursuit of nondrug may be caused by a transient reentrant mechanism within tempo-
therapies for arrhythmias, such as ablation and implantable devices. rarily ischemic or dying ventricular tissue. In contrast, some patients
Despite the discouraging results of the CAST, post-MI patients have a chronic recurrent form of VT that is almost always associated
with complex ventricular ectopy remain at risk for death. Other with some type of underlying structural heart disease. Common
drugs, besides the type Ic agents, have been studied, including sotalol. examples are paroxysmal VT associated with idiopathic dilated car-
Sotalol is marketed as a racemic mixture of a d and l isomer: both are diomyopathy or remote MI with a LV aneurysm. Indeed, severe LV
type III potassium blockers but the l isomer has β-blocking actions. dysfunction and aneurysm formation are risk factors for the develop-
Chronic therapy with d-sotalol was studied in patients with remote ment of VT on a recurrent basis after MI. In chronic, recurrent VT,
MI complicated by complex ectopy in the Survival With Oral d- microreentry within the distal Purkinje network is presumed to be
Sotalol trial.65 Unlike the CAST, d-sotalol treatment was not designed responsible for the underlying substrate in a large majority of patients
to cause PVC suppression, yet (like the CAST) the trial was halted (see Fig. 19–3). Theoretically, electrophysiologic discrepancies occur
prematurely because of excessive mortality in the treatment arm. as a result of structural damage and heart disease within the ventricu-
Again, the presumed reason for this observation was d-sotalol–related lar conducting system. The reentrant circuit may possess both ana-
proarrhythmia. Currently, only two antiarrhythmic drugs have been tomically determined and functional properties coursing through
 302
normal tissue, damaged (but not dead) tissue and islands of necrosed Management
tissue. In a minority of patients, macro-reentrant circuits may be
SECTION 2

responsible for recurrent VT, including reentry incorporating the Consider the patient with the more common form of sustained
bundle branches. monomorphic VT (i.e., those with structural heart disease, usually
Patients with acute VT associated with a precipitating factor often ischemic in nature). Like other rapid tachycardias, the initial manage-
suffer severe symptoms, requiring immediate treatment measures. ment of an acute episode of VT (with a pulse) requires a quick
Chronic recurrent VT may also cause severe hemodynamic compro- assessment of the patient’s status and symptoms. If severe symptoms
mise, but may also be associated with only mild symptoms, which are are present (i.e., severe hypotension, angina, pulmonary edema),
generally well tolerated. Sustained VT is that which requires thera- synchronized DCC should be delivered immediately to attempt to
peutic intervention to restore a stable rhythm or persists for a restore sinus rhythm. An investigation should be made into possible
Cardiovascular Disorders

relatively long time (usually longer than 30 seconds). Nonsustained precipitating factors and these should be corrected if possible. The
VT is that which self-terminates after a brief duration (usually less diagnosis of acute MI should be entertained. If the episode of VT is
than 30 seconds). If the patient has VT more frequently than sinus thought to be an isolated electrical event associated with a transient
rhythm (i.e., VT is the dominant rhythm), this is referred to as initiating factor (such as acute myocardial ischemia or digitalis toxic-
incessant VT. In monomorphic VT, the QRS complexes are similar in ity), there is no need for long-term antiarrhythmic therapy once the
morphologic characteristics from beat to beat. In polymorphic VT, precipitating factors are corrected (e.g., an infarct has been reperfused
the QRS complexes vary in shape between beats. A characteristic type and healed and the patient is stable). Nevertheless, the patient should
of polymorphic VT, in which the QRS complexes appear to undulate be monitored closely for possible recurrences of VT.
around a central axis and is associated with evidence of delayed Patients presenting with an acute episode of VT (with a pulse)
ventricular repolarization (long QT interval or prominent U waves), associated with only mild symptoms can be initially treated with
is referred to as TdP. antiarrhythmic drugs (synchronized DCC should be readily avail-
Most but not all forms of recurrent VT occur in patients with able). The reader is referred to the most recent guidelines for CPR
extensive structural heart disease. Ventricular tachycardia occurring in and emergency cardiovascular care put forth by the AHA.53 Intrave-
a patient without structural heart disease is sometimes referred to as nous amiodarone is now recommended as first-line antiarrhythmic
“idiopathic VT” and may take several forms.72–74 Fascicular tachycar- therapy in this situation. Intravenous procainamide or lidocaine are
dia arises from a fascicle of the left bundle branch (usually posterior) suitable alternatives, although in one small study comparing these
and is usually not associated with severe underlying structural heart two agents, procainamide was shown to be superior in terminating
disease. In distinct contrast to the common form of recurrent VT VT.78 Synchronized DCC should be delivered if the patient’s status
associated with extensive structural heart disease, nondihydropyridine deteriorates, VT degenerates to VF (would be unsynchronized in
CCBs (but not adenosine) are effective in terminating an acute this situation), or drug therapy fails.
episode of fascicular VT. Ventricular outflow tract tachycardia (usu- Once an acute episode of sustained VT has been successfully
ally originating from the right ventricular outflow tract) originates terminated by electrical or pharmacologic means and an acute MI has
from near the pulmonic valve (or uncommonly the aortic valve) and been ruled out, the possibility of a patient having recurrent episodes
also occurs in patients with normal LV function without discernible of VT should be considered. Evidence for the possibility of VT
cardiac disease.74 Unlike other forms of VT, right ventricular outflow recurrence can often be gleaned from invasive electrophysiologic
tract tachycardia often terminates with adenosine and may be pre- studies using programmed ventricular stimulation. The management
vented with β-blockers and/or nondihydropyridine CCBs. of the patient with chronic, recurrent, sustained VT deserves consid-
Some unusual forms of VT are congenital or heritable (Table 19–10). erable attention. Because these patients are at extremely high risk for
Torsade de pointes can be associated with heritable defects in the flux death, trial-and-error attempts to find effective therapy are unwar-
of ions that govern ventricular repolarization. Although nine syn- ranted. To gain some objective evidence of a response to a specific
dromes and genetic mutations have been described, the more com- antiarrhythmic regimen, serial testing of these drugs using the follow-
mon examples are long QT syndrome 1 (depressed IKs), long QT ing two surrogate end points has been used: (a) inability to induce
syndrome 2 (depressed IKr), and long QT syndrome 3 (enhanced sustained VT with programmed extrastimuli by invasive electrophys-
inward sodium ion flux during repolarization).75,76 Polymorphic VT iologic studies and (b) suppression of ventricular ectopic beats by
(without a long QT interval) or VF may also occur as a result of a serial 24-hour continuous electrocardiographic (Holter) monitoring.
heritable defect in the sodium channel. This is the case in Brugada These two strategies have been compared79,80 but largely abandoned
syndrome, described as a typical ECG pattern (ST-segment elevation for several reasons. First, the yield for finding an effective drug is low.
in leads V1 to V3) in sinus rhythm associated with SCD, commonly in For instance, sustained monomorphic VT can be rendered noninduc-
males of Asian descent.77 It is estimated that Brugada syndrome ible or nonsustained by programmed stimulation protocols in only
accounts for approximately 40% of all cases of VF in patients without 20% to 25% of patients. Therefore, the clinician frequently must
heart disease. search for other therapeutic options or settle for other treatment end

TABLE 19-10 Heritable Polymorphic Ventricular Tachycardia

Syndrome Channel Defect Mutant Gene Characteristics Treatment
LQTS1 ↓ IKs KVLQT1 SCD/TdP with exercise BB/ICD
LQTS2 ↓ IKr HERG SCD/TdP with arousal BB/ICD
LQTS3 ↑ INa+ during plateau/ SCN5A SCD/TdP at rest/sleep Flecainide
repolarization Mexiletine/ICD
Brugada ↓ INa+ SCN5A SCD/PMVT or VF at rest/sleep in ICD/quinidine
Asian males
BB, β-blocker; ICD, implantable cardioverter-defibrillator; LQTS, long QT syndrome; PMVT, polymorphic ventricular tachycardia; SCD, sudden death;
TdP, torsade de pointes; VF, ventricular fibrillation.
Note: LQTS can be provoked by potassium channel blockers (e.g., quinidine, sotalol) and Brugada syndrome can be provoked by potent sodium
channel blockers (e.g., cocaine, flecainide). LQTS3 and Brugada syndrome may coexist.
 303
points such as slower and more tolerable inducible VT. Second, shocks. In addition, backup antibradycardia pacing and extended
amiodarone is clearly the most effective (approximately 50% effective battery lives have made these newer devices much more attractive. All

CHAPTER 19
after 2 years) agent in patients with recurrent VT; however, electro- models store recordings during delivery of pacing shocks; this is
physiologic drug testing does not necessarily predict the clinical extremely important in discerning appropriate from inappropriate
efficacy of amiodarone. Patients may have continued inducibility of shocks (i.e., delivers shock for AF with rapid ventricular rate) and in
VT on amiodarone despite long-term success. Indeed, empiric amio- documenting true recurrences of the patient’s tachycardia.
darone has been compared to therapy (with other agents) guided by Although the ICD is a highly effective method for preventing SCD
electrophysiologic testing in patients at high risk for recurrent VT.81 due to recurrent VT or VF,84 several problems remain. First, the
In this trial, amiodarone therapy without invasive testing was supe- device itself, implantation procedure, electrophysiologic studies, hos-
rior in preventing SCD and recurrences of severe ventricular arrhyth- pitalization, and physician fees are costly. Given that the indications

The Arrhythmias
mias at all time points. Third, the recurrence rate of life-threatening for receiving an ICD have significantly expanded over the past several
VT is high (20% to 50% per year depending on the drug chosen), years, the total cost associated with the implantation of this device is
regardless of the method of acute drug testing. Fourth, is the substan- likely to place a great burden on the healthcare system. Second, many
tial side-effect profile of the type I and type III antiarrhythmic agents patients (as high as 70% of patients) end up receiving antiarrhythmic
referred to previously. Lastly, and perhaps most importantly, is the drugs (usually amiodarone or sotalol) in addition to the ICD.85,86
impressive demonstrated effectiveness of nondrug approaches to the Antiarrhythmic drugs can be initiated in these patients for a number
treatment of recurrent VT/VF.82 For instance, some forms of recur- of reasons, including: (a) decreasing the frequency of VT/VF epi-
rent VT are amenable to catheter ablation therapy using radiofre- sodes to subsequently reduce the frequency of appropriate shocks;
quency current. This approach is highly effective (approximately (b) reducing the rate of VT so that it can be terminated with
90%) in idiopathic VT (right ventricular outflow tract or fascicular antitachycardia pacing; and (c) decreasing episodes of supraventricu-
VT), but less so in recurrent VT associated with a cardiomyopathic lar arrhythmias (e.g., AF, atrial flutter) that may trigger inappropriate
process or remote MI with LV aneurysm. In the latter patients, shocks. As result of these potential benefits, the concomitant use of
ablation is usually regarded as second-line therapy after other meth- antiarrhythmic drugs can minimize patient discomfort and prolong
ods have failed. the battery life of the ICD. The decision to initiate concomitant
antiarrhythmic therapy should be individualized, with treatment
The Implantable Cardioverter-Defibrillator The introduc-
usually being reserved for those with frequent shocks because of VT
tion of and advances in the ICD (Fig. 19–12) have obviated the
or AF. If antiarrhythmic drugs are added to ICD therapy, one should
need for serial drug testing (by invasive or noninvasive methods).83
note that many agents alter defibrillation thresholds; consequently,
Numerous advancements in device technology have allowed the
the device should be reprogrammed to account for this alteration.87
ICD to become smaller, less invasive to implant, and programmable.
Early ICDs required a thoracotomy to place the generator in the Secondary Prevention of Sudden Cardiac Death Over the
abdomen, whereas with the newer, smaller models, the leads are past decade, numerous trials have established the ICD as a superior
implanted transvenously with the generator placed into the pectoral treatment over antiarrhythmic therapy not only for the secondary
region in a manner similar to cardiac pacemakers. Modern ICDs now prevention of SCD in patients who have been resuscitated from
employ a “tiered-therapy approach” meaning that overdrive pacing cardiac arrest or had sustained VT (“secondary prevention”), but also
(i.e., antitachycardia pacing) can be attempted first to terminate the for the prevention of an initial episode of SCD in certain high-risk
tachyarrhythmia (no painful shock delivered), followed by low-energy patient populations (“primary prevention”). With regard to the use of
cardioversion, and, finally, by painful, high-energy defibrillation ICDs for secondary prevention, the results of three trials, the Antiar-
rhythmics Versus Implantable Defibrillators (AVID), Cardiac Arrest
Study Hamburg (CASH), and Canadian Implantable Defibrillator
Pulse generator Study (CIDS), definitively support this device as first-line therapy in
this patient population.88–90 Of these, the AVID trial was the largest,
randomizing more than 1,000 patients with resuscitated VF, sustained
Circuitry VT with syncope, or hemodynamically significant sustained VT (with
LVEF ≤40%) to either an ICD or antiarrhythmic drugs (~95% receiv-
ing amiodarone at discharge).88 The trial was stopped early because of
a demonstrated superiority of the ICD; patients in the ICD group had
a better overall survival when compared to those in the antiarrhythmic
drug group (75% vs. 64%, respectively, at 3 years). Although they were
Battery
smaller trials, both CASH and CIDS demonstrated the efficacy of an
Casing ICD compared with amiodarone in patients with a history of sustained
(cut away)
VT or VF, with the ICD reducing overall mortality by 20% to 25%.89,90
Despite the high costs, the results of AVID, CASH, and CIDS provide
strong support for the aggressive use of the ICD in patients who are at
high risk for recurrent, life-threatening ventricular arrhythmias.
Implantation of an ICD can be cost-effective, particularly in patients
with poor LV function. Although nearly all clinicians now consider the
Shock coil
ICD as first-line treatment for secondary prevention of SCD, there is
at least one possible patient group that may do as well with antiar-
rhythmic drug therapy alone. In the AVID trial, there was no differ-
ence in survival between ICD and antiarrhytmic drug treatment in
patients with mild LV dysfunction (LVEF >35%), which suggests that
long-term amiodarone therapy may be appropriate to use in this
Pacing electrodes
lower-risk patient population.88 However, because this data was
FIGURE 19-12. Drawing showing implantable cardioverter defibrillator. obtained from a post-hoc analysis, additional trials need to be per-
(From reference 83 with permission.) formed to confirm these findings.
 304
Primary Prevention of Sudden Cardiac Death Over the past trials targeted patients who had a history of nonsustained VT. The
decade, the above trials have established the ICD as an effective results of two landmark trials, the MADIT II and Sudden Cardiac
SECTION 2

treatment for the secondary prevention of SCD in patients who have Death in Heart Failure Trial (SCD-HeFT), have provided clinicians
previously suffered a documented episode of VT or VF. Most of the with additional information regarding the treatment of other groups
studies that have been performed in the past several years have of high-risk patients who have no prior history of ventricular arrhyth-
focused on the efficacy of the ICD for primary prevention in mia (see Fig. 19–13).93,94 In the MADIT II, patients with a prior MI
patients deemed to be at high risk for SCD.91–94 and LVEF ≤30% were randomized to receive either an ICD or
One of the patient populations that appears to be at high risk for conventional therapy (routine post-MI and HF therapy).93 Neither a
a first episode of SCD are those with a prior MI, LV dysfunction, history of ventricular arrhythmia nor electrophysiologic testing was
and nonsustained VT. The use of antiarrhythmic drugs to prevent required for inclusion in this study. Patients in the ICD group
Cardiovascular Disorders

SCD in this high-risk group has been significantly limited by the experienced a significant reduction in mortality when compared to
results of the CAST and other similar trials that have collectively the conventional therapy group; the reduction in mortality in the ICD
demonstrated that these drugs may actually increase the risk of group was primarily due to a reduction in arrhythmic death. Whereas
mortality in these patients. As a result of these trials, clinicians have the MADIT, MUSTT, and MADIT II limited enrollment to patients
sought a more clearly defined strategy for risk stratification in these with ischemic cardiomyopathy, the SCD-HeFT is the largest trial, to
patients before initiating drug therapy. date, to evaluate the efficacy of an ICD in a nonischemic HF popula-
Traditionally, there are three strategies to approach the treatment of tion. In this trial, patients with NYHA class II or III HF (of either
nonsustained VT: (a) conservative (i.e., no antiarrhythmic drug treat- ischemic or nonischemic etiology) and LVEF ≤35% were randomized
ment beyond β-blockers), (b) empiric amiodarone, and (c) aggressive to receive placebo, amiodarone, or an ICD.94 All patients were treated
(i.e., electrophysiologic studies with possible insertion of an ICD) (Fig. with appropriate HF therapies, as indicated. Implantation of an ICD
19–13).
A number of early studies95,96 suggested that tests such as resulted in a significantly lower mortality rate compared to treatment
electrophysiologic studies could be used to determine long-term risk with either placebo or amiodarone (there was no difference between
in patients with nonsustained VT. For instance, Wilbur et al.95 dem- placebo and amiodarone). The survival benefits of the ICD were
onstrated that post-MI patients with nonsustained VT and inducible observed regardless of the etiology of the HF.
sustained VT after programmed stimulation were at increased risk for Overall, as the ICD trials have evolved over the past decade, the
subsequent VT/VF or SCD compared to those in whom sustained VT indications for implanting these devices have significantly expanded
could not be induced. These data provided the basis for the Multi- (Table 19–11).97 Based on the results of the MUSTT, MADIT,
center Automatic Defibrillator Implantation Trial (MADIT) and the MADIT II, and SCD-HeFT, many patients will be eligible for an
Multicenter Unsustained Tachycardia Trial (MUSTT).91,92 The ICD.
In fact, just based on the results of the MADIT II and SCD-
MADIT was the first of these trials to be conducted to evaluate the HeFT alone, it is estimated that an additional 500,000 Medicare
efficacy of ICD therapy in this high-risk patient population. Specifi- beneficiaries will now qualify for implantation of an ICD for
cally, this trial randomized patients with a previous MI, LVEF ≤36%, primary prevention of SCD.
asymptomatic nonsustained VT, and inducible VT that was not
suppressed with the use of IV procainamide to receive an ICD or
conventional medical therapy (74% of patients in this particular VENTRICULAR PROARRHYTHMIA
group received amiodarone).91 This trial was terminated prematurely
All antiarrhythmic agents have the potential to aggravate existing
after a significant survival benefit was detected in the ICD group. The
arrhythmias or to cause new arrhythmias. It is believed that antiar-
findings of the MADIT were subsequently supported by those of the
rhythmic drugs may cause proarrhythmia in 5% to 20% of patients.10
MUSTT. In the MUSTT, patients with a history of MI, LVEF ≤40%,
Although drug-induced arrhythmias have been recognized for several
asymptomatic nonsustained VT, and inducible sustained VT were
years, only recently has this adverse effect gained widespread atten-
randomized to the conservative approach (no antiarrhythmic drug
tion. Many definitions for proarrhythmia have been proposed; how-
therapy beyond β-blockers) or electrophysiologically-guided therapy
ever, in the simplest terms, it indicates the development of a
(antiarrhythmic drugs and/or ICD).92 The results showed that the
significant new arrhythmia (such as VT, VF, or TdP) or worsening of
conservative approach had a significantly higher event rate (cardiac
an existing arrhythmia (episodes are longer, faster, or more frequent).
arrest or death from arrhythmia). However, when the results of the
As with all arrhythmias, the consequences of proarrhythmia are
electrophysiologically-guided group were further stratified, those
varied. Some patients who develop proarrhythmia may be totally
receiving only antiarrhythmic drugs (no ICD) were no different in
asymptomatic, others may notice a worsening of symptoms, and
terms of outcomes than those who received no treatment. In other
some may die suddenly from this side effect. The development of
words, only those treated with an ICD had a significantly lower event
proarrhythmia results from the same mechanisms that cause arrhyth-
rate and greater survival. One problem with the MUSTT, however, is
mias in general (e.g., quinidine-induced TdP due to EADs) or from
that because of when the trial was initiated (1989), nearly 50% of
an alteration in the underlying substrate due to the antiarrhythmic
patients received type I antiarrhythmic drugs or drugs that are now
agent (e.g., development of an accelerated tachycardia caused by
known not to improve survival in patients with coronary artery
flecainide which decreases conduction velocity without significantly
disease, LV dysfunction, and ventricular arrhythmias; only 10% of
altering the refractory period) (see Fig. 19–4).10 The diagnosis of
patients received the most effective agent in this setting, amiodarone.
proarrhythmia is sometimes difficult to make because of the variable
Based on the results of the MADIT and MUSTT, it is reasonable for
nature of the underlying arrhythmias. However, in all cases, the agent
patients with coronary artery disease, LV dysfunction, and nonsus-
should be discontinued if proarrhythmia is detected or suspected.
tained VT to undergo electrophysiologic testing;97 that is, invasive
electrophysiologic studies with programmed stimulation are used to
Incessant Monomorphic VT
determine risk and guide subsequent therapy. If these patients do not
have inducible sustained VT/VF, chronic antiarrhythmic drug therapy The prototypical form of proarrhythmia caused by the type Ic antiar-
is unnecessary; however, if these patients do have inducible sustained rhythmic drugs is a rapid, sustained, monomorphic VT with a charac-
VT/VF, implantation of an ICD is warranted. teristic sinusoidal QRS pattern that is often resistant to resuscitation
Although the MADIT and MUSTT provided clinicians with with cardioversion or overdrive pacing.  It is sometimes referred to
important information regarding risk stratification, both of these as sinusoidal or incessant VT and is the result of excessive sodium
 305

CHAPTER 19
Post-Ml Nonischemic Dilated Cardiomyopathy

NSVT No arrhythmia

The Arrhythmias
LVEF >35% LVEF ≤35% LVEF >35% LVEF ≤35%

Optimize
post-Ml and
HF drug
Asymptomatic Symptomatic therapies
EPS

ȕ-Blockera ȕ-Blocker Conservative Aggressive

approach approach
Inducible VT/VF
VT/VF noninducible

Optimize
post-Ml and
ICDc
HF drug
ȕ-Blocker or therapies
ICDb
amiodarone

Add Yes No
Frequent No additional
amiodarone
discharges? therapy
or sotalol

FIGURE 19-13. Algorithm for the primary prevention of sudden cardiac death in patients with a history of myocardial infarction or with a
nonischemic dilated cardiomyopathy. aIn these patients, the β-blocker is being used to reduce post-MI mortality. bPatients should be >40 days
post-MI prior to insertion of ICD. cPatients with an ischemic cardiomyopathy should be >40 days post-MI prior to insertion of ICD. (EPS,
electrophysiologic study; HF, heart failure; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MI, myocardial
infarction; NSVT, nonsustained VT; VF, ventricular fibrillation; VT, ventricular tachycardia.)

channel blockade and slowed conduction. Sinusoidal VT caused by the uncommon in those without risks, such as patients with supraventric-
type Ic drugs was thought to occur within the first several days of drug ular tachycardias and normal LV function. In one study, in patients
initiation; however, the results of the CAST indicate that the risk for with risk factors, the incidence of death due to proarrhythmia from
this type of proarrhythmia may exist as long as the agent is continued. encainide and flecainide was approximately the same as the chance of
Factors that definitely predispose a patient to this form of proar- long-term effectiveness!98 Other factors that have a less well-defined
rhythmia are: (a) the presence of underlying ventricular arrhyth- association with proarrhythmia are elevated antiarrhythmic serum
mias, (b) ischemic heart disease, and (c) LV dysfunction. Provocation concentrations and rapid dosage escalation. It has been proposed that
of proarrhythmia by the type Ic drugs is sometimes reported during the presence of underlying ventricular conduction delays may also
exercise, which is most likely a result of augmented slowed conduction pose a risk for proarrhythmia. As mentioned earlier, this arrhythmia is
at rapid heart rates (i.e., rate-dependent sodium blockade). The inci- resistant to resuscitation; however, some have had success with lido-
dence of proarrhythmia caused by type Ic drugs is greatest in patients caine (competes for sodium channel receptor) or sodium bicarbonate
with all three risk factors (approximately 10% to 20%) and extremely (reverses the excessive sodium channel blockade).
 306

TABLE 19-11 Current Indications for ICD Implantation tion in an inhomogeneous way (termed dispersion of refractoriness),
which facilitates the formation of multiple reentrant loops in the
SECTION 2

Secondary prevention indications

ventricle.99 Torsade de pointes may occur in association with heredi-
1. Documented episode of cardiac arrest caused by VF (not a result of transient
tary syndromes or as an acquired form (i.e., a result of drugs or
or reversible cause)a
2. Documented sustained VT, either spontaneous or induced at electrophysio-
diseases). The underlying etiology in both cases is delayed ventricular
logic study, not associated with an acute MI and not a result of transient or repolarization due to blockade of potassium conductance. It is
reversible cause possible, however, that some individuals have a partially expressed
Primary prevention indications form of these congenital syndromes but never suffer TdP unless
1. Documented familial or inherited conditions with a high-risk of life-threatening VT some other external factor (drugs, diseases) further delays ventricu-
(i.e., long QT syndrome, Brugada syndrome, or hypertrophic cardiomyopathy) lar repolarization. Acquired forms of TdP are associated with
Cardiovascular Disorders

2. Coronary artery disease (with prior MI >40 days before ICD insertion), LVEF electrolyte disturbances (hypokalemia or hypomagnesemia), sub-
≤35%, and sustained VT or VF induced at electrophysiologic studya arachnoid hemorrhage, myocarditis, liquid protein diets, arsenic
3. Prior MI (>40 days before ICD insertion) and LVEF ≤30% poisoning, hypothyroidism, or, most commonly, drug therapy (nota-
4. Ischemic dilated cardiomyopathy, prior MI (>40 days before ICD insertion),
bly phenothiazines, antibiotics, antihistamines, antidepressants, and
NYHA class II or III HF, and LVEF ≤35%
antiarrhythmics) (Table 19–12). 
5. Nonischemic dilated cardiomyopathy (>9 months), NYHA class II or III HF, and
LVEF ≤35% The type Ia antiarrhythmic drugs (especially quinidine) and type
6. Nonischemic dilated cardiomyopathy (>3 months but <9 months), NYHA III IKr blockers are most notorious for precipitating TdP; the types Ib
class II or III HF, and LVEF ≤35% and Ic antiarrhythmic drugs rarely, if ever, cause TdP. Most antiar-
7. Patients meeting requirements for cardiac resynchronization therapy with rhythmic drugs with IKr blocking activity cause TdP in approximately
NYHA class IV HF 2% to 4% of patients, with the exception being amiodarone (<1%).
HF, heart failure; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MI,
Risk factors and associated features of drug-induced TdP have been
myocardial infarction; NYHA, New York Heart Association; VF, ventricular fibrillation; VT, ventricular identified and can be summarized as follows28,100: (a) high dosages or
tachycardia. plasma concentrations of the offending agent (“dose-related”)
a
The electrophysiologic study must be performed >4 weeks after the MI. (except for quinidine-induced TdP, which tends to occur more
frequently at low-to-therapeutic concentrations); (b) concurrent
structural heart disease (e.g., ischemic heart disease, HF, and/or LV
Torsade de Pointes hypertrophy); (c) evidence of mild delayed repolarization (prolonged
As defined previously, TdP is a rapid form of polymorphic VT (Fig. QT interval) at baseline; (d) evidence of a prolonged QT interval
19–14) that is associated with evidence of delayed ventricular repolar- shortly after initiation of the offending agent; (e) concomitant
ization (long QT interval or prominent U waves) on ECG. It is electrolyte disturbances such as hypokalemia or hypomagnesemia;
important to note that most forms of polymorphic VT occurring in (f) female gender; and (g) a characteristic long–short initiating
the setting of a normal QT interval are similar to monomorphic VT sequence (so-called “pause” dependence) of the episode of TdP (see
in terms of etiology and treatment strategies (thus, a long QT interval Fig. 19–14). However, none of these associations are absolute prereq-
is crucial to the diagnosis of TdP). Much has been learned about the uisites to the occurrence of drug-induced TdP. For instance, although
underlying etiology of TdP. Basic defects (genetic, drugs or diseases) usually documented early in the course of therapy, patients may suffer
that delay repolarization by influencing ion movement (usually by TdP during chronic quinidine treatment.101 The reason for quini-
blocking potassium efflux) provoke EADs, preferentially in cells deep dine’s relatively unique propensity for causing TdP at relatively low
in the heart muscle (termed M cells), which, in turn, trigger reentry dosages and concentrations requires explanation. Quinidine’s ability
and TdP. Drugs that cause TdP usually delay ventricular repolariza- to block IKr is clinically manifest at low concentrations; at higher

FIGURE 19-14. Torsade de pointes caused by quinidine. Note the presence of a couplet and two triplets following each extra systolic pause. The pause
gets progressively longer until it is long enough to result in an episode of sustained torsade de pointes. Also, as the pause lengthens, discernible U waves
(labeled ↑) (EADs?) begin to appear. The amplitude of the U wave is somewhat greater with the longest pause. (From Bauman JL. Drug safety: Car-
diac arrhythmias. Antihistamine update symposium. Hosp Med 1995;31:24, with permission.)
 307
concentrations its sodium-blocking properties predominate. Other TABLE 19-12 Potential Causes of QT Prolongation and
agents that block IKr usually do so in a concentration-dependent

CHAPTER 19
Torsade de Pointes
fashion. The observation that most patients who suffer drug-induced
Conditions
TdP have evidence of mildly delayed repolarization (long QT inter-
Congenital long QT syndromes
vals) even before they are prescribed the offending agent has stimu- Myocarditis
lated a search for a potential genetically linked risk. Could it be that Myocardial ischemia/infarction
patients with drug-induced TdP have a partially expressed form of the Heart failure
congenital long QT syndrome? Indeed, it does appear that at least Severe bradycardia (<50 beats/min)
some of these patients with acquired drug-induced TdP appear to Hypokalemia
possess mutations of genes that encode for IKr or IKs.100 Severe hypothermia

The Arrhythmias
The common underlying electrophysiologic cause of TdP is a delay Hypomagnesemia
in ventricular repolarization (provoking EADs), which usually results Severe starvation/liquid-protein diets
from inhibition (drug-induced or genetic) of IK current and manifests Subarachnoid hemorrhage
Drugs
as QT interval prolongation on the ECG. Therefore, the extent of QT
Antiarrhythmic drugs
interval prolongation has been used as a measurement of risk of TdP;
Quinidine
however, considerable controversy exists. Amiodarone, for example, Procainamide (also N-acetylprocainamide)
commonly causes significant QT prolongation but is a relatively Disopyramide
infrequent cause of TdP. Nonetheless, the QT interval should be Amiodarone
measured and monitored in all patients prescribed drugs that have a Dofetilide
high potential for causing TdP (see Table 19–12). Patients with a Sotalol
baseline QTc interval (QT interval corrected for heart rate) >450 msec Ibutilide
should not be given these agents; an increase in the QTc interval to Bepridila
≥560 msec after the initiation of the drug is an indication to discon- Psychotropics
tinue the agent or, at least, to reduce its dosage and carefully observe Phenothiazines (e.g. thioridazine, mesoridazine, chlorpromazine)
Tricyclic and tetracyclic antidepressants
and monitor. The QTc interval can be calculated using Bazett’s
Haloperidol/droperidol
formula: QTc = QT measured/√R-R interval.
Pimozide
Drug-induced TdP has become an extremely visible hazard plagu- Atypical antipsychotics (e.g. quetiapine, ziprasidone)
ing new drugs, sometimes resulting in public health disasters. For Toxins
instance, six drugs (cisapride, astemizole, terodiline, levomethadyl, Organophosphate insecticides
grepafloxacin, and terfenadine) have been withdrawn from the mar- Arsenic
ket in the United States because of TdP. One of the most visible and Antihistamines
striking examples was with regard to the popular nonsedating antihis- Terfenadinea
tamine, terfenadine. Terfenadine is a potent IKr blocker but is rapidly Astemizolea
metabolized by CYP3A4 to an active moiety (fexofenadine) that is not Antibiotics
associated with delayed repolarization. Consequently, in the presence Pentamidine
Macrolides (erythromycin and clarithromycin)
of drugs that block the CYP3A4 isoenzyme (e.g., ketoconazole,
Trimethoprim-sulfamethoxazole
erythromycin, diltiazem), accumulation of the parent compound,
Fluoroquinolones (grepafloxacin,a sparfloxacin,a moxifloxacin, gatifloxacin,
terfenadine, causes clinically significant blockade of IKr that could gemifloxacin)
result in TdP and even death.102 Because of experiences like this, all Voriconazole
new drug entities under investigation are screened for their ability to Pain
block IK and cause significant QT prolongation. Methadone
Acute treatment of TdP is different than treatment for the more Levomethadyla
common acute monomorphic VT. For an acute episode of TdP, most Miscellaneous
patients will require and respond to DCC. However, TdP tends to be Liquid-protein dietsb
paroxysmal in nature and often will rapidly recur after DCC. There- Corticosteroidsb
fore, after the initial restoration of a stable rhythm, therapy designed Diureticsb
to prevent recurrences of TdP should be instituted. Drugs that further Quinine
Chloroquine
prolong repolarization such as IV procainamide are absolutely con-
Chloral hydrate
traindicated. Lidocaine is usually ineffective. Although there are no Cisapridea
true efficacy trials, IV magnesium sulfate, by suppressing EADs, is Terodilinea
now considered the drug of choice in preventing recurrences of Tacrolimus
TdP.103 If IV magnesium sulfate is ineffective, treatment strategies
a
Withdrawn from market because of torsade de pointes.
designed to increase heart rate, shorten ventricular repolarization, b
More than likely a result of severe electrolyte imbalance.
and prevent the pause dependency should be initiated. Either tempo- Note: For a complete list, see www.qtdrugs.org.
rary transvenous pacing (105 to 120 beats/min) or pharmacologic
pacing (isoproterenol or epinephrine infusion) can be initiated for this
rapidly if effective treatment measures are not taken. Patients who die
purpose. All agents that prolong QT interval should be discontinued
abruptly (within 1 hour of initial symptoms) and unexpectedly (i.e.,
and exacerbating factors (such as hypokalemia or hypomagnesemia)
“sudden death”) usually have VF recorded at the time of death.61
should be corrected.
Sudden cardiac death accounts for about 330,000 deaths per year in
the United States. Sudden cardiac death occurs most commonly in
VENTRICULAR FIBRILLATION patients with ischemic heart disease and primary myocardial disease
associated with LV dysfunction; it occurs less commonly in those with
Background and Prevention
WPW syndrome or mitral valve prolapse, and occasionally in those
Ventricular fibrillation is electrical anarchy of the ventricle resulting without associated heart disease (e.g., Brugada syndrome). Patients
in no cardiac output and cardiovascular collapse. Death will ensue who have SCD (not associated with acute MI) but survive because of
 308
appropriate CPR, often have inducible sustained VT and/or VF after two rescue breaths are provided; in these patients, there is no
during electrophysiologic studies. These individuals are at high risk need for an initial period of CPR. Because of the increased availabil-
SECTION 2

for the recurrence of VT and/or VF. ity of biphasic defibrillators which have a higher first-shock efficacy
In contrast, patients who have VF associated with acute MI (i.e., than monophasic defibrillators, delivery of only one shock at a time
within the first 24 hours after symptoms) usually have little risk of is recommended. For biphasic defibrillators, the dose of the shock
recurrence. Of all patients who die as a result of an acute MI, to be used is device-specific; however, 200 joules can be used as the
approximately 50% die suddenly prior to hospitalization. Ventricular default if the effective dose range of the device is unknown. For all
fibrillation associated with acute MI can be subdivided into two types: subsequent shocks, the initial dose or a higher dose can be used. If a
primary VF and complicated or secondary VF. Primary VF occurs in monophasic defibrillator is used, 360 joules should be used for the
an uncomplicated MI not associated with HF; secondary VF occurs in initial as well as all subsequent shocks. After delivery of the initial
Cardiovascular Disorders

an MI complicated by HF. The time course, incidence, mechanisms, shock, five cycles of CPR should be delivered, followed by a check of
treatment, and complications of these two forms of VF are different. the patient’s pulse and rhythm. If pulseless VT/VF is still present,
For example, approximately 2% to 6% of patients with acute MI another shock can be delivered, followed by five cycles of CPR. This
suffer primary VF within 24 hours of chest pain, but the risk of VF general sequence of providing shocks followed by CPR can be
declines rapidly over time and is nearly zero after the initial 24-hour followed as long as the patient remains in pulseless VT/VF.
period. Complicated or secondary VF does not follow such a predict- Although there is very little, if any, evidence that demonstrates an
able time course and may occur in the late infarction period. The increased survival rate with either vasopressor or antiarrhythmic
premise of prophylactic antiarrhythmic drugs administered to all agents in patients with pulseless VT/VF, these drugs still continue to
patients with uncomplicated MI is based on (a) the inability to predict play a role in the management of these ventricular arrhythmias.53 To
which patients are at risk for primary VF and (b) the predictable time minimize interruptions in chest compressions, any vasopressor or
course of primary VF (in contrast to complicated VF). Of the antiarrhythmic administered during the course of the cardiac arrest
prophylactic therapies used, lidocaine has been the most widely should be given during CPR either before or after a shock. With
debated and studied. Lie et al.104 performed the classic study showing regard to vasopressor therapy, either epinephrine or vasopressin can
the effectiveness of lidocaine in preventing primary VF. Although be administered if pulseless VT/VF persists after delivery of one or
lidocaine significantly reduced the incidence of VF compared to two shocks plus CPR. More specifically, epinephrine can be adminis-
placebo, there was no significant difference in mortality due to VF tered every 3 to 5 minutes while the patient remains in pulseless VT/
between the groups. This data, along with the effectiveness of rapidly VF. Alternatively, one dose of vasopressin can be given to replace
instituted DCC in modern coronary care units with sophisticated either the first or second dose of epinephrine. In a recent comparative
monitoring techniques, have caused most to reject the notion of trial, patients with out-of-hospital cardiac arrest (60% with asystole
prophylactic lidocaine administration for all patients with uncompli- or pulseless electrical activity, 40% with VF) were randomized to
cated MI. In support of this, two meta-analyses105,106 concluded receive up to two doses of either vasopressin or epinephrine, followed
against the routine use of prophylactic lidocaine because of a possible by an additional dose of epinephrine if a stable rhythm was not
increase in mortality in lidocaine-treated patients105 as well as the restored.110 Overall, no significant differences were observed between
declining incidence of primary VF documented in recent years (prob- the treatment groups with regard to the end points of survival to
ably a result of the more aggressive and rapid use of β-blockers, hospital admission or survival to hospital discharge (in patients with
thrombolytics, and percutaneous intervention for the treatment of asystole, however, vasopressin was superior for both of these end
acute coronary syndromes).106 points).
The use of IV magnesium sulfate has also been entertained for the If pulseless VT/VF persists after delivery of two or three shocks plus
prevention of VF during the acute infarct period. Small trials imply- CPR and after administration of a vasopressor, antiarrhythmic ther-
ing its effectiveness were subsequently incorporated into a meta- apy can then be initiated.53 It appears clear from the most recent AHA
analysis.107 This meta-analysis found a decrease in the incidence of guidelines for CPR and emergency cardiovascular care that IV amio-
VT/VF and a reduction in total mortality with magnesium therapy. A darone continues to be the antiarrhythmic drug of first choice in
subsequent large multicenter trial108 found similar results, although patients with pulseless VT/VF. Amiodarone’s status as the first-line
most of the reduction in mortality was (surprisingly) attributed to HF antiarrhythmic drug during pulseless VT/VF (and lidocaine’s result-
deaths rather than to deaths caused by ventricular arrhythmia. These ing role as second-line antiarrhythmic therapy) is the result of (a) a
results would lead one to conclude that magnesium sulfate should be lack of data demonstrating the effectiveness of other antiarrhythmic
routinely administered to patients with suspected MI because of its agents; (b) the Amiodarone in Out-of-Hospital Resuscitation of
ease of administration and safety. However, data from another large Refractory Sustained Ventricular Tachyarrhythmias (ARREST)
trial apparently has verified no such effectiveness of magnesium trial;111 and (c) the Amiodarone versus Lidocaine in Prehospital
therapy in this setting.109 Hence, prophylactic magnesium cannot be Ventricular Fibrillation Evaluation (ALIVE) trial.112 In the ARREST
recommended. Indeed, no therapy (lidocaine, magnesium, or other trial,111 significantly more patients with out-of-hospital pulseless VT/
antiarrhythmic drugs) has shown a conclusive benefit to prevent VF VF who received 300 mg of IV amiodarone survived to hospital
in the acute infarct period and no form of therapy can be recom- admission than did a corresponding placebo group. Noteworthy was
mended at this time. that survival to hospital discharge was no different between the
groups (although the study was not powered to determine this end
point). In the ALIVE trial,112 IV amiodarone was significantly more
Acute Management effective than lidocaine in increasing survival to hospital admission in
A patient with pulseless VT or VF (with or without associated patients with out-of-hospital VF. Again, there were no differences in
myocardial ischemia) should be managed according to the most survival to hospital discharge between the groups. Nonetheless, the
recent AHA guidelines for CPR and emergency cardiovascular results of these trials stimulated a change (away from lidocaine and
care.53 To summarize, in patients with an unwitnessed arrest, five toward amiodarone) in the treatment of pulseless VT/VF. In the event
cycles (or 2 minutes) of CPR (one cycle of CPR = 30 chest that a patient remains in pulseless VT/VF despite the administration
compressions followed by 2 breaths) should be given before of IV amiodarone and/or lidocaine, it is interesting to note that IV
defibrillation. When the arrest is witnessed, and a defibrillator is procainamide is no longer recommended in the treatment algorithm
readily available, defibrillation should be instituted immediately because of limited evidence and the need for a prolonged infusion.53
 309
Once the patient is successfully resuscitated, antiarrhythmics threshold and result in loss of capture if the pacemaker is not
should be continued until the patient’s rhythm and overall status is appropriately interrogated and adjusted.87 Other drugs that depress

CHAPTER 19
stable. If the episode of pulseless VT/VF was associated with acute SA or AV nodal function, such as β-blockers and nondihydropyridine
ischemia, long-term antiarrhythmic drugs are probably unnecessary CCBs, may also significantly exacerbate bradycardia. Even agents with
provided that the patient undergoes successful revascularization; indirect sympatholytic actions, such as methyldopa and clonidine,
however, the patient should be monitored closely for recurrence of may worsen sinus node dysfunction. The use of digoxin in these
VT and/or VF. If, on the other hand, the pulseless VT/VF was not patients is controversial, but in most cases, it can be used safely.
associated with acute MI (or a known precipitating factor), the
patient should undergo ICD implantation. Other Causes
Another reason for paroxysmal bradycardia and sinus arrest that is not

The Arrhythmias
BRADYARRHYTHMIAS directly due to sinus node dysfunction is carotid-sinus hypersensitiv-
ity.115,116 Again, this syndrome occurs commonly in the aged with
SINUS NODE DYSFUNCTION underlying structural heart disease, and may precipitate falls and hip
fractures. Symptoms occur when the carotid sinus is stimulated,
The previous sections reviewed the pathophysiology and treatment resulting in an accentuated baroreceptor reflex. Often, however, symp-
of tachyarrhythmias, and this section serves to briefly consider the toms are not well correlated with the obvious physical manipulation of
bradyarrhythmias. For the most part, the symptoms of bradyar- the carotid sinus (in the lateral neck region). Patients may experience
rhythmias result from a decline in cardiac output. Because cardiac intermittent episodes of dizziness or syncope because of sinus arrest
output decreases as heart rate decreases (to a point), patients with caused by increased vagal tone and sympathetic withdrawal (the
bradyarrhythmias may experience symptoms in association with cardioinhibitory type), a drop in systemic blood pressure caused by
hypotension, such as dizziness, syncope, fatigue, and confusion. If sympathetic withdrawal (the vasodepressor type), or both (mixed
LV dysfunction exists, patients may experience worsening HF cardioinhibitory and vasodepressor types). The diagnosis can be con-
symptoms. Except in the case of recurrent syncope, symptoms firmed by performing carotid-sinus massage with electrocardiographic
associated with bradyarrhythmias are often subtle and nonspecific. and blood pressure monitoring in controlled conditions. Symptomatic
carotid-sinus hypersensitivity should also be treated with permanent
SINUS BRADYCARDIA pacemaker therapy.115 However, some patients, particularly those with
a significant vasodepressor component, still experience syncope or
Sinus bradyarrhythmias (heart rate <60 beats/min) is a common dizziness. The choice of definitive drug therapy in this situation is
finding, especially in young, athletically active individuals, and usually marred by the lack of controlled trials although α-adrenergic stimu-
is neither symptomatic nor requires therapeutic intervention. On the lants such as midodrine are often tried in addition to the pacemaker.116
other hand, some patients, particularly the elderly, have sinus node Vasovagal syndrome, by causing bradycardia, sinus arrest, and/or
dysfunction. This may be the result of underlying structural heart hypotension, is the cause of syncope in many patients who present
disease and the normal aging process which, over time, attenuate SA with recurrent fainting of unknown origin.117–119 By history, many
nodal function. Sick sinus syndrome refers to this process resulting in individuals can recount rare instances of fainting spells at times of
symptomatic sinus bradycardia and/or periods of sinus arrest.113,114 duress or fear. These are most often caused by vasovagal syncope.
Sinus node dysfunction is usually reflective of diffuse conduction However, some have extremely frequent, unexpected syncopal epi-
disease, and accompanying AV block is relatively common. Further- sodes that interfere with the patient’s quality of life and cause
more, symptomatic bradyarrhythmias may be accompanied by alter- physical danger (sometimes referred to as neurocardiogenic syncope
nating periods of paroxysmal tachycardias such as AF. In this instance, syndrome or malignant vasovagal syndrome). Vasovagal syncope is
AF sometimes presents with a rather slow ventricular response (in the presumed to be a neurally mediated, paradoxical reaction involving
absence of AV nodal blocking drugs) because of diffuse conduction stimulation of cardiac mechanoreceptors (i.e., Bezold-Jarisch reflex).
disease. The occurrence of alternating bradyarrhythmias and tachyar- Forceful contraction of the ventricle (e.g., as with adrenergic stimu-
rhythmias is referred to as the “tachy-brady syndrome.” The occur- lation) coupled with low ventricular volumes (e.g., with upright
rence of paroxysmal AF in a patient with sinus node dysfunction may posture or dehydration) provide a powerful stimulus for cardiac
be a result of underlying structural heart disease with atrial dysfunc- mechanoreceptors. Syncope results from the spontaneous develop-
tion or to atrial escape in response to reduced sinus node automatic- ment of transient hypotension (sympathetic withdrawal) and brady-
ity. In fact, because the rate of impulse generation by the sinus node is cardia (vagotonia). However, the true mechanism of vasovagal
generally depressed or may fail altogether, other automatic pacemak- syncope remains to be definitively determined. For instance, patients
ers within the conduction system may “rescue” the sinus node. These with denervated hearts (e.g., heart transplant recipients) can still
rescue rhythms often present as paroxysmal atrial rhythms (e.g., AF) experience this form of syncope. This observation has led some to
or as a junctional escape rhythm. question the ultimate role of the Bezold-Jarisch reflex in these
The treatment of sinus node dysfunction involves the elimination patients. Regardless, patients believed to have frequent episodes of
of symptomatic bradycardia and the possibility of managing alternat- vasovagal syncope have been evaluated and diagnosed using the
ing tachycardias such as AF. In general, the long-term therapy of upright body-tilt test,121 a potent stimulus for the development of
choice is a permanent ventricular pacemaker. Dual-chamber, rate- vasovagal symptoms. Although commonly used, the sensitivity and
adaptive chronic pacing clearly improves symptoms and overall reproducibility of this test has been questioned.120
quality of life and decreases the incidence of paroxysmal AF and Traditionally, oral β-blockers, such as metoprolol, were frequently
systemic embolism.113 Drugs that are commonly employed to treat chosen as the drugs of choice in preventing episodes of vasovagal
supraventricular tachycardias should be used with caution, if at all, in syncope. Although these agents may seem inappropriate to treat a
the absence of a functioning pacemaker. Antiarrhythmic drugs pre- syndrome resulting from vasodilation and bradycardia, the therapeu-
scribed to prevent recurrences of AF may also suppress the escape or tic approach is designed to block an inappropriate vasovagal reaction
rescue rhythms that appear in severe sinus bradycardia or sinus arrest. (i.e., they inhibit the sympathetic surge that causes forceful ventricular
In this way, these drugs may transform an asymptomatic patient with contraction and precedes the onset of hypotension and bradycardia).
bradycardia into a symptomatic one. It is also important to remember To most clinicians’ surprise, most controlled trials of the use of β-
that the addition of type I antiarrhythmic agents can affect pacemaker blockers in patients with severe vasovagal syncope have shown no
 310
effect compared to placebo in preventing syncopal episodes.122 Some when vagal tone is high. Also, AV block may be transient where the
trials have suggested that β-blockers are more effective and should be underlying etiology is reversible such as in myocarditis, myocardial
SECTION 2

used in older patients (>40 years of age) with vasovagal syncope rather ischemia, after cardiovascular surgery, or during drug therapy. β-
than the relatively young.123 Other drugs that have been used success- blockers, digoxin, or nondihydropyridine CCBs may cause AV
fully (with or without β-blockers) include mineralocorticoids as block, primarily in the AV nodal area. Type I antiarrhythmic agents
volume expanders (fludrocortisone), anticholinergic agents (scopola- may exacerbate conduction delays below the level of the AV node
mine patches, disopyramide), α-adrenergic agonists (midodrine), (sodium-dependent tissue). In other cases, AV block may be irre-
adenosine analogs (theophylline, dipyridamole), and selective seroto- versible, such as that caused by acute MI, rare degenerative diseases,
nin receptor antagonists (sertraline, paroxetine).124 Permanent pacing primary myocardial disease, or congenital forms.
has been used for patients with malignant vasovagal syncope but its If patients with Mobitz II AV block or third-degree AV block
Cardiovascular Disorders

routine use is controversial. Chronic pacing has been used with some develop signs or symptoms of poor perfusion (e.g., altered mental
success but should be reserved for drug-refractory patients.118,119 status, chest pain, hypotension, shock) associated with bradycardia
Because of the questionable effectiveness of β-blockers and the paucity or AV block, transcutaneous pacing should be initiated immedi-
of controlled or comparative trials, there is not a true drug of choice ately.53,125 Intravenous atropine (0.5 mg given every 3 to 5 minutes,
for severe vasovagal syncope and clinicians are left with choosing up to 3 mg total dose) should be given as the leads for pacing are
agents and judging clinical effectiveness in individual patients on a being placed. Drugs such as atropine will facilitate the effectiveness
case-by-case basis. of transcutaneous pacing. In the past, isoproterenol infusion was
frequently chosen for this purpose but is now not recommended
ATRIOVENTRICULAR BLOCK because of its vasodilating properties and its ability to increase
myocardial oxygen consumption (particularly during acute MI). If
Conduction delay or block may occur in any area of the AV conduc- patients do not respond to atropine, transcutaneous pacing is
tion system: the AV node, the His bundle, or the bundle branches. usually indicated. Sympathomimetic infusions such as epinephrine
Atrioventricular block is usually categorized into three different types (2 to 10 mcg/min) or dopamine (2 to 10 mcg/kg/min) can also be
based on ECG findings (Table 19–13). First-degree AV block is 1:1 used in the event of atropine failure and are particularly effective in
AV conduction with a prolonged PR interval. Second-degree AV sinus bradycardia/arrest and AV nodal block. These agents usually
block is divided into two forms: Mobitz I AV block (Wenckebach do not help when the site of AV block is below the AV node (e.g.,
periodicity) is less than 1:1 AV conduction with progressively length- Mobitz II or trifascicular AV block). If patients with bradycardia or
ening PR intervals until a ventricular complex is dropped; Mobitz II AV block present with signs and symptoms of adequate perfusion,
AV block is intermittently dropped ventricular beats in a random no therapy other than close observation is recommended.
fashion without progressive PR lengthening. Third-degree AV block Patients with chronic symptomatic AV block should be treated with
is complete heart block where AV conduction is totally absent (AV the insertion of a permanent pacemaker. Patients without symptoms
dissociation). By using intracardiac His bundle ECGs, the actual site can sometimes be followed closely without the need for a pacemaker.
of conduction delay/block can be correlated to the above diagnosis. The reader is referred for more detail to the national consensus
First-degree AV block usually represents prolonged conduction in the guidelines for pacemaker implantation, which were last updated in
AV node. Mobitz I, second-degree AV block is also usually caused by 2002.125 Because symptoms often correlate with the ventricular rate
prolonged conduction in the AV node. Indeed, Wenckebach period- and the ventricular rate corresponds to the site of block, pacemaker
icity is a normal AV nodal response to rapid supraventricular stimu- therapy is usually necessary in distal AV blocks such as those occurring
lation or high vagal tone. In contrast, Mobitz II AV block is usually in the His bundle or the bundle branches. Patients with acute MI and
caused by conduction disease below the AV node (i.e., His bundle). evidence of new AV block or conduction disturbances will often
Third-degree AV block may be caused by disease at any level of the require the insertion of a temporary transvenous pacemaker. Atrio-
AV conduction system: complete AV nodal block, His bundle block, ventricular block more commonly occurs as a complication of inferior
or trifascicular block. In this situation, the ventricle beats indepen- wall infarcts because of high vagal innervation at this site, and the
dently of the atria (AV dissociation), and the rate of ventricular coronary blood flow to the nodal areas usually supplies the inferior
activation and QRS configuration are determined by the site of AV wall. However, the AV block may only be transient, obviating the need
block. The usual degree of automaticity of ventricular pacemakers for permanent pacing. In patients with chronic AV conduction distur-
progressively declines as impulses move down the conduction system. bances, intracardiac recordings (His bundle ECGs) are sometimes
Therefore, the ventricular escape rate in cases of trifascicular block used to document the actual site of block and define the potential need
will be significantly less than complete AV nodal block. for and specific type of pacemaker therapy.
Atrioventricular block may be found in patients without under-
lying structural heart disease such as trained athletes or during sleep
EVALUATION OF THERAPEUTIC AND
ECONOMIC OUTCOMES
TABLE 19-13 Forms of Atrioventricular Block
Type Criteria Site of Block Generally, patients who suffer from tachyarrhythmias can be moni-
First-degree block Prolonged PR interval (>0.2 sec); 1:1 Usually AVN tored for one or several possible therapeutic outcomes. Obviously, the
AV conduction presence or recurrence of any arrhythmia can be documented by
Second-degree block electrocardiographic means (e.g., surface ECG, Holter monitor, or
Mobitz I Progressive PR prolongation until QRS AVN event monitor). Furthermore, patients may experience a decrease in
is dropped; <1:1 AV conduction blood pressure that may result in symptoms ranging from lightheaded-
Mobitz II Random nonconducted beats Below AVN ness to abrupt syncope, depending on the rate of the arrhythmia and
(absence of QRS); <1:1 AV conduc- the status of the underlying heart disease. For some patients, the
tion potential alteration in hemodynamics may result in death if the
Third-degree block AV dissociation AVN or below arrhythmia is not detected and treated immediately. Besides these
Absence of AV conduction
clinical outcomes, many patients with tachyarrhythmias experience
AV, atrioventricular; AVN, atrioventricular node. alterations in quality of life as a result of recurrent symptoms of the
 311

TABLE 19-14 Arrhythmia Outcomes AHA: American Heart Association

CHAPTER 19
Mortality ALIVE: Amiodarone versus Lidocaine in Prehospital Ventricular
Total, all-cause Fibrillation Evaluation
Arrhythmic death (i.e., sudden cardiac death) ARREST: Amiodarone in Out-of-Hospital Resuscitation of Refrac-
Recurrences documented by electrocardiogram tory Sustained Ventricular Tachycardia trial
Time to recurrence
Frequency of recurrences
AV: atrioventricular
Tolerance AVID: Antiarrhythmics Versus Implantable Defibrillators trial
Symptoms CASH: Cardiac Arrest Study Hamburg
Blood pressure
CAST: Cardiac Arrhythmia Suppression Trial

The Arrhythmias
Rate of tachycardia
Surrogate markers of efficacy such as: CCB: calcium channel blocker
Number of premature ventricular contractions/day
CIDS: Canadian Implantable Defibrillator Study
Inducibility of tachycardia with programmed stimulation
Necessity of nondrug interventions (e.g., ICD) CPR: cardiopulmonary resuscitation
ICD shocks CYP: cytochrome P450
Side effects of drugs/treatment complications
Quality of life DCC: direct-current cardioversion
Economics EADs: early after-depolarizations
Outcomes specific to tachycardia (e.g., systemic embolism in atrial fibrillation)
ECG: electrocardiogram
ICD, implantable cardioverter-defibrillator. ESC: European Society of Cardiology
arrhythmia or from side effects of therapy. And, finally, there are the HF: heart failure
economic considerations of medical or surgical intervention, continued HOT-CAFE: How to Treat Chronic Atrial Fibrillation trial
medical care, and chronic drug or nondrug treatment.126,127 Most of the ICD: implantable cardioverter-defibrillator
studies are limited to the use of nondrug therapies such as the ICD or
INR: international normalized ratio
radiofrequency ablation.43,97 Because that technology is rapidly evolv-
ing, what is not very cost-effective now, indeed may be cost-effective in IV: intravenous
the next several years. For example, original cost-effectiveness analysis LADs: late after-depolarizations
of the ICD showed it to be highly sensitive to the life of the generator, LV: left ventricular
yet newer-generation devices have made significant advances in not
LVEF: left ventricular ejection fraction
only the size, but also with regard to battery life. More recent data on
the effect of the ICD on mortality coupled with the declining costs of an MADIT: Multicenter Automatic Defibrillator Implantation Trial
ICD imply that the device is indeed cost-effective in certain subsets of MI: myocardial infarction
patients, not unlike well-proven drug therapies used for other disor- MUSTT: Multicenter Unsustained Tachycardia Trial
ders.97 Other nondrug treatments, such as radiofrequency ablation, for
PSVT not only improve quality of life, but also save money on medical NYHA: New York Heart Association
expenditures compared to chronic drug therapy.43 PIAF: Pharmacological Intervention in Atrial Fibrillation trial
There are some therapeutic outcomes that are unique to certain PSVT: paroxysmal supraventricular tachycardia
arrhythmias. For instance, patients with AF or atrial flutter need to be
PVCs: premature ventricular complexes
monitored for thromboembolism and for complications of anticoagu-
lation therapy (bleeding, drug interactions) prescribed to prevent RACE: Rate Control versus Electrical Cardioversion for Persistent
thromboembolic events. However, the most important monitor- Atrial Fibrillation trial
ing parameters for most patients fall into the following categories: RMP: resting membrane potential
(a) mortality (total and arrhythmic), (b) arrhythmia recurrence (dura- SA: sinoatrial
tion, frequency, symptoms), (c) hemodynamic consequences (heart
SCD: sudden cardiac death
rate, blood pressure, symptoms), and (d) treatment complications
(need for alternative or additional drugs, devices, surgery) (Table SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial
19–14). When evaluating the arrhythmia literature, care should be STAF: Strategies of Treatment of Atrial Fibrillation trial
taken to consider real outcomes. For example, total mortality is more TdP: torsade de pointes
meaningful than only SCD rates; it is possible an intervention prevents
arrhythmic death but patients die from other causes, leaving all-cause TEE: transesophageal echocardiography
mortality unaltered. Likewise, surrogate markers of drug efficacy (e.g., VF: ventricular fibrillation
noninducible tachycardia, suppression of minor arrhythmias) should VT: ventricular tachycardia
be judged with a degree of skepticism. One should ask: Did the
WPW: Wolff-Parkinson-White syndrome
treatment make patients live longer (reduce mortality)? Did it make
them feel better (improve humanistic outcomes or quality of life)? Was
it economically worth it (cost-effective)?
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 315

C HAP T E R

20 Diastolic Heart Failure

and the Cardiomyopathies

JEAN M. NAPPI AND ROBERT L. PAGE, II

DIASTOLIC HEART FAILURE

KEY CONCEPTS
 Diastolic heart failure is a frequent cause of heart failure (prev- Heart failure (HF) may be caused by a primary abnormality in
alence 35% to 50%) and has a significant effect on mortality systolic function, diastolic function, or both. Making the distinction
(25% to 35% 5-year mortality rate) and morbidity (50% 1- is important because the prevalence, prognosis, and treatment of
year readmission rate). HF may be quite different depending on whether the predominant
mechanism causing the symptoms is systolic or diastolic dysfunc-
 Hypertension is a common cause of diastolic heart failure. tion. Clinical studies have reported that up to 74% of patients with
 The diagnosis of diastolic heart failure can be made when a pa- HF have preserved left ventricular (LV) ejection fraction (EF),
tient has both (a) symptoms and signs of congestive heart fail- variably defined as exceeding 40%, 45%, or 50%.1–3 When patients
ure on physical examination and (b) preserved left ventricular with preserved EF exhibit symptoms consistent with effort intoler-
(LV) function. ance and dyspnea, especially in the presence of venous congestion
and edema, the term diastolic heart failure (DHF) is used.4 Despite
 Treatment should be targeted at symptom reduction, causal recognition of its importance, no strong consensus exists regarding
clinical disease, and underlying basic mechanisms. Patients appropriate terminology for this syndrome; therefore, the terms
with diastolic heart failure may be treated differently than those DHF and HF with preserved EF may be used synonymously.
with systolic dysfunction. DHF can be defined as a condition in which myocardial relaxation
 Symptom-targeted therapy includes decreasing pulmonary and filling are impaired and incomplete. The ventricle is unable to
venous pressure, maintaining atrial contraction and atrioven- accept an adequate volume of blood from the venous system, does
tricular synchrony, and reducing heart rate. Exercise tolerance not fill at low pressure, and/or is unable to maintain normal stroke
is increased by reducing exercise-induced increases in blood volume. In its most severe form, DHF results in overt symptoms of
pressure and heart rate. HF. In modest DHF, symptoms of dyspnea and fatigue occur only
during stress or activity, when heart rate and/or end-diastolic vol-
 Disease-targeted therapy includes preventing or treating ume increase. In its mildest form, DHF can be manifested as a slow
myocardial ischemia and preventing or regressing LV hyper- or delayed pattern of relaxation and filling with little or no elevation
trophy. in diastolic pressure and few or no cardiac symptoms. The congestive
symptoms that occur with DHF are a manifestation of increased
 Future directions may include modifying neurohormonal acti-
pulmonary venous pressures. DHF is caused by impaired myocardial
vation, inhibiting endothelin, and altering intracellular mecha-
relaxation and/or increased diastolic stiffness. When HF is caused by
nisms and extracellular matrix structures.
a predominant abnormality in diastolic function, the ventricular
Treatment strategies for patients with hypertrophic cardiomy- chamber is not enlarged, and EF may normal or even elevated.5
opathy (HCM) are aimed at improving symptoms and prevent- Figure 20–1 shows the pressure–volume relationship in a patient
ing sudden cardiac death. with normal versus abnormal diastolic function. Changes in the
myocardium are associated with a shift upward and to the left of the

Patients with HCM who are at high risk for sudden cardiac
death should receive an implantable cardioverter-defibrillator.
 Patients with HCM who are symptomatic may benefit from β-
blockade or verapamil.
Diastolic
 Antibiotic prophylaxis for endocarditis is appropriate for HCM
Dysfunction
patients with evidence of outflow obstruction. Left Ventricular
Pressure

Normal

Learning objectives, review questions,

Left Ventricular Volume
and other resources can be found at
www.pharmacotherapyonline.com. FIGURE 20-1. Diastolic pressure–volume relationship in a normal
patient (right trace) and a patient with diastolic dysfunction (left trace).

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 316
pressure–volume curve so that for any increase in LV volume, TABLE 20-1 Potential Pathologic Mechanisms of Diastolic Heart Failure
diastolic pressure rises to a much greater level than normally would
SECTION 2

Mechanisms directly affecting myocardial tissue

occur. Clinically, patients present with reduced exercise tolerance
Cardiomyocyte Increased intracellular calcium, producing
and dyspnea when they have elevated LV diastolic pressures. Patients
calcium overload
with DHF have a predominant abnormality in diastolic function, Myofilaments
whereas patients with systolic heart failure (SHF) have a predomi- Increased troponin C calcium binding and
nant abnormality in systolic function of the LV.6 increased myofilament calcium sensitivity
Cytoskeleton
EPIDEMIOLOGY Changes in cytoskeletal proteins
Energetics
Cardiovascular Disorders

 Recent studies suggest that as many as half of patients presenting Decrease in ATP availability, leading to
with overt HF have preserved EF.7,8 The prevalence of DHF depends decreased rate or extent of actomyosin
dissociation
on a number of determinants: patient age, patient gender, study
Extracellular matrix Increased content of fibrillar collagen
design, particular population under consideration, and EF. It is
Thickening of existing fibrillar collagen
important to recognize that these determinants are not independent Decreased MMP and/or increased TIMP
but interdependent. The most important determinant appears to be Neurohormones Increased renin–angiotensin–aldosterone
patient age. DHF is relatively uncommon in young and middle-aged Increased endothelin
patients. The prevalence of DHF increases with age, approximating Extramyocardial mechanisms
15% in patients younger than 60 years, 35% in patients between 60 Increased hemodynamic load: pre-
and 70 years, and 50% in patients older than 70 years. Prospective load or afterload
community-based studies showed that in patients older than 70 Increased heterogeneity
years, the prevalence of DHF approaches 50%.9,10 As the proportion Systemic neurohormones Increased levels of angiotensin II
Pericardium Pericardium may have a constraining effect
of the population older than 65 years continues to grow, it has been
as LV filling pressure and end-diastolic
estimated that DHF may eventually become the most common
volume increase
form of HF.11
ATP, adenosine triphosphate; LV, left ventricular; MMP, matrix metalloproteinase; TIMP, tissue
inhibitor of MMP.
ETIOLOGY
stitial fibrosis severely alter the passive elastic properties of the
 Several disorders can impair ventricular function and play a role myocardium. Patients with HCM and LV outflow obstruction are
in the development of DHF. DHF is seen often in patients with sensitive to small changes in volume such that a small decrease in
hypertension, coronary artery disease (CAD), valvular heart disease, filling pressure can lead to a decrease in LV end-diastolic volume
atrial fibrillation, diabetes, and hypertrophic cardiomyopathies.11–13 and a dramatic fall in stroke volume and cardiac output.
Hypertension is the most common underlying cardiovascular disor- The basic mechanisms by which pressure-overload hypertrophy
der in patients with DHF.14 There are several proposed mechanisms and genetic hypertrophy cause DHF include extramyocardial factors
by which hypertension may impair diastolic function. Hypertension and factors intrinsic to the myocardium, which include changes in
can alter diastolic function through its effects on (a) wall tension, the cardiac muscle cell and in the extracellular matrix that surrounds
(b) myocardial hypertrophy and fibrosis, (c) small-vessel structure the cardiomyocyte (Table 20–1).18,19 Intracellular processes, such as
and function, and (d) by predisposing to epicardial CAD. An changes in calcium homeostasis, contractile and noncontractile pro-
association between impaired LV filling and subnormal high-energy teins, energetics, and the cytoskeleton, contribute to abnormalities in
phosphate metabolism has been shown in hypertensive patients, myocardial relaxation and stiffness. Changes in the extracellular
even in the absence of left ventricular hypertrophy (LVH).15 matrix, particularly changes in fibrillar collagen, alter relaxation and
LVH plays a central role in the adaptation of the myocardium to stiffness. In addition to the cardiomyocyte and the extracellular
pressure overload. Severe and long-standing pressure overload has matrix, local myocardial neuroendocrine activation can impair
been associated with phenotypic alterations at the myocyte level, relaxation and increase stiffness. Activation of neurohormones such
which differs from the physiologic hypertrophy seen in athletes.16 as the renin–angiotensin–aldosterone system may act directly to alter
Long-term chronic pressure overload stimulates cardiac growth and diastolic properties or act indirectly by altering calcium homeostasis.
collagen production, which lead to an increase in myocardial mass Finally, extramyocardial changes in loading conditions and changes
and structural remodeling. The results of these changes are an in heterogeneity occur in hypertrophied ventricles and contribute to
increase in myocardial stiffness and a decrease in diastolic filling. changes in relaxation and stiffness so that even when the myocar-
Diastolic dysfunction has been reported to be present in 90% of dium itself is normal, changes in these extramyocardial factors can
patients with CAD.17 Patients with CAD, such as those with (a) exercise- cause abnormalities in diastolic function.19
induced ischemia but normal function at rest, (b) myocardial stunning, Myocardial ischemia, particularly in the subendocardial region, is
and (c) previous myocardial infarction (MI), all may exhibit signs of common when ventricular hypertrophy is present. Slow or delayed
diastolic dysfunction. myocardial relaxation and perivascular fibrosis can adversely affect
coronary blood flow and coronary blood flow reserve. This may
PATHOPHYSIOLOGY contribute to the development of myocardial ischemia and sudden
death.20,21 Therefore, myocardial ischemia may be part of the
The pathologic disease processes that cause DHF include myocardial clinical syndrome of DHF even if no epicardial CAD is present.
ischemia with or without epicardial CAD, pressure overload hypertro- Endothelial dysfunction is associated with the progression of
phy, and genetic hypertrophy. Hypertrophy consequent to the physio- myocardial diastolic dysfunction in patients with CAD.22 Both in
logic adaptation to pregnancy, hypertrophy that occurs in athletes, and the acute manifestation of myocardial ischemia and within the
volume-overload hypertrophy do not cause abnormalities in diastolic chronic consequences of myocardial fibrosis, epicardial CAD is
function and do not result in the development of DHF. frequently the underlying pathologic cause of DHF.23 Myocardial
Hypertrophic cardiomyopathy (HCM) is a prototype for DHF. ischemia caused by either an acute decrease in supply or an increase
The grossly thickened myocardium, structural changes, and inter- in demand (exercise and tachycardia) results in impaired relaxation
 317
5,15
and an acute increase in myocardial stiffness. Chronic coronary study, patients with DHF had a higher prevalence of hypertension
occlusions may result in myocardial fibrosis, remodeling, and DHF. with higher systolic, diastolic, and pulse pressures when compared

CHAPTER 20
It is clear that the same basic mechanisms causing diastolic dysfunc- with control patients and patients with SHF.26
tion in the presence of pressure-overload hypertrophy also underlie The data from a number of studies demonstrate that signs and
changes produced by CAD. symptoms of HF do not predict EF. In contrast, they do predict the
presence of increased LV diastolic pressure. The question then
DIAGNOSIS becomes whether the increase in LV diastolic pressure occurs in
association with normal LV volume and EF, as would occur in DHF,
 The criteria used to make the diagnosis of DHF remain contro- or whether the increase in LV diastolic pressure occurs in associa-
versial. However, making an accurate diagnosis is extremely impor- tion with an increased LV volume and decreased EF, as would occur

Diastolic Heart Failure and the Cardiomyopathies

tant. Guidelines from the European Society of Cardiology (ESC) with SHF. Therefore, determining whether HF is caused by systolic
propose that three requirements must be present to make the or diastolic dysfunction requires some estimate of LV size and EF.
diagnosis of DHF: (a) symptoms or signs of HF, (b) normal or only These measurements can be made using echocardiography, radio-
mildly abnormal systolic function (EF exceeding 45% to 50%), and nuclide ventriculography, or contrast ventriculography. When a
(c) abnormal diastolic function (e.g., abnormal relaxation, filling, patient presents with dyspnea, pulmonary rales, and radiographic
distensibility, or stiffness).24 The first two requirements appear to be evidence of pulmonary venous hypertension, the detection of nor-
well justified; the third requirement may not be.6 mal LV end-diastolic volume and normal EF supports the diagnosis
of DHF. Conditions such as mitral stenosis, pulmonary disease,
CLINICAL PRESENTATION OF sleep apnea, anemia, cirrhosis, hypothyroidism, and drug-induced
DIASTOLIC DYSFUNCTION fluid retention must be ruled out because they can cause similar
General symptoms.27
B-type natriuretic peptide (BNP) and its biologically inactive
■ The majority of patients do not show symptoms at rest but in fragment N-terminal proBNP (NT-proBNP) are cardiac neurohor-
response to stress conditions. Symptoms may be induced or mones secreted from the myocardium in response to increases in
worsened by physical exercise but also by events such as ventricular volume and pressure. Both are used as an aid in the
anemia, fever, tachycardia, and systemic pathologies. differential diagnosis of dyspnea. The Breathing Not Properly study
Symptoms evaluated 452 patients with echocardiography within 30 days of an
■ The patient may complain of exertional dyspnea, orthopnea, emergency department visit. Of the 452 patients, 165 (36.5%) had
paroxysmal dyspnea, and exercise intolerance. EF >45% (mean EF 59%).28 In these patients with preserved EF who
had been admitted to the hospital for dyspnea, BNP levels were
Signs
significantly lower than those found in patients with SHF (413
■ Pulmonary congestion (rales) versus 821 pg/mL). However, there was considerable overlap in the
■ Exaggerated rise in blood pressure and heart rate in response BNP levels in patients with DHF compared with those without HF,
to exercise making BNP levels less useful. Furthermore, the sensitivity, specific-
■ Presence of an S4 gallop ity, and predictive accuracy of BNP levels in DHF are limited in part
because BNP is altered by age, adiposity, gender, and other factors.
Laboratory Tests
Similar findings have been documented with NT-proBNP. In a
■ B-type natriuretic peptide and N-terminal pro–B-type natri- study of 68 symptomatic patients with isolated DHF (EF >50%),
uretic peptide will be elevated. NT-proBNP was significantly increased in patients with isolated
Other Diagnostic Tests DHF and correlated with disease severity. Compared to conven-
■ Two-dimensional echocardiography will show a normal or
tional echocardiography, Doppler imaging, and heart catheteriza-
elevated ejection fraction, normal or decreased cardiac out- tion, NT-proBNP exhibited the best negative predictive value for
put, and LVH and/or concentric remodeling. detection of DFH.29

■ Doppler echocardiography will show elevated pulmonary

venous pressures. PROGNOSIS
■ Chest radiography will show pulmonary congestion. The prognosis in patients with DHF, although less ominous than in
■ Electrocardiography may reflect LVH. patients with SHF, is worse than that of age-matched control
patients. The 5-year mortality of these patients approximates 25%,
Vasan and Levy proposed criteria for DHF according to the degree although mortality rates as high as 13% over a 6-month period have
of diagnostic certainty.25 Three conditions would be met for a been reported.1,7 In comparison, the annual mortality of patients
definite diagnosis of DHF: (a) definitive evidence of HF, (b) objec- with SHF approximates 10% to 15%, whereas age-matched control
tive evidence of normal LV systolic function within 72 hours of a HF mortality approaches 1%. However, in a population-based cohort
event, and (c) objective evidence of LV diastolic dysfunction. If the study of 2,802 patients with HF, no significant difference was
third criterion is lacking, then the patient would have probable DHF. demonstrated in the adjusted 1-year mortality rate for patients with
If the objective evidence for normal systolic function is not apparent EF <40% compared to those with EF >50%.30 Unfortunately,
at the time of the HF event and there is no conclusive information on compared to SHF, little improvement in the survival rate among
LV dysfunction, then the patient would be classified as having patients with DHF has been seen.11
possible DHF. In patients with DHF, the prognosis is also affected by the clinical
With few exceptions, DHF cannot be distinguished from SHF on pathologic etiology causing the disease. When patients with CAD
the basis of the history, physical examination, chest x-ray, and are excluded, the annual mortality for DHF approximates 2% to
electrocardiogram (ECG) alone. The frequency with which patients 3%. In addition to the clinical pathologic etiology causing HF, other
have symptoms of HF and signs of HF on physical examination or predictors of mortality include impaired renal function ≤60 mL/
chest x-ray is not dependent on whether they have SHF or DHF.21 min/m2, worse functional class (New York Heart Association
Patients with DHF are often elderly, hypertensive females.1 In one [NYHA] class III–IV), male gender, and older age >74 years).31,32
 318
The mode of death appears similar in patients with systolic versus congestion by decreasing LV volume using sodium and fluid restric-
diastolic HF. Sudden death and death from progressive pump tion. A low-sodium diet (≤2 g/day) and moderate fluid restriction
SECTION 2

failure occurred with equal frequency in patients with SHF versus will help to prevent volume overload. Both sodium and fluid
those with DHF. Morbidity also is similar between patients with restriction must be done with care. Excessive restriction can lead to
SHF and DHF. The 1-year hospital readmission rate can approach hypotension, low-output state, and/or renal insufficiency. Daily
50%, thereby placing significant expenditures on healthcare weights may help to assess volume status. Dietary and lifestyle
resources. However, compared to patients with SHF, those with factors that decrease the risk of development of epicardial CAD and
DHF appear to have a higher risk of nonfatal MI and stroke.12,30 high blood pressure should be encouraged.24

Exercise
Cardiovascular Disorders

TREATMENT Moderate aerobic exercise to improve cardiovascular conditioning

is beneficial to maintain a slower heart rate, improve cardiac
Diastolic Heart Failure reserve, and maintain skeletal muscle function. Isometric exercise
should be avoided.34
The general principles used to guide the treatment of SHF are based
on numerous large, randomized, double-blind, multicenter trials. Interventional/Surgical Procedures
Until recently, no such randomized trials had been performed in
patients with DHF. Consequently, the guidelines for the management An important step in symptom-targeted therapy that acts to
of DHF are based primarily on clinical investigations in relatively decrease pulmonary venous pressures is to maintain atrial contrac-
small groups of patients, clinical experience, and concepts based on tion and atrioventricular (AV) synchrony. Maintaining atrial con-
the knowledge and understanding of the pathophysiology of the traction and AV synchrony is important both in preserving normal
disease process. The treatment regimen outlined in Table 20–2 applies cardiac output and in keeping LV diastolic pressure low. Chemical
to patients with DHF who have clear manifestations of congestion or electrical cardioversion of persistent atrial tachyarrhythmias will
either at rest or with exertion. Whether treatment of asymptomatic decrease diastolic pressure, increase cardiac output, and resolve
diastolic dysfunction confers any benefit has not been examined. pulmonary edema. An AV sequential pacemaker should be used to
treat bradyarrhythmias in patients requiring pacing.
Therapy also should be aimed at preventing or treating the
■ DESIRED OUTCOME underlying pathologic cause of DHF. Aortic valve replacement
 Treatment should be targeted at reducing symptoms, principally should be performed in symptomatic patients with pressure-over-
those of increased pulmonary venous pressure. Treatment should load hypertrophy caused by aortic stenosis. Revascularization
include decreasing diastolic pressure by decreasing LV volume, should be performed in selected patients with DHF caused by CAD-
maintaining atrial contraction, and reducing heart rate without induced myocardial ischemia. In addition, myocardial oxygen con-
reducing cardiac output. Second, treatment should be targeted at sumption and myocardial blood flow should be increased using
the pathologic diseases that cause DHF. For example, CAD, hyper- medical treatment, including nitrates, β-blockers, and calcium
tensive heart disease, and aortic stenosis provide relatively specific channel blockers.23
therapeutic targets, such as lowering blood pressure, inducing LVH
regression, performing aortic valve replacement, and treating Indications for Hospitalization
ischemia by increasing myocardial blood flow and reducing myo-
Patients with DHF may present with an acute onset of pulmonary
cardial oxygen demand. Third, treatment should be targeted at the
edema. A number of potential causes for the acute decompensation
underlying mechanisms that are altered by the disease processes just
of these patients include volume overload, uncontrolled hyperten-
mentioned.33
sion, acute myocardial ischemia, progressive valvular disease (aortic
stenosis), and new-onset or uncontrolled tachyarrhythmias. Treat-
■ NONPHARMACOLOGIC THERAPY ment strategies for these patients eventually may include the need
for surgery, as in the case of valvular disease.
Diet and Lifestyle The initial management focuses on relieving pulmonary conges-
The initial effort in the treatment of DHF is aimed at decreasing tion and maintaining oxygenation. Intravenous diuretic agents and
symptoms. The first step in this effort is to decrease pulmonary nesiritide for patients are effective for volume overload. Caution

TABLE 20-2 Targeted Approach to Treatment of Diastolic Heart Failure

Symptom-targeted treatment
Decrease pulmonary venous pressure Reduce left ventricular volume Diuretics, nitrates, salt restriction
Maintain atrial contraction Cardioversion of atrial fibrillation
Reduce heart rate β-Blockers, diltiazem, verapamil
Improve exercise tolerance As above
Use positive inotropic agents with caution
Disease-targeted treatment
Prevent/treat myocardial ischemia β-Blockers, diltiazem, verapamil, nitrates
Prevent/regress ventricular hypertrophy Antihypertensive therapy
Mechanism-targeted treatment
Modify myocardial and extramyocardial mechanisms Possibly ACE inhibitors or angiotensin receptor blockers, diuretics,
spironolactone
Modify intracellular and extracellular mechanisms Possibly ACE inhibitors or angiotensin receptor blockers,
spironolactone
ACE, angiotensin-converting enzyme.
 319
must be exercised to avoid overdiuresis or excessive lowering of LV pressure, alleviating causes of myocardial ischemia, reducing vol-
end-diastolic volume, which can lead to a decrease in stroke vol- ume, and restoring and maintaining sinus rhythm. Table 20–3

CHAPTER 20
ume. Morphine and nitroglycerin also are effective in reducing LV summarizes the therapeutic recommendations from the HFSA.
end-diastolic pressure.35
General Information
■ PHARMACOLOGIC TREATMENT Although dozens of trials evaluating pharmacologic therapy have
been conducted in patients with SHF, few trials have focused on
Drug Treatments of First Choice patients with isolated DHF. In fact, most published HF trials have
specifically excluded patients with preserved EF. A few published
With a few notable exceptions, many of the drugs used to treat SHF
large clinical studies and several trials examining various agents in

Diastolic Heart Failure and the Cardiomyopathies

are the same as those used to treat DHF. However, the rationale for
the treatment of DHF are underway (Table 20–4). With these
their use, the pathophysiologic process that is being altered by the
studies and others that currently are under development, an effec-
drug, and the dosing regimen may be entirely different depending
tive treatment for DHF will be defined more completely.
on whether the patient has SHF or DHF. For example, β-blockers
are recommended for the treatment of both SHF and DHF. In
DHF, however, β-blockers are used to decrease heart rate, increase Alternative Drug Treatment
diastolic duration, and modify the hemodynamic response to As a result of the controversy regarding the diagnosis of DHF, the
exercise. In SHF, β-blockers are used in the long run to increase development and design of large clinical trials have been hindered.
inotropic state and modify LV remodeling. Diuretics also are used At this time, most antihypertensive agents would be acceptable
in the treatment of both SHF and DHF. However, the doses of forms of therapy for hypertensive heart disease, with the exception
diuretics used to treat DHF are in general much smaller than the of α-blockers (e.g., doxazosin). In the Antihypertensive and Lipid-
doses used to treat SHF. Antagonists of the renin–angiotensin– Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the
aldosterone system are useful in lowering blood pressure and doxazosin treatment arm was dropped because patients randomized
reducing LVH. Some drugs, however, are used only to treat either to doxazosin had an increased risk for developing HF and stroke
SHF or DHF but not both. Calcium channel blockers such as compared with the chlorthalidone arm.38
diltiazem, nifedipine, and verapamil have little utility in the treat-
ment of SHF. In contrast, each of these drugs has been proposed as Special Populations
being useful in the treatment of DHF.
DHF is associated with hypertension and aging, making it a common
diagnosis in elderly white women. Because these women often are
Published Guidelines frail and have low muscle mass, their creatinine clearance and renal
Much less objective information on the treatment of DHF is function may be compromised. Special care must be taken when
available. This relative paucity of objective information is reflected selecting and titrating doses of drugs, monitoring levels of serum
in guidelines for the diagnosis and management of HF published creatinine and electrolytes, and using diuretics, angiotensin-convert-
from the American College of Cardiology (ACC)/American Heart ing enzyme (ACE) inhibitors, and angiotensin receptor blockers.39
Association (AHA), the ESC, and the Heart Failure Society of Diabetes is often a comorbid condition in patients with HF. Because
America (HFSA).24,36,37 In general, all three guidelines recommend the thiazolidinediones (pioglitazone and rosiglitazone) are associated
treating comorbid conditions by controlling heart rate and blood with fluid retention, caution is warranted when initiating these drugs in

TABLE 20-3 Evidence-Based Pharmacotherapy for Diastolic Heart Failure

Recommendation
Recommendations Gradea
Diuretics
• A loop and a thiazide diuretic should be considered for patients with volume overload. However, with more severe volume overload or inadequate C
response to a thiazide, a loop diuretic should be implemented. Caution is warranted not to lower preload excessively, which may reduce stroke
volume and cardiac output.
ACE inhibitors
• ACE inhibitors should be considered in all patients. C
• ACE inhibitors should be considered in all patients who have symptomatic atherosclerotic cardiovascular disease or diabetes and one additional C
risk factor.
Angiotensin receptor blockers
• Angiotensin receptor blockers should be considered in all patients. B
• In patients who are intolerant of ACE inhibitors, an angiotensin receptor blocker can be considered an alternative. C
β-Blockers
• β-Blockers should be considered in patients with one or more of the following conditions:
Myocardial infarction A
Hypertension B
Atrial fibrillation requiring ventricular rate control. B
Calcium channel blockers
• In patients with atrial fibrillation warranting ventricular rate control who either are intolerant to or have not responded to a β-blocker, diltiazem or C
verapamil should be considered.
• A nondihydropyridine or dihydropyridine calcium channel blocker can be considered for symptom-limiting angina. A
• A nondihydropyridine or dihydropyridine calcium channel blocker can be considered for hypertension; however, amlodipine is recommended. C
a
Strength of recommendations: A, randomized controlled clinical trials; B, cohort and case control studies based upon observations from observational studies or registries, post hoc, subgroup, and meta-analysis;
C, expert opinion, epidemiologic findings from observational studies, and safety findings from large-scale use.
ACE, angiotensin-converting enzyme.
Data from Heart Failure Society of America.36
 320

TABLE 20-4 Completed and Ongoing Large Clinical Trials for Diastolic Heart Failure
SECTION 2

Trial (No. of Patients) Treatment Inclusion Criteria Primary End Point Results
30
DIG Ancillary Study Digoxin vs placebo for a mean EF >45%, NYHA II–IV, Composite of HF hospital- No significant difference was found in the primary
(n = 988) of 37 months. Patients normal sinus rhythm ization or HF mortality end point between treatment groups (HR = 0.82,
received ACE inhibitor P = 0.136). Digoxin had no effect on all-cause
(86%) and diuretics (85%). mortality or cause-specific mortality or on all-
cause or CV hospitalization. Compared to pla-
cebo, digoxin use was associated with a trend
toward a reduction in HF hospitalizations (HR =
0.79, P = 0.094) and an increase in unstable
Cardiovascular Disorders

angina admissions (HR = 1.37, P = 0.061).

CHARM-Preserved13 Candesartan vs placebo for a EF >40%, NYHA II–IV, ≥1 Composite of CV mortal- No significant difference was found in the primary
(n = 3,023) mean of 36.6 months. hospitalization for CV ity or HF hospitalization end point between treatment groups (adjusted
Patients continued their reason HR = 0.86, P = 0.051) or in CV deaths (adjusted
background HF medica- HR = 0.95, P = 0.635). Compared to placebo,
tions: ACE inhibitor (19%), candesartan use was associated with fewer HF
β-blocker (55%), diuretics admissions (P = 0.017), lower incidence of new
(75%), spironolactone diabetes (HR = 0.60, P = 0.005), and a reduction
(11%). in the composite of CV death, HF hospitalization,
nonfatal MI, and nonfatal stroke (adjusted HR =
0.91, P = 0.037).
PEP-CHF46 (n = 850) Perindopril vs placebo for a Clinical criteria for HF, EF Composite of total mor- At 1 year and at study completion, no significant
mean of 2.1 years. ≥40%, age ≥70 years tality and HF hospital- difference was found in the primary end point
ization between treatment groups (HR = 0.69, P = 0.055;
HR = 0.70, P = 0.545). In a subgroup analysis,
patients ≤75 years of age (HR = 0.29, P = 0.035)
and with a history of MI (HR = 0.38, P = 0.004)
showed a reduction in the primary end point.
Compared to placebo, perindopril use at 1 year
was associated with fewer unplanned hospital
admissions (HR = 0.63, P = 0.033), greater
improvements in exercise tolerance (P = 0.011),
and improvement in NYHA class (P = 0.030).
I-Preserve65 (n = 4,100) Irbesartan vs placebo for 2 Clinical criteria for HF or Composite of all-cause Expected to be completed in 2007
years. ACE inhibitor can be hospitalized within 6 mortality or CV
used for any indication months for HF, age ≥60 hospitalization
other than HTN. years, NYHA II–IV, EF
≥45%
TOPCAT65 (n = 4,500) Spironolactone vs placebo for Clinical criteria for HF, age CV mortality, aborted car- Expected to be completed in 2011
2 years. ≥50 years, EF ≥45%, diac arrest, HF hospital-
≥1 hospitalization for ization
HF, controlled SBP
Trials: CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; DIG, Digitalis Investigational Group; I-Preserve, Irbesartan in Heart Failure with Preserved EF; PEP-CHF,
Perindopril for Elderly Persons with Chronic Heart Failure; TOPCAT, Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure.
ACE, angiotensin-converting enzyme; CV, cardiovascular; EF, ejection fraction; HF, heart failure; HR, hazard ratio; HTN, hypertension; MI, myocardial infarction; NYHA, New York Heart Association; SBP, systolic blood pressure.

patients with a history of DHF. Thiazolidinediones should be discon- Treatment with diuretics should be initiated at low doses in order
tinued in patients with symptoms related to volume overload.3,37 to avoid hypotension and fatigue. Hypotension can be a significant
problem in the treatment of DHF because these patients have a very
steep LV diastolic pressure–volume curve such that a small change
■ DRUG CLASS INFORMATION in volume causes a large change in filling pressure and cardiac
output. After the acute treatment of DHF has been completed, long-
Diuretics term treatment should include small-to-moderate doses of diuretics
 Diuretics can provide symptom-targeted therapy by decreasing (furosemide 20 to 40 mg/day orally or hydrochlorothiazide 12.5 to
systemic and LV volume. By decreasing LV diastolic volumes, LV 25 mg/day orally). If prompt and sustained diuresis is not achieved,
pressures slide down the curvilinear diastolic pressure–volume the dosage of a single diuretic should be increased, or a loop and
relationship toward a lower, less steep portion of the curve. As thiazide or thiazide-like diuretic should be used in combination.
pressure throughout diastole falls, mean diastolic pressure, pulmo- Aldosterone antagonists such as spironolactone and eplerenone
nary capillary wedge pressure, and pulmonary venous pressure fall. may be especially effective for long-term use because of their
These agents effectively reduce the central blood volume and lower potassium-sparing effects and because their antagonism of renin–
diastolic pressures, thus alleviating the symptoms of the congestive angiotensin–aldosterone system activation may alter intramyocar-
state. Diuretics can provide disease-targeted therapy by decreasing dial and extramyocardial mechanisms causing abnormalities in
blood pressure and favorably affecting the myocardial oxygen sup- diastolic function.40 Thiazide diuretics generally are ineffective as
ply-versus-demand ratio. Lower LV diastolic pressures may increase diuretics in patients with a creatinine clearance <30 mL/min.
subendocardial blood flow, preventing or alleviating the imbalance Excessive diuresis may result in hypotension, low-output syndrome,
between myocardial oxygen supply and demand (see Fig. 20–1). and worsening renal insufficiency. In some cases, loop diuretics may
Diuretics alone and especially in combination with other antihyper- be withdrawn safely from elderly patients without any worsening of
tensive drugs are an effective approach to therapy. HF symptoms and with improvement in symptoms of orthostatic
 321
41
hypotension. Electrolyte imbalances, including hypokalemia and is older, it is prudent to start with a moderate dose of β-blockers,
hypomagnesemia, are common with diuretics. Carbohydrate intoler- such as metoprolol tartrate 25 mg twice daily, metoprolol succinate

CHAPTER 20
ance and hyperuricemia are dose-related adverse drug reactions seen 25 mg daily, atenolol 25 mg daily, or carvedilol 3.125 mg twice daily
with thiazide diuretics. Spironolactone can cause hyperkalemia and and titrate to a higher dose with a treatment target of a heart rate of
gynecomastia. Eplerenone may be used as an alternative to spironolac- approximately 60 beats/min.
tone in patients who complain of gynecomastia. In general, diuretic Prinzmetal vasospastic angina, occlusive peripheral vascular dis-
agents are very cost-effective agents in the management of DHF. ease, type 1 diabetes mellitus that is prone to hypoglycemia, severe
heart block, and excessive bradycardia are contraindications to β-
Nitrates blockers. β-Blockers may be considered in patients with reactive
airway disease or asymptomatic bradycardia but should be used
 Similar to diuretics, nitrates can provide symptom-targeted
with extreme caution. The main side effects of β-blockers are

Diastolic Heart Failure and the Cardiomyopathies

therapy by acting to decrease LV volume by increasing venous
depression, fatigue, bradycardia, bronchospasm, and impotence.
capacitance. In addition, nitrates can provide disease-targeted ther-
Many of the β-blockers are eliminated via hepatic metabolism and
apy by providing antiischemic effects in patients with DHF due to
may be affected by other drugs that either inhibit (e.g., cimetidine
CAD.
and verapamil) or enhance (e.g., barbiturates) hepatic enzymes.
Like diuretics, therapy should be initiated at low doses in order to
Because the doses are titrated to patient response, these interactions
avoid hypotension. Isosorbide dinitrate 10 mg three or four times
are managed easily.
daily, isosorbide mononitrate (Imdur) 30 mg/day, nitroglycerin
paste 0.5 to 1 inch every 4 to 6 hours, and nitroglycerin patch 0.1 to
0.2 mg/h applied each day are common initial doses. Doses can be Calcium Channel Blockers
increased during long-term therapy and titrated against symptoms. Calcium channel blockers can provide symptom-targeted treatment
Nitrate tolerance has not been studied in this patient population but by decreasing heart rate and increasing exercise tolerance. They can
probably occurs (for more detail regarding nitrate tolerance, see provide disease-targeted treatment by treating high blood pressure
Chap. 17). Similar to diuretics, nitrates can cause hypotension and and CAD. However, the beneficial effect of these agents on exercise
a low-output syndrome. Headaches are common but may be less tolerance is not always paralleled by improved LV diastolic function
frequent with continued use. or increased relaxation rate. Nonetheless, a number of small clinical
Sublingual nitroglycerin tablets or nitroglycerin spray may be trials have shown that the use of these agents results in both short-
used for patients who develop shortness of breath with mild term and long-term improvement in exercise capacity in patients
exercise, and they can be used much in the same way as in patients with DHF.33,36
with ischemic symptoms. Nitroglycerin will decrease LV end- Of the calcium channel blockers, the nondihydropyridines (ver-
diastolic volume, resulting in relief of breathlessness. apamil and diltiazem) are the most effective because they lower
heart rate in addition to lowering blood pressure.42 Sustained-
β-Adrenergic Blockers release nifedipine, because of its strong vasodilator properties, tends
to cause hypotension and reflex tachycardia. In addition, nifedipine
β-Blockers can provide symptom-targeted therapy by decreasing
causes peripheral edema. These characteristics make it less useful in
heart rate and can provide disease-targeted therapy by treating high
DHF. Amlodipine may be effective because it reduces blood pres-
blood pressure and CAD. By decreasing heart rate and increasing
sure. Initial doses are verapamil 120 to 240 mg/day, diltiazem 90 to
the duration of diastole, β-blockers can help to lower and maintain
120 mg/day, and amlodipine 2.5 mg/day.
low pulmonary venous pressures. Tachycardia is poorly tolerated in
Heart block is a contraindication for the nondihydropyridines.
patients with DHF for several reasons. First, rapid heart rates cause
The most common side effects are bradycardia and heart block (for
an increase in myocardial oxygen demand and a decrease in coro-
the nondihydropyridines). Peripheral edema and headache also are
nary perfusion time. This rapid rate can promote ischemic diastolic
common. Nondihydropyridines exacerbate the bradycardic effects
dysfunction even in the absence of epicardial CAD, especially in
of β-blockers, and verapamil raises digoxin serum concentrations
patients with LVH. Second, incomplete relaxation between cardiac
by 70%. Diltiazem raises cyclosporine, tacrolimus, and sirolimus
cycles may result in an increase in diastolic pressure relative to
serum concentrations. Intravenous calcium salts inhibit the phar-
volume. Thus, LV distensibility is reduced. Third, a rapid rate
macologic effect of calcium channel blockers. Generic formulations
reduces diastolic filling time and ventricular filling. Fourth, hearts
or similar products, but not necessarily generic equivalents to the
with diastolic dysfunction exhibit a flat or even negative relaxation
original brand names, are available for some of the calcium channel
rate versus frequency relationship. Thus, as heart rate increases in
blockers.
these hearts, relaxation does not become augmented and may
become slower and incomplete, causing diastolic pressures, espe-
cially early in diastole, to increase.9 For these and other reasons, Neurohormonal Antagonists
most clinicians use β-blockers (and calcium channel blockers) to  Both basic and clinical studies suggest that DHF is associated
prevent excessive tachycardia and produce a relative bradycardia in with activation of systemic and local cardiac neuroendocrine sys-
patients with diastolic dysfunction. However, excessive bradycardia tems such as the renin–angiotensin–aldosterone system. One mech-
can result in a fall of cardiac output despite an increase in LV filling. anism causing fluid retention and the increases in central and
Such considerations underscore the need for individualizing thera- systemic volume in patients with DHF is activation of these neu-
peutic interventions that affect heart rate. Although the optimal roendocrine systems. Therefore, treatment of DHF should include
heart rate must be individualized, an initial goal might be a resting agents such as ACE inhibitors, angiotensin receptor blockers, and
heart rate of approximately 60 beats/min with a blunted exercise- aldosterone antagonists that attenuate the fluid retention caused by
induced increase in heart rate not to exceed 110 beats/min.9 neuroendocrine activation. In addition to promoting fluid reten-
No evidence suggests a specific therapeutic advantage of one β- tion, neuroendocrine activation can have direct effects on cellular
blocker over another. Selective and nonselective β-blockers appear and extracellular mechanisms that contribute to the development of
equally effective in DHF. In general, it is not necessary to start the DHF. Modulation of neuroendocrine activation may provide mech-
drug at an extremely low dose and titrate the β-blocker in a slow, anism-targeted treatment by decreasing fibroblast activity and
progressive fashion in DHF, as it is in SHF. Because the population interstitial fibrosis, improving intracellular calcium handling, and
 322
decreasing myocardial stiffness. Finally, renin–angiotensin–aldos- receptor blocker in patients with preserved EF currently receiving
terone system antagonists provide disease-targeted treatment by usual treatment.13 However, 22% of candesartan-treated patients
SECTION 2

treating hypertension.43 discontinued therapy because of hypotension (P = 0.009), increased

The mechanisms that evoke activation of the neuroendocrine serum creatinine (P = 0.0005), and hyperkalemia (P = 0.029).
system remain incompletely understood in patients with DHF. A Presently, no angiotensin receptor blocker has yet been shown to
number of factors have been suggested. Myocardial ischemia, uncon- have any major advantage over another. Initial doses of candesartan
trolled hypertension, and excessive dietary sodium or sodium-retain- start at 4 mg/day, irbesartan 150 mg/day, losartan 25 mg/day,
ing medications may contribute to neuroendocrine activation. telmisartan 40 mg/day, and valsartan 80 mg/day. As with the ACE
Limited distensibility of the atria may attenuate the secretion of atrial inhibitors, angiotensin receptor blockers are contraindicated in
natriuretic factor and thereby reduce its diuretic effect. In others, low pregnancy. The side effects of angiotensin receptor blockers are
Cardiovascular Disorders

systemic vascular resistance and/or low arterial pressure may contrib- similar to those of ACE inhibitors, but they are not associated with
ute to an increase in renin–angiotensin–aldosterone system activation persistent cough.
and salt and water retention. Elevated venous pressure may cause
renal sodium retention directly. The reduction in blood volume that Aldosterone Antagonists
follows the use of diuretics triggers an increase in sympathetic tone
and further activation of the renin–angiotensin–aldosterone system. Aldosterone antagonists can provide improved myocardial function-
Such neurohormonal activation can lead to vasoconstriction and a ing by decreasing LV volume and chamber stiffness.47,48 They can
worsening of the congestive state. Some vasodilators, particularly provide disease-targeted treatment by decreasing the fibrosis that
nitrates and pure arteriolar vasodilators, evoke a similar response. By accompanies LVH. An analysis of the Randomized Aldactone Evalu-
contrast, ACE inhibitors, aldosterone antagonists, and β-blockers ation Study (RALES) found that spironolactone significantly
blunt neurohormonal activation and decrease the salt and water decreased the levels of serum markers for cardiac collagen turnover.
retention that complicates the treatment of HF. The benefit from spironolactone was seen in patients with higher
levels of collagen synthesis markers. This was the first study to show
that serum levels of markers of cardiac collagen synthesis were
Angiotensin-Converting Enzyme Inhibitors associated with a poor clinical outcome and could be decreased with
ACE inhibitors can provide symptom-targeted treatment by spironolactone. This property distinguishes spironolactone from
decreasing LV volume and directly improving relaxation. They can other diuretics that have no effect on myocardial necrosis or collagen
provide disease-targeted treatment by treating high blood pressure, turnover.
preventing LVH, promoting regression, and preventing fibrosis. Like other diuretics, spironolactone should be initiated at a low
Treatment of high blood pressure with ACE inhibitors has been dose and increased to treat symptoms. Spironolactone may be
shown to normalize load, prevent and/or regress LVH, correct the initiated at doses of 12.5 to 25 mg/day. Spironolactone should be
abnormality in intracellular processes, and modify the extracellular avoided in patients severe renal failure. Hyperkalemia and gyneco-
matrix response.43 ACE inhibitors may reduce the incidence of HF mastia are the most common side effects. Eplerenone is a viable
by 23% among patients with CAD and preserved EF.44 alternative to spironolactone in patients complaining of sex hor-
A small, prospective, double-blind, randomized trial compared mone–related side effects and may be initiated at 25 mg/day.40
lisinopril with hydrochlorothiazide in 35 patients with primary
hypertension, LVH, and LV diastolic dysfunction.45 After 6 months
of therapy, lisinopril caused regression of myocardial fibrosis and
Positive Inotropic Agents
improved LV diastolic function, although LVH was unchanged. Positive inotropic agents, such as β-agonists and phosphodiesterase
However, the largest study, the Perindopril for Elderly Persons with inhibitors, generally are not used in the treatment of patients with
Chronic Heart Failure (PEP-CHF) trial, failed to find a significant isolated DHF because LV EF is preserved and there appears to be
effect on clinical outcomes at 1 year in patients with DHF who little potential for a beneficial effect. Positive inotropic agents have
received perindopril (see Table 20–4). Based on these limited data, the potential to worsen DHF by adversely affecting energetics,
it appears that ACE inhibitors may improve HF symptomatology inducing ischemia, raising heart rate, and inducing arrhythmias.9 In
and exercise capacity while not impacting mortality.46 contrast to long-term use, positive inotropic drugs may be benefi-
At this time, no evidence suggests an advantage of one ACE cial in the short-term treatment of pulmonary edema associated
inhibitor over another. Their effects appear to be a class effect. with DHF. These agents can enhance sarcoplasmic reticular func-
Initial doses should be small to moderate in order to avoid hypoten- tion, promote more rapid and complete relaxation, increase
sion, especially if the patient examination does not indicate volume splanchnic blood flow, increase venous capacitance, and facilitate
overload. Examples of initial starting doses are captopril 6.25 mg diuresis.9 However, these agents should be used with caution, if
three times daily, enalapril 2.5 mg/day, or lisinopril 2.5 mg/day. they are used at all, because the risk-to-benefit ratio is not clearly
Severe renal failure, history of angioedema, and pregnancy are established.
contraindications to ACE inhibitors. Hyperkalemia, persistent
cough, hypotension, taste disturbances, and worsening renal func- Digitalis Derivatives
tion are common side effects but are managed by decreasing the
Digoxin, by inhibiting the Na+,K+-adenosine triphosphatase (ATPase)
dose or discontinuing the drug.
pump, augments intracellular calcium and thereby augments con-
tractile state. In this manner, digoxin produces an increase in
Angiotensin Receptor Blockers systolic energy demands while adding to a relative calcium overload
Angiotensin receptor blockers can provide symptom-targeted treat- in diastole. These effects may not be apparent clinically under many
ment by decreasing LV pressure, decreasing LV volume, and circumstances, but during hemodynamic stress or ischemia, digoxin
increasing exercise tolerance. They can provide disease-targeted may promote or contribute to diastolic dysfunction.9 However,
treatment by lowering blood pressure. The Candesartan in Heart based on the data from the Digitalis Investigational Group (DIG)
Failure: Assessment of Reduction in Mortality and Morbidity Ancillary Study (see Table 20–4), it appears that digoxin has, at
(CHARM)-Preserved trial (see Table 20–4) was the first large most, a very limited role in the management of patients with DHF
prospective study to demonstrate the benefits of an angiotensin in normal sinus rhythm.49
 323

TABLE 20-5 Characteristics of the Cardiomyopathies

CHAPTER 20
Dilated Hypertrophic Restrictive
Myocardial mass ↑→ ↑↑ ↑↑↑ nl→↑
Ventricular cavity size ↑↑↑↑↑ ↓↓→nl nl→↓
Contractile function ↓↓↓ ↑↑→ nl→↓
LV filling pressure ↑↑ nl→↑ ↑
Chest x-ray film Moderate to marked cardiac enlargement Mild to moderate cardiac enlargement Mild cardiac enlargement
Electrocardiogram ST-segment and T-wave abnormalities ST-segment and T-wave abnormalities, LV hypertrophy Low voltage, conduction defects
Echocardiogram LV dilation and dysfunction Asymmetric septal hypertrophy, systolic anterior motion Increased LV wall thickness possible
of the mitral valve

Diastolic Heart Failure and the Cardiomyopathies

Radionuclide studies LV dilatation and dysfunction Vigorous systolic function Normal systolic function
↑, increased; ↓, decreased; LV, left ventricular; nl, normal.

PHARMACOECONOMIC CONSIDERATIONS tension, and CAD. Therefore, the commonly used term “ischemic
cardiomyopathy” is not considered a “true” cardiomyopathy.
Frequent admission to the hospital is common in patients with Frequently, a specific etiology is not evident. Therefore,
DHF. Unfortunately, there are no pharmacoeconomic data associ- another commonly used categorization of the cardiomyopathies
ated with the only large clinical outcome trial (CHARM-Preserved) is based on the structural and/or functional abnormalities
published to date. Because DHF is primarily a disease of the elderly, present. The three groups of primary cardiomyopathies usually
comorbid conditions will create challenges in any trial designed. At are described as dilated, hypertrophic, and restrictive. An under-
the present time, cost to the patient should be considered because standing of the pathophysiologic basis for each type of cardiomy-
adherence to an antihypertensive regimen is paramount to a bene- opathy leads to a rational selection of drug therapy or other
ficial outcome. treatment modality. The characteristics for each of the types of
cardiomyopathy are listed in Table 20–5. The distinction among
the cardiomyopathies is not absolute, and there is some overlap
CLINICAL CONTROVERSIES in the functional abnormalities.
• Digoxin may increase hospitalizations for unstable angina in In dilated cardiomyopathy, the cardinal feature is ventricular
patients with DHF and normal sinus rhythm. chamber enlargement. Systolic function is abnormal with normal LV
wall thickness, leading to a decreased cardiac output. In patients with
• Drugs that antagonize the renin–angiotensin–aldosterone
HCM, the ventricular cavity is not dilated, but the ventricular muscle
system may be the preferred antihypertensive drugs for
mass is increased, existing in the absence of known causes of LVH.
patients with DHF.
Ventricular cavity size is normal or decreased, and systolic function
often is preserved. Patients with HCM may have an obstructive or
EVALUATION OF THERAPEUTIC OUTCOMES nonobstructive form. Patients with restrictive cardiomyopathy have
inadequate ventricular compliance causing diastolic dysfunction as a
The end points used in assessing effective therapies for DHF include
result of endocardial and/or myocardial disease. The clinical presen-
mortality, hospitalization for worsening HF, functional status or
tation is similar to that of constrictive pericarditis.
quality-of-life indicators, and cost. Other end points may target
underlying mechanisms of disease, such as calcium homeostasis or
regression of fibrosis. A number of clinical trials addressing this HYPERTROPHIC CARDIOMYOPATHY
important clinical problem are underway.
HCM is a primary, genetic cardiomyopathy that is inherited as an
autosomal dominant trait caused by mutations in any of 10 genes.
CARDIOMYOPATHIES The distribution of the hypertrophy usually is asymmetric, meaning
that segments of the LV are thickened to varying degrees. There also
Diastolic dysfunction plays a role in the presentation of some types may be enlargement of the atria, thickening of the mitral valve
of cardiomyopathy. Over the past decade, the terminology and leaflets, and fibrotic areas within the ventricular wall. In the past, the
classification used for the cardiomyopathies have been confusing terms of idiopathic hypertrophic subaortic stenosis and hypertrophic
because of overlap among the diseases and/or classification obstructive cardiomyopathy were used to describe patients with
schemes. In 2006, the ACC/AHA suggested a broader definition for HCM with an outflow obstruction. These terms are used less
the cardiomyopathies. The expert panel defined the cardiomyop- frequently now because they overemphasize the obstructive compo-
athies as “a heterogeneous group of diseases of the myocardium nent of the disease, which is present in a minority of patients.50
associated with mechanical and/or electrical dysfunction that usu-
ally (but not invariably) exhibit inappropriate ventricular hypertro- Epidemiology
phy or dilation and are due to variety of causes that frequently are
Recent epidemiologic investigations estimate the prevalence of
genetic. Cardiomyopathies either are confined to the heart (primary
phenotypically expressed HCM in the general adult population to
cardiomyopathy) or are part of generalized systemic disorders
be approximately 0.2% (1:500), making it the most frequently
(secondary cardiomyopathy), often leading to cardiovascular death
occurring cardiomyopathy. HCM is the most common genetic
or progressive HF-related disability.”50
cardiovascular disease. However, many individuals have a mutant
The primary cardiomyopathies are further divided into genetic,
gene but go undetected.51
mixed (genetic and nongenetic), and acquired. Endocrine conditions,
inflammation, metabolic disorders, infiltrative diseases, and toxins
are a few of the causative factors of secondary cardiomyopathy.50 It is
Etiology
important to note that this new contemporary classification does not The genetic predisposition to HCM is thought to be an autosomal
include pathologic myocardial processes that are a direct result of dominant trait with variable penetrance. Because of the wide vari-
other cardiovascular conditions such as valvular heart disease, hyper- ability of presentation, not all cases in a family may be detected.
 324
HCM usually is caused by mutations in the genes for β-myosin TABLE 20-6 Factors Known to Affect Outflow Gradients in
heavy chain, myosin-binding protein C, and cardiac troponin T.52 Hypertrophic Cardiomyopathy
SECTION 2

Factors that diminish gradients

Pathophysiology Decreasing myocardial contractility
HCM appears to have several different pathophysiologic mechanisms β-Blocking drugs
leading to similar clinical manifestations, although the prognoses for Verapamil
patients will vary. The pathophysiology of HCM is a complex relation- Increasing ventricular volume
Increasing arterial pressure
ship among several factors, including (a) asymmetric LVH, (b) dia-
Factors that enhance gradients
stolic dysfunction, (c) dynamic obstruction of the outflow tract, and
Increasing myocardial contractility
(d) myocardial ischemia. Each of these components contributes to the Exercise
Cardiovascular Disorders

overall presentation of the patient to a varying degree.51,52 Inotropic agents

Left Ventricular Hypertrophy The hypertrophy seen in HCM Decreasing ventricular volume
Decreasing arterial pressure
usually is diffuse and involves the septum and LV anterolateral free wall
to a greater degree than the posterior segment. Asymmetric septal
hypertrophy is a sensitive marker for HCM but is not specific for this approximately 25% of patients with HCM.50 The obstruction that
disorder. In patients with outflow obstruction, the basal septum usu- occurs usually shows spontaneous variability and may be reduced by
ally is markedly thickened at the level of the mitral valve. In patients interventions that decrease myocardial contractility. The gradient can
with nonobstructive HCM, the outflow tract is larger, and the septal be augmented by factors that increase contractility (Table 20–6).54 LV
hypertrophy that occurs has a more distal or apical distribution.53 outflow tract obstruction at rest has been found to be a predictor of
Cellular disorganization is a common histologic finding in HCM. progression to severe HF symptoms, stroke, and death.55
Morphologic abnormalities are found at the gross, microscopic, and
Myocardial Ischemia Chest pain in the absence of CAD is a
ultrastructural levels. The disarray of myocytes may contribute to
common symptom of patients with HCM. However, it is appropriate
diastolic and systolic dysfunction, as well as serving as a nidus for
to consider typical CAD in any patient with HCM if they have the
ventricular arrhythmias. The degree of LVH is associated with a
usual risk factors for atherosclerosis.50,54,56 Several mechanisms are
worse clinical course. The presence of hypertrophy correlates
proposed for the myocardial ischemia seen in this patient popula-
directly with myocardial infarction, HF, stroke, and ventricular
tion. There may be inadequate capillary density in relation to the
arrhythmias. Spirito and Autore51 found that the magnitude of LVH
increased LV muscle mass. The small intramural coronary arteries
was directly related to the risk of sudden cardiac death.
may be abnormally narrowed or excessively compressed during
Diastolic Dysfunction Diastolic dysfunction is the most com- systole. Impaired relaxation during diastole may inhibit blood flow
mon abnormality found in patients with HCM. Approximately 80% to the subendocardium. Once myocardial ischemia develops, further
of patients exhibit symptoms associated with diastolic dysfunction. increases in LV filling pressure may occur, which, in turn, lead to
Studies of the LV led to the realization that diastolic dysfunction is more ischemia. Repeated episodes of ischemia may be responsible
the result of abnormalities in relaxation, distensibility (compliance), for progressive myocyte loss and fibrosis. The subendocardium is at
and filling. The abnormalities of diastolic function can be both greatest risk for ischemic damage because of the lower capillary
regional and global and lead to an incoordination of contraction density and higher oxygen demand secondary to wall tension.54
and relaxation. β-Adrenergic stimulation can aggravate these
abnormalities, whereas β-receptor blockade may diminish them.52 Diagnosis
Abnormalities in filling are also associated with changes in cham-
Making the diagnosis of HCM may be difficult because the disorder may
ber stiffness that occur in HCM. This stiffness may be the result of
be confused with CAD, aortic stenosis, or mitral regurgitation. Patients
myocardial fibrosis, cellular disorganization, or increased myocardial
with HCM can be young and physically active. The physical signs of the
mass. The decreased distensibility leads to an abnormally steep slope
cardiac examination depend on the presence of a systolic pressure
of the diastolic pressure–volume curve such that an increase in LV
gradient within the LV. If a gradient is present, a late-onset systolic
volume results in a disproportionate increase in diastolic pressure.
murmur is heard often. The murmur is intensified by standing and the
Myocardial relaxation is an energy-dependent process that is
Valsalva maneuver and lessened with squatting or handgrip. Very rarely,
sensitive to episodes of ischemia. Diastolic resequestration of cal-
some patients develop an end-stage LV dilation and a declining LV EF,
cium ions by the sarcoplasmic reticulum is an energy-dependent
which often are confused with idiopathic dilated cardiomyopathy.
process. In the event of ischemia, the sequestration of calcium is
Echocardiography is used to confirm the diagnosis. The diagnosis
inhibited, allowing the calcium to continue its interaction with the
of HCM is made with two-dimensional echocardiography, with the
myofibrillar contractile proteins. Calcium channel blockers have
usual criterion of LV wall thickness ≥15 mm. Magnetic resonance
been used with some success in patients with diastolic dysfunction.54
imaging of the entire LV may add valuable information, especially if
Systolic Function and Outflow Tract Obstruction Abnormal- the echocardiogram is of suboptimal quality.50,56
ities of systolic function also occur in patients with HCM. The The development of or increase in a murmur suggests progres-
hypertrophied LV may cause a powerful but sometimes uncoordi- sion of disease, but disappearance of a murmur does not imply
nated contraction presumably as a result of the abnormal architec- improvement. In fact, disappearance of a murmur may herald
ture of the myocardium. The increase in LV wall thickness results in further impairment of systolic function. Some patients will progress
decreased wall stress during systole. Therefore, the LV contracts to CHF a result of atrial fibrillation, mitral regurgitation, or myo-
against a decreased afterload so that the LV is described as being cardial infarction. If SHF develops, the patient has a poor prognosis.
hyperdynamic. EF often is increased. Contemporary methods of diagnosis consist of genotype assess-
Considerable controversy has surrounded the issue of the impor- ment. Genetic testing allows for a definitive diagnosis and precise
tance of outflow tract obstruction in conjunction with HCM. The identification of mutations in myocardial sarcomere proteins.
presence of a gradient (the systolic pressure difference between the Unfortunately, screening for more than 200 mutations in multiple
body and the outflow tract of the LV) is indicative of a dynamic genes is complex, time consuming, costly, and restricted to a small
obstruction of the LV outflow tract. Outflow tract gradients occur in number of research laboratories. Furthermore, genetic screening
 325
identifies gene variants in only 50% to 60% of patients. Based on cumulative risk nearly zero for patients with a wall thickness ≤19
these limitations, genotype assessment has not become a standard mm. Young patients with severe hypertrophy (wall thickness >30

CHAPTER 20
part of routine clinical evaluation.50,51 mm) are at high risk for sudden death even if they are asymptom-
atic. A high LV outflow tract pressure gradient ≥30 mm Hg is a
CLINICAL PRESENTATION OF strong predictor for older patients.57 Presentation of HCM in the
HYPERTROPHIC CARDIOMYOPATHY latter decades of life is common. Patients who present with HCM at
an advanced age of 65 years or older usually have a prognosis that is
General
no different from that of age- and gender-matched controls. Elderly
■ The clinical presentation varies widely, ranging from no patients with HCM tend to have mild degrees of LVH, and their
symptoms to severe symptoms of angina, HF, and/or sudden symptoms are not severe.58 Because systolic hypertension and dia-
death. The severity of symptoms corresponds to the degree of

Diastolic Heart Failure and the Cardiomyopathies

stolic HF are common in the elderly, the diagnosis of HCM may be
LVH, but this relationship is not absolute. challenging. However, marked LVH out of proportion to blood
Symptoms pressure, unusual patterns of LVH, or an outflow obstruction at rest
■ The patient may complain of dyspnea, chest pain, fatigue, strongly suggests HCM.50
palpitations, presyncope, and syncope.
Signs TREATMENT
■ Systolic murmur
Other Diagnostic Tests Hypertrophic Cardiomyopathy
■ Echocardiography will show increased myocardial mass. ■ DESIRED OUTCOMES
■ Electrocardiography will reveal LVH with or without ST-
Because no known means are available for preventing HCM, the
segment and T-wave abnormalities.
focus must be on methods to minimize the consequences of the
disorder.
Prognosis
The clinical course for a patient with HCM should be viewed in terms
of the specific subtypes of the disease spectrum. Patients fall into one
■ GENERAL APPROACH TO TREATMENT
of several relatively discrete pathways: (a) high risk for sudden death; The treatment of HCM is designed to reduce symptoms,
(b) symptoms of DHF, including syncope; (c) progression toward improve exercise tolerance, retard disease progression, and improve
advanced end-stage HF; and (d) atrial fibrillation and its sequelae. Of prognosis. Agents that decrease contractility, improve diastolic
major concern is the incidence of sudden cardiac death among dysfunction, reduce ischemia, and suppress arrhythmias have been
patients with HCM. Approximately 10% to 20% of HCM patients are used with some success (Fig. 20–2). In 2003, the ACC in conjunc-
at increased risk for sudden death. The mechanism responsible for tion with the ESC published a consensus document on HCM.59
sudden cardiac death is thought to be related to an electrically
unstable myocardium leading to complex ventricular arrhythmias. ■ NONPHARMACOLOGIC THERAPY
Less often, sudden death may be the result of hemodynamic changes.
The onset of atrial fibrillation in the face of severe LV diastolic Surgical treatment generally is reserved for patients who are refrac-
dysfunction may result in a significant decrease in stroke volume. tory to medical management, have an outflow gradient ≥50 mm Hg,
This decrease in cardiac output could lead acute LV failure, MI, or a very thick ventricular septum, and high LV pressures. Surgical
sudden death. Sudden death can be a complication, especially in intervention is designed to relieve the outflow obstruction and the
young athletes with HCM. It is recommended that young patients elevated LV pressures. The surgeon accomplishes this by perform-
with HCM refrain from competitive athletics.50,56 ing a myectomy (i.e., removal of excess tissue). The procedure
Quantification of the risk of sudden death remains elusive for results in a reduction in LV filling pressures and a long-term
patients with HCM. The clinical markers associated with an improvement in symptoms. However, early mortality rates of up to
increased risk for sudden death (Table 20–7) have a high negative 5% have been reported.52,59 Other complications may include septal
predictive value. The absence of all these markers can be used to perforation and late occurrence of HF.
develop a profile for a patient at low risk for sudden death. The The results of uncontrolled studies suggested that dual-chamber
magnitude of hypertrophy appears to be a strong predictor, with the pacing decreased LV outflow gradients and improved symptoms.
Subsequent controlled trials were not able to replicate the initial
findings but demonstrated more modest improvement. Conse-
TABLE 20-7 Risk Factors Associated with Sudden Cardiac Death in quently, the ACC/AHA and the North American Society of Pacing
Hypertrophic Cardiomyopathy and Electrophysiology have issued guidelines suggesting pacing for
Major risk factors severely symptomatic patients who have not responded to medical
Prior cardiac arrest management (class IIb recommendation, or one in which the
Spontaneous sustained ventricular tachycardia efficacy is less well established by evidence).60
Positive family history of premature death Ablation of the myocardium using alcohol is another alternative
Multiple syncopal or near-syncopal episodes, especially if associated with exertion to surgery. Septal ablation with alcohol results in the same type of
Multiple and repetitive or prolonged episodes of nonsustained ventricular tachycardia
Marked left ventricular hypertrophy ≥30 mm outcomes as seen with myectomy. Long-term followup is limited
Hypotensive blood pressure response to exercise because this procedure has been used for less than a decade. Because
Potential individual risk factors it is a percutaneous procedure (similar to cardiac catheterizations),
Atrial fibrillation it is being performed more frequently than myectomy. There is
Myocardial ischemia some concern that the risk for arrhythmia-related cardiac events
Left ventricular outflow obstruction may increase following alcohol ablation. Long-term followup is
Identification of a malignant genotype needed to assess this risk. Complete heart block is a common
Intense (competitive) physical exertion complication of septal ablation (14% in one case series) and
Data from Zipes et al.62 requires a permanent pacemaker if it occurs.52,59
 326
SECTION 2

Symptoms Treatment

Asymptomatic ? ȕ-blocker or verapamil

Cardiovascular Disorders

No NSVT ȕ-Blocker or verapamil

Mild-moderate
symptoms
ICD +/– amiodarone +
Positive NSVT ȕ-blocker if needed

ȕ-Blocker + diuretic or
Verapamil + diuretic

Atrial fibrillation Warfarin + amiodarone or

Warfarin + ȕ-blocker or verapamil

Severe symptoms LV outflow obstruction Alcohol ablation or myectomy

Non-obstructive form Cardiac transplant

High risk for SCD ICD implantation

FIGURE 20-2. Treatment algorithm for hypertrophic cardiomyopathy. (ICD, implantable cardioverter-defibrillator; LV, left ventricular; NSVT, nonsustained
ventricular tachycardia; SCD, sudden cardiac death; ?, questionable role.)

■ IMPLANTABLE CARDIOVERTER- of propranolol or its equivalent are used. Resting heart rate should be
DEFIBRILLATOR 60 beats/min, and the maximum exercise heart rate should be <120
beats/min. The mechanism by which β-blockade is beneficial is by

Sudden death is the most worrisome outcome of HCM, and the inhibiting sympathetic stimulation of the heart. Myocardial oxygen
implantable cardioverter-defibrillator (ICD) is the most effective demand is reduced by decreasing heart rate, LV contractility, and
therapy for prevention of sudden death.61 It is difficult to know myocardial wall stress during systole. Outflow tract obstruction may
when to implant an ICD, especially in a young patient diagnosed be minimized with β-blockade, especially under conditions of stress
with HCM. Patients who are candidates for an ICD for primary or exercise, when sympathetic stimulation is high.
prevention will be young and relatively asymptomatic. In 2006, the
ACC/AHA with the ESC published updated guidelines designating
the ICD for primary prevention of sudden death (class IIa recom-
Calcium Channel Blockers
mendation or one in which the weight of the evidence or opinion Patients who have an inadequate response to β-blockade may
favors efficacy). These guidelines stipulate that patients should respond to verapamil.51 Doses of verapamil up to 480 mg/day have
exhibit one or more major risk factors for sudden death (see Table beneficial effects on symptoms.59 Calcium channel blockers may be of
20–7), currently be receiving chronic medical therapy, and have a benefit to patients with HCM for several reasons. Increased calcium
reasonable survival with good functional status at 1 year. For concentrations have been shown to play a role in prolonging ventric-
secondary prevention following cardiac arrest, ICD placement is ular depolarization, as well as the duration of isometric contraction
considered a class I recommendation, where there is evidence or and relaxation. Patients with HCM have a hyperdynamic ventricle in
general agreement that the procedure is beneficial.60 Conducting a systole and delayed relaxation and decreased compliance during
clinical trial to provide evidence for a higher-level recommendation diastole. Calcium channel blockers decrease the myocardial oxygen
for primary prevention is unlikely to occur.61 demand, resulting in an improved balance between oxygen supply
and demand; therefore, diastolic function may be improved.
Most patients with HCM who have been treated with a calcium
■ PHARMACOLOGIC THERAPY channel blocker have received verapamil, although others also have
been used. Intravenous verapamil has been noted to acutely reduce
β-Adrenergic Blockers the outflow tract gradient in patients with obstructive HCM. The
 β-Blocking agents have been used in obstructive and nonobstruc- mechanism may be a decrease in systolic function as well as an
tive forms of HCM since the 1960s. Approximately one third to half increase in LV volumes as a result of enhanced LV diastolic filling.
of patients with angina, dyspnea, light-headedness, or syncope will The adverse effects associated with use of verapamil include
have a favorable response to these agents.54 Doses up to 480 mg/day constipation, sinus nodal blockade, prolongation of the PR interval,
 327
AV dissociation, hypotension, and pulmonary congestion. The 54
blocker or calcium channel blockers can be used. If a β-blocker is
risks may outweigh the benefits in patients with (a) a markedly chosen, it is best to use an agent that does not have intrinsic

CHAPTER 20
elevated pulmonary capillary wedge pressure or pulmonary artery sympathomimetic activity. The dose should be maximized. If the
occlusion pressure, (b) a history of paroxysmal nocturnal dyspnea patient does not tolerate a β-blocker or has a contraindication to use
or orthopnea, (c) sick sinus syndrome or significant AV nodal of a β-blocker, then verapamil can be tried. Patients should be
disease in the absence of a permanent pacemaker, (d) low systolic monitored for resolution of symptoms and an increase in exercise
blood pressure, and (e) a substantial outflow gradient. Verapamil tolerance. Resolution of symptoms may take months to occur. In
should be avoided in patients with HF as a result of systolic addition, both β-blockers and calcium channel blockers may cause
dysfunction.59 There is no evidence that either β-blockade or hypotension and conduction abnormalities. β-Blockers may worsen
verapamil protects the patient from sudden cardiac death. pulmonary function. If dyspnea continues with maximal doses of a
β-blocker or calcium channel blocker, a diuretic agent or a nitrate

Diastolic Heart Failure and the Cardiomyopathies

Studies using other calcium channel blockers are limited.
Improvement in diastolic dysfunction may occur, but the dihydro- may be added with caution. Patients who are at high risk for sudden
pyridines may cause a reflex increase in heart rate or hypotension or cardiac death should be considered candidates for an ICD.
worsen the outflow tract gradient. For patients with significant obstruction to LV outflow who do
not respond to medical management, a surgical approach may be
Antiarrhythmic Agents necessary. Septal myectomy and alcohol ablation have been used.
These approaches generally are reserved for patients who have an
Disopyramide has been used for treating both the supraventricular and
outflow gradient >50 mm Hg and/or severe symptoms and who
ventricular arrhythmias occurring in patients with HCM. In addition,
have not responded an adequate trial of medical therapy.
the negative inotropic effect and the ability to increase peripheral
vascular resistance attributed to disopyramide have been used to reduce
outflow tract obstruction. The anticholinergic side effects (blurred RESTRICTIVE CARDIOMYOPATHY
vision, dry mouth, and urinary retention) make disopyramide a prob-
lematic agent for long-term therapy in some patients. The QT interval Restrictive cardiomyopathy is primarily an abnormality of diastolic
on the ECG should be monitored in patients on disopyramide.59 function that results in impaired filling and increases in ventricular
The role of amiodarone for the prevention of sudden death in end-diastolic pressures with normal or decreased diastolic volume. It is
patients with HCM has been questionable. A few nonrandomized associated with normal systolic function early in the course of the
studies have suggested a protective effect, whereas others demon- disease but a decrease in systolic function later in the disease process.
strate only symptomatic improvement. Nonetheless, the 2006 ACC/ Either one or both of the ventricles may be affected; therefore, restric-
AHA/ESC give amiodarone a class IIb recommendation for primary tive cardiomyopathy may present as either left- or right-sided HF.50
prophylaxis against sudden death in patients with HCM when ICD
placement is not feasible and who demonstrate one or more major CLINICAL PRESENTATION OF
risk factors for sudden death (see Table 20–7). Furthermore, in RESTRICTIVE CARDIOMYOPATHY
patients with HCM who are not candidates for ICD placement and General
have suffered a cardiac arrest, amiodarone therapy is considered the
preferred treatment (class I recommendation).62 ■ The majority of patients remain asymptomatic but experience
A significant number of patients with HCM develop atrial fibril- symptoms during exercise or vigorous activity.
lation. Amiodarone is one of the most effective agents available to Symptoms
maintain normal sinus rhythm in these patients. For patients in ■ The patient may complain of dyspnea, orthopnea, fatigue,
chronic atrial fibrillation requiring rate control, a β-blocker or edema, ascites, or chest pain.
verapamil may be used. Anticoagulation should be considered
Signs
because these patients are at risk for systemic embolization and
stroke. If amiodarone is added to the therapy of a patient already ■ Significant jugular venous distension
receiving warfarin, the prothrombin time or international normal- ■ Mitral and/or tricuspid regurgitant murmurs
ized ratio will be increased and should be monitored closely.51 ■ Thromboembolic complications
■ Kussmaul sign may be present
Other Drugs
Laboratory Tests
 There is a small risk for bacterial endocarditis in HCM patients
■ BNP and N-proBNP levels will be elevated.
with LV outflow obstruction under resting conditions and in those
with intrinsic mitral valve disease. Patients undergoing dental or Other Diagnostic Tests
selected surgical procedures that cause bloodborne bacteremia ■ ECG may reflect atrial arrhythmias, tachybrady syndrome, or
should receive appropriate antibiotic therapy. The administration conduction abnormalities.
of nitroglycerin and digoxin generally is discouraged in the presence ■ Echocardiography may reveal small ventricles and dilated
of LV outflow obstruction.59 atria.

Epidemiology and Etiology

CLINICAL CONTROVERSY
Restrictive cardiomyopathy is the type of cardiomyopathy encoun-
Some clinicians believe that ACE inhibitors have no role in the
tered least frequently in western countries. Because restrictive car-
management of HCM with LV outflow obstruction. Others believe
diomyopathy is rare, the natural course of the disease is not well
that ACE inhibitors may be beneficial by limiting hypertrophy.
characterized, and reports on prognosis have been highly variable.
Restrictive cardiomyopathies may be classified as either myocardial
Evaluation of Therapeutic Outcomes or endomyocardial. The myocardial types may be noninfiltrative,
The goal of treatment of patients with HCM is primarily to reduce infiltrative, or storage diseases. The endomyocardial types are due to
their symptoms of dyspnea and exercise intolerance. Either β- endomyocardial fibrosis, hypereosinophilic syndrome, carcinoid
 328
heart disease, metastatic cancers, radiation, and anthracycline toxic- relieving the symptoms associated with high filling pressures. This is
ity or secondary to drugs known to cause fibrosis.54 achieved generally through the use of diuretics. Diuretic therapy
SECTION 2

Restrictive myocardial disease may result from several local or should be initiated with low doses. Normalization of filling pressures
systemic disorders. Amyloidosis, hemochromatosis, scleroderma, is not possible or desirable. Patients’ symptoms should be monitored
carcinoid, sarcoidosis, diabetes, pseudoxanthoma elasticum, and for improvement. Excessive diuresis will result in inadequate cardiac
endomyocardial fibrosis have been known to cause restrictive cardio- output. Chelation therapy has been advocated for patients with hemo-
myopathy. The most common cause of restrictive cardiomyopathy in chromatosis. Prednisone has been suggested for patients with sarcoi-
the industrialized world is amyloidosis, whereas endomyocardial dosis. There is no curative treatment for restrictive cardiomyopathy.
fibrosis is a common cause in tropical areas of the world. There may
be a genetic predisposition to idiopathic restrictive cardiomyopathy.54
ABBREVIATIONS
Cardiovascular Disorders

The cause of the disease, the severity of HF symptoms, and the

presence of cardiac thrombi and arrhythmias are factors that affect
ACC: American College of Cardiology
long-term survival. Children diagnosed with restrictive cardiomy-
opathy have a worse prognosis than do adults and should be ACE: angiotensin-converting enzyme
considered for early cardiac transplantation.63 AHA: American Heart Association
ALLHAT: antihypertensive and lipid-lowering treatment to prevent
Pathophysiology heart attack trial
The major hemodynamic abnormality in restrictive cardiomyopa- AV: atrioventricular
thy is a limitation in ventricular filling leading to increased filling BNP: B-type natriuretic peptide
pressures. The cavity size and wall thickness of the ventricles usually
are normal. Atrial dimensions often are increased. Thrombi are CAD: coronary artery disease
found frequently in the cardiac chambers. Patients have signs and CHARM: candesartan in heart failure: assessment of reduction in
symptoms consistent with HF. The abnormality is similar to that mortality and morbidity
seen in pericardial disease causing constriction or tamponade. DHF: diastolic heart failure
DIG: Digitalis Investigational Group
Diagnosis
ECG: electrocardiogram
The diagnosis of restrictive cardiomyopathy should be considered
EF: ejection fraction
in any patient who presents with signs and symptoms of HF but has
only mild cardiomegaly. Differentiation from constrictive peri- ESC: European Society of Cardiology
carditis is important because pericardectomy is an effective form of HCM: hypertrophic cardiomyopathy
treatment of constrictive pericarditis. Recent studies have focused HF: heart failure
on using BNP as a potential noninvasive marker for differentiation
of the two conditions.64 HFSA: Heart Failure Society of America
HR: hazard ratio
ICD: implantable cardioverter-defibrillator
TREATMENT
I-Preserve: irbesartan in heart failure with preserved ejection frac-
Restrictive Cardiomyopathy tion
LV: left ventricular
The treatment of restrictive cardiomyopathy is complex because of LVH: left ventricular hypertrophy
the heterogeneity of the pathophysiologic abnormalities. Diuretics
are used for the symptoms of venous congestion in the presence of MI: myocardial infarction
restrictive cardiomyopathy, but caution is advised because these MMP: matrix metalloproteinase
patients require high filling pressures to maintain an adequate NT-proBNP: N-terminal proBNP
stroke volume and cardiac output. Hypotension and hypoperfusion
NYHA: New York Heart Association
may occur as a result of excessive use of diuretics. Because systolic
function often is normal, digoxin is of little benefit and may be PEP-CHF: perindopril for elderly persons with chronic heart failure
proarrhythmic. Amiodarone can be used to maintain normal sinus RALES: randomized aldactone evaluation study
rhythm in patients who have episodes of atrial fibrillation. Antico- SBP: systolic blood pressure
agulation is needed to decrease the risk of systemic embolization,
SHF: systolic heart failure
particularly in patients with atrial fibrillation, valvular regurgita-
tion, and low cardiac output. In the case of hemochromatosis, TOPCAT: trial of aldosterone antagonist therapy in adults with
chelation therapy and/or repeated phlebotomy may be of benefit. preserved ejection
Treatment with corticosteroids and cytotoxic drugs has been used
with some success in the early phase of endomyocardial fibrosis and
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Cardiovascular Disorders

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 331

C HAP T E R

21 Venous Thromboembolism

STUART T. HAINES, DANIEL M. WITT, AND EDITH A. NUTESCU

venous circulation (Fig. 21–1), VTE is manifested as deep vein

KEY CONCEPTS thrombosis (DVT) and pulmonary embolism (PE). Death from PE
can occur within minutes after the onset of symptoms, before
 The risk of venous thromboembolism (VTE) is related to several effective treatment can be given.
easily identifiable factors, including age, major surgery (particu- Unfortunately, the disease is often clinically silent, and the first
larly orthopedic procedures of the lower extremities), previous manifestation may be sudden death. In some case series, 80% of
VTE, trauma, malignancy, and hypercoagulable states. These patients who died suddenly had some evidence of PE at the time of
risks are additive. autopsy.3 Beyond the symptoms produced by the acute event, the
 The diagnosis of VTE must be confirmed by objective testing. long-term sequelae of VTE, such as the postthrombotic syndrome
and recurrent thromboembolic events, also cause substantial pain
 Antithrombotic therapies require meticulous and systematic and suffering.1
monitoring as well as ongoing patient education. Well-orga- The treatment of VTE is fraught with substantial risks.4 Antithrom-
nized anticoagulation management services improve the qual- botic drugs require precise dosing and meticulous monitoring.5–7
ity of patient care and reduce overall cost. Systematic approaches to drug therapy management substantially
 Bleeding is the most common adverse effect associated with reduce the risks, but bleeding remains an all too common and serious
anticoagulant drugs. A patient’s risk of major hemorrhage is re- complication of administering antithrombotic drugs.7,8 Consequently,
lated to the intensity and stability of therapy, concurrent drug the prevention of VTE in at-risk patients is paramount to improving
use, history of gastrointestinal bleeding, risk of falls, recent sur- outcomes.3 When there is a suspicion of VTE, the rapid and accurate
gery or trauma, and age. diagnosis of the disorder is critical to making appropriate treatment
decisions.9 The optimal use of antithrombotic drugs requires not
 At the time of hospital admission, all patients should receive only an in-depth knowledge of their pharmacology and pharmaco-
prophylaxis against venous thromboembolism that corre- kinetic properties, but also a comprehensive approach to patient
sponds to their level of risk. Prophylaxis should be continued management.5
throughout the period of risk.
 In the absence of contraindications, the treatment of VTE should EPIDEMIOLOGY
initially include a rapid-acting anticoagulant (e.g., unfractionated
heparin, low-molecular-weight heparin, or fondaparinux) over- The true incidence of VTE in the general population is unknown,
lapped with warfarin for at least 5 days and until the patient’s in- because a substantial portion of patients, perhaps more than 50%,
ternational normalized ratio is greater than 2.0. Anticoagulation have clinically silent disease. An estimated 2 million people in the
therapy should be continued for a minimum of 3 months. The United States develop VTE each year; 600,000 are hospitalized, and
duration of anticoagulation therapy should be based on the pa- 60,000 die.2 The estimated annual direct medical costs of managing
tient’s risk of VTE recurrence and major bleeding. the disease are well over $1 billion and growing. The best available
 Most patients with an uncomplicated deep vein thrombosis, data indicate the age-adjusted annual incidence of symptomatic
with or without pulmonary embolism, can be safely treated as VTE in whites to be 117 per 100,000 population.10 The incidence of
an outpatient. VTE nearly doubles in each decade of life over the age of 50 years
and is slightly higher in men. The age-adjusted incidence of PE has
declined slightly in recent years, presumably because of heightened
awareness of VTE, effective prevention strategies, early diagnosis,
Venous thromboembolism (VTE) is a potentially fatal disorder and
and prompt treatment. However, as the population ages, the total
a significant national health problem in our aging society.1,2
number of cases of DVT and PE continues to climb.
Although it can strike young, otherwise healthy adults, it most
Relatively little is known about the risk of VTE in ethnic popula-
frequently occurs in patients who sustain multiple trauma, undergo
tions. African Americans appear to be at somewhat higher risk of
major surgery, are immobile for a lengthy period of time, or have a
VTE than are Americans of predominantly European ancestry,
hypercoagulable disorder. Resulting from clot formation within the
whereas Hispanic Americans may be at slightly lower risk.11 Asian
Americans and Pacific Islanders appear to have a strikingly low
incidence of VTE.
Learning objectives, review questions, The incidence of VTE in specific high-risk patient populations has
and other resources can be found at been extensively studied.3 Patients who sustain multiple traumas or
www.pharmacotherapyonline.com. undergo an orthopedic procedure involving a lower extremity are at
particularly high risk, with the incidence of VTE often exceeding

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 332
SECTION 2

Jugular vein
Subclavian vein
Superior vena cava Cephalic vein
Cardiovascular Disorders

Basilic vein
Inferior vena cava

Iliac vein

Femoral vein

Great saphenous vein

Popliteal vein

Small saphenous vein

Anterior tibial vein

Dorsal venous arch

FIGURE 21-1. Venous circulation.

50% in the absence of effective prophylaxis. Among those undergo- blood flow explains, at least in part, why numerous medical condi-
ing major surgeries other than procedures involving the lower tions and surgical procedures are associated with an increased risk of
extremities, the incidence of VTE is 20% to 40% when one or more VTE (Table 21–1). Greater-than-normal blood viscosity, seen in
other risk factors are present, such as age older than 60 years. The myeloproliferative disorders like polycythemia vera, for example,
long-term incidence of VTE among patients who have a prior history may also contribute to slowed blood flow and thrombus formation.
of VTE and who have metastatic cancer is extremely high.12,13 A growing list of hereditary deficiencies, gene mutations, and
Likewise, the incidence of VTE after a myocardial infarction, stroke, acquired diseases have been linked to hypercoagulability (see Table
and spinal cord injury is high.3 Several disorders of hypercoagulabil- 21–1).12–14 Activated protein C resistance is the most common genetic
ity have also been linked to a high lifetime incidence of VTE.3,14 disorder of hypercoagulability, with a prevalence rate approaching
5% among community-dwelling whites, and a rate as high as 40%
among those who suffer an idiopathic DVT or who have a strong
ETIOLOGY family history of VTE. Although these patients have normal plasma
concentrations of protein C, they often have a mutation on factor V
 A number of factors increase the risk of developing VTE (Table that renders it resistant to degradation by activated protein C. This
21–1). These risk factors are additive and can be easily identified in mutation is known as factor V Leiden, named after the city of Leiden,
clinical practice. A prior history of VTE is perhaps the strongest risk Holland, where the defect was initially reported. The prothrombin
factor for recurrent VTE, presumably because of the destruction of G20210A mutation also appears to be a relatively common defect,
venous valves and obstruction of blood flow caused by the initial occurring in as many as 3% of healthy individuals of southern
event.15 Rapid blood flow has an inhibitory effect on thrombus European descent and 16% of those with an idiopathic DVT.
formation, but a slow rate of flow reduces the clearance and dilution Although less common, inherited deficiencies of the natural anticoag-
of activated clotting factors in the zone of injury and slows the influx ulants protein C, protein S, and antithrombin place patients at a high
of regulatory substances. Stasis of blood tips the delicate balance of lifetime risk for VTE. Conversely, excessively high concentrations of
procoagulation and anticoagulation in favor of thrombogenesis. The factors VIII, IX, and XI also increase the risk of VTE. Given the
rate of blood flow in the venous circulation, particularly in the deep prevalence of these inherited abnormalities in the general population,
veins of the lower extremities, is relatively slow. Valves in the deep some patients have multiple genetic defects that have additive effects
veins of the legs, as well as contraction of the calf and thigh muscles, in terms of increasing the lifetime thrombotic risk.
facilitate the flow of blood back to the heart and lungs; thus, damage Acquired disorders of hypercoagulability may result from malig-
to the venous valves and prolonged periods of immobility result in nancy, the presence of antiphospholipid antibodies, and estrogen
venous stasis. Vessel obstruction, either from external compression use.12–15 The strong link between cancer and thrombosis has been
or a thrombus, also promotes clot propagation. Reduced venous recognized since the late 1800s.13 Tumor cells secrete a number of
 333

TABLE 21-1 Risk Factors for Venous Thromboembolism waste. With vascular injury, a dynamic series of reactions involving a
complex interplay of thrombogenic and antithrombotic stimuli

CHAPTER 21
Risk Factor Example
result in the local formation of a hemostatic plug that seals the vessel
Age Risk doubles with each decade after age 50 y wall and prevents further blood loss (Figs. 21–2, 21–3, and 21–4). A
History of VTE Strongest known risk factor of DVT and PE disruption of this delicate system of checks and balances may lead to
Venous stasis Major medical illness (e.g., CHF, status post-MI) inappropriate clot formation within the blood vessel that subse-
Major surgery (e.g., general anesthesia >30 minutes) quently obstructs blood flow or embolizes to a distant vascular bed.
Paralysis (e.g., status post-stroke, spinal cord injury)
In the late 1800s, Dr. Rudolf Virchow, a German pathologist, recog-
Polycythemia vera
nized the role played by blood vessels, circulating elements in the
Obesity
Varicose veins blood, and the speed of blood flow in the regulation of clot formation

Venous Thromboembolism
Vascular injury Major orthopedic surgery (e.g., knee and hip replacement) (Table 21–2). Alterations in any one of these elements, known today
Trauma (especially fractures of the pelvis, hip, or leg) as Virchow’s triad, may lead to pathologic clot formation.
Indwelling venous catheters Under normal circumstances, the endothelial cells that form the
Hypercoagulable Malignancy, diagnosed or occult intima of vessels maintain blood flow by producing a number of
states Activated protein C resistance/factor V Leiden substances that inhibit platelet adherence, prevent the activation of
Prothrombin (G20210A) gene mutation the coagulation cascade, and facilitate fibrinolysis.18,19 Vascular
Protein C deficiency injury can expose the subendothelium (see Fig. 21–3). Platelets
Protein S deficiency readily adhere to the subendothelium, using glycoprotein Ib recep-
Antithrombin deficiency
tors found on their surfaces and facilitated by von Willebrand
Factor VIII excess (>90th percentile)
factor. This causes platelets to become activated, releasing a number
Factor XI excess (>90th percentile)
Antiphospholipid antibodies of procoagulant substances into the local circulation that stimulate
Dysfibrinogenemia platelets to expose glycoprotein IIb/IIIa receptors. These receptors
Hyperhomocysteinemia allow the platelets to adhere to one another, resulting in platelet
Plasminogen activator inhibitor-1 excess aggregation. In addition, the damaged vascular tissue releases tissue
Inflammatory bowel disease factor, also known as tissue thromboplastin, which activates the
Nephrotic syndrome extrinsic pathway of the coagulation cascade (see Fig. 21–4).
Pregnancy/postpartum The coagulation cascade is a stepwise series of enzymatic reactions
Drug therapy Estrogen-containing contraception that result in the formation of a fibrin mesh.18,19 Clotting factors
Estrogen replacement therapy circulate in the blood in inactive forms. Specific stimuli convert an
Selective estrogen receptor modulators
inactive precursor into an active form that, in turn, converts the next
Heparin-induced thrombocytopenia
precursor in the sequence. It was once believed that all clotting
CHF, congestive heart failure; DVT, deep vein thrombosis; MI, myocardial infarction; PE, pulmonary factors were proteolytic enzymes, known as zymogens. It is now
embolism; VTE, venous thromboembolism. known that factors V and VIII have no enzymatic activity them-
From Geerts et al., Thomas, and Federman and Kirsner.3,14,111
selves, but rather serve as cofactors that greatly accelerate the enzy-
matic activity of their respective partners. The final steps in the
cascade are the conversion of prothrombin to thrombin and fibrin-
procoagulant substances that activate the coagulation cascade. Fur-
ogen to fibrin. Thrombin plays a key role in the coagulation cascade;
thermore, patients with cancer often have suppressed levels of
it is responsible not only for the production of fibrin, but also for the
protein C, protein S, and antithrombin. It has been postulated that
conversion of factors V and VIII to their active forms, creating a
cancer cells use thrombotic mechanisms to recruit a blood supply
positive feedback loop that greatly accelerates the production of
(angiogenesis), metastasize, and create a barrier against host defense
more thrombin. Additionally, thrombin enhances platelet aggrega-
mechanisms. Antiphospholipid antibodies, most commonly found
tion through its interactions with the glycoprotein IIb/IIIa receptor.
in patients with autoimmune disorders such as systemic lupus
Traditionally, the coagulation cascade has been divided into three
erythematosus and inflammatory bowel disease, can cause venous
distinct parts: the intrinsic, extrinsic, and common pathways (see
and arterial thrombosis.14 These antibodies are also associated with
Fig. 21–4).18,19 This artificial division is somewhat misleading, as
repeated pregnancy loss presumably caused by placental thrombosis.
there are numerous interactions between the three pathways. The
The precise mechanism by which the antiphospholipid antibodies
extrinsic pathway, sometimes referred to as the tissue factor pathway,
provoke thrombosis is unclear, but they appear to activate the
appears to be the principal mechanism that triggers the coagulation
coagulation cascade and platelets, as well as to inhibit the anticoagu-
cascade. Tissue factor, released from the subendothelium, forms a
lant activity of proteins C and S. Estrogen-containing contraception,
complex with factor VIIa. The factor VIIa–tissue factor complex
estrogen replacement therapy, and the selective estrogen receptor
activates factor X in the common pathway and factor IX in the
modulators are all linked to venous thrombosis.16 Women with an
intrinsic pathway. The intrinsic pathway plays a key role in the
underlying disorder of hypercoagulability are at particularly high risk
propagation of clot formation. The activation and inhibition of
of developing venous thrombosis while taking estrogens. Although
factor X in the common pathway is a key step in the regulation of clot
the mechanisms are not clearly understood, estrogens increase serum
formation. With its cofactor, factor Va, factor Xa converts pro-
clotting factor concentrations and induce activated protein C resis-
thrombin (II) to thrombin (IIa), which then cleaves fibrinogen to
tance. Increased serum estrogen concentrations may explain, in part,
form fibrin monomers. Finally, as the fibrin monomers reach a
the increased risk of VTE observed during pregnancy and the
critical concentration, they begin to precipitate and polymerize to
immediate postpartum period.17
form fibrin strands. Factor XIIIa covalently bonds these strands to
one another.
PATHOPHYSIOLOGY Normally, a number of tempering mechanisms control coagula-
tion (see Table 21–2 and Fig. 21–2).18,19 Without effective self-
The arrest of bleeding following vascular injury (hemostasis) is regulation, the coagulation cascade would proceed unabated until all
essential to life.18,19 Within the vascular system, blood remains in a the clotting factors and platelets were consumed. The intact endothe-
fluid state, transporting oxygen, nutrients, plasma proteins, and lium adjacent to the damaged tissue actively secretes several anti-
 334

Activators Inhibitors
SECTION 2

Vessel Wall Injury

Endothelium
von Willebrand Factor Heparan
Thrombomodulin

Platelet Adhesion
and Aggregation
Cardiovascular Disorders

Coagulation
Tissue Factor Cascade Activated Antithrombin
Factor VIIa Protein C
Factor Xa Protein S
Factor XIIa Tissue Factor Pathway Inhibitor
Thrombin
Thrombin

Fibrin Formation
Factor XIIIa

Stabilized Fibrin Clot

Fibrinolysis and
Clot Degradation
Tissue Plasminogen Plasminogen Activator
Activator Inhibitor-1

Recanalization
FIGURE 21-2. Hemostasis and thrombosis. and Healing

thrombotic substances. As its name implies, thrombomodulin thrombus may either (a) remain asymptomatic, (b) spontaneously
modulates thrombin activity by converting protein C to its active lyse, (c) obstruct the venous circulation, (d) propagate into more
form. When joined with its cofactor protein S, protein C enzymati- proximal veins, (e) embolize, or (f ) act in any combination of these
cally inactivates factors Va and VIIIa. Activated protein C also ways.20 The majority of patients with VTE never develop symptoms
stimulates the release of tissue plasminogen activator. Antithrombin from the acute event.21 However, even those who experience no
is a circulating protein that inhibits thrombin and factor Xa. Hepa- symptoms may suffer long-term consequences, such as the post-
ran sulfate, a heparin-like compound secreted by endothelial cells, thrombotic syndrome and recurrent VTE. Even when symptoms of
exponentially accelerates antithrombin activity. By a similar mecha- DVT or PE are present (Tables 21–3 and 21–4), they are nonspecific.1
nism, heparin cofactor II also inhibits thrombin. Tissue factor It is extremely difficult to distinguish VTE from other disorders, and
pathway inhibitor plays an important role by regulating the initia- additional objective tests are required to confirm or exclude the
tion of the coagulation cascade. When these self-regulatory mecha- diagnosis. Patients with DVT frequently present with unilateral leg
nisms are intact, the formation of the fibrin clot is limited to the zone pain and swelling. The postthrombotic syndrome, a long-term com-
of tissue injury. However, disruptions in the system, so-called hyper- plication of DVT caused by damage to the venous valves, can produce
coagulable states, often result in thrombosis. symptoms very similar to those of an acute thrombotic event includ-
The fibrinolytic protein plasmin degrades the fibrin mesh into ing chronic lower-extremity swelling, pain, tenderness, skin discolor-
soluble end products collectively known as fibrin split products or ation, and ulceration. Symptomatic PE often produces dyspnea,
fibrin degradation products.18,19 The fibrinolytic system is also tachypnea, and tachycardia. Hemoptysis, while distressing, occurs in
under the control of a series of stimulatory and inhibitory sub- less than one-third of patients. Cardiovascular collapse, characterized
stances. Tissue plasminogen activator and urokinase plasminogen by cyanosis, shock, and oliguria, is an ominous sign.
activator convert plasminogen to plasmin. Plasminogen activator  Given that VTE can be debilitating or fatal, it is important to
inhibitor-1 inhibits the plasminogen activators, and α2-antiplasmin treat it quickly and aggressively.9 Conversely, because major bleeding
inhibits plasmin activity. Aberrations in the fibrinolytic system have induced by antithrombotic drugs can be equally harmful, it is impor-
also been linked to hypercoagulability. tant to avoid treatment when the diagnosis is not a reasonable
certainty. Assessment of the patient’s status should focus on the search
for risk factors in the patient’s medical history (see Table 21–1).
CLINICAL PRESENTATION AND DIAGNOSIS Venous thrombosis is uncommon in the absence of risk factors, and
the effects of these risks are additive. Even in the presence of mild,
Although a thrombus can form in any part of the venous circulation, seemingly inconsequential symptoms, VTE should be strongly sus-
the majority begin in the lower extremities. Once formed, a venous pected in those with multiple risk factors.
 335

Extrinsic coagulation pathway

CHAPTER 21
Endothelium
(see Fig. 21–4)
Subendothelium
X

t-PA VIIIa Ca

platelet
IXa
u-PA II
ADP surface
Xa
receptors Va Ca
PAF
Tissue Collagen

Venous Thromboembolism
Factor Thrombin IIa
TXA2/PGH2 phospholipid
Epinephrine
PLA2 -Granule ADP
Vessel Serotonin
vWF
wall arachidonic
acid Dense vW
GP Ib body PF-4
receptor HK
Fibrinogen
TS
PGG2/PGH2 TXA2
PAI-1

Fibrinogen

Platelet FIGURE 21-3. Vascular injury and

TXA2
Heparan sulfate thrombosis. (ADP, adenosine diphos-
phate; CO, cyclooxygenase; GP Ib, glyco-
GP IIb/IIIa protein Ib; GP IIb/IIa, glycoprotein IIb/IIa;
Thrombomodulin receptor
complex HK, high-molecular-weight kininogen; PAF,
platelet-activating factor; PAI-1, plasmino-
gen activator inhibitor; PF-4, platelet factor-
4; PGG/PGH, prostaglandins; PGI, prosta-
cyclin; PLA, phospholipase A; TS, throm-
boxane synthetase; TXA2, thromboxane
A2; t-PA, tissue plasmogen activator; u-PA,
urokinase plasmogen activator; vWF, von
Willebrand factor.)

Because radiographic contrast studies are the most accurate and scanning, and D-dimer.1,9 Simple assessment checklists can be used to
reliable methods for the diagnosis of VTE, they are considered the determine if a patient has a high, moderate, or low probability of a
gold standards in clinical trials.9 Contrast venography allows visual- DVT or PE (Table 21–5). Patients with a high pretest probability of
ization of the entire venous system in the lower extremity and VTE have a greater than 60% chance of having VTE, compared with
abdomen. Pulmonary angiography allows the visualization of the only 5% for the low pretest probability group. Clinical assessment can
pulmonary arteries. The diagnosis of VTE can be made if there is a rule in or out the diagnosis of VTE with reasonable certainty when the
persistent intraluminal filling defect observed on multiple radio- results are consistent with those of a noninvasive test.9 For example,
graphic films. Contrast studies are expensive, invasive procedures in patients with a high or moderate pretest probability of VTE and an
that are technically difficult to perform and evaluate. Severely ill abnormal lower-extremity ultrasonogram, the diagnosis of VTE can
patients often are unable to tolerate the procedure, and many be reasonably concluded. In patients with a low pretest probability of
develop hypotension and cardiac arrhythmias. Furthermore, the VTE and a negative D-dimer test, the diagnosis of VTE can be
contrast medium is irritating to vessel walls and toxic to the kidneys. excluded. However, if the results of the clinical assessment and the
For these reasons, noninvasive tests, such as ultrasonography, com- ultrasonogram are discordant, venography should be performed to
puted tomography scans, and the ventilation–perfusion scan, are make the definitive diagnosis.
frequently used in clinical practice for the initial evaluation of
patients with suspected VTE.1
D-dimer is a simple blood test frequently used in the diagnostic PHARMACOLOGIC AGENTS USED
evaluation of patients suspected to have VTE.9 D-dimer is a degra- IN THE MANAGEMENT OF
dation product of a fibrin blood clot and levels of D-dimer are VENOUS THROMBOEMBOLISM
significantly elevated in patients with acute thrombosis. Although
the D-dimer test is a very sensitive marker of clot formation, it is not UNFRACTIONATED HEPARIN
sufficiently specific. A variety of conditions can cause elevations of
serum D-dimer, including recent surgery or trauma, pregnancy, and Unfractionated heparin (UFH) has been used for the prevention
cancer. Therefore, a negative test can help to “rule out” a DVT or PE and treatment of thrombosis for decades. Commercially available
but a positive test should not be used to “rule in” the diagnosis. UFH preparations are derived from bovine lung or porcine intesti-
Clinical assessment significantly improves the diagnostic accuracy nal mucosa. Although some differences exist between the two
of noninvasive tests such as ultrasonography, ventilation–perfusion sources, no differences in antithrombotic activity have been demon-
 336

Intrinsic Extrinsic
SECTION 2

Pathway Pathway

Contact with (-) (Proconvertin) Vascular

charged surface XIIf Injury
VII
XII XIIa
Cardiovascular Disorders

(Hageman Factor) Tissue

Platelets Factor
T VIIa
XII XIa F +
(Plasma Thromboplastin P Tissue
Antecedent) I Factor

IX
(Christmas Factor)
IXa
+ TFPI
VIII VIIIa
(Antihemophiliac Factor)

AT

Common
Pathway X Xa
(Stuart-Prower Factor) +
Va V
HCII
AT (Fibrin
AT Stabilizing
Factor)
Prothrombin Thrombin XIII
(II) (IIa)
HCII HCII
AT AT

Fibrinogen Fibrin
(I) (Ia)
XIIIa

Stabilized Fibrin Clot

(polymers)
FIGURE 21-4. Coagulation cascade. (AT, antithrombin; HCII, heparin cofactor II; TFPI, tissue factor pathway inhibitor.)

strated. Today, UFH and the low-molecular-weight heparins 15,000 daltons. The anticoagulant profile and clearance of each
(LMWHs) are the most commonly used therapies for the acute UFH molecule varies based on its length. The smaller chains are
treatment of arterial and venous thrombosis.22 cleared less rapidly than their longer counterparts.22
The anticoagulant effect of UFH is mediated through a specific
pentasaccharide sequence on the heparin molecule that binds to
Pharmacology antithrombin, provoking a conformational change (Fig. 21–5).
Unfractionated heparin is a heterogeneous mixture of sulfated Only one-third of the UFH molecules possess the unique pentasac-
glycosaminoglycans of variable lengths and pharmacologic proper- charide sequence with affinity for antithrombin. The UFH–anti-
ties (Table 21–6). Each heparin molecule is composed of repetitive thrombin complex is 100 to 1,000 times more potent as an
units of D-glycosamine and uronic acid. The molecular weight of anticoagulant compared to antithrombin alone. Antithrombin
UFH molecules ranges from 3,000 to 30,000 daltons, with a mean of inhibits the activity of several clotting factors including IXa, Xa,
 337

TABLE 21-2 Factors Regulating Hemostasis and Thrombosi TABLE 21-4 Clinical Presentation of Pulmonary Embolism

CHAPTER 21
Thrombogenic Antithrombotic General
Pulmonary embolism (PE) most commonly develops in patients with risk factors
Vessel wall Exposed subendothelium Heparan sulfate
for venous thromboembolism (see Table 21–2) during or following a
Tissue factor Dermatan sulfate
hospitalization. Although many patients develop a symptomatic deep vein
Plasminogen activator Thrombomodulin
thrombosis prior to developing a PE, many do not. Patients may die suddenly
inhibitor-1 Tissue plasminogen activator
before effective treatment can be initiated.
Urokinase Plasminogen Activator
Symptoms
Circulating Platelets Antithrombin
The patient may complain of cough, chest pain, chest tightness, shortness of
elements Platelet activating factor Heparin cofactor II
breath, or palpitation. The patient may spit or cough up blood (hemoptysis).
The clotting factors Protein C

Venous Thromboembolism
When PE is massive, the patient may complain of dizziness or lightheadedness.
Prothrombin (factor II) Protein S
Symptoms may be confused for a myocardial infarction, requiring objective
Fibrinogen (factor I) Plasminogen
testing to establish the diagnosis.
von Willebrand factor Tissue factor pathway inhibitor
Signs
α2-Antiplasmin Proteolytic enzymes
The patient may have tachypnea (increased respiratory rate) and tachycardia
Blood flow Slow rate of flow Fast rate of flow
(increased heart rate). The patient may appear diaphoretic (sweaty). The
Turbulent flow Laminar flow
patient’s neck veins may be distended. In massive PE, the patient may appear
cyanotic and may become hypotensive. In such cases, oxygen saturation by
pulse oximetry or arterial blood gas will likely indicate that the patient is
XIIa, and thrombin (see Fig. 21–4). Through its action on throm- hypoxic. In the worse cases, the patient may go into circulatory shock and die
bin, the UFH–antithrombin complex also inhibits the thrombin- within minutes.
Laboratory tests
induced activation of factors V and VIII.22 Unfractionated heparin
Serum concentrations of D-dimer, a byproduct of thrombin generation, is usually
prevents the growth and propagation of a formed thrombus and
elevated.
allows the patient’s own thrombolytic system to degrade the clot. The patient may have an elevated erythrocyte sedimentation rate and white
Factors IIa (thrombin) and Xa are the most sensitive to inhibition blood cell count.
by the UFH–antithrombin complex. To inactivate thrombin, the Diagnostic tests
heparin molecule must form a ternary complex bridging between Ventilation–perfusion (V/Q) and computerized tomography (CT) scans are the
antithrombin and thrombin (see Fig. 21–5). Only molecules that most commonly used tests to diagnosis PE. A V/Q scan measures the distribution
contain more than 18 saccharides are able to bind to both antithrom- of blood and air flow in the lungs. When there is a large mismatch between
bin and thrombin simultaneously. Smaller heparin molecules cannot blood and air flow in one area of the lung, there is a high probability that the
facilitate the interaction between antithrombin and thrombin. In patient has a PE. Spiral CT scans can detect emboli in the pulmonary arteries.
contrast, the inactivation of factor Xa does not require UFH to form Pulmonary angiography is the gold standard for the diagnosis of PE. However, it
is an invasive test that involves injection of radiopaque contrast dye into the
a bridge with antithrombin. It only requires that UFH bind to
pulmonary artery. The test is expensive and associated with a significant risk of
antithrombin using the specific pentasaccharide sequence. Heparin mortality.
molecules with as few as 5 saccharide units are able to catalyze the

TABLE 21-5 Clinical Assessment Models for Deep Vein

TABLE 21-3 Clinical Presentation of Deep Vein Thrombosis Thrombosis and Pulmonary Embolism
Pretest Probability of Deep Vein Thrombosis
General
Venous thromboembolism most commonly develops in patients with identifi- Clinical feature Score
able risk factors (see Table 21–2) during or following a hospitalization. Many, Tenderness along entire deep vein system 1.0
perhaps the majority, of patients have asymptomatic disease. Patients may die Swelling of the entire leg 1.0
suddenly of pulmonary embolism. Greater than 3 cm difference in calf circumference 1.0
Symptoms
Pitting edema 1.0
The patient may complain of leg swelling, pain, or warmth. Symptoms are Collateral superficial veins 1.0
nonspecific and objective testing must be performed to establish the diagnosis.
Risk factors present:
Signs
Active cancer 1.0
The patient’s superficial veins may be dilated and a “palpable cord” may be felt
Prolonged immobility or paralysis 1.0
in the affected leg.
Recent surgery or major medical illness 1.0
The patient may experience pain in back of the knee when the examiner
Alternative diagnosis likely (ruptured Baker cyst, rheumatoid arthritis, –2.0
dorsiflexes the foot of the affected leg (known as Homans sign).
superficial thrombophlebitis, or infective cellulitis)
Laboratory tests
Serum concentrations of D-dimer, a byproduct of thrombin generation, is usually Score ≥3 = high probability; 1–2 = moderate probability; ≤0 = low probability
elevated. Pretest Probability of Pulmonary Embolism
The patient may have an elevated erythrocyte sedimentation rate and white
blood cell count. Clinical feature Score
Diagnostic tests Deep vein thrombosis suspected
Duplex ultrasonography is the most commonly used test to diagnosis deep vein Clinical features of deep vein thrombosis 3.0
thrombosis. It is a noninvasive test that can measure the rate and direction of Recent prolonged immobility or surgery 1.5
blood flow and visualize clot formation in proximal veins of the legs. It cannot Active cancer 1.0
reliably detect small blood clots in distal veins. Coupled with a careful clinical History of deep vein thrombosis or pulmonary embolism 1.5
assessment, it can rule in or out the diagnosis in the majority of cases. Hemoptysis 1.0
Venography (also known as phlebography) is the gold standard for the diagnosis Resting heart rate >100 beats/min 1.5
of deep vein thrombosis. However, it is an invasive test that involves injection No alternative explanation for acute shortness of breath or chest pain 3.0
of radiopaque contrast dye into a foot vein. It is expensive and can cause
anaphylaxis and nephrotoxicity. Score ≥6 = high probability; 2–6 = moderate probability; ≤1.5 = low probability
From Wells et al.9
 338

TABLE 21-6 Comparison of the Chemical and Pharmacokinetic Properties of Antithrombotic Drugs Used for Venous Thrombosis
SECTION 2

Mean
Molecular Anti-Xa:
Weight Plasma Anti-IIa
Agent FDA-Approved Method of Preparation (Daltons) Half-Life Activity Bioavailability
Unfractionated heparin Yes Extracted from porcine gut ≈15,000 30–90 min (dose 1:1 SC: 30–70% (dose
mucosa or beef lung dependent) dependent)
Low molecular weight heparins
Ardeparin (Normiflo) Yes (no longer marketed in U.S.) Peroxidative depolymerization ≈6,000 200 min 1.9:1 SC: 90%
Dalteparin (Fragmin) Yes Nitrous acid depolymerization ≈6,000 119–139 min 2.7:1 SC: 87%
Cardiovascular Disorders

Enoxaparin (Lovenox) Yes Benzoylation and alkaline ≈4,200 129–180 min 3.8:1 SC: 92%
depolymerization
Nadroparin (Fraxiparine) No (Available in Canada and Nitrous acid depolymerization ≈4,500 132–162 min 3.6:1 SC: 99%
Mexico)
Tinzaparin (Innohep) Yes Heparinase digestion ≈4,500 111–234 min 2.8:1 SC: 90%
Heparinoid
Danaparoid (Orgaran) Yes (no longer marketed in Extracted from porcine gut ≈6,500 22–24 h 20:1 SC: 95%
U.S.) mucosa
Anti–factor Xa inhibitors
Fondaparinux (Arixtra) Yes Synthetic 1,728 15–18 h 100% anti-Xa SC: 100%
Idraparinux (SanOrg 34006) No Synthetic ≈1,700 ≈80 h 100% anti-Xa SC: 100%
Direct thrombin inhibitors
Argatroban (Argatroban) Yes Synthetic 509 30–50 min 100% anti-IIa
Bivalirudin (Angiomax) Yes Semisynthetic 2,180 25 min 100% anti-IIa
Desirudin (Iprivask) Yes Recombinant DNA technology 6,964 120 min 100% anti-IIa SC: >90%
Lepirudin (Refludan) Yes Recombinant DNA technology 6,980 80 min 100% anti-IIa SC: 70%
Dabigatran No Synthetic 471 14 h 100% anti-IIa Oral: 7%
Vitamin K antagonists
Warfarin (Coumadin) Yes Synthetic 330 40 h 1:1 Oral: 90–100%
SC, subcutaneous.
From Haines and Bussey and Nutescu et al.19,46

Unfractionated heparin (Xa:IIa 1:1)

Thrombin (IIa)
Pentasaccharide Thrombin (IIa) Ternary
complex

Conformational change
Factor Xa Factor Xa
Antithrombin

Low-molecular-weight heparin (Xa:IIa 3-4:1)

Most LMWH
Thrombin (IIa) chains too short
Pentasaccharide to form ternary
Thrombin (IIa) complex

Conformational change
Factor Xa Factor Xa
Antithrombin

Fondaparinux (100% Xa)

Pentasaccharide

Antithrombin 
Factor Xa Factor Xa

Conformational change

FIGURE 21-5. Pharmacologic activity of unfractionated heparin, low-molecular-weight heparins (LMWHs), and fondaparinux.
 339
inhibition of factor Xa. Heparin uncouples from antithrombin after TABLE 21-7 Weight-Baseda Dosing for Unfractionated Heparin
it has produced its effect and quickly recouples with another anti-

CHAPTER 21
Administered by Continuous Intravenous Infusion
thrombin molecule. Because of its relatively large size, the UFH–
Initial Loading Initial Infusion
antithrombin complex is incapable of inactivating thrombin or
Indication Dose Rate
factor Xa within a formed clot or bound to surfaces. At high doses,
UFH also binds to heparin cofactor II, further inhibiting the activity Deep venous thrombosis/pulmonary 80–100 units/kg 17–20 units/kg/h
of thrombin. UFH increases the release of tissue factor pathway embolism
Maximum = Maximum =
inhibitor from vascular endothelium, augmenting its inhibitory
10,000 units 2,300 units/h
effect on factor Xa. UFH, especially high-molecular-weight heparin
fractions, also binds to platelets and inhibits platelet aggregation.22 Maintenance Infusion Rate
Activated Partial Thromboplastin

Venous Thromboembolism
Time (seconds) Dose adjustment
Pharmacokinetics <37 (or >12 s below institution-specific 80 units/kg bolus then increase infu-
Unfractionated heparin is not reliably absorbed when taken orally therapeutic range) sion by 4 units/kg/h
as a result of its large molecular size and anionic structure. The 37–47 (or 1–12 s below institution- 40 units/kg bolus then increase infu-
specific therapeutic range) sion by 2 units/kg/h
bioavailability and biologic activity of UFH is limited by its propen-
48–71 (within institution-specific thera- No change
sity to bind to plasma proteins, platelet factor-4 (PF-4), macro-
peutic range)
phages, fibrinogen, lipoproteins, and endothelial cells.22 This may 72–93 (or 1–22 s above institution- Decrease infusion by 2 units/kg/h
explain the substantial inter- and intrapatient variability observed in specific therapeutic range)
the anticoagulation response to UFH.22 >93 (or >22 s above institution-specific Hold infusion for 1 h then decrease by
The subcutaneous bioavailability of UFH is dose dependent and therapeutic range) 3 units/kg/h
ranges from 30% at low doses to as much as 70% at high doses. a
Use actual body weight for all calculations. Adjusted body weight may be used for obese patients
Higher doses presumably saturate protein-binding sites, thereby (>130% of ideal body weight).
permitting a larger proportion to reach the systemic circulation. From Hirsh and Raschke.22
The onset of anticoagulant effect is usually evident 1 to 2 hours after
subcutaneous injection and peaks at 3 hours.22 When UFH is
administered via the IV route, a continuous infusion is preferable. Therapeutic Monitoring
Intermittent IV boluses produce relatively high peaks in anticoagu-
 Administration of UFH has traditionally required close monitor-
lation activity and have been associated with a greater risk of major
ing because of the unpredictable anticoagulant patient response.22
bleeding.22 Intramuscular administration is discouraged because of
Several tests are available to monitor UFH therapy including whole
erratic absorption and risk of large hematoma formation.
blood clotting time, activated partial thromboplastin time (aPTT),
Unfractionated heparin has a dose-dependent half-life of approx-
activated clotting time (ACT), antifactor Xa activity, and plasma
imately 30 to 90 minutes, but may be prolonged to as much as 150
heparin concentrations. The aPTT is the most widely used test to
minutes when given in high doses to some patients. There are two
determine the degree of anticoagulation. The therapeutic range of
primary mechanisms for the elimination of UFH. The relative
aPTT has traditionally been considered to be 1.5 to 2.5 times the
contribution of each mechanism to the total clearance of heparin is
mean normal control value.22 Many currently available aPTT reagents
related to the dose and size of the UFH molecules. One mechanism
do not accurately measure the response to heparin within this fixed
is a rapid, but saturable zero-order process. Heparinases and des-
therapeutic range; thus, the use of a fixed aPTT therapeutic range of
ulfatases enzymatically inactivate heparin molecules bound to
1.5 to 2.5 times the control represents a subtherapeutic dose of UFH
endothelial cells and macrophages, reducing them to smaller and
in many instances.22 Because of substantial interlaboratory variability
less-sulfated molecules. Heparin is also eliminated renally. This
in the aPTT, an institution-specific aPTT therapeutic range that
first-order process is slower and nonsaturable. Low doses of UFH
correlates with a plasma heparin concentration of 0.3 to 0.7 units/mL
are cleared principally by the saturable, rapid, zero-order mecha-
by an amidolytic antifactor Xa assay should be established.22
nism, whereas the renal route predominates at very high doses.
Although most experts advocate using the aPTT to monitor UFH
With typical therapeutic regimens, a combination of the two mech-
provided that institution-specific therapeutic ranges are defined, the
anisms are used to eliminate UFH with the saturable mechanism
use of aPTT has several limitations. First, preanalytical variables
predominating. Renal and hepatic dysfunction reduces the rate of
such as reagent sensitivity, temperature, phlebotomy methods, and
clearance of UFH. Patients with active thrombosis may eliminate
hemodilution may result in aPTT results that do not correlate with
UFH more rapidly, possibly because of increased binding to acute
the in vivo level of heparin anticoagulation present.22 Second, the
phase reactants.22
aPTT response exhibits diurnal variation, with a peak response
occurring around 3 AM during continuous IV infusion. Adjusting
Dose and Administration infusion rates in response to this diurnal variation could lead to
The dose and route of administration for UFH are based on the subsequent over- or underdosing.24 Third, the aPTT is prolonged
indication, the therapeutic goals, and the patient’s individual beyond measurable limits when the heparin concentration exceeds
response to therapy. The dose of UFH is expressed in units of 1 unit/mL; consequently, the aPTT is unsuitable for monitoring
activity. The number of units per milligram is variable and heparin therapy in patients who require doses of heparin that will
depends on the manufacturing process. For the prevention of VTE, produce serum concentrations >1 unit/mL. The ACT is the most
UFH is given by subcutaneous injection in the abdominal fat layer suitable assay when high doses of heparin are used, especially during
over the iliac crest. The typical dose for prophylaxis is 5,000 units coronary angioplasty or coronary bypass surgery.25 Fourth, the
every 8 to 12 hours. When immediate and full anticoagulation is lower-weight heparin fragments accumulate but have little effect on
required, a weight-based IV bolus dose followed by a continuous the aPTT in vivo.22 Lastly, the data supporting the currently recom-
infusion is preferred (Table 21–7).22 Subcutaneous UFH (initial mended heparin concentration therapeutic range is not derived
dose of 333 units/kg followed by 250 units/kg every 12 hours) also from scientifically rigorous research.
provides adequate therapeutic anticoagulation for the treatment of The aPTT should be measured prior to the initiation of therapy
acute VTE.23 to determine the patient’s baseline. When administered by IV
 340

TABLE 21-8 Risk Factors for Major Bleeding While Taking TABLE 21-9 Contraindications to Anticoagulation Therapy
Anticoagulation Therapy
SECTION 2

General
Anticoagulation intensity (e.g., international normalized ratio >4.0) Active bleeding
Initiation of therapy (first few days and weeks) Hemophilia or other hemorrhagic tendencies
Unstable anticoagulation response Severe liver disease with elevated baseline PT
Age >65 years Severe thrombocytopenia (platelet count <20,000)
Concurrent antiplatelet drug use Malignant hypertension
Concurrent nonsteroidal antiinflammatory drug use Inability to meticulously supervise and monitor treatment
History of gastrointestinal bleeding Product-specific contraindications
Recent surgery or trauma Argatroban
Cardiovascular Disorders

High risk for fall/trauma Hypersensitivity to argatroban

Heavy alcohol use Bivalirudin
Renal failure Hypersensitivity to bivalirubin
Cerebrovascular disease Fondaparinux
Malignancy Hypersensitivity to fondaparinux
Severe renal insufficiency (creatinine clearance <30 mL/min)
Data from Levine MN, Raskob G, Beyth RJ, et al. Hemorrhagic complications of anticoagulant
Body weight <50 kg
treatment: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
2004;126:287S–310S.
Bacterial endocarditis
Thrombocytopenia with a positive in vitro test for anti-platelet antibodies in
the presence of fondaparinux
infusion, the response to therapy should be measured 6 hours after Lepirudin
the initiation of therapy or a dose change. This is usually sufficient Hypersensitivity to hirudins
time for heparin to reach steady state. The dose of heparin should LMWHs
be promptly adjusted based on the patient’s response and the Hypersensitivity to LMWH, UFH, pork products, methylparaben, or propylpa-
institution-specific therapeutic range (see Table 21–7).22 raben
History of HIT or suspected HIT
Some patients with acute VTE and myocardial infarction have a
UFH
diminished response to UFH (so-called heparin resistance), presum-
Hypersensitivity to UFH
ably because of variations in the plasma concentrations of heparin- History of HIT
binding proteins. Some patients are reported to have acute elevations Warfarin
in factor VIII, preventing the prolongation of the aPTT by UFH. In Hypersensitivity to warfarin
some cases, antithrombin deficiency might be the culprit. The possi- Pregnancy
bility of this phenomenon should be suspected in patients who History of warfarin-induced skin necrosis
require more than 40,000 units of UFH per 24-hour period. The Inability to obtain followup PT/INR measurements
recommended management of patients with “heparin resistance” is Inappropriate medication use or lifestyle behaviors
to adjust the UFH dose based on antifactor Xa concentrations.22 HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; LMWH, low-molecular-
weight heparin; PT, prothrombin time; UFH, unfractionated heparin.
Adverse Effects
appreciable decline in their platelet count. Two distinct clinical
 Bleeding is the primary adverse effect associated with all anticoag-
presentations for thrombocytopenia can occur during heparin ther-
ulant drugs (Table 21–8).4 There is not solid evidence linking
apy. Heparin-associated thrombocytopenia (HAT) is a benign,
supratherapeutic aPTT values and the risk for bleeding in patients
transient, and mild phenomena, generally occurring within the first
receiving UFH. The risk for bleeding is more closely related to
few days of treatment in the heparin-naive patient. Platelet counts
underlying risk factors than to high aPTT values.24 Therefore, UFH
rarely drop below 100,000 in patients with HAT, and recover with
should not be administered to patients with contraindications to
continued therapy. Conversely, heparin-induced thrombocytopenia
anticoagulation therapy (Table 21–9). Low-dose subcutaneous UFH
(HIT) is a serious drug-induced problem requiring immediate
is associated with a minimal risk of major bleeding. The rates of
intervention (see Heparin-Induced Thrombocytopenia below). A
major bleeding for patients with VTE receiving full therapeutic doses
baseline platelet count should be obtained before UFH therapy is
of UFH via IV infusion for 5 to 10 days range from 2% to 4% and the
initiated. If the patient has received UFH within the previous 100
rate of fatal bleeding ranges from approximately 0% to 2%.4 The
days, or if previous UFH exposure is uncertain, a repeat platelet
presence of concomitant bleeding risks such as thrombocytopenia,
count should be performed within 24 hours.26 Monitoring platelet
the use other antithrombotic therapy, and a preexisting source of
counts every other day for 14 days or until UFH therapy is stopped,
bleeding increase the risk of UFH-induced hemorrhage. The risk of
whichever occurs first, is recommended for patients who are receiv-
bleeding also increases with age. Recent surgery, hemostatic defects,
ing therapeutic doses of UFH.26
heavy alcohol consumption, renal failure, peptic ulcers, and neo-
Long-term UFH has been reported to cause alopecia, priapism,
plasms also increase the risk of major bleeding while receiving UFH.4
and suppressed aldosterone synthesis with subsequent hyperkale-
Anatomic sites commonly associated with UFH-related bleeding
mia. The use of UFH in doses ≥20,000 units/day for more than 6
include the gastrointestinal and urinary tracts, as well as soft tissues.
months, especially during pregnancy, is associated with significant
Minor bleeding, such as epistaxis, gingival bleeding, and prolonged
bone loss and may lead to osteoporosis.24 Few drug interactions are
bleeding from cuts and scrapes, is frequently reported. Bruising
reported with UFH. Concurrent use with other antithrombotic
from minor trauma and at the sites of subcutaneous injections and
drugs, thrombolytics, and antiplatelet agents increases the risk of
venous access is also common. Local irritation, mild pain, erythema,
bleeding, however.
histamine-like reactions, and hematoma can occur during UFH
administration. Even small amounts of bleeding into critical sites
such as the central nervous system (CNS) or the structures of the eye
Management of Bleeding and
can cause catastrophic consequences.
Excessive Anticoagulation
Thrombocytopenia, defined as a platelet count less than 150,000, Hemorrhage can occur at any site in patients receiving UFH and
is common with UFH therapy.26 Up to 30% of patients have some close monitoring for signs and symptoms of bleeding is crucial.4,22
 341
In addition to an appropriate coagulation study to measure the risk for excessive bleeding during delivery. Long-term use of UFH
response to UFH, it is necessary to regularly monitor hemoglobin, during pregnancy may result in bone loss and increased risk for

CHAPTER 21
hematocrit, and blood pressure. Bleeding can produce a wide osteoporosis-related fractures.27 Unfractionated heparin is not
variety of symptoms, depending on the site of hemorrhage. Symp- excreted in breast milk and is considered safe to use by women who
toms can include severe headache, joint pain, chest pain, abdominal are breast-feeding.27
pain, swelling, tarry stools, frank hematuria, or the passage of bright Advances in tertiary care for pediatric patients have resulted in
red blood through the rectum. Life-threatening bleeding, either as a increasing numbers of children requiring antithrombotic therapy,
consequence of a significant volume loss or because of the location and UFH is commonly used in this setting.28 For the treatment of
(e.g., bleeding into a critical space), must be recognized swiftly and acute thrombosis in children, the dosage of UFH is an initial loading
immediately treated. Critical areas include intracranial, pericardial, dose of 75 to 100 units/kg over 10 minutes followed by a mainte-

Venous Thromboembolism
and intraocular sites, as well as the adrenal glands. nance dose of 28 units/kg/h for infants up to 12 months of age and
When major bleeding occurs, UFH should be immediately discon- 20 units/kg/h for children 1 year old and older.28
tinued and the underlying source of bleeding should be identified and
treated. Intravenous protamine sulfate, given in a dose of 1 mg per
100 units of UFH up to a maximum of 50 mg, can be administered to LOW-MOLECULAR-WEIGHT HEPARINS
reverse the anticoagulant effects of UFH. Protamine sulfate has
Produced by either chemical or enzymatic depolymerization (see
intrinsic anticoagulation activity, but when administered with UFH,
Table 21–6), LMWHs are fragments of UFH. They are heterogeneous
it forms a stable salt that results in the loss of anticoagulation activity
mixtures of sulfated glycosaminoglycans with approximately one-
of both drugs. Protamine sulfate neutralizes UFH in 5 minutes, and
third the molecular weight of UFH. Although all the LMWHs share
its activity persists for 2 hours. It should be given by slow IV infusion
similarities in their mechanisms of action with UFH, their molecular
over 10 minutes.22 In cases of large heparin overdoses or in patients
weight distributions vary, resulting in differences in their activity
with renal failure, a “rebound” effect may occur with a return of some
against factor Xa and thrombin, affinity for plasma proteins, propen-
anticoagulant activity several hours after the administration of prota-
sity to release tissue factor pathway inhibitor, and duration of activ-
mine sulfate. Therefore, the patient’s coagulation status should be
ity.22 The mean molecular weight of the LMWHs is product specific.
closely monitored. Multiple doses of protamine sulfate may be neces-
These agents have several advantages over UFH, including (a) pre-
sary if hemorrhage continues.
dictable anticoagulation dose response, (b) improved subcutaneous
bioavailability, (c) dose-independent clearance, (d) longer biologic
Use in Special Populations half-life, (e) lower incidence of thrombocytopenia, and (f ) a reduced
Heparin-related compounds such as UFH or LMWH are the anti- need for routine laboratory monitoring.22
coagulants of choice during pregnancy.27 Because UFH does not Currently, there are three LMWH products available in the United
cross the placenta, it is not associated with teratogenicity or fetal States. The usefulness of LMWHs has been extensively evaluated for
bleeding complications.27 UFH should be used cautiously during a wide array of indications, including the treatment of acute coro-
the last trimester of pregnancy and the peripartum period because nary syndromes, DVT, and PE, as well as for the prevention of VTE
of the risk of maternal hemorrhage. Induction of labor is advisable in several high-risk populations. The FDA-approved indications and
so that UFH can be discontinued prior to delivery to minimize the doses for the LMWHs are product specific (Table 21–10). The

TABLE 21-10 Indications and Doses for Low-Molecular-Weight Heparins

Indications Enoxaparin Dalteparin Tinzaparin
Hip-replacement surgery 30 mg SC q 12 h initiated 12–24 h after 2,500 units SC given 2 h prior to surgery, followed 75 units/kg SC q 24 h initiated the
(prophylaxis) surgery by 2,500 international units the evening after evening prior to surgery or 12 h
or surgery and at least 6 h after first dose, then 5,000 after surgery
40 mg SC q 24 h initiated 12 h prior to international units SC q 24 ha or
surgerya or 4,500 unit SC q 24 h initiated 12 h
Extended prophylaxis may be given for 5,000 international units SC q 24 h initiated the prior to surgery
up to 3 weeksa evening prior to surgerya
Knee-replacement surgery 30 mg SC q 12 h initiated 12–24 h prior 75 units/kg SC q 24 h initiated the
(prophylaxis) to surgery a evening prior to surgery or 12 h
after surgery
Abdominal surgery (prophylaxis) 40 mg SC q 24 h initiated 2 h prior to 2,500 units SC q 24 h initiated 1–2 h prior to 3,500 unit SC q 24 h initiated 1–2 h
surgery a surgerya prior to surgery
Patients with malignancy: 5,000 units SC the
evening prior surgery then 5,000 units SC q 24 ha
or
2,500 units SC 1–2 h prior to surgery then 2,500
units 12 h after surgery followed by 5,000 units SC
q 24 ha
Acute medical illness (prophylaxis) 40 mg SC q 24 ha 2,500 units SC q 24 h
Trauma (prophylaxis) 30 mg SC q 12 h starting 12–36 h after
injury
Deep vein thrombosis treatment 1 mg/kg SC q 12 ha 100 units/kg SC q 12 h 175 units/kg SC q 24 ha
(with or without pulmonary or or
embolism) 1.5 mg/kg SC q 24 ha 200 units/kg SC q 24 h
Unstable angina or non–Q-wave 1 mg/kg SC q 12 ha 100 units/kg SC q 12 ha (maximum dose 10,000
myocardial infarction units)
a
FDA approved dose for indication.
Data from Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism. ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S–400S.3
 342
LMWHs have largely replaced UFH for the prevention and treat- significant accumulation in these patients. The enoxaparin dose
ment of VTE in some hospitals. However, institutional resources and should be reduced and the dosing interval extended to once daily in
SECTION 2

individual patient needs should determine their precise role in the patients with creatinine clearance <30 mL/min.29 The pharmacokinet-
management of VTE. ics of dalteparin and tinzaparin are less-well characterized in patients
with renal insufficiency, but some studies suggest that there is a lower
Pharmacology degree of accumulation. Data on the use of LMWH in patients with
end-stage renal disease receiving hemodialysis is very limited, thus
The LMWHs prevent the growth and propagation of formed
UFH should be recommended for these patients. Given that few
thrombi. Like UFH, the LMWHs enhance and accelerate the activity
published data are available regarding the use of LMWHs in the
of antithrombin through binding to a specific pentasaccharide
setting of renal insufficiency, some experts recommend measuring
sequence. Fewer than one-third of LMWH molecules contain the
Cardiovascular Disorders

antifactor Xa activity if therapy is continued for more than a few days.

specific sequence necessary to interact with antithrombin. The prin-
For the prevention of VTE, the LMWHs have been studied in a
cipal difference in the pharmacologic activity of the LMWHs and
variety of high-risk circumstances, including orthopedic surgery,
UFH is their relative inhibition of factor Xa and thrombin. Because
abdominal surgery, acute spinal cord injury, neurosurgery, multiple
of their smaller chain length, the LMWHs have limited activity
trauma, and critical illness.3 The effectiveness of the LMWHs has
against thrombin (see Fig. 21–6). Fewer than 50% of the LMWH
been extensively evaluated for the treatment of VTE in hospitalized
molecules have the requisite chain length to simultaneously bind
patients and used in the outpatient management of DVT.2 They are
antithrombin and thrombin. For this reason, the LMWHs have
also a reasonable alternative to warfarin therapy in circumstances
proportionally greater antifactor Xa activity. The ratio of antifactor
when a prothrombin time (PT)/international normalized ratio
Xa-to-IIa activity varies between 5.3:1 and 1.9:1. By comparison,
(INR) can not be routinely obtained.
UFH has an antifactor Xa-to-IIa activity ratio of 1:1. Like UFH, the
LMWHs cause the endothelium to release tissue factor pathway
inhibitor, which is believed to enhance the inhibition of factor Xa Therapeutic Monitoring
and to inactivate factor VIIa.22 Because the LMWHs achieve predictable anticoagulant response
when given subcutaneously, routine laboratory monitoring is unnec-
Pharmacokinetics essary to guide the dosing of these agents. The PT, the ACT, and the
Compared with UFH, the LMWHs have a more predictable antico- aPTT are minimally affected by LMWHs.22 Prior to initiation of
agulation response. The improved pharmacokinetic profile of LMWH, a baseline PT/INR, aPTT, complete blood cell count with
LMWHs is the result of reduced binding to proteins and cells.22 The platelet count, and serum creatinine should be obtained. Most experts
bioavailability of LMWHs approaches 100% when administered recommend monitoring the complete blood cell count every 5 to 10
subcutaneously, whereas the absorption of UFH is relatively poor days during the first 2 weeks of LMWH therapy and every 2 to 4 weeks
and erratic. The subcutaneous bioavailability of the available thereafter.
LMWH products differs only slightly. The peak anticoagulation Although several methods to monitor LMWHs have been
effect is seen in 3 to 5 hours.22 explored, measurement of antifactor Xa activity has been the most
The renal route is the predominant mode of elimination for the widely used method in clinical practice. Routine antifactor Xa
LMWHs. Consequently, their biologic half-life may be prolonged in activity measurement is unnecessary in patients whose condition is
patients with renal impairment. Longer heparin chains bind to stable and uncomplicated.22 Although very limited data support the
macrophages and are rapidly degraded. Therefore, antifactor Xa use of laboratory monitoring to guide LMWH therapy, measuring
activity, which is mediated by smaller heparin molecules, persists antifactor Xa activity may be helpful in patients who have significant
longer than antithrombin activity. The plasma half-life of the renal impairment (e.g., creatinine clearance <30 mL/min), weigh less
LMWH preparations is two to four times longer than UFH. The than 50 kg, are morbidly obese, or require prolonged therapy (e.g.,
clearance of LMWHs is independent of dose.22 longer than 14 days). Periodic antifactor Xa activity monitoring may
also be useful in women treated with a LMWH during pregnancy
Dosing and Administration because of changing pharmacokinetic variables (e.g., volume of
distribution and renal function).27 Patients who are at very high risk
The LMWHs are given in fixed or weight-based doses based on the of bleeding or thrombotic recurrence may also benefit from antifac-
product and indication (see Table 21–10).22 Doses should be based on tor Xa monitoring to avoid periods of over- or underanticoagula-
actual body weight and studies in obese patients indicate that full tion. Because newborns and pediatric patients have unpredictable
weight-based doses do not lead to elevated LMWH concentrations pharmacokinetic profiles, they may require monitoring to ensure
when compared with normal subjects; consequently, capping of the adequate therapy.
dose is not recommended.24 The dose for enoxaparin is expressed in When antifactor Xa activity is used to monitor LMWH therapy,
milligrams, whereas dalteparin and tinzaparin are expressed in units the sample should be drawn after steady state has been achieved
of antifactor Xa activity. Although they can be given by continuous (after the second or third dose) and approximately 4 hours after the
intravenous infusion, the LMWHs are generally given by subcutane- subcutaneous injection, during the peak period of antifactor Xa
ous injection in the abdominal area or the upper outer part of the activity.22 A calibrated LMWH heparin should be used to establish
thigh while the patient is in a supine position. The clinician or patient the standard curve for the assay. The therapeutic range for antifac-
pinches a layer of skin between the thumb and forefinger, and then tor Xa activity is not well defined and as of this writing has not been
introduces the entire length of the needle into a skin fold at a 90° clearly correlated with efficacy or the risk of bleeding.30 For the
angle. Injection sites should be alternated between right and left sides. treatment of VTE, an acceptable target range for the peak level is 0.5
Following subcutaneous administration, the drug is absorbed slowly, to 1.0 units/mL and for the prevention of VTE an acceptable target
resulting in sustained antithrombotic activity over several hours. range for the peak level is 0.2 to 0.4 units/mL.
The dosing interval for the LMWHs is every 12 or 24 hours
depending on the indication and product. Larger doses are given once
daily and produce significantly higher peak plasma concentrations.
Adverse Effects
Given that the elimination half-life of the LMWHs is prolonged in As with UFH, bleeding is the most common adverse effect of the
patients with severe renal impairment, high doses may lead to a LMWHs.4 Although not consistently demonstrated in clinical trials,
 343
the frequency of major bleeding is purported to be less with the data are available, it is prudent to periodically monitor antifactor Xa
LMWHs than with UFH.22 This difference may be partly a result of activity in these special populations during long-term use.

CHAPTER 21
their reduced effects on platelet function, endothelial cells, and
microvascular permeability. The incidence of major bleeding FONDAPARINUX
reported in clinical trials is less than 3% and varies among the
LMWH preparations, their indication for use, patient population, Pharmacology
and dose administered. Minor bleeding, particularly at the site of
Fondaparinux, also known as pentasaccharide, is a synthetic mole-
injection, occurs frequently with LMWH use. Several cases of
cule consisting of the five critical saccharide units that bind specifi-
epidural and spinal hematoma resulting in long-term or permanent
cally, but reversibly, to antithrombin (see Fig. 21–5).19 Fondaparinux
paralysis have been reported with the use of enoxaparin during
is the first in a class of anticoagulants that selectively inhibits factor

Venous Thromboembolism
spinal and epidural anesthesia or spinal puncture.29 The risk of these
Xa activity.31 Similar to UFH and the LMWHs, fondaparinux pre-
events is higher with the use of indwelling epidural catheters and
vents thrombus generation and clot formation by indirectly inhibit-
concomitant use of drugs that affect hemostasis. Epidural catheters
ing factor Xa activity through its interaction with antithrombin.
should be removed only after a minimum of 12 hours has elapsed
When fondaparinux binds to antithrombin it causes a permanent
after the last dose of the LMWH, and any subsequent dose should
conformational change in antithrombin’s active site and catalyzes
be given at least 2 hours later.
antifactor Xa activity by about 300-fold. Fondaparinux is not
Although there is no proven method for reversing LMWH, if
destroyed during this process and is released to bind many other
major bleeding does occur in a patient receiving an LMWH, it is
antithrombin molecules.31 Unlike UFH and LMWH, fondaparinux
recommended that IV protamine sulfate be administered.22 How-
has no direct effect on thrombin activity at therapeutic plasma
ever, because of its limited binding to the shorter LMWH chains,
concentrations.19 Selective inhibition of factor Xa may provide more
protamine sulfate cannot completely neutralize the anticoagulant
efficient control over fibrin generation while preserving thrombin’s
effects of LMWH. When given in equimolar concentrations, prota-
regulatory functions in the control of hemostasis. Fondaparinux has
mine sulfate neutralizes an estimated 60% to 75% of the antithrom-
no known effect on platelet function.19
botic activity of LMWH. The recommended dose of protamine
sulfate is 1 mg/1 mg of enoxaparin or 1 mg/100 antifactor Xa units
Pharmacokinetics
of dalteparin or tinzaparin administered in the previous 8 hours. If
the LMWH dose was given in the previous 8 to 12 hours, a 0.5-mg Fondaparinux is rapidly and completely absorbed following subcu-
dose of protamine should be given for every 100 antifactor Xa units. taneous administration (absolute bioavailability 100%). Peak plasma
The use of protamine sulfate is not recommended if the LMWH was concentrations are achieved in approximately 2 hours after a single
administered more than 12 hours earlier.22 dose and 3 hours with repeated once-daily dosing. It is distributed
Although thrombocytopenia can occur with the use of a LMWH, primarily in blood. At therapeutic concentrations, fondaparinux is
the incidence of HIT is substantially lower than that observed with highly and specifically bound to antithrombin.31 It does not bind to
the use of UFH.22,26 The explanation may lie in the reduced red blood cells or other plasma proteins including albumin, glyco-
propensity of the LMWHs to bind to platelets and PF-4. Because the protein, platelets, or PF-4.19 Fondaparinux is primarily eliminated
LMWHs exhibit nearly 100% cross-reactivity with heparin antibod- unchanged in the urine. It is contraindicated in patients with severe
ies in vitro, the LMWHs should be avoided in patients with an renal function impairment (creatinine clearance <30 mL/min)
established diagnosis or history of HIT.26 Platelet counts must be because of an increased risk for bleeding. The terminal elimination
periodically monitored in all patients who are receiving a LMWH, half-life is 17 to 21 hours and is independent of the patient’s age or
and thrombocytopenia of any degree should be promptly evaluated. sex.32 The anticoagulant effect of fondaparinux persists for 2 to 4
The risk of osteoporosis appears to be substantially lower with the days following discontinuation of the drug in patients with normal
LMWHs than with UFH. The LMWHs have not caused appreciable renal function. Fondaparinux has no known pharmacokinetic drug
changes in bone mineral density after several months of use.27 They interactions. However, concurrent use with other antithrombotic
have been used in a limited number of patients with established agents increases the risk of hemorrhage.
heparin-induced osteoporosis. Although these reports are promis-
ing, it cannot be concluded that the LMWHs have no effect on bone Dose and Administration
formation until well-designed clinical trials are available.
Fondaparinux is FDA-approved for the prevention of VTE follow-
ing orthopedic (hip fracture, hip replacement, and knee replace-
Use in Special Populations ment) surgery and for the treatment of DVT and PE.32 In the setting
There is growing experience with the use of LMWHs during preg- of VTE prevention, the dose of fondaparinux is 2.5 mg injected
nancy.27 The LMWHs do not cross the placenta. According to the subcutaneously once daily starting 6 to 8 hours following surgery. It
results of a few large case series, the LMWH appear to be relatively is important to avoid initiating fondaparinux too soon because
safe to use during pregnancy and are an attractive alternative to UFH there is a significant relationship between the timing of the first dose
when long-term anticoagulation therapy is required. Furthermore, and the risk of major bleeding complications. Patients who weigh
the LMWHs do not appear to affect bone formation.27 Dalteparin, less than 50 kg should not be given fondaparinux for VTE prophy-
enoxaparin, and tinzaparin are classified as FDA pregnancy category laxis. The usual duration of therapy is 5 to 9 days, but may be given
B. The LMWHs are becoming the preferred agents in pediatric as extended prophylaxis following hospital discharge for up to 21
populations despite the fact that the safety and effectiveness of the days.33 Fondaparinux has been evaluated for the treatment of DVT
LMWHs to treat VTE in children and infants has not been exten- and PE in two phase III clinical trials.19 For the treatment of DVT or
sively studied.28 Weight-based LMWH doses provide a less-predict- PE, the dose of fondaparinux is 7.5 mg given subcutaneously once
able anticoagulant response in children compared to adults.28 For daily. Patients who weight more than 100 kg should be given 10 mg
enoxaparin, suggested therapeutic doses are 1.5 mg/kg every 12 once daily and those who weigh less than 50 kg should receive only
hours for infants <2 months old and 1.0 mg/kg every 12 hours for 5 mg daily.32
those >2 months old. The suggested dose for dalteparin is 86 to 172 Similar to the LMWHs, fondaparinux is administered into the
units/kg every 24 hours, keeping in mind that neonates appear to fatty tissue of the abdominal wall. Patients should be instructed to
require higher doses/kg than older children or adults.28 Until more pinch a fold of skin at the injection site and hold it throughout the
 344
injection. The needle should be inserted at a 90° angle. Injection patients who undergo orthopedic surgery are elderly. Elderly
sites should be alternated from side to side.32 patients are also more likely to have decreased renal function and
SECTION 2

careful assessment of renal status should be conducted prior to

Therapeutic Monitoring initiating therapy. Fondaparinux is contraindicated in patients with
a creatinine clearance less than 30 mL/min.
A complete blood cell count should be measured at baseline and
Fondaparinux is a pregnancy category B drug.32 However, there
monitored periodically to detect the possibility of occult bleeding.32
is very limited information regarding fondaparinux use during
Baseline kidney function should be determined and monitored
pregnancy. The drug is excreted in the milk of lactating rats, but
closely in patients at risk of developing renal failure. Fondaparinux
excretion in human milk is unknown. Until more data becomes
should be discontinued if the creatinine clearance drops below 30
available, UFH and LMWH should remain the agents of choice
mL/min. Signs and symptoms of bleeding should be monitored
Cardiovascular Disorders

during pregnancy. Fondaparinux use in pediatric populations has

daily, particularly in patients with a baseline creatinine clearance
not been studied.
between 30 and 50 mL/min. If neuraxial anesthesia has been used,
patients should be closely monitored for signs and symptoms of
neurologic impairment. IDRAPARINUX
Fondaparinux does not alter coagulation tests such as the aPTT
Idraparinux is an analog of fondaparinux that has very long dura-
and PT. The role of antifactor Xa monitoring during fondaparinux
tion of effect (see Table 21–6) and was developed to be administered
is not well defined. Patients receiving fondaparinux therapy do not
once weekly by subcutaneous injection. Idraparinux is currently
require routine coagulation testing.
undergoing phase III clinical trials evaluating its usefulness for both
the acute and long-term management of VTE.34
Adverse Effects
The primary adverse effect associated with fondaparinux therapy is DIRECT THROMBIN INHIBITORS
bleeding.32 The rate of major bleeding in the VTE prophylaxis trials
was approximately 2% to 3%. Because the risk of major bleeding In recent years, research has focused on the development of direct
appears to be related to weight, in patients who weigh less than 50 thrombin inhibitors (DTIs) that may offer benefits over traditional
kg, fondaparinux is contraindicated for VTE prophylaxis and the agents in the treatment and prevention of various thrombotic
treatment dose is only 5 mg every 24 hours. Similar to UFH and the disorders. The DTIs have been studied for many indications such as
LMWHs, fondaparinux should be used with extreme caution in HIT, prophylaxis and treatment of VTE, acute coronary syndromes
patients with neuraxial anesthesia or following a spinal puncture with and without percutaneous transluminal coronary angioplasty,
because of the risk for spinal or epidural hematoma formation. and nonvalvular atrial fibrillation. Currently four parenteral
Unlike UFH and the LMWHs, fondaparinux does not cause hep- agents—lepirudin, desirudin, bivalirudin, and argatroban—are
arin-induced thrombocytopenia and does not produce cross-sensi- approved for use in the United States, and several oral compounds
tivity in vitro.19 A specific antidote to reverse the antithrombotic are in various phases of clinical development (Table 21–11).19,35,36
activity of fondaparinux is not currently available, but several
potential products have been evaluated.31 Pharmacology and Pharmacokinetics
The direct thrombin inhibitors, as their name implies, directly
Use in Special Populations interact with the thrombin molecule (Fig. 21–6). The agents in this
Fondaparinux has been used safely in elderly patients but the risk of class differ in terms of their molecular weight, chemical structure,
major bleeding increases with age (1.8% in patients <65 years of age, and binding to the thrombin molecule. Unlike UFH, LMWH, and
2.2% in patients age 65 to 74 years, and 2.7% in patients age 75 years fondaparinux, DTIs do not require a cofactor (antithrombin) to
or older).32 This is an important consideration because many exert their antithrombotic activity. They are capable of inhibiting

TABLE 21-11 Pharmacologic and Clinical Properties of Direct Thrombin Inhibitors

Lepirudin Desirudin Bivalirudin Argatroban Dabigatrana
Route of administration IV or SC IV or SC IV IV PO
Indication Treatment of thrombo- DVT prevention after THA Patients with UA under- Treatment of thrombosis Investigational for VTE preven-
sis in patients with (not available in the going PTCA; PCI with in patients with HIT; tion and treatment, and
HIT U.S.) provisional use of GPI patients at risk for HIT stroke prevention in AF
undergoing PCI
Binding to thrombin Irreversible catalytic site Irreversible catalytic site Partially Reversible cata- Reversible catalytic site Reversible catalytic site
and exosite-1 and exosite-1 lytic site and exosite-1
b
Monitoring aPTT (IV) Scr /Clcr aPTT (IV) Scr /Clcr aPTT/ACT Scr /Clcr aPTT/ACT Liver function Scr /Clcr Effect on liver function
unclear at this time
Clearance Renal Renal Enzymatic (80)% and Hepatic Renal
Renal (20%)
Antibody development Antihirudin antibodies Possible; lower incidence May cross-react with anti- No Unknown
in up to 60% of than with lepirudin hirudin antibodies
patients
Effect on INR Slight increase Slight increase Slight increase Increase Unpredictable and variable
ACT, activated clotting time; AF, atrial fibrillation; aPTT, activated partial thromboplastin time; bid, twice daily; Clcr, creatinine clearance; DVT, deep vein thrombosis; GPI, glycoprotein IIb/IIIa inhibitor; HIT, heparin
induced thrombocytopenia; INR, international normalized ratio; IV, intravenous ; PCI, percutaneous coronary intervention; PO, oral ; PTCA, percutaneous transluminal coronary angioplasty; qd, daily; SC,
subcutaneous; Scr, serum creatinine; THA, total hip arthroplasty; UA, unstable angina; VTE, venous thromboembolism.
a
Investigational.
b
Routine monitoring of anticoagulant effect may not be necessary.
From Nutescu et al.35
 345
Substrate
Recognition Site

CHAPTER 21
Thrombin Catalytic Thrombin
(IIa) Site (IIa)

Venous Thromboembolism
Fibrin Binding Site Lepirudin

Thrombin
Thrombin
(IIa)
(IIa)

Argatroban Bivalirudin
Or FIGURE 21-6. Pharmacologic activity of lepirudin, biva-
Darbigatran lirudin, argatroban, and dabigatran.

both circulating and clot-bound thrombin, a potential advantage anaphylaxis has been reported in patients who developed antibod-
over UFH and LMWH. Furthermore, DTIs do not induce immune- ies, patients should not be treated with lepirudin more than once.38
mediated thrombocytopenia and are widely used for the treatment Desirudin, also a recombinant hirudin analogue, is administered
of HIT.19,35,36 by subcutaneous injection and approved by the FDA in 2003 for the
Hirudin, the prototype of this class, is a 65-amino-acid polypep-
tide (7,000 Da) that was originally isolated from the salivary secre-
TABLE 21-12 Dosing Considerations for Direct Thrombin Inhibitors
tions of the medicinal leech (Hirudo medicinalis). Although not in Patients with Renal and Hepatic Dysfunction
commercially available, the discovery of hirudin led to the develop-
ment of derivatives such as lepirudin and desirudin via recombinant Renal Impairment Hepatic Impairment
DNA technology. The hirudins (lepirudin, desirudin, and bivaliru- Lepirudin Bolus: 0.2 mg/kg (bolus dose is should Dose adjustment not
din) form a stoichiometric and very slowly reversible complex by be avoided in patients with renal required
binding to both the active site and exosite-1 of the thrombin impairment)
molecule (see Fig. 21–6). Because of this bivalent bond, hirudins are Infusion:
considered the most potent inhibitors of thrombin.19,35,36 Clcr 45–60 mL/min: 0.075 mg/kg/h
Lepirudin, a recombinant analogue of hirudin, is a 65-amino- Clcr 30–44 mL/min: 0.045 mg/kg/h
Clcr 15–29 mL/min: 0.0225 mg/kg/h
acid polypeptide that is administered parenterally, either by contin-
Clcr<15 mL/min: no bolus; avoid or
uous IV infusion or subcutaneous injection.19,37 It is indicated for
stop infusion
anticoagulation in patients with HIT and associated thrombosis so HD: stop infusion & additional IV bolus
as to prevent further thromboembolic complications. Research is doses of 0.1 mg/kg every other day
also being conducted on the use of lepirudin for other indications, should be considered if the aPTT
such as acute coronary syndromes and VTE. Because of the strong, ratio falls below 1.5
almost irreversible bond between lepirudin and thrombin, lepirudin Desirudin Clcr 31–60 mL/min: 5mg SC q 12 h Dose adjustment not
is associated with bleeding complications.37 The primary route of Clcr <30 mL/min: 1.7 mg SC q 12 h required
elimination for lepirudin is through renal excretion, and systemic Bivalirudin Bolus: no dose adjustment Dose adjustment not
clearance is directly proportional to the glomerular filtration rate. Infusion: required
Lepirudin has a terminal half-life of 1.3 hours in young healthy Clcr <30: 1 mg/kg/h
HD: 0.25 mg/kg/h
volunteers. In patients with marked renal insufficiency (Clcr <15
Argatroban Dose adjustment not required Initiate at 0.5 mcg/kg/
mL/min) and on hemodialysis, elimination half-lives are prolonged min then titrate to
up to 2 days.36 Thus, dose adjustment is required in the setting of aPTT 1.5–3.0 ×
impaired renal function, a potential disadvantage of this agent baseline
(Table 21–12). Many patients develop antibodies to lepirudin. Up Dabigatran Dose adjustment will be required; Unclear at this time
to 60% of patients treated with lepirudin for 10 days or more will degree of dose decrease not defined
develop antibodies. This may increase the anticoagulant effect of at this time.
lepirudin, possibly as a result of delayed renal elimination of active aPTT, activated partial thromboplastin time; Clcr, creatinine clearance; HD, hemodialysis; SC,
lepirudin–antihirudin complexes. Consequently, strict monitoring subcutaneous.
of aPTT is necessary during prolonged therapy.19,35 Because fatal From Nutescu et al.35
 346
prevention of venous thrombosis in patients undergoing elective Therapeutic Monitoring
hip surgery.39 Although approved for use, the agent is not currently
Although the DTIs produce changes in the prothrombin time, the
SECTION 2

commercially available in the United States. For acute myocardial

aPTT is used to monitor the patient’s response to lepirudin,
infarction and unstable angina, desirudin has been given via contin-
desirudin, and argatroban.19,35,40 After obtaining baseline coagula-
uous IV infusion.35,40 Desirudin has a terminal elimination half-life
tion studies, doses of lepirudin and argatroban should be titrated
after subcutaneous dosing of approximately 2 hours, and 80% to
to achieve the institution-specific therapeutic range or an aPTT 1.5
90% of the elimination is by renal clearance and metabolism. The
to 3.0 times the mean normal control. Daily aPTT monitoring is
total urinary excretion of unchanged drug amounts to 40% to 50%
also recommended for patients on desirudin, particularly those
of the administered dose. Similar to lepirudin, in patients with
with impaired renal function.41 Although bivalirudin doses should
moderate to severe renal impairment, the dosage should be reduced
be adjusted based on the ACT, some experience is also available
Cardiovascular Disorders

(see Table 21–12). Although antihirudin antibodies also have been

using the aPTT.42,43 The ecarin clotting time is a potentially more
documented with desirudin, the incidence appears to be lower than
suitable test to measure the antithrombotic activity of the direct
with lepirudin.35,41
thrombin inhibitors, but it is not readily available in most clinical
Bivalirudin, formerly known as Hirulog, is a semisynthetic 20-
labs in the United States. Oral DTIs appear to produce a predict-
amino-acid polypeptide analogue of recombinant hirudin that is
able antithrombotic response in fixed doses and have a relatively
FDA approved for use in patients with unstable angina who are
large therapeutic window.35 Consequently, routine anticoagulation
undergoing percutaneous transluminal coronary angioplasty and
monitoring may not be required for these agents. A complete blood
with provisional use of glycoprotein IIb/IIIa inhibitor for use as an
count should be obtained at baseline and periodically thereafter to
anticoagulant in patients undergoing percutaneous coronary inter-
detect potential bleeding.
vention.42 Recent reports also support the use of bivalirudin in
patients with acute ST elevation myocardial infarction and in
patients with HIT, although the agent is not currently FDA approved Adverse Effects
for these indications. Unlike lepirudin, bivalirudin is a reversible Contraindications for use of the DTIs and risk factors for bleeding are
inhibitor of thrombin and provides transient antithrombotic activity similar to other antithrombotic drugs (see Tables 21–8 and 21–9).
with an estimated 20- to 30-minute half-life. This difference may Hemorrhage is the most serious and common adverse effect related
reduce the risk of bleeding and antibody production.35,43 The ACT to the DTIs.19,35,40 In studies evaluating the use of lepirudin for the
can be used to monitor the anticoagulant effect of bivalirudin. treatment of patients with HIT, the incidence of major bleeding was
Therapeutic ACT levels are achieved within 5 minutes after initiating relatively high (13% to 17%).37 However, no fatal or intracranial
bivalirudin therapy, and ACT levels return to subtherapeutic levels bleeding events occurred. A slightly lower rate of major hemorrhage
within 1 hour of discontinuing the infusion. The aPTT test has also was reported in HIT trials using argatroban (approximately 5%)
been used to monitor the anticoagulant effect of bivalirudin in and, similarly, there were no reports of fatal or intracranial bleed-
patients with HIT. Bivalirudin is mostly cleared by proteolytic ing.45 Bleeding complications with desirudin were similar to enox-
cleavage and by hepatic metabolism, with approximately 20% elimi- aparin in a trial of patients undergoing elective hip surgery. Serious
nated renally. The manufacturer recommends reducing the dose by bleeding occurred in less than 1% of all patients in the trial.41 Minor
20% to 60% in patients with renal impairment and monitoring the bleeding and small reductions in red blood cell counts occurred
ACT closely (see Table 21–12).35,43 relatively frequently but typically did not require drug discontinua-
Argatroban differs from the hirudins in that it is a small, synthetic tion. There are no known agents that reverse the activity of the
molecule derived from arginine that reversibly binds only to the DTIs. Nonhemorrhagic effects such as fever, nausea, vomiting, and
active catalytic site of thrombin. Its small size relative to other DTIs allergic reactions occur infrequently.
enables it to inhibit both clot-bound and soluble thrombin, offering
a potential therapeutic advantage over other agents in its class.26,44
Drug–Drug and Drug–Food Interactions
Argatroban is primarily eliminated by hydroxylation and aromati-
zation in the liver to inactive metabolites. A small percentage is The concurrent use of DTIs and thrombolytic agents substantially
excreted unchanged in the bile. The elimination half-life is 39 to 51 increases the bleeding risk, particularly intracranial hemorrhage,
minutes, but extends to approximately 181 minutes in hepatic and should be undertaken with great caution. Warfarin and anti-
impairment. Dose adjustment is required in patients with hepatic platelet agents can be concurrently initiated with these agents.
impairment (see Table 21–12). The aPTT and ACT can be used to Because the DTIs prolong the PT and INR, close monitoring for
monitor the anticoagulant effect of argatroban. It is FDA approved bleeding complications is required. Few pharmacokinetic drug
for the prophylaxis or treatment of thrombosis in patients with HIT, interactions with this class of agents are known. Drugs that alter
and also as an anticoagulant in patients with HIT, or at risk of HIT, renal function could prolong lepirudin, desirudin, and bivalirudin
who are undergoing percutaneous coronary intervention.35,45 activity. Drugs that inhibit liver enzymes have the potential to
interact with argatroban.46
Oral Direct Thrombin Inhibitors
Recent progress has also been made in the development of oral
Use in Special Populations
DTIs. These agents appear promising and offer various advantages Lepirudin, bivalirudin, and argatroban are classified by the FDA as
such as oral administration, predictable pharmacokinetics and pregnancy category B drugs but they should be used cautiously in
pharmacodynamics, a broad therapeutic window, no routine women of child bearing age because experience is very limited.37,42,45
laboratory monitoring, no significant drug interactions, and fixed- Desirudin is classified as pregnancy category C with no controlled
dose administration. Several of these compounds are being inves- trials in pregnant women.41 Lepirudin and argatroban have been
tigated with dabigatran etexilate being in most advanced phases of evaluated in a very small number of children. Dosing requirements
clinical development. A previous agent of the class (ximelagatran) can vary widely in pediatric patients, thus product-specific dosing
was denied FDA approval because of concerns of drug-induced guidelines and monitoring should be followed.47 Critically ill
liver toxicity. The first safe, oral DTI to make it to the U.S. market patients and patients with renal or hepatic impairment will require
has the potential to revolutionize the provision of antithrombotic dosage adjustments according to the specific DTI used, and lower
therapy.35,36 initiation doses are recommended (see Table 21–12).48
 347

CHAPTER 21
Warfarin
Liver cell

CYP2C9 S R CYP1A2
CYP3A4

Venous Thromboembolism
Vitamin K
reductase

Reduced vitamin K
Oxidized vitamin K

Vitamin K-dependent Dietary

carboxylase vitamin K

Precursors: Functional:
Factors II, VII, IX, X Factors II, VII, IX, X
Proteins C & S Proteins C & S

FIGURE 21-7. Pharmacologic activity and metab-

olism of warfarin.

WARFARIN Warfarin is rapidly and extensively absorbed from the gastrointesti-

nal tract and reaches peak plasma concentration in approximately 90
The most widely prescribed anticoagulant in North American is minutes with a bioavailability of greater than 90% following oral
warfarin sodium (Coumadin). It was serendipitously discovered in administration. In plasma, both the R and S isomers are extensively
the early 1940s at the University of Wisconsin after hemorrhagic (97% to 99%) bound to albumin.5,46 Warfarin undergoes stereose-
deaths occurred in cattle eating spoiled sweet clover. Warfarin is the lective metabolism via cytochrome P450 (CYP) 1A2, 2C9, 2C19,
anticoagulant of choice when long-term or extended anticoagula- 2C8, 2C18, and 3A4 isoenzymes in the liver (see Fig. 21–7). The
tion is indicated. Warfarin is FDA-approved for the prevention and pharmacokinetic parameters of warfarin, particularly hepatic metab-
treatment of VTE, as well as for the prevention of thromboembolic olism, vary substantially between individuals leading to large inter-
complications associated with atrial fibrillation, heart valve replace- patient differences in dose requirements. Genetic variations in the
ment, and myocardial infarction. Because of its narrow therapeutic 2C9 isoenzyme and vitamin K epoxide reductase (VKOR) have been
index, predisposition to drug and food interactions, and propensity shown to correlate with warfarin dose requirements.49,50 Given the
to cause hemorrhage, warfarin requires continuous patient moni- relatively greater potency of S-warfarin, coadministration of drugs
toring and education to achieve optimal outcomes.5 that induce or inhibit the CYP2C isoenzymes are more likely to cause
a clinically significant interaction.5 These and other pharmacokinetic
Pharmacology variations in warfarin metabolism likely explain the large interpa-
Warfarin exerts its anticoagulation effect by inhibiting the enzymes tient dose–response seen with warfarin in clinical practice.
responsible for the cyclic interconversion of vitamin K in the liver
(Fig. 21–7). Reduced vitamin K is a cofactor required for the carbox- Dosing and Administration
ylation of the vitamin K-dependent coagulation proteins, namely The dose of warfarin is patient-specific based on the desired
factors II (prothrombin), VII, IX, and X, as well as the endogenous intensity of anticoagulation and the patient’s individual response.5,6
anticoagulant proteins C and S. Carboxylation of the N-terminal There is tremendous interpatient variability with regard to the
region of these proteins in the liver is required for biologic activity. By pharmacodynamic response and pharmacokinetic disposition of
inhibiting the supply of vitamin K to serve as a cofactor in the warfarin. In addition, there is significant intrapatient variability in
production of these proteins, warfarin indirectly slows their rate of these parameters over time. Therefore, the dose of warfarin must be
synthesis. Warfarin has no direct effect on previously circulating based on continual clinical and laboratory monitoring. At the
clotting factors or previously formed thrombus.5,6 The time required
for warfarin to achieve its pharmacologic effect is dependant on the
elimination half-lives of the coagulation proteins (Table 21–13). TABLE 21-13 Biologic Half-Life of Vitamin K-Dependent
Given that prothrombin has a 2- to 3-day half-life, warfarin’s full Coagulation Proteins
antithrombotic effect is not achieved for 8 to 15 days after the Protein Half-Life (hours)
initiation of therapy. By suppressing the production of clotting
Prothrombin (factor II) 60–100
factors, warfarin prevents the initial formation and propagation of
Factor VII 6–8
thrombus.5,46 Factor IX 20–30
Factor X 24–40
Pharmacokinetics Protein C 8–10
Protein S 40–60
Commercially available warfarin is a racemic mixture of R and S
isomers. The S isomer is 2 to 5 times more potent that the R isomer. From Haines and Bussey.19
 348

TABLE 21-14 Clinically Important Warfarin Drug Interactions TABLE 21-15 Warfarin Dietary Supplements Interactions Involving
Cytochrome P450 Metabolism
SECTION 2

Increase Anticoagula- Decrease Anticoagula- Increase Bleeding

tion Effect (↑INR) tion Effect (↓INR) Risk Dietary Supplement Mechanism
Acetminophen Amobarbital Argatroban Bergamottin (component of grapefruit juice) 2C9 inhibitor
Alcohol binge Butabarbital Aspirin Bishop’s weed (Bergapten) 3A4 inhibitor
Allopurinol Carbamazepine Clopidogrel Bitter orange 3A4 Inhibitor
Amiodarone Cholestyramine Danaparoid Cat’s claw 3A4 inhibitor
Cephalosporins (with Dicloxacillin Dipyridamole Chrysin 1A2 inhibitor
NMTT side chain) Griseofulvin Unfractionated/low- Cranberry 2C9 inhibitor
Chloral hydrate Nafcillin molecular-weight Devil’s claw 2C9 Inhibitor
Cardiovascular Disorders

Cimetidine Phenobarbital heparins Dehydroepiandrosterone (DHEA) 3A4 inhibitor

Ciprofloxacin Phenytoin Nonsteroidal antiin- Diindolymethane 1A2 inducer
Clofibrate Primidone flammatory drugs Echinacea 3A4 inhibitor
Chloramphenicol Rifampin Ticlopidine Eucalyptus 3A4, 2C9, 2C19, 1A2 inhibitor
Danazol Rifabutin Feverfew 1A2, 2C9, 2C19, 3A4 inhibitor
Disulfuram Secobarbital Fo-ti 1A2, 2C9, 2C19, 3A4 inhibitor
Doxycycline Sucralfate Garlic 2C9, 2C19, and 3A4 inhibitor
Erythromycin Vitamin K Ginseng CYP P450 inducer
Fenofibrate Goldenseal 3A4 inhibitor
Fluconazole Guggul 3A4 inducer
Fluorouracil Grape 1A2 inducer
Fluoxetine Grapefruit juice 1A2, 2A6, and 3A4 inhibitor
Fluvoxamine Indole-3-carbinol 1A2 Inducer
Gemfibrozil Ipriflavone 2C9, 1A2 inhibitor
Influenza vaccine Kava 1A2, 2C9, 2C19, 2D6, 3A4 inhibitor
Isoniazid Licorice 3A4 inhibitor
Itraconazole Lime 3A4 inhibitor
Lovastatin Limonene 2C9, 2C19 substrate, and 2C9 inducer
Moxalactam Lycium (Chinese wolfberry) 2C9 inhibitor
Metronidazole Milk thistle 2C9 and 3A4 inhibitor
Miconazole Peppermint 1A2, 2C9, 2C19, 3A4 inhibitor
Neomycin Red clover 1A2, 2C9, 2C19, 3A4 inhibitor
Norfloxacin Resveratrol 1A, 2E1 3A4 inhibitor
Ofloxacin St. John’s wort 1A2, 2C9, 3A4 inducer
Omeprazole Sulforaphane 1A2 inhibitor
Phenylbutazone Valerian 3A4 inhibitor
Piroxicam Wild cherry 3A4 inhibitor
Propafenone
From Nutescu et al.64
Propoxyphene
Quinidine
Sertraline
Sulfamethoxazole CLINICAL CONTROVERSY
Sulfinpyrazone
Tamoxifen Some clinicians recommend that warfarin therapy be started
Testosterone using no more than 5 mg daily based on evidence that the
Vitamin E majority of patients will achieve a therapeutic INR by day 5.
Zafirlukast Furthermore, some patients become excessively anticoagulated
INR, international normalized ratio; NMTT, N-methylthiotetrazole.
when higher doses are used. However, some clinicians recom-
From Holbrook et al.63 mend initiating warfarin therapy with 10 mg daily because a
therapeutic INR is achieved 1 day sooner, thereby facilitating
earlier hospital discharge and more rapid discontinuation of
initiation of therapy, it is difficult to predict the specific dose that an LMWH therapy. In addition, they argue, there is no evidence
individual will require. Warfarin dosing algorithms that incorporate that bleeding complications occur more frequently when a
pharmacogenetic information regarding CYP2C9 and VKOR poly- higher initial dose is used.
morphisms are currently being evaluated. The usefulness of phar-
macogenetic information in managing patients is not yet known. There is some controversy regarding the optimal dosing regimen
Although the average weekly dose of warfarin is between 25 mg when initiating warfarin therapy.5,51,52 To achieve a therapeutic INR
and 55 mg, some patient-related variables are associated with lower in the least amount of time, some clinicians have used relatively high
than usual dose requirement including: advanced age (>65 years doses of warfarin (10 or 15 mg) and then adjusted the dose based on
old), elevated baseline INR, poor nutritional status, liver disease, the patient’s response. Studies in patients with atrial fibrillation that
hyperthyroidism, genetic polymorphisms in CYP2C9 and VKOR, compared a 5-mg initial dose to a 10-mg dose questioned this
and concurrent use of medications known to enhance the effect of practice.53 Although a 10-mg dose produced a more rapid response in
warfarin (Table 21–14).5,6 Prior to initiating therapy, the clinician the INR, many patients subsequently became excessively anticoagu-
should screen for the presence of contraindications to anticoagula- lated. However, a more recent study in patients with acute venous
tion therapy and risk factors for major bleeding (see Tables 21–8 thrombosis demonstrated that 10-mg initial doses can be used safely
and 21–9). It is essential to collect a complete medication history, when the subsequent INR response is monitored appropriately.51
including the use of herbal and nutritional products (Tables 21–15 Although data on the optimal induction regimen is conflicting,
and 21–16). there is a pharmacodynamic rationale for avoiding doses larger than
 349

TABLE 21-16 Dietary Supplements That Can Affect Platelet Function and Anticoagulation Status

CHAPTER 21
Agent Mechanism Comments
Bladderwrack Has anticoagulant effects Increased risk of bleeding or bruising
Boldo Constituents may have antiplatelet effects Increased risk of bleeding or bruising
Bromelain Decreased platelet aggregation Increased risk of bleeding or bruising
Burdock Decreased platelet aggregation by inhibiting platelet activation factor Increased risk of bleeding or bruising
Caffeine May have antiplatelet activity; not reported in humans Increased risk of bleeding or bruising; found in black tea, green
tea, guarana, mate, oolong tea
Clove Eugenol has antiplatelet activity Increased risk of bleeding or bruising
Cod liver oil May inhibit platelet aggregation Increased risk of bleeding or bruising; avoid concomitant use

Venous Thromboembolism
Coltsfoot May inhibit platelet aggregation Increased risk of bleeding or bruising; avoid concomitant use
Danshen Decreased platelet aggregation; may also have antithrombotic effects Increased risk of bleeding or bruising; avoid concomitant use
Dong quai May inhibit platelet aggregation Increased risk of bleeding or bruising
Fenugreek Constituents may have antiplatelet effects; concentration may not be clinically Increased risk of bleeding or bruising
significant
Fish oil Has antiplatelet effects Increased risk of bleeding or bruising
Flax seed Decreased platelet aggregation and increased bleeding time Increased risk of bleeding or bruising
Gamma linolenic acid Has anticoagulant effects Increased risk of bleeding or bruising; found in borage and
(GLA) evening primrose oil
Garlic Has anticoagulant effects and may inhibit platelet aggregation Increased risk of bleeding or bruising
Ginger Inhibit thromboxane synthetase and decrease platelet aggregation Increased risk of bleeding or bruising
Ginkgo Decreased platelet aggregation; ginkgolide B, a component of ginkgo, is a potent Increased risk of bleeding or bruising
inhibitor of PAF
Ginseng, panax Components may decrease platelet aggregation through PAF antagonism; not Increased risk of bleeding or bruising; use with caution until more
shown in humans is known.
Ginseng, Siberian A component, dihydroxybenzoic acid, may inhibit platelet aggregation Increased risk of bleeding or bruising
Melatonin Unknown; might increase the anticoagulant or antiplatelet effect; decreased Increased risk of bleeding or bruising
prothrombin activity observed
Nattokinase Has thrombolytic activity Increased risk of bleeding or bruising
Onion Decreased platelet aggregation Increased risk of bleeding or bruising
Pantethine Decreased platelet aggregation Increased risk of bleeding or bruising
Policosanol Inhibits platelet aggregation Increased risk of bleeding or bruising
Poplar Contains salicylates and may cause decreased platelet aggregation Increased risk of bleeding or bruising
Resveratrol Has antiplatelet effects Increased risk of bleeding or bruising
Sea buckthorn Inhibits platelet aggregation Increased risk of bleeding or bruising
Turmeric Decreased platelet aggregation; has antiplatelet effects Increased risk of bleeding or bruising
Vinpocetine Has antiplatelet effects Increased risk of bleeding or bruising
Vitamin E Inhibits platelet aggregation and antagonizes the effects of vitamin K-dependent Dose dependent and significant with doses greater than 800 units
clotting factors per day; advise patients to avoid high doses of vitamin E;
increased risk of bleeding or bruising
Willow bark Decreased platelet aggregation; has antiplatelet effects but less than aspirin Increased risk of bleeding or bruising
PAF, platelet activating factor.
From Nutescu et al.64

10 mg.5 Large doses result in a more rapid depression in factor VII Warfarin therapy can be safely initiated on an outpatient basis
concentrations.53 This early response to therapy may give the provided there is no urgent need for anticoagulation (i.e., preven-
clinician a false impression that a therapeutic INR has been achieved tion of venous thrombosis). Given that laboratory monitoring is
after only 2 or 3 days. It is important to remember that patients are performed less frequently in the outpatient setting, warfarin therapy
not truly anticoagulated at this point because a significant reduction should be undertaken a bit more cautiously. In most circumstances,
in prothrombin concentrations requires at least 5 days to occur. the initial dose should not exceed the anticipated maintenance dose.
Large doses may also increase the theoretical risk for early throm- The response to therapy should be measured every 3 to 5 days until
botic complications, such as warfarin-induced skin necrosis. After stabilized. The full antithrombotic effect may require up to 15 days
the initiation of warfarin therapy protein C becomes rapidly to be achieved.5,46
depleted, but prothrombin concentrations will remain near normal When adjusting the dose of warfarin, the clinician should allow
for several days. If protein C concentrations are severely suppressed sufficient time for changes in the INR to occur. In general, dose
relative to prothrombin, there is a potential for inducing a hyperco- changes should not be made more frequently than every 3 days.
agulable state. Doses should be adjusted by calculating the weekly dose and
For most patients, initiating therapy with 5 mg daily and adjusting reducing or increasing the weekly dose by 5% to 25%. The effect of
the dose based on the INR response will produce therapeutic INRs in a small dose change may not become evident for 5 to 7 days.
4 to 5 days (Fig. 21–8). Lower or higher starting doses may be Patients should not have followup INR tests sooner than anticipated
acceptable based on patient-related factors and how quickly followup changes are likely to occur.5
laboratory monitoring can be performed. Several dosing nomograms
have been developed and prospectively evaluated.5,51,54 For patients
with acute venous thrombosis, UFH, LMWH, or fondaparinux
Therapeutic Monitoring
should be overlapped with warfarin therapy for at least 5 days Warfarin requires frequent laboratory monitoring to ensure opti-
regardless of whether the target INR has been achieved earlier.2 mal therapeutic outcomes and minimize bleeding complications.
 350

Can a PTINR be obtained

SECTION 2

daily?
No Yes

Start warfarin with 5 mg daily Start warfarin with 5 mg daily

Consider 2.5 mg dose if patient age Consider 7.5 −10 mg dose if patient
>60 years; concurrent use of age <60 years; concurrent use of
interacting medications; or interacting medications; and
Cardiovascular Disorders

bleeding risk is high bleeding risk is low

Measure PT/INR on day 3 or 4 Measure PT/INR on day 2

INR < 1.5—increase weekly dose 10%–25% INR < 1.5—no dose change
INR = 1.5−19—no dose change INR = 1.5−1.9—decrease dose 25%–50%
INR = 2.0−2.5—decrease weekly dose 25–50% INR = 2.0−2.5—decrease dose 50%–75%
INR = 2.5—decrease weekly dose 50% or hold INR > 2.5—hold next dose

Measure PT/INR on days 5–7 Measure PT/INR on day 3

INR < 1.5—increase weekly dose 10%–25% INR < 1.5—increase dose 0%–25%
INR = 1.5 – 19—increase weekly dose 0%–20% INR = 1.5−1.9—no dose change
INR = 2.0 – 3.0—no dose change INR = 2.0−2.5—decrease dose 25%–50%
INR > 3.0—decrease weekly dose 10%–25% or hold INR = 2.5—decrease 50% or hold next dose

Measure PT/INR on days 8–10 Measure PT/INR on day 4

INR < 1.5—increase weekly dose 15%–35% INR < 1.5—increase dose 0%–25%
INR = 1.5 – 1.9—increase weekly dose 5%–20% INR = 1.5−1.9—no dose change or
INR = 2.0 – 3.0—no dose change increase 10%–25%
INR > 3.0—decrease weekly dose 10%–25% or hold INR = 2.0−3.0—decrease dose 0%–25%
INR > 3.0—decrease 50% or hold next dose

Measure PT/INR on days 11–14

INR < 1.6—increase weekly dose 15%–35%
INR = 1.6 – 1.9—increase dose 5%–20% Measure PT/INR on day 5
INR = 2.0 – 3.0—no dose change INR < 1.5—increase dose 25%
INR > 3.0—decrease weekly dose 5–20% or hold INR = 1.5−1.9—increase dose 0%–25%
INR = 2.0−3.0—no dose change or
decrease dose 10%–25%
INR > 3.0—decrease 25%–50%

FIGURE 21-8. Initiation of warfarin therapy. (INR, international normalized ratio; PT, prothrombin time.)

The prothrombin time (PT), also known as the protime and one- Patient ISI
PT
step Quick test, has been used for decades to monitor the anticoag- INR = ⎛ ⎞
ulation effects of warfarin.5,55 The PT measures the biologic activity ⎝ PT Control⎠
of factors II, VII, and X activity and correlates well to warfarin’s
anticoagulation effect. The test is performed by measuring the time The International Sensitivity Index (ISI) is a measure of the
required for clot formation after adding calcium and thromboplas- thromboplastin’s responsiveness compared to the WHO reference
tin to citrated plasma. Several thromboplastins are commercially standard. Each thromboplastin reagent manufactured has an ISI
available and are extracted from mammalian tissue rich in tissue value that should be used to calculate the INR. Although the INR
factor (e.g., rabbit brain) or produced from recombinant human system has a number of potential problems, it is currently the best
tissue factor. Although an effective tool for monitoring warfarin means available to interpret the PT and the preferred method for
therapy, the PT is problematic to interpret because there is wide monitoring oral anticoagulation therapy.
variability in the sensitivity of thromboplastin reagents. Given the The recommended target INR and goal range is based on the
same blood sample, different thromboplastins will produce sub- therapeutic indication.5,55 For most indications, the target INR is 2.5
stantially different results that may prompt clinicians to make with an acceptable range of 2.0 to 3.0. The target INR is higher for
potentially inappropriate dosing decisions. The World Health Orga- some patients with mechanical prosthetic heart valves (target INR =
nization (WHO) addressed the need for standardization in the late 3.0, range 2.5 to 3.5). A baseline PT and complete blood cell count
1970s by developing a reference thromboplastin and recommend- should be obtained prior to initiating warfarin therapy. In patients
ing the use of the INR to monitor warfarin therapy. The INR with an acute thromboembolic event, a PT should be measured
corrects for differences in thromboplastin reagents through the minimally every 3 days during the first week of therapy. In this
following formula: situation, UFH or LMWH therapy should be continued for at least
 351

TABLE 21-17 Vitamin K Content of Select Foodsa

CHAPTER 21
Very High (>200 mcg) High (100–200 mcg) Medium (50–100 mcg) Low (<50 mcg)
Brussel sprouts Basil Apple, green Apple, red
Chickpea Broccoli Asparagus Avocado
Collard greens Chive Cabbage Beans
Coriander Coleslaw Cauliflower Breads, grains
Endive Cucumber (with peel) Mayonnaise Carrot
Kale Canola oil Nuts, pistachio Cereal
Lettuce, red leaf Green onion/scallion Squash, summer Celery
Parsley Lettuce, butterhead Coffee

Venous Thromboembolism
Spinach Mustard greens Corn
Swiss chard Soybean oil Cucumber (without peel)
Tea, green Dairy products
Tea, black Eggs
Turnip greens Fruit (varies)
Watercress Lettuce, iceberg
Meats, fish, poultry
Pasta
Peanuts
Peas
Potato
Rice
Tomato
a
Approximate amount of vitamin K per 100 g (3.5 oz) serving.
From Booth and Centurelli.112

5 days and until the INR is greater than 2.0 and stable. The Adverse Effects
concurrent use of antithrombotic drugs with warfarin may prolong
the prothrombin time slightly. Once the patient’s dose–response is Warfarin’s primary adverse effect is bleeding.4 Hemorrhagic com-
established, an INR should be determined every 7 to 14 days until it plications, ranging from mild to life-threatening, can occur at any
stabilizes and optimally every 4 weeks thereafter.2,5,6 site in the body. Although warfarin is not believed to cause bleeding
At each encounter, patients should be meticulously questioned per se, it can “unmask” an existing lesion or enable a massive
regarding their medication use and symptoms related to bleeding and hemorrhage from an ordinarily minor bleeding source. The gas-
thromboembolic complications. Any changes in medications, includ- trointestinal tract is the most frequent site of bleeding. Bruising on
ing changes in dose as well as non-prescription drug and dietary the arms and legs is commonplace, but a painful hematoma may
supplement use, should be carefully explored (see Tables 21–14, necessitate the temporary discontinuation of therapy. Intracranial
21–15, and 21–16). Dietary intake of vitamin K rich foods should also hemorrhage is the most serious and feared complication related to
be evaluated (Table 21–17). warfarin therapy, often resulting in permanent disability or death.
Anticoagulation therapy management services can improve the The annual incidence of major bleeding ranges from 1% in highly
care of patients who take warfarin therapy by providing structured, selected patient populations who are carefully managed, to greater
comprehensive patient education and evaluation.5 When staffed by than 10% in patients managed in less-structured environments,
experienced and knowledgeable practitioners, anticoagulation man- according to some studies.4,5 There are no universally accepted
agement services improve the safety and effectiveness of warfarin criteria for defining a bleeding event as major or minor. Most
therapy compared to “usual” medical care. Anticoagulation patient studies have defined major bleeding as any bleeding event that
management services lower the overall cost of care by reducing the required hospitalization, transfusion of 2 or more units of blood or
frequency of major bleeding and recurrent thromboembolic plasma, or that led to a greater than 2 g/dL drop in hemoglobin
events.7,56 concentration. Bleeding that does not meet the criteria for a major
Portable prothrombin time monitoring devices have enhanced hemorrhage is generally considered to be a minor. Minor bleeding
patient management. Not only do these devices permit clinicians to is very common. Few studies have prospectively evaluated the
do “real-time” therapeutic drug monitoring, but they enable incidence of minor bleeding but it is likely to be greater than 15%
patients to engage in self-testing at home.57,58 Self-monitoring, in its annually even in the most expertly managed patients.4,5
simplest form, requires the patient to report their test results to a Several risk factors for bleeding while taking anticoagulation
healthcare professional. In such arrangements, the clinician contin- therapy have been identified (see Table 21–8). Intensity of anticoag-
ues to make warfarin dosing decisions. Highly motivated and ulation therapy appears to be the most powerful risk factor. Patients
sophisticated patients can be trained to manage themselves, inde- whose target INR is greater than 3.0 have twice the incidence of
pendently altering the dose of warfarin therapy based on their INR major bleeding compared to those with a target of 2.5. The risk of
results. Patients who engage in INR self-monitoring and warfarin intracranial hemorrhage increases significantly when the INR
self-management report high levels of satisfaction with care and remains greater than 4.0 for prolonged periods of time especially in
maintain the INR within the therapeutic range more frequently the elderly. Patients given low-intensity warfarin therapy (goal INR
than those managed by “usual care.” Home INR testing and self- 1.3 to 1.9) may have a lower incidence of bleeding, but this level of
management are clearly not for everyone, however. It requires anticoagulation is insufficient protection against thrombosis for
careful patient selection and considerable education. Unfortunately, most indications. Wide variability in the anticoagulation response,
PT monitoring systems remain relatively expensive and are rarely as seen in patients with very unstable INR values, also appears to be
covered by medical insurance. associated with an increased risk of bleeding. The risk of hemor-
 352
rhage is greatest during the first few weeks of therapy; however, INRs between 5 and 9 within 48 to 72 hours in most patients.62 The
bleeding can occur at any time and the cumulative incidence decision to administer vitamin K should be individualized based on
SECTION 2

steadily increases over time.4,5 the patient’s bleeding risk and the underlying indication for anticoag-
Nonhemorrhagic adverse effects associated with warfarin are ulation therapy. Vitamin K should be used with caution in patients at
uncommon, but can be serious when they do occur.5,6 The “purple high risk of recurrent thromboembolism because of the possibility of
toe syndrome,” manifested as a purplish discoloration of the toes, is INR overcorrection. Conversely, simply withholding warfarin ther-
an extremely rare event reported in a small percentage of patients apy may not lower a high INR quickly enough in patients at high risk
receiving warfarin. The etiology of this unusual phenomenon is for developing bleeding complications. If the INR is greater than 9, a
unknown, but is thought to be the result of cholesterol microembo- 5-mg oral dose of vitamin K is recommended. High doses of vitamin
lization into the arterial circulation of the toes. K (e.g., 10 mg) are associated with prolonged resistance to warfarin
Cardiovascular Disorders

Warfarin-induced skin necrosis is an uncommon but very serious and the occurrence of thromboembolic complications. In the event of
dermatologic reaction that is manifested by a painful maculopapular a serious or life-threatening bleed, intravenous vitamin K should be
rash and ecchymosis or purpura that subsequently progresses to administered as well as fresh-frozen plasma, clotting factor concen-
necrotic gangrene.59 It most frequently appears in areas of the body trates, or recombinant FVII.
rich in subcutaneous fat, such as the breasts, thighs, buttocks, and
abdomen. The incidence of warfarin-induced skin necrosis is less Drug–Drug and Drug–Food Interactions
than 0.1%. It is occurs most commonly in middle-aged women who
are being treated for acute venous thrombosis. Although symptoms The pharmacokinetic and pharmacodynamic properties of war-
generally appear during the first week of therapy, it has been farin, coupled with its narrow therapeutic index, predispose this
reported in a small number of patients who had taken warfarin for agent to numerous clinically important food and drug interactions
months and even years. The pathogenesis of warfarin-induced skin (see Tables 21–14, 21–15, 21–16, and 21–17).5,63,64 Vitamin K can
necrosis is not clearly understood. Many believe imbalances between reverse warfarin’s pharmacologic activity, and many foods contain
procoagulant and anticoagulant proteins that occur early in the sufficient vitamin K to reduce the anticoagulation effect of warfarin
course of warfarin therapy resulting in capillary thrombosis and if a patient consumes them in large portions or repetitively within a
secondary hemorrhages. The observation that patients with proteins short period of time.64 Patients should be given a list of vitamin K-
C or S deficiency appear to be at greater risk for warfarin-induced rich foods and instructed to maintain a relatively consistent intake.
skin necrosis supports this theory. Warfarin-induced skin necrosis It is important to stress consistency and moderation rather than
has also been reported in patients with other disorders of hypercoag- absolute abstinence. Abrupt changes in vitamin K intake should be
ulability, such as antithrombin deficiency and antiphospholipid considered when unexplained changes in the INR occur. Alternative
antibodies. Patients who receive large “loading” doses of warfarin sources of vitamin K, such as multivitamins and nutritional supple-
may also be at greater risk. It is recommended that heparin therapy ments (e.g., Sustacal and Ensure) should also be considered.
be overlapped for a minimum of 7 days when initiating therapy in Patients who require parenteral nutrition should not receive a
any patient suspected to have a hypercoagulable state or who has a weekly bolus dose of vitamin K if they are taking warfarin therapy.
strong family history of venous thrombosis. If the diagnosis of skin Pharmacokinetic drug interactions with warfarin are primarily a
necrosis is suspected, warfarin therapy should be immediately dis- result of alterations in hepatic metabolism or binding to plasma
continued, vitamin K administered, and full-dose UFH or LMWH proteins. Drugs that inhibit or induce the CYP2C9, CYP1A2, and
therapy initiated. Warfarin therapy should be restarted with extreme CYP3A4 isoenzymes have the greatest potential to significantly alter
caution in patients with a history of skin necrosis, if at all. the response to warfarin therapy. Protein-binding displacement
Gastrointestinal side effects of warfarin therapy are uncommon and interactions can also occur. However, in the absence of hepatic
usually self-limited. Because warfarin interferes with vitamin K metab- disease or a diminished capacity to metabolize warfarin, changes in
olism, there has been some theoretical concern that it may adversely protein binding result in only transient changes in the INR. Drugs
affect bone formation and cause osteoporosis with long-term use. In that alter hemostasis, platelet function, or the clearance of clotting
one recent analysis, long-term use of warfarin was associated with factors (e.g., thyroid hormone replacement) can alter the response to
osteoporotic fractures, in men with atrial fibrillation.60 warfarin therapy or increase the risk of bleeding by pharmacody-
namic mechanisms.5,63
Management of Bleeding and The explosive increase in the use of herbal and alternative
Excessive Anticoagulation therapies in North America has raised concern regarding their
potential to interact with warfarin therapy.64 All patients on war-
Specific recommendations for the management of patients with an farin therapy should be questioned regarding the use of herbal drugs
elevated INR are published by the American College of Chest Physi- and dietary supplements. Clinicians should advise patients on
cians (ACCP) Consensus Conference on Antithrombotic Therapy warfarin therapy to seek information about potential interactions
(Fig. 21–9).5 Patients with a mildly elevated INR (3.5 to 5.0) should be with warfarin whenever they start to take a new drug product,
examined for signs and symptoms of bleeding, as well as factors that whether it is prescribed or purchased over the counter. If there is a
increase bleeding risk. In this circumstance, either reducing the dose known drug interaction or doubt about its potential to alter the
of warfarin or holding one or two doses will safely manage most response to warfarin, more frequent INR testing following the
patients. When a swift reduction in an elevated INR is required, oral initiation of the new agent is prudent.
or intravenous vitamin K1 (phytonadione) can be given.5,61 In the
absence of major bleeding, the oral route of administration is pre-
ferred. While the IV route produces a more rapid reversal, it is
Use in Special Populations
associated with rare but serious anaphylactoid reactions. If the INR is In the absence of a clear and compelling indication, warfarin should
between 5 and 9, doses of warfarin should be withheld and may be not be used during pregnancy because of the potential for fetal
combined with a low dose of oral vitamin K (≤5 mg). Low doses of hemorrhage and teratogenic complications.27 Warfarin crosses the
oral vitamin K will consistently reduce the INR within 24 hours placenta and is associated with several embryopathies, particularly
without making the patient refractory to warfarin therapy. Overcor- CNS abnormalities, that have occurred throughout gestation. The
rection of the INR in the patient who is not bleeding is unnecessary FDA has designated warfarin a pregnancy category X agent. As UFH
but common. Simply withholding warfarin will result in correction of and the LMWHs are large molecules that do not cross the placental
 353

Is the patient experiencing signs or symptoms of bleeding?

CHAPTER 21
or
Is rapid reversal of excessive anticoagulation required?

Yes No

Determine the site and severity of What is the INR

bleeding. value?
Administer vitamin K 10 mg via slow
IV infusion, along with fresh-frozen

Venous Thromboembolism
plasma, rFVII, or prothrombin complex
as needed Above therapeutic
Check INR in 12 hours and repeat 5.0–9.0 >9.0
range but <5.0
vitamin K infusion as needed until
INR normalized or within therapeutic
range
Does the patient have risk
factors for bleeding?

Omit next 1–2 doses of Yes

warfarin. No
Check INR in 3–7 days.
Restart warfarin at Omit next 1–3 doses of Are conditions present that
reduced dose warfarin increase the patient’s risk of
and thromboembolic
administer vitamin K complications?
2.5 mg orally. Check INR
every 24–48 hours.
Restart at reduced dose
Omit next 1–3 doses of
Yes warfarin
No and
Administer vitamin K
Omit next 1–3 doses of Omit next 1–3 doses of 5–10 mg orally.
warfarin. Consider warfarin Check INR in 12–24 hours.
administering vitamin K and If INR still elevated
2.5 mg orally if INR > 8.0. administer vitamin K 2.5– above 9, repeat
Avoid using higher doses 5.0 mg orally and check administeration of
(5–10 mg) of vitamin K INR every 24–48 hrs. vitamin K.
Check INR every 24–48 hours. Restart at reduced dose Check INR every 24 hours.
Restart at reduced dose once therapeutic Restart warfarin at
once therapeutic reduced dose once
therapeutic

FIGURE 21-9. Management of an elevated international normalized ratio (INR) in patients taking warfarin. Dose reductions
should be made by determining the weekly warfarin dose and reducing the weekly dose by 10% to 25% based on degree of
INR elevation. Conditions that increase the risk of thromboembolic complications include history of hypercoagulability disorders
(e.g., protein C or S deficiency, presence of antiphospholipid antibodies, antithrombin deficiency, activated protein C resistance),
arterial or venous thrombosis within the previous month, thromboembolism associated with malignancy, and mechanical mitral
valve in conjunction with atrial fibrillation, previous stroke, poor ventricular function, or coexisting mechanical aortic valve. (INR,
international normalized ratio; rFVII, recombinant factor VII.)

barrier, they are considered the drugs of choice for anticoagulation bolism (i.e., DVT or PE in the previous month) should be given so-
during pregnancy. Warfarin is excreted into the breast milk in very called bridge therapy with UFH or a LMWH before and/or after the
low concentrations and is generally considered safe to use by procedure (Table 21–18).
women who are breast-feeding. Warfarin use among elderly patients is increasingly common.
Patients scheduled to undergo major surgery or other invasive Although the drug has been extensively studied in this population,
procedures often require temporary discontinuation of warfarin some debate still remains regarding the relative risks of warfarin
therapy.5 The decision to withhold warfarin therapy should be therapy in the elderly.5,6 Data supporting the notion that age increases
based on the type of surgical procedure being performed and the hemorrhagic risk are somewhat conflicting. Age greater than 75 years
patient’s risk of bleeding and thromboembolism. Warfarin therapy is associated with an increased risk of intracranial hemorrhage, but
should generally not be discontinued in patients undergoing mini- the overall incidence of major bleeding is similar to younger users.
mally invasive procedures such as dental work.5,65 If the bleeding Elderly patients may be more prone to excessive anticoagulation as a
risk from the procedure is considerable, warfarin should be stopped consequence of nutritional deficiencies, comorbidities, and multiple-
4 to 5 days prior to the procedure in order to allow the INR to drug interactions. Furthermore, they are often at greater risk of falls.
return to near-normal values. Alternatively, warfarin can be stopped Although they often derive the greatest benefit from anticoagulation
and a low dose (2.5 mg) of oral vitamin K may be given 2 days prior therapy, elderly patients should be monitored with greater vigilance,
to the procedure.5 Patients at moderate or high risk of thromboem- and warfarin dose changes should be made more cautiously.
 354

TABLE 21-18 General Approach to Periprocedural Anticoagulation on patient outcomes.3 To rely on the early diagnosis and treatment of
Therapy Management VTE is unacceptable because many patients will die before treatment
SECTION 2

can be initiated. Furthermore, even clinically silent disease is associ-

Days Relative to Procedure Anticoagulation Management
ated with long-term morbidity from the postthrombotic syndrome
–7 to –10 Assess thrombosis and bleeding risk and predisposes the patient to future thromboembolic events. Despite
Determine appropriate bridging plan an immense body of literature that overwhelmingly supports the
Obtain INR widespread use of pharmacologic and nonpharmacologic strategies to
–7 Stop aspirin or other antiplatelet therapy
prevent VTE, prophylaxis is underused in most hospitals. Even when
–6 or –5 Stop Warfarina
prophylaxis is given, many patients receive prophylaxis that is less
–4 or –3 Start LMWHb
–2 LMWH
than optimal. Educational programs and clinical decision support
Cardiovascular Disorders

–1 Give last dose of LMWH 12–24 hours systems have been shown to improve the appropriate use of VTE
before procedure prevention methods.3
Obtain INR  The goal of an effective VTE prophylaxis program is to identify
0 = Surgery Resume warfarinc at usual maintenance all patients at risk, determine each patient’s level of risk, select and
dose on evening after procedure implement regimens that provide sufficient protection for the level of
+1 Resume LMWHd risk, and avoid or limit complications from the selected regimens. As
Warfarin hospitalized patients are frequently at high risk for VTE, screening all
+2 to + 3 LMWHd patients prior to or at the time of admission to determine their level
Warfarin
of risk is the first step in an effective prophylaxis program. The risk
Obtain INR and CBC
classification criteria and recommended prophylaxis strategies pro-
+4 to +5 LMWH
Warfarin
mulgated by the ACCP Conference on Antithrombotic Therapy is
Obtain INR and CBC widely used in North America (Table 21–19).3 Several pharmacologic
> +6 Stop LMWH once INR is therapeutic and nonpharmacologic methods are effective for preventing VTE,
and these can be used alone or in combination. Nonpharmacologic
CBC, complete blood count; INR, international normalized ratio; LMWH, low-molecular-weight heparin.
a methods improve venous blood flow by mechanical means, whereas
Warfarin stopped on day –5 if INR drawn on day –7 to –10 is 2.0 to 3.0 or day –6 if INR drawn on
day –7 to –10 is 2.5 to 3.5. drug therapy counteracts the propensity for thrombus formation by
b
LMWH is initiated 2 days (36 to 48 hours) after warfarin is discontinued. dampening the coagulation cascade.
c
Prophylactic dose LMWH may be used in low bleeding-risk procedures.
d
Full (treatment) doses of LMWH can be resumed on days 1, 2, and 3 once hemostasis is adequate.
Nonpharmacologic Strategies
From Ansell et al.5
Resumption of ambulation as soon as possible following surgery
GENERAL APPROACH TO THE PREVENTION reduces the incidence of VTE in low-risk patients.3 Walking increases
OF VENOUS THROMBOEMBOLISM venous blood flow and promotes the flow of natural antithrombotic
factors into the lower extremities. During prolonged surgeries, electri-
Given that VTE is often clinically silent and potentially fatal, strategies cal calf muscle stimulation devices that mimic the pumping action
to prevent DVT in at-risk populations will have the greatest impact produced during ambulation can be beneficial. Although these

TABLE 21-19 Risk Classification and Consensus Guidelines for Venous Thromboembolism Prevention
Calf Vein Symptomatic Fatal PE
Level of Risk Thrombosis (%) PE (%) (%) Prevention Strategies
Low
Minor surgery, age <40 years, and no clinical risk factors 2 0.2 0.002 Ambulation
Moderate 10–20 1–2 0.1–0.4 UFH 5,000 units SC q 12 h
Major or minor surgery, age 40–60 years, and no clinical risk factors Dalteparin 2,500 units SC q 24 h
Major surgery, age <40 years, and no clinic risk factors Enoxaparin 40 mg SC q 24 h
Minor surgery, with clinical risk factor(s) Tinzaparin 3,500 units SC q 24 h
Acutely ill (e.g., MI, ischemic stroke, CHF exacerbation), and no clinical IPC
risk factors Graduated compression stockings
High
Major surgery, age >60 years, and no clinical risk factors 20–40 2–4 0.4–1.0 UFH 5,000 units SC q 8 h
Major surgery, age 40–60 years, with clinical risk factor(s) Dalteparin 5,000 units SC q 24 h
Acutely ill (e.g., MI, ischemic stroke, CHF exacerbation), with risk factor(s) Enoxaparin 40 mg SC q 24 h
Fondaparinux 2.5 mg SC q 24 h
Tinzaparin 75 units/kg SC q 24 h
IPC
Highest
Major lower-extremity orthopedic surgery 40–80 4–10 0.2–5 Adjusted dose UFH SC q 8 h (aPTT >36 s)
Hip fracture Dalteparin 5,000 units SC q 24 h
Multiple trauma Desirudin 15 mg SC q 12 h
Major surgery, age >40 years, and prior history of VTE Enoxaparin 30 mg SC q 12 h
Major surgery, age >40 years, and malignancy Fondaparinux 2.5 mg SC q 24 h
Major surgery, age >40 years, and hypercoagulable state Tinzaparin 75 units/kg SC q 24 h
Spinal cord injury or stroke with limb paralysis Warfarin (INR = 2.0–3.0)
IPC with UFH 5,000 units SC q 8 h
aPTT, activated partial thromboplastin time; CHF, congestive heart failure; INR, international normalized ratio; IPC, intermittent pneumatic compression; MI, myocardial infarction; SC, subcutaneous; UFH,
unfractionated heparin; VTE, venous thromboembolism.
From Geerts et al.3
 355
devices can reduce the risk of DVT by more than 50%, their use is Most randomized controlled trials fail to show a significant
painful, and they can be used only when the patient is under general benefit from aspirin therapy in the prevention of VTE.3 The ACCP

CHAPTER 21
anesthesia. Continuous passive motion devices and plantar compres- Consensus Conference continues to recommend against the use of
sion systems are also available but their effectiveness is uncertain. aspirin as the primary method of VTE prophylaxis. Antiplatelet
Graduated compression stockings reduce the incidence of VTE by drugs clearly reduce the risk of coronary artery and cerebrovascular
approximately 60% following general surgery, neurosurgery, and events in patients with arterial disease, but aspirin produces a very
stroke.3,66 Compression stockings work by increasing the velocity of modest reduction in VTE following orthopedic surgeries of the
venous blood flow. They apply a graded amount of pressure, with the lower extremities. The relative contribution of platelets in the
greatest amount of pressure applied at the ankle. Inexpensive and pathogenesis of venous thrombosis compared with that of arterial
safe, they are an excellent choice when pharmacologic interventions thrombosis can explain the reason for this difference. Venous

Venous Thromboembolism
are either contraindicated or difficult to monitor adequately. When thrombosis results primarily from venous stasis, while arterial
combined with pharmacologic interventions, graduated compres- thrombosis is most often the result of vascular wall injury.
sion stockings have an additive effect. Some patients are unable to
wear compression stockings because of the size or shape of their legs,
however. CLINICAL CONTROVERSY
Similar to graduated compression stockings, intermittent pneu-
In a series of large, well-designed phase III clinical trials, fonda-
matic compression (IPC) devices increase the velocity of blood flow
parinux was superior to enoxaparin for the prevention of VTE in
in the lower extremities.3,67 The technique involves the sequential
patients who were undergoing lower-extremity orthopedic sur-
inflation of a series of cuffs wrapped around the patient’s legs. Using gery. However, the rate of symptomatic pulmonary embolism
graded pressure, the cuffs inflate in 1- to 2-minute cycles continually and death was not different between the two treatments in any
throughout the day from the ankles to the thighs. IPC reduces the of these studies. Furthermore, fondaparinux has not been com-
risk of VTE by more than 60% following general surgery, neurosur- pared to warfarin for the prevention of VTE in high-risk
gery, and orthopedic surgery.3 There is some theoretical concern that patients. Based on these findings, some experts contend that
external compression may dislodge a previously formed clot.68 fondaparinux offers no clinical advantages over enoxaparin or
Although IPC is well tolerated and safe to use in patients who have warfarin. In addition, although there was no difference in the
contraindications to pharmacologic therapies, it does have a few risk of major hemorrhage seen in the clinical trials when com-
drawbacks. It is more expensive than the use of graduated compres- pared to enoxaparin, some clinicians worry about the potential
sion stockings, it is a relatively cumbersome technique, and some for bleeding with fondaparinux because it has a long half-life and
patients may have difficulty sleeping while using it.3 Like graduated it cannot be reversed with protamine sulfate. Despite these
compression hose, IPC can increase the effectiveness of pharmaco- concerns, some experts believe fondaparinux should be used
logic prophylaxis. preferentially because asymptomatic DVTs and PEs may
Inferior vena cava (IVC) filters, also known as Greenfield filters, increase the future risk of recurrent thrombotic events and the
provide short-term protection against PE in very-high-risk patients postthrombotic syndrome.
by preventing the embolization of a thrombus formed in the lower
extremities into the pulmonary circulation.3,69,70 Percutaneous inser-
The most extensively studied agents for the prevention of VTE
tion of a filter into the IVC is a minimally invasive procedure
are UFH, the LMWHs, and fondaparinux.3,71 The LMWHs and
performed via fluoroscopy. Despite the widespread use of IVC filters,
fondaparinux provide superior protection against VTE when com-
there are very limited data regarding their effectiveness and long-term
pared to low-dose UFH.3,71 Their more predictable absorption when
safety. The evidence suggests that IVC filters, particularly in the
given by subcutaneous injection may be the explanation. Even so,
absence of effective antithrombotic therapy, increase the long-term
UFH remains a highly effective, cost-conscious choice for many
risk of recurrent DVT. In the only randomized clinical trial examin-
patient populations, provided that it is given in the appropriate dose
ing the short- and long-term effectiveness of the filters in patients
(see Table 21–19). Low-dose UFH (5,000 units every 12 hours or
with a documented proximal DVT, treatment with IVC filters in
every 8 hours) given subcutaneously reduces the risk of VTE by 55%
combination with anticoagulation therapy reduced the risk of pulmo-
to 70% in patients undergoing a wide range of general surgical
nary embolism by more than 75% during the first 12 days following
procedures and following a myocardial infarction or stroke. For the
insertion.70 However, this benefit was not sustained during 2 years of
prevention of VTE following hip and knee replacement surgery, the
followup and the long-term risk of recurrent deep vein thrombosis
effectiveness of low-dose UFH is considerably lower.3 Adjusted-
was nearly twofold higher in those who received a filter. Although
dose UFH therapy provided subcutaneously, which requires dose
IVC filters can reduce the short-term risk of PE in patients who are at
adjustments to maintain the aPTT at the high end of the normal
highest risk, they should be reserved for patients in whom other
range, appears to be substantially more effective than low-dose UFH
prophylactic strategies cannot be used. Furthermore, to reduce the
in the highest-risk patient populations. However, adjusted-dose
long-term risk of VTE in association with IVC filters, pharmacologic
UFH has been studied in only a few relatively small clinical trials
prophylaxis is necessary, and warfarin therapy should begin as soon
and requires frequent laboratory monitoring. The LMWHs and
as the patient is able to tolerate it.
fondaparinux appear to provide a high degree of protection against
VTE in most high-risk populations. The appropriate prophylactic
Pharmacologic Strategies dose for each LMWH product is indication specific (see Table 21–
Several pharmacologic interventions have been extensively evalu- 10). There is no evidence that one LMWH is superior to another for
ated in numerous randomized clinical trials.3 Appropriately selected the prevention of VTE. Fondaparinux was significantly more effec-
drug therapies can dramatically reduce the incidence of VTE follow- tive than enoxaparin in several clinical trials that enrolled patients
ing hip replacement, knee replacement, general surgery, myocardial undergoing high risk orthopedic procedures but has not been
infarction, and ischemic stroke (see Table 21–19). The choice of shown to reduce the incidence of symptomatic PE or mortality.71 To
agent and dose to use for VTE prevention must be based on the provide optimal protection, some experts believe that the LMWHs
patient’s level of risk for thrombosis and bleeding complications, as should be initiated prior to surgery.3,72
well as cost and the availability of an adequate drug therapy Warfarin is a commonly used option for the prevention of VTE
monitoring system. following orthopedic surgeries of the lower extremities.3 The evi-
 356
dence is equivocal regarding the relative effectiveness of warfarin avoided.77 Based on typical drug-acquisition costs, LMWH and
compared to the LMWHs for the prevention of clinically important fondaparinux appear to be cost-effective choices in the highest-risk
SECTION 2

VTE events in the highest risk populations. When used to prevent patient populations.82
VTE, the dose of warfarin should be adjusted to maintain an INR
between 2.0 and 3.0; however, some orthopedic surgeons favor
lower initial INR goal ranges (e.g., 1.5 to 2.5) because of fear of GENERAL APPROACH TO THE TREATMENT
bleeding at the surgical site. Oral administration and low drug cost OF VENOUS THROMBOEMBOLISM
give warfarin some advantages over the LMWHs and fondaparinux.
However, warfarin does not achieve its full antithrombotic effect for  Before initiating anticoagulation therapy for the treatment of
several days, requires frequent monitoring and periodic dosage VTE, it is imperative to establish an accurate diagnosis; thus
preventing unnecessary risk and expense to the patient.83 Anticoag-
Cardiovascular Disorders

adjustments, and carries a substantial risk of major bleeding. For

these reasons, warfarin is reserved for the highest-risk patients. ulation therapy remains the mainstay of treatment for VTE. DVT
Furthermore, warfarin should be recommended only when a well- and PE are manifestations of the same disease process and are
developed monitoring system is available.5 treated similarly.2 Full “therapeutic” doses of antithrombotic drugs
The optimal duration for VTE prophylaxis following surgery is prevent thrombus extension and embolization as well as reduce the
not well established.3,73 Prophylaxis should be given throughout the risk of long-term sequelae such as the postthrombotic syndrome,
period of risk. For general surgical procedures and medical condi- pulmonary hypertension, and recurrent thromboembolism.2,84 The
tions, once the patient is able to ambulate regularly and other risk standard approach is to initiate therapy with UFH by continuous IV
factors are no longer present, prophylaxis can be discontinued. infusion or a LMWH or fondaparinux by subcutaneous injection
Because of the relatively high incidence of VTE in the first month and to make the transition to warfarin for maintenance therapy
following hospital discharge among patients who have undergone a (Table 21–20 and Fig. 21–10). In rare circumstances, elimination of
lower extremity orthopedic procedure, extended prophylaxis fol- the obstructing thrombus is warranted and the use of venous
lowing hospital discharge with either a LMWH, fondaparinux, or thrombectomy or thrombolysis can be considered.2 Inferior vena
warfarin appears to be beneficial. Most clinical trials support the use
of antithrombotic therapy for 21 to 35 days following total hip
replacement and hip fracture repair surgeries.33,74,75 TABLE 21-20 Consensus Guidelines for Venous
Thromboembolism Treatment
Pharmacoeconomic Considerations Recommendation Gradea

Only a handful of studies have formally evaluated the cost-effective- Acute Acute treatment of DVT or PE should be with 1A
ness of VTE prevention strategies. The acquisition costs of gradu- anticoagulation LMWH, fondaparinux, intravenous UFH, or
adjusted-dose subcutaneous UFH
ated compression stockings, heparin, and warfarin are considerably
The dose of UFH should be sufficient to prolong 1C+
less than those of the LMWHs and fondaparinux. However, the
the aPTT to a range that corresponds to a
acquisition cost for drug therapy is relatively small when compared plasma heparin level of 0.2 to 0.4 international
with the overall cost of care.76 Economic analyses must take into units/mL by protamine titration or an anti-Xa
account the efficacy of the strategy, treatment complications, and level of 0.3 to 0.6 international units/mL
monitoring costs. LMWH and fondaparinux are preferred over UFH 2B
The determination of the cost-effectiveness of VTE prophylaxis is A LMWH is preferred in patients with cancer 1A
based on the premise that a reduction in future VTE events will Duration of acute Treatment with UFH, LMWH, or fondaparinux 1A
reduce overall healthcare costs.77 Furthermore, the incremental cost treatment should be overlapped with warfarin for at least 5
per patient will decrease proportionally with an increase in the days and can be stopped when the INR is >2.0;
most patients should have warfarin started at the
frequency of VTE in the population. Stated another way, the cost of
same time as UFH, LMWH, or fondaparinux
providing prophylaxis to 1,000 patients will decline as the incidence
Patients with cancer should be treated with a 1A
of VTE in the given population increases. Consequently, more LMWH for at least 6 months
expensive and effective strategies become more cost-effective in A longer period of heparin therapy (approximately 1C
higher-risk populations. In populations at low risk for VTE, early 10 days) is recommended for massive PE or
ambulation appears to be the most cost-effective strategy. In popu- severe iliofemoral thrombosis
lations at moderate risk, the use of graduated compression stock- Long-term Oral anticoagulation therapy (target INR 2.5, range: 1A
ings, the least expensive intervention, results in a lower overall cost anticoagulation 2.0 to 3.0) should be continued for at least 3
of care, whereas low-dose UFH is estimated to increase the cost $50 months; if oral anticoagulation therapy is contra-
(in 1990 dollars) per patient when compared with no prophylaxis.78 indicated (e.g., pregnancy), a treatment dose of
This compares favorably with the incremental costs associated with LMWH or adjusted-dose UFH should be used
Patients with an idiopathic VTE, an inherited disor- 1A
other routinely employed preventative measures. Although LMWH
der of hypercoagulability, or antiphospholipid
provides slightly greater reductions in the risk of VTE in patients antibodies should be treated indefinitely (at
who are at moderate risk of VTE, the additional cost is estimated to least 2.5 years)
be $107 (in 1999 dollars) per patient when compared to low-dose Patients with continuing risk factors (e.g., malig- 1C
UFH.79 Whether universal use of LMWH in moderate-risk patients nancy, immobility) should be treated for at
is a cost-effective strategy remains controversial. least 12 months
In high-risk patients, the cost-effectiveness of prevention is far
aPTT, activated partial thromboplastin time; DVT, deep vein thrombosis; INR, international normal-
greater because the incidence of VTE is higher. Following hip ized ratio; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; UFH, unfractionated
replacement surgery, regardless of the strategy selected, prophylaxis heparin; VTE, venous thromboembolism.
saves money when compared with no prophylaxis.77 The LMWHs a
Refers to grade of recommendation (1A, strong recommendation applying to most patients without
and fondaparinux slightly increase the total mean cost of care after reservation; 1C, intermediate-strength recommendation that may change when stronger evidence
becomes available; 1C+, strong recommendation that applies to most patients in most circumstances;
total hip and knee replacement when compared with low-dose UFH 2B, weak recommendation where alternative approaches likely to be better for some patients under
and warfarin.80,81 However, because of their superior effectiveness, some circumstances).
the LMWHs have a significantly lower cost per DVT and PE From Buller et al.2
 357

CHAPTER 21
-If VTE not objectively confirmed order
appropriate diagnostic testing
-Consider giving UFH 5000 units IV
Objectively
confirmed VTE

Venous Thromboembolism
Consider vena Anticoagulant
Yes
cava filter contraindicated?

SBP < 90 mm Hg
No vasopressor
therapy

Contraindication to PE with evidence

No thrombolytic Yes
of shock?
therapy?
Consider outpatient treatment
if patient is:
Consider -Hemodynamically stable
No
thrombolytic -Free of severe renal disease
therapy -Low bleeding risk
-Free of coexisting conditions that
Initiate would require hospitalization
anticoagulation
Yes therapy with:
Consider UFH or LMWH or
embolectomy in Fondaparinux
critically ill patients and warfarin

Consider long- Hypercoagulable

term warfarin Yes state or idiopathic
therapy VTE?

No

Warfarin therapy
for 3 to 6 months

FIGURE 21-10. Treatment of venous thromboembolism (VTE). (LMWH, low-molecular-weight heparin; PE, pulmonary embolism;
SBP, systolic blood pressure; UFH, unfractionated heparin.)

cava interruption with a filter is also an option in those with Although UFH can be given by either subcutaneous or IV injection,
contraindications to anticoagulation therapy or in whom anticoag- continuous IV infusion has been preferred because of improved
ulant therapy has failed. dosing precision (see Table 21–7).2 When UFH is administered by
Once the diagnosis of VTE has been objectively confirmed (see IV infusion, the aPTT or a suitable coagulation study should be used
Clinical Presentation and Diagnosis below), anticoagulant therapy to monitor the anticoagulant effect.24 The infusion rate should be
with either UFH, LMWH, or fondaparinux should be instituted as adjusted to maintain an appropriate range corresponding to a
soon as possible. LMWHs and fondaparinux are highly effective and heparin concentration of 0.3 to 0.7 international units/mL anti-Xa
can be administered in the outpatient setting. The decision to activity by the amidolytic assay. Weight-based dosing of UFH
initiate therapy with a LMWH or fondaparinux on an outpatient achieves a therapeutic aPTT in the vast majority of patients in the
basis should be based on institutional resources and patient specific first 24 hours (see Table 21–7).22 Failure to give a sufficient dose of
variables (Table 21–21).  IV UFH has been shown to increase the risk of VTE recurrence not
only during the initial treatment but also during long-term ther-
UNFRACTIONATED HEPARIN apy.24 Intravenous UFH requires hospitalization with frequent
monitoring and dose adjustment. Well organized inpatient antico-
The parenteral administration of UFH followed by warfarin has agulation management services have been shown to improve patient
been the conventional treatment of patients with VTE for decades. care by increasing the proportion of aPTT values in the therapeutic
 358

TABLE 21-21 Outpatient Treatment Protocol for Deep Venous Thrombosis

SECTION 2

Target Population: Inclusion/exclusion criteria for outpatient venous thromboembolism (VTE) treatment
Inclusion: Patients with objectively diagnosed VTE
Relative exclusion: Patients with clinical evidence of pulmonary embolus or suspected embolism who are hemodynamically stable
Exclusion: Arterial thromboembolism or patients who are currently receiving dialysis, actively bleeding, have had recent (within 2 weeks) major surgery/trauma, or
have other severe uncompensated comorbid conditions
Recommended Procedure: May vary depending on the patient’s clinical condition
A. Confirm diagnosis of VTE by objective testing
1. Venous ultrasonogram
2. Ventilation–perfusion (V/Q) scan
Cardiovascular Disorders

3. Computed tomography (CT) scan

B. Day 1
1. Baseline laboratory evaluation
a. Prothrombin time (PT) and calculated international normalized ration (INR)
b. Activated partial thromboplastin time (aPTT)
c. Serum creatinine (Scr)
d. Complete blood count (CBC) with platelets
2. Medication
a. Low-molecular-weight heparin (LMWH) or fondaparinux injections
i. Enoxaparin 1 mg/kg subcutaneously (SC) q 12 h or
ii. Enoxaparin 1.5 mg/kg SC q 24 h (not recommended for patients with cancer or for obese patients)
iii. Dalteparin 100 units/kg SC q 12 h or
iv. Dalteparin 200 units/kg SC q 24 h or
v. Tinzaparin 175 units/kg SC q 24 h or
vi. Fondaparinux 7.5 mg SC q 24 h (5 mg if <50 kg and 10 mg if >100 kg)
b. Warfarin sodium 5–10 mg orally every evening
c. Pain medication if necessary (avoid nonsteroidal antiinflammatory drugs [NSAIDs])
3. Patient education
a. Clinical pharmacy/nursing
i. Educate patient regarding the importance of proper monitoring of anticoagulation therapy and indications for additional medical evaluation; document activities in
the medical record
ii. Teach patient how to self-administer LMWH (if patient or family member unwilling or unable to self-administer LMWH injection, visiting nurse services should be
arranged); initial LMWH injection should be administered in the medical office or hospital
iii. Instruct patient regarding local therapy: elevation of affected extremity; localized heat, antiembolic exercises (flexion–extension of ankle for lower-extremity VTE, or
hand squeezing–relaxation for upper-extremity VTE)
b. Pharmacy operations
i. Provide backup for clinical pharmacy/nursing; reinforce patient education regarding indication, use, monitoring, side effects, and drug interactions with
antithrombotic therapy
ii. Repackage LMWH syringes (if indicated) in patient-specific doses and dispense 5 to 7 days of therapy
iii. Screen patient’s pharmacy profile for potential drug–drug interactions with anticoagulation therapy
c. Clinical pharmacy anticoagulation service enrollment
i. The physician should forward outpatient VTE treatment orders to the anticoagulation service
C. Day 2
1. Laboratory evaluation: not required on day 2 of therapy
2. Medications: continue LMWH and warfarin as directed
3. Anticoagulation service
a. Contact patient and evaluate for symptoms of pulmonary embolism (PE), clot extension, and/or bleeding
b. Arrange for visiting nursing service if family or family member is having difficulty with outpatient therapy
c. Continue reduced activity as long as pain persists (when possible, elevate extremity); increase activity as tolerated
d. Document activities in medical record
D. Day 3
1. Laboratory evaluation: check INR
2. Medications: continue LMWH and warfarin directed
3. Anticoagulation service
a. Contact patient and evaluate for symptoms of PE, clot extension, and/or bleeding
b. Interpret results of INR and adjust dose of warfarin to achieve a target INR of 2.5
c. Patient activity: continue reduced activity as long as pain persists (when possible, elevate extremity); increase activity as tolerated
d. Document activities in medical record
E. Day 4
1. Laboratory evaluation: check INR
2. Medications: continue LMWH and warfarin as directed
3. Anticoagulation service
a. Contact patient and evaluate for symptoms of PE, clot extensions, and/or bleeding
b. Interpret results of INR and adjust dose of warfarin to achieve a target INR of 2.5
c. Patient activity: no restrictions; if pain increases, contact anticoagulation service or provider
d. Document activities in medical record
(continued)
 359

TABLE 21-21 Outpatient Treatment Protocol for Deep Venous Thrombosis (continued)

CHAPTER 21
F. Day 5
1. Laboratory evaluation: check INR and CBC with platelets
2. Medications: continue LMWH if indicated and warfarin as directed
3. Anticoagulation service
a. Contact patient and evaluate for symptoms of PE, clot extension, and/or bleeding
b. Interpret results of INR and adjust does of warfarin to achieve a target INR of 2.5
c. Patient activity: no restriction; if pain increases, contact primary care provider
d. Document activities in medical record

Venous Thromboembolism
range, reducing the length of hospital stay, and lowering total therapy or embolectomy is anticipated, UFH, which can be rapidly
hospital costs when compared to usual care.8 However, despite the reversed, is preferred.89 Patients with PE who present with shock
widespread use of weight-based dosing protocols, some patients still have the highest risk of mortality and require aggressive interven-
fail to achieve an adequate response to UFH therapy.24 There is also tions such as volume expansion, vasopressor therapy, intubation
evidence that UFH does not prevent thrombus progression in some and mechanical ventilation in addition to antithrombotic therapy.90
patients with DVT, and rebound thrombin generation has been Not all patients are appropriate candidates for outpatient DVT
observed when UFH is discontinued abruptly.24 These limitations of treatment. At a minimum, patients with objectively diagnosed DVT
traditional IV UFH in the acute treatment of VTE have led to the must be reliable or have adequate caregiver support.87 Patients and
investigation of alternative approaches. their caregivers must be willing and active participants in the outpa-
tient management of DVT (Table 21–22). Patients who are unable to
LOW-MOLECULAR-WEIGHT HEPARIN manage or who decline at-home treatment should be admitted to the
hospital. These patients may subsequently opt for early discharge on
Because of their improved pharmacokinetic and pharmacodynamic LMWH. Daily patient contact either in person or via telephone is
profile as well as ease of use, the LMWHs have replaced UFH for the essential to identify potential complications and to address questions
treatment of VTE in many institutions. The LMWHs given subcu- and concerns promptly. During daily contacts patients must be
taneously in fixed, weight-based doses (see Table 21–10) are at least asked about symptoms that may indicate bleeding, thrombus exten-
as effective as UFH given IV for the treatment of VTE.2 A number sion, and PE.87 Once acute treatment with a LMWH or fondaparinux
of meta-analyses comparing LMWH to UFH in the treatment of has been transitioned to long-term warfarin therapy (approximately
venous thromboembolism have been conducted. These analyses 5 to 10 days), patient contact can occur less frequently.
demonstrate no differences in clinically important end points,
including recurrent DVT, PE, major or minor bleeding, and throm- FONDAPARINUX
bocytopenia.2 Surprisingly, patients who received LMWH had a
significantly lower mortality rate. The reduction in mortality was Two clinical trials have shown fondaparinux to be a safe and effective
primarily seen in patients with cancer.2 The explanation for this alternative to enoxaparin and intravenous UFH for the treatment of
survival advantage is unknown. There appears to be no difference in VTE.91,92 In the Mondial Assessment of Thromboembolism Treat-
the risk of recurrent VTE between patients who are treated on an ment Initiated by Synthetic Pentasaccharide with Symptomatic End-
inpatient or outpatient basis with a LMWH for DVT.85 However, points-Deep Venous Thrombosis (MATISSE-DVT) trial, a fixed-dose
outpatient treatment was associated with a slightly greater risk of regimen of fondaparinux (7.5 mg q 24 h) given by subcutaneous
major bleeding indicating the need for close monitoring when injection was compared to the standard weight-adjusted dosing of
LMWH is given in this setting. There appears to be no difference in enoxaparin (1 mg/kg q 12 h) for the acute treatment DVT followed by
the efficacy or safety of once-daily versus twice-daily dosing regi- 3 months of warfarin therapy.91 In the MATISSE-PE trial, fonda-
mens.2 However, a subgroup analysis in one study suggested that parinux (7.5 mg subcutaneously [SC] q 24 h) was compared to UFH
patients with cancer and obese patients have higher recurrence rates administered by IV infusion.92 In both trials, the dose of fonda-
with once-daily enoxaparin.86 parinux was increased to 10 mg SC every 24 hours for patients who
Given the predictable response and the reduced need for labora- weighed more than 100 kg and reduced to 5 mg SC every 24 hours for
tory monitoring with LMWH, stable patients with DVT who have those who weighed less than 50 kg. Fondaparinux received FDA
normal vital signs, low bleeding risk and no other comorbid condi- approval for the acute treatment of DVT and PE in 2004.32
tions requiring hospitalization can be discharged early or treated
entirely on an outpatient basis (see Table 21–21).87 The efficacy and WARFARIN
safety of LMWH in the home-based treatment of proximal DVT was
initially established in large clinical studies.87,88 The results of ran- Warfarin monotherapy is an unacceptable choice for the acute
domized controlled clinical trials, as well as the experience of several treatment of VTE because it does not produce a rapid anticoagula-
successful outpatient DVT treatment programs in a variety of health- tion effect and is associated high incidence of recurrent throm-
care settings, have led to an increased acceptance for outpatient boembolism. However, warfarin is very effective in the long-term
management. Indeed, surveys of patients who received outpatient management of VTE and should be started concurrently with rapid
DVT treatment indicate a high degree of satisfaction and comfort, acting injectable anticoagulant therapy.2 The rapid acting injectable
with 91% expressing satisfaction with home treatment.87 anticoagulant should overlap with warfarin therapy for at least 5
Patients presenting with PE and no evidence of hemodynamic days and until a therapeutic INR has been achieved. The initial dose
instability are at low risk of subsequent morbidity and mortality. of warfarin should be 5 to 10 mg (see Fig. 21–8) and periodically
Evidence exists suggesting that patients with submassive PE who are adjusted to achieve and maintain an INR between 2.0 and 3.0.
hemodynamically stable can be managed safely as outpatients with The appropriate duration of warfarin maintenance therapy
LMWH or fondaparinux.24 However, hemodynamically unstable requires careful consideration of the circumstances surrounding the
patients with PE should generally be admitted and treated with initial thromboembolic event, the presence of ongoing thromboem-
either intravenous UFH, LMWH, or fondaparinux. If thrombolytic bolic risk factors, and the risk of bleeding.2,93 A major consideration
 360

TABLE 21-22 Patient Education for Outpatient Deep Vein Thrombosis Therapy
SECTION 2

General information regarding DVT and the goals of treatment

• Anticoagulant medications (injections and warfarin tablets) have been prescribed to prevent the blood clot from growing larger so that the body can begin to dissolve the clot
• Your body may be able to completely dissolve the clot, but in some cases the clot never goes completely away; even with adequate anticoagulation therapy, some people will
have chronic pain and swelling in the affected extremity; people who have had one clot are at increased risk of having future clots
• Warfarin tablets take several days to begin to work; LMWH injections work right away so at first LMWH injections and warfarin tablets are used together
• When the warfarin has become effective, you will be able to stop the LMWH injections; you will continue to take warfarin tablets for 3 to 6 months or longer to prevent
blood clots from returning
• It is important for you to administer your LMWH or fondaparinux and warfarin exactly as directed
Subcutaneous injection technique
Cardiovascular Disorders

• You must learn to give yourself a subcutaneous injection of LMWH or fondaparinux; alternatively, you may have a family member or visiting nurse give it to you
• If your LMWH or fondaparinux syringes were filled by the manufacturer, they can be stored at room temperature; if your syringes were filled by the pharmacy, they should
be stored in the refrigerator; if you were instructed to fill your own syringes, you should prepare the syringe immediately prior to injecting its contents
• If you see a bubble in the syringe, do not try to get it out, you may accidentally squirt out part of your dose
• Choose an injection site on your abdomen; clean the area with alcohol, then position an uncapped syringe at a 90-degree angle; pinch the skin, stick the needle in as far as
it will go and gently but firmly push the plunger down; this will inject the medicine into the skin; when all the medication has been injected, remove the needle and dispose
of it in an appropriate container
• You will likely experience a burning sensation when the medication is injected; this will go away after a few minutes
• Rotate injection sites from side to side, do not inject into the same site more than once; avoid the area around your navel; do not inject into any bruises
Blood test monitoring
• Regular blood tests are required to make sure your medication is working properly
• The prothrombin time tells how quickly your blood forms a clot; it is used to tell how well warfarin is working
• The INR is a way to standardize the prothrombin time between laboratories; your goal INR range is between 2.0 and 3.0; if your INR is less than 2.0, you are at higher risk
for clotting, if your INR is greater than 3.0, you are at higher risk for bleeding; your dose of warfarin will be adjusted based on the results of this test
• You need to have a complete blood count test both before you begin therapy and after you have been on LMWH or fondaparinux for about 5 days; this will help detect
internal bleeding and the occurrence of a rare side effect of heparin therapy that can decrease a component of your blood called platelets
Warfarin information
• Each strength of warfarin has a unique color; each time you refill your prescription, make sure your new tablets are the same color you have been taking; if they are not the
same color, ask your pharmacist why
• Warfarin should be taken at approximately the same time each day
• The most common and serious side effect of warfarin is bleeding; you should be careful to avoid situations or activities that increase your risk of injury; apply direct pressure
to control bleeding from superficial cuts
• Warfarin has many drug interactions; always check with your provider before taking any new medications (including over-the-counter medications and dietary supplements)
• Foods rich in vitamin K (green leafy vegetables, etc.) may interfere with warfarin; you do not need to avoid foods rich in vitamin K, but you should try to maintain consistent
dietary habits
• Alcohol can increase your risk for bleeding and interfere with warfarin therapy; drink alcohol in moderation (1 to 2 drinks per day); avoid binge drinking
Contact your provider if you experience
• Persistent bleeding from a cut or scrape
• Blood in your urine
• Blood in your stool
• Persistent nose bleeding
• Increased swelling or pain in your affected extremity
Go to the emergency department if you experience
• Shortness of breath
• Chest pain
• Coughing up blood
• Black tarry-appearing stool
• Severe headache of sudden onset
• Slurred speech
DVT, deep vein thrombosis; INR, international normalized ratio; LMWH, low-molecular-weight heparin.

in determining the risk of recurrent VTE once anticoagulation 12 months of therapy.2 Factors that may lead to the decision to stop
therapy is stopped is whether the initial thrombotic event was oral anticoagulation therapy after 6 to 12 months include noncom-
associated with a major transient or reversible risk factor (e.g., pliance with warfarin therapy, initial clot although idiopathic was
within 3 months of surgery with general anesthesia, plaster cast isolated in calf veins, or a moderate to high risk of bleeding.93 Risk
immobilization of a leg, or hospitalization). For patients in this factors for bleeding include age >65 years, previous stroke, history
situation, the risk of recurrence is relatively small, approximately of bleeding (e.g., gastrointestinal), active peptic ulcer disease, renal
3% in the first year and approximately 10% over 5 years, and only 3 impairment, anemia, thrombocytopenia, liver disease, diabetes mel-
months of oral anticoagulation treatment is warranted.93 For VTE litus, concurrent antiplatelet use, noncompliance, and the presence
associated with a minor transient or reversible risk factor (e.g., of a structural lesion (e.g., tumor, recent surgery) expected to be
within 6 weeks of initiation of estrogen therapy, air travel lasting associated with bleeding. Presence of one to two bleeding risk
>10 hours, pregnancy, or less marked leg injuries or immobiliza- factors suggests moderate bleeding risk while three or more risk
tion) 3 months of oral anticoagulation therapy is reasonable, but factors suggest a high bleeding risk.93
some experts prefer 6 months of treatment.93 Increasingly, patients with VTE are being tested for hereditary
Patients with unprovoked (idiopathic) VTE have a recurrence and acquired hypercoagulable states (thrombophilia). With the
risk of approximately 10% in the first year and approximately 30% exception of individuals with the antiphospholipid antibody syn-
over 5 years. These patients should be considered for indefinite oral drome, homozygotes for the factor V Leiden mutation, and hetero-
anticoagulation therapy if possible, but should receive at least 6 to zygotes with both the factor V Leiden and prothrombin 20210 gene
 361
mutations, the presence of thrombophilia does not appear to confer TABLE 21-23 Thrombolysis for the Treatment of
a clinically important risk for VTE recurrence.93 Indefinite or life-

CHAPTER 21
Venous Thromboembolism
long anticoagulation therapy should be considered for those
• Thrombolytic therapy should be reserved for patients who present with shock,
patients with recurrent VTE events or one of the thrombophilias
hypotension, right ventricular strain, or massive DVT with limb gangrene
known to impart a high life-time risk of thrombosis. Otherwise
• Diagnosis must be objectively confirmed before initiating thrombolytic therapy
decisions regarding duration of therapy should be guided by the • Thrombolytic therapy is most effective when administered as soon as possible
presence or absence of transient VTE risk factors.93 The decision to after PE diagnosis, but benefit may extend up to 14 days after symptom onset
continue anticoagulation therapy indefinitely should be reassessed • Approved PE thrombolytic regimens
annually. Patients should be involved in any decision to continue • Streptokinase 250,000 units intravenously over 30 minutes followed by
anticoagulation therapy with consideration given to the patient’s 100,000 units/h for 24 hoursa

Venous Thromboembolism
long-term prognosis, risk of bleeding, ability to adhere to anticoag- • Urokinase 4,400 units/kg intravenously over 10 minutes followed by 4,400
ulation therapy instructions, financial resources, lifestyle, and qual- units/kg/h for 12 to 24 hoursa
ity of life. When the benefits of continued anticoagulation therapy • Alteplase 100 mg intravenously over 2 hours
no longer outweigh the risks, therapy should be discontinued.93 • Factors that increase the risk of bleeding must be evaluated before thrombolytic
therapy is initiated (i.e., recent surgery, trauma or internal bleeding, uncontrolled
hypertension, recent stroke or intracranial hemorrhage)
THROMBOLYSIS AND THROMBECTOMY • Baseline labs should include CBC and blood typing in case transfusion is needed
• UFH should not be used during thrombolytic therapy; the aPTT nor any other
Most cases of VTE require only anticoagulation therapy. In some anticoagulation parameter should not be monitored during the thrombolytic
cases, however, removal of the occluding thrombus by either phar- infusion
macologic or surgical means may be warranted.2 There is a relative • aPTT should be measured following the completion of thrombolytic therapy
paucity of data supporting either thrombolysis or thrombectomy in • If aPTT less than 2.5 times control value, UFH infusion should be started and
the routine management of VTE, and more study is clearly needed adjusted to maintain aPTT in therapeutic range
to clarify their precise role. • If aPTT greater than 2.5 times control value, remeasure every 2 to 4 hours and
Thrombolytic agents are proteolytic enzymes that enhance the start UFH infusion when aPTT is less than 2.5
conversion of plasminogen to plasmin which subsequently degrades • Avoid phlebotomy, arterial puncture, and other invasive procedures during
thrombolytic therapy to minimize the risk of bleeding
the fibrin matrix. Thrombolytic therapy for DVT was once believed
to improve long-term outcomes by preventing the postthrombotic aPTT, activated partial thromboplastin time; CBC, complete blood cell count; DVT, deep vein
syndrome. Indeed, thrombolytic therapy improves venous patency. thrombosis; PE, pulmonary embolism; UFH, unfractionated heparin.
a
Two hour infusions of streptokinase and urokinase are as effective and safe as alteplase.
However, clinical trials have failed to demonstrate any sustained
benefit from the routine use of thrombolytic therapy and the
evidence that thrombolytic therapy is superior to anticoagulation associated with thrombolytic therapy. Although thrombolytic ther-
therapy alone in preventing the postthrombotic syndrome is uncer- apy for patients with massive PE manifested by shock and cardiovas-
tain.2 Patients who present with massive DVT and limb gangrene cular collapse is considered the standard of care, only one trial has
despite anticoagulation therapy are candidates for thrombolysis demonstrated a mortality benefit.90
(Table 21–23).2 Some authorities recommend thrombolytic treat- A significant number of hemodynamically stable patients with PE
ment for patients with massive iliofemoral VTE who are at low risk have evidence of right ventricular dysfunction and appear to be at
for bleeding. Catheter-directed instillation of a thrombolytic agent higher risk for recurrent PE and death when treated with heparin
directly into the clot is increasingly being used. The risk of bleeding alone. Some experts believe that thrombolytic therapy is beneficial
associated with catheter-directed drug administration appears to be in patients with evidence of right ventricular dysfunction because it
less than systemic administration. Prospective clinical trials are restores pulmonary blood flow and reduces pulmonary artery
necessary to clarify the clinical utility of catheter-directed thrombol- pressure. However, convincing data are lacking.89
ysis in the treatment of DVT but most experts recommend against Although it is an uncommon choice, venous thrombectomy is a
its routine use.2 reasonable approach to remove a massive obstructive thrombus in
In the management of acute PE, alteplase, streptokinase, and a patient with significant iliofemoral venous thrombosis, particu-
urokinase have all been shown to restore pulmonary artery patency larly if the patient is either not a candidate for or has not responded
more rapidly than UFH alone. However, this early benefit does not to thrombolysis.2 In cases of chronic PE—where persistent emboli
improve long-term patient outcomes. One week following acute produce progressive pulmonary hypertension, hypoxemia, and
treatment, clot lysis and vessel patency are similar with or without right-sided heart failure—surgical embolectomy offers greater ben-
thrombolytic therapy. Thrombolytic therapy has never been shown efit than anticoagulants and may be the treatment of choice if
to improve morbidity or mortality, but is associated with a substan- performed by an experienced surgical team.2 The surgical technique
tial risk of hemorrhage.2 For this reason, patients being considered has been refined over the past 20 years. The procedure uses a
for thrombolytic therapy should be screened carefully for contrain- balloon catheter to extract the thrombus while the patient is under
dications relating to bleeding risk.89 Admittedly, clinical trials to date general anesthesia. Fluoroscopy and venography guide the proce-
have been underpowered to detect a benefit from thrombolytic dure. Balloon angioplasty, with or without stent placement, can be
therapy. The association of thrombolytic therapy with hemorrhage is used if a focal iliac vein stenosis is discovered. Full-dose anticoagu-
particularly problematic because PE frequently occurs following a lation therapy is essential during the entire operative and postoper-
surgical procedure when the risk of bleeding is high. Given the ative period. These patients need indefinite oral anticoagulation
relative lack of data to support their routine use, thrombolytic agents therapy targeted to an INR of 2.5 (range 2.0 to 3.0).2
should be reserved for those patients with PE who are most likely to
benefit (see Table 21–23). Patients who have hemodynamic compro- VENA CAVA INTERRUPTION
mise as evidenced by significant hypotension (systolic blood pressure
90 mm Hg or less) or severe right ventricular strain because of a large Anticoagulation therapy is the accepted standard for treating DVT
clot burden may benefit from thrombolytic therapy.2 Five percent to and PE. However, an IVC filter may be indicated in special
10% of patients diagnosed with a PE present with shock. Mortality situations when anticoagulants are ineffective or unsafe, including
among these patients is as high as 50%, thus justifying the risks in (a) patients with an absolute contraindication to anticoagulation
 362
therapy because of active bleeding or anticipated bleeding from a TABLE 21-24 Unfractionated and Low-Molecular-Weight Heparin
predisposing lesion; (b) patients with a massive PE who survives but Use during Pregnancy
SECTION 2

in whom recurrent embolism might be fatal; and (c) patients who

Acute LMWH
have recurrent VTE despite adequate anticoagulation therapy.2
treatment • Enoxaparin 1 mg/kg SC q 12 h or 1.5 mg/kg q 24 h
Interruption of the IVC can be accomplished with an occlusive
or
filter, often called a Greenfield filter, inserted percutaneously • Dalteparin 100 U/kg SC q 12 h or 200 U/kg q 24 h
through the femoral or jugular vein and advanced into place using or
fluoroscopic guidance, usually below the renal veins. There is little • Tinzaparin 175 U/kg SC q 24 h
evidence to support the widespread use of vena cava filters. Vena or
cava filters reduce the risk of PE in the short-term, but also appear UFH
Cardiovascular Disorders

to increase the long-term risk for recurrent DVT presumably as a • Initiate using weight-based intravenous therapy and adjust
consequence of the accumulation of thrombus on the filter, which dose to achieve therapeutic anti-Xa level for at least 5 days
may partially occlude the vena cava, resulting in venous stasis.2 Data • Transition to SC adjusted-dose UFH administered q 8–12
from the International Cooperative Pulmonary Embolism Registry h with midinterval anti-Xa activity in the therapeutic rangea
Long-term LMWH
have documented a reduction in 90-day mortality associated with
treatmentb Maintain initial LMWH dose regimen throughout pregnancy
IVC filters, but this observation was not confirmed in a randomized
or
study of filter placement where all patients were treated with Alter LMWH dose in proportion to any weight change
anticoagulants.2,89 Whether patients with permanent IVC filters (usually gain)
should receive anticoagulant therapy remains unresolved but many or
clinicians opt to resume warfarin therapy as soon as possible and Obtain monthly anti-Xa level measurements 4 to 6 hours
continue it indefinitely.2 Given these concerns, retrievable filters after morning dose and adjust LMWH dose based on anti-
that can be removed after the period of greatest risk for PE have Xa level (target = 0.5 to 1.2 units/mL if twice daily dosing;
been developed and have been suggested for use in patients with 1.0 to 2.0 units/mL if once-daily dosing)
transient contraindications to anticoagulation therapy.89 or
UFH
Obtain monthly anti-Xa level at the midpoint of the dosing
ANCILLARY THERAPY interval and adjust UFH dose to achieve an anti-Xa level of
0.3 to 0.7 units/mL
In addition to anticoagulant therapy for patients with proximal
Issues at time Elective induction of labor
DVT, wearing graduated compression stockings can reduce the risk of delivery • Discontinue UFH or LMWH 24 hours prior to induction
of developing the postthrombotic syndrome by as much as 50%.94 • Initiate therapeutic doses of UFH by IV infusion and
To be effective, graduated compression stockings must fit properly discontinue 4 to 6 hours prior to expected time of delivery
and provide adequate pressure at the ankle (30 to 40 mm Hg). The if risk of recurrent VTE is deemed high
discomfort associated with wearing properly fitted stockings along Spontaneous labor
with the expense and unflattering cosmetic appeal makes routine • For LMWH, if there is a reasonable expectation that
use of compression stockings undesirable for many patients. significant anticoagulant effect will be present at time of
During the acute phase of DVT, antiembolic leg exercise may also delivery (a) epidural should be avoided, and (b) reversal
with protamine sulfate may be considered
be useful. To perform the exercise, patients should elevate the legs
• For UFH, monitor the aPTT and reverse with protamine
above the hips (7° to 10°) with feet supported. The patient then
sulfate if aPTT is prolonged near the time of delivery
flexes one foot at a time back and forth for 3 to 5 minutes or until Postpartum
the calf muscle group is fatigued. This exercise should be repeated 4 • Commence UFH or LMWH as soon as safely possible
to 6 times daily. Patients should also be instructed not to remain in (usually 12 hours following delivery)
a sitting position for more than 20 minutes without ambulating • Concurrently initiate warfarin therapy and discontinue UFH
briefly or stretching the leg for a few minutes. or LMWH when the INR is 2.0 or greater
Strict bedrest was traditionally recommended following acute DVT • Continue anticoagulants for at least 4 weeks following
based on the assumption that leg movement would dislodge the clot, delivery
resulting in PE. However, the evidence contradicts this assumption. • Warfarin can be safely used by women who are breast-feeding
Ambulation in conjunction with graduated compression stockings aPTT, activated partial thromboplastin time; INR, international normalized ratio; IV, intravenous;
results in faster reduction in pain and swelling with no apparent LMWH, low-molecular-weight heparin; SC, subcutaneously; UFH, unfractionated heparin; VTE,
increase in the rate of clot embolization.95 Patients should be encour- venous thromboembolism.
a
Anti-Xa monitoring preferred as the relationship between aPTT and heparin levels differs in pregnant
aged to ambulate as much as their symptoms permit. If pain and
compared to nonpregnant patients.
swelling increase with ambulation, the patient should be instructed to b
As pregnancy progresses the volume of distribution of LMWH changes, glomerular filtration rate
lie down and elevate the affected leg until symptoms subside. increases, and most women gain weight.
From Bates et al. and Ginsberg and Bates.27,113

TREATMENT OF VENOUS
THROMBOEMBOLISM IN placenta. To date, fondaparinux has not been formally evaluated in
SPECIAL POPULATIONS pregnant patients.
Long-term UFH therapy has been linked to significant bone loss
Pregnancy and osteoporosis, requires multiple daily injections, and must be
monitored frequently (every 1 to 2 weeks) throughout pregnancy.
The use of anticoagulation therapy for the treatment of DVT or PE
Because of these limitations, many experts recommend the use of
in pregnant women is common.27 UFH and LMWH are the pre-
LMWH over UFH throughout pregnancy.27
ferred anticoagulants for use during pregnancy (Table 21–24). They
do not cross the placenta and evidence suggests they are safe for the
fetus.27 Warfarin should be avoided because it crosses the placenta
Pediatric Patients
and can produce fetal bleeding, central nervous system abnormali- Although seen far more frequently in adults, VTE in children has
ties, and embryopathy. The direct thrombin inhibitors also cross the become increasing common secondary to prematurity, cancer, trauma,
 363
surgery, congenital heart disease, and systemic lupus erythematosus. recurrent VTE without increasing bleeding risks compared to tradi-
Children often develop DVTs associated with an indwelling central tional therapy with oral anticoagulants.34 In one relatively small

CHAPTER 21
venous catheter. In contrast to adults, children rarely develop idio- study in cancer patients with VTE, fixed-dose SC enoxaparin for 3
pathic VTE.28 months appeared to be more effective than conventional warfarin
Anticoagulation with UFH and warfarin remains the most fre- therapy, with only 10.5% of enoxaparin-treated patient compared to
quently used approach for the treatment of VTE in pediatric patients. 21% of warfarin-treated patients reaching the composite outcome of
The recommended target aPTT and INR ranges as well as the duration major bleeding and recurrent VTE (p = 0.09).96 In the Comparison
of therapy are extrapolated from clinical trials in adults. The recom- of LMWH versus Oral Anticoagulation Therapy for the Prevention
mended initial bolus dose of UFH is 75 to 100 units/kg given intrave- of Recurrent Venous Thrombosis (CLOT) trial, continuous treat-
nously over 10 minutes followed by a maintenance infusion of 28 ment with dalteparin for 6 months (200 units/kg SC every day for 1

Venous Thromboembolism
units/kg/h for infants 2 to 12 months of age and 20 unit/kg/h for month followed by 150 units/kg every day thereafter) was compared
children age 1 year or older. Subsequent adjustments should be made to conventional therapy with dalteparin followed by warfarin in
every 4 to 6 hours to maintain the aPTT within the institution-specific cancer patients following an acute VTE.97 The probability of recur-
therapeutic range. The usual warfarin starting dose is 0.2 mg/kg with a rent VTE was reduced by nearly 50% in the long-term dalteparin
maximum of 10 mg.28 Infants require higher doses of warfarin per kg treatment group, from 17.4% to 8.8% (p = 0.0017). There was no
to maintain a target INR of 2.0 to 3.0 compared to teenagers and adults difference in the rate of major bleeding. Although this provides
(mean dose 0.33 mg/kg, 0.09 mg/g, and 0.04 to 0.08 mg/kg, respec- compelling data that cancer patients should be given LMWH instead
tively). The INR target range is 2.0 to 3.0. Frequent INR monitoring of warfarin for the long-term treatment of VTE, the economic
and warfarin dose adjustments are typically required. When compared implications of this strategy have not yet been evaluated. In the
to adults, only 10% to 20% of pediatric patients can be safely moni- absence of insurance coverage to offset the relatively high cost of
tored once monthly. Obtaining coagulation monitoring tests in pedi- long-term LMWH therapy, most patients are unable to afford it.
atric patients is problematic because many have poor or nonexistent For patients with VTE and cancer who do receive LMWH,
venous access. To address this problem, many clinicians recommend therapy should continue for at least the first 3 to 6 months of long-
using fingerstick blood samples with a portable point-of-care monitor. term treatment, at which time further LMWH can be considered or
Because LMWHs have low drug-interaction potential, are less likely to warfarin therapy can be substituted.2 Anticoagulation therapy
cause HIT or osteoporosis, and require less-frequent laboratory test- should continue for as long as the cancer is “active” and while the
ing, they are an attractive alternative in pediatric patients.28 Enox- patient is receiving antitumor therapy.34 A risk-to-benefit assess-
aparin, dalteparin, tinzaparin, and reviparin have been evaluated in ment should be performed on a regular basis and the overall clinical
pediatric patients. Most experts recommend that anti-Xa activity be status of the patient should be considered, along with the risk for
monitored and the dose adjusted to maintain antifactor Xa levels bleeding, quality of life, and life expectancy.34 Many patients with
between 0.5 and 1.0 units/mL. Compared to adults, children younger terminal cancer receiving palliative care prefer LMWH over war-
than 2 to 3 years of age or who weigh less than 5 kg have higher per- farin.98 Consideration should be given to stopping anticoagulant
kilogram dose requirements to achieve a “therapeutic” response. The therapy even in the presence of active cancer for patients who are at
doses of LMWH for older children are generally similar to the weight- very high risk of bleeding complications.93
adjusted doses used in adults.28 Warfarin can be initiated concurrently
with UFH or LMWH therapy. Therapy should be overlapped for a PHARMACOECONOMIC CONSIDERATIONS
minimum of 5 days and until the INR is therapeutic. Warfarin should
be continued for at least 3 months. Thrombolysis and thrombectomy Hospitalization is the main cost driver in the management of VTE.88
have been successfully employed in pediatric patients but published Although the drug acquisition cost for the LMWHs and fondaparinux
data are very limited. are substantially higher than UFH, avoiding hospitalization dramati-
cally decreases the overall costs of DVT treatment. A number of cost-
Patients with Cancer effectiveness analyses using decision modeling suggest that the treat-
ment of DVT with LMWHs is more cost effective than the treatment
VTE is a frequent complication of malignancy. Furthermore, com- with UFH in both inpatient and outpatient settings.99 Based on this
pared to patients without cancer, the rate of recurrent VTE in decision model, the LMWHs will reduce overall healthcare cost if as
patients with cancer is threefold higher and the risk of bleeding is few as 8% of patients are treated entirely on an outpatients basis or
two- to sixfold higher.34 Warfarin therapy in cancer patients is often 13% of patients are discharged from hospital early.
complicated by drug interactions (e.g., chemotherapy and antibi- Despite the substantial cost savings stemming from outpatient
otics) and the need to frequently interrupt therapy for invasive DVT treatment from the perspective of the insurer, the reality is that
procedures (e.g., thoracentesis, percutaneous biopsies, and abdomi- some patients are unable to afford LMWH or fondaparinux pre-
nal paracentesis). Maintaining stable INR control is more difficult in scriptions and are therefore denied outpatient treatment. The results
this patient population because of nausea, anorexia, and vomiting.34 of a recent study may provide a therapeutic option for patients in this
situation. The objective of this trial was to determine if fixed-dose,
weight-adjusted, subcutaneous UFH is as effective and safe as
CLINICAL CONTROVERSY LMWH for the treatment of VTE.23 Eligible patients were random-
Evidence suggests that LMWH administered for 3 to 6 months ized to receive either UFH administered subcutaneously as an initial
after a DVT or PE is more effective than warfarin in preventing dose of 333 units/kg, followed by a fixed dose of 250 units/kg every
recurrent VTE events in patients with cancer. Despite the fact 12 hours or a weight-based dose of LMWH. Both treatments could
that current consensus guidelines recommend the use of a be administered at home and both were overlapped with warfarin
LMWH over warfarin for the long-term treatment of VTE in therapy in the traditional manner. End points included recurrent
cancer patients, many practitioners still prefer the use of war- VTE within 3 months and major bleeding within 10 days of study
farin in these patients. entry. The groups did not differ significantly in either of the study
end points and treatment was administered completely at home in
Randomized trials provide evidence that long-term LMWH ther- 72% of the UFH group and in 68% of the LMWH group. Further
apy for VTE in cancer patients significantly decreases the rate of evidence is required to confirm these results; however, this lower cost
 364
option may facilitate the outpatient treatment of VTE for selected nia can be delayed (delayed-onset HIT) up to 20 days, and begin
patients who otherwise would not have been able to afford it. several days after heparin has been stopped in patients naive to
SECTION 2

heparin therapy. Conversely, so-called rapid-onset HIT can occur

rapidly and abruptly (within 24 hours following heparin initiation)
HEPARIN-INDUCED THROMBOCYTOPENIA in patients with a recent exposure to heparin (i.e., previous 3
months).26 Platelet counts commonly fall below 150,000 mm3 but
HIT is an uncommon but extremely serious adverse effect associ- rarely nadir as low as 20,000 mm.3 In some cases, overt thrombocy-
ated with heparin use.26 The immune-mediated platelet activation topenia may not occur, but a drop in platelet count greater than
and thrombin generation seen during HIT can lead to severe and 50% from baseline is considered indicative of HIT.
unusual thrombotic complications. Morbidity and mortality associ- The frequency of immune-mediated HIT is most powerfully
ated with HIT is disturbingly high—up to 50% of patients who
Cardiovascular Disorders

related to the duration and type of heparin used and to a lesser

develop the disorder will suffer a thrombotic complication or die extent the dose and route of administration.26,38The incidence of
within 30 days in the absence of treatment. The diagnosis of HIT is
HIT associated with intravenous full dose UFH given for prolonged
based on laboratory findings that confirm heparin antibody forma-
periods is significantly higher than that of low-dose subcutaneous
tion and platelet activation (Table 21–25). To prevent the throm-
UFH or LMWHs. The estimated overall incidence of HIT after 5
botic complications associated with HIT, prompt discontinuation
days of UFH use is 1% to 3% but the cumulative incidence may be
of heparin and initiation of an alternative anticoagulant therapy is
as high as 6% after 14 days of continuous intravenous use. The
imperative.
incidence of HIT with low dose subcutaneous UFH in medical
patients has been reported to be approximately 1%.101 Low-molec-
ETIOLOGY AND PATHOPHYSIOLOGY OF HIT ular-weight heparins are associated with a significantly lower risk of
HIT (<1%).26 The incidence of HIT is higher with bovine UFH
Two types of thrombocytopenia associated with heparin use have
versus porcine UFH. In addition, the HIT risk varies with the
been described.100 As many as 25% of patients receiving heparin
exposed patient population: surgical patients > medical patients >
therapy develop a benign, mild reduction in platelet counts referred
pregnant patients.26,102
to as non–immune-mediated heparin-associated thrombocytopenia
The pathogenesis of HIT involves an immunoglobulin mediated
(previously called HIT type 1). HAT produces a transient fall in
response to the heparin molecule leading to platelet activation and
platelet count that occurs early, typically between days 2 and 4,
thrombin generation (Fig. 21–11).38,100 With platelet activation there
during the course of therapy. The degree of thrombocytopenia is
is release of PF-4 from platelet granules. Heparin binds to PF-4
usually mild, with platelet counts rarely going below 100,000. It is
forming a negatively charged polysaccharide molecule that is highly
not necessary to discontinue heparin therapy in these patients as
antigenic and stimulates the production of immunoglobulin (Ig) G
platelet counts generally rebound to baseline values despite contin-
antibodies. Although heparin-induced antibody formation occurs in
ued use. The exact mechanism of HAT is unknown; however, it may
10% to 20% of patients treated with heparin, the vast majority of
be the result of platelet aggregation, a dilutional effect, or dimin-
these patients never develop HIT. In patients who develop HIT, the
ished platelet production often seen in acutely ill patients. No
heparin–PF-4–IgG complexes bind to the Fc receptor on platelets,
clinical sequelae are associated with this benign phenomenon.
leading to further platelet activation and the release of PF-4 and
The second type of thrombocytopenia associated with heparin
procoagulant microparticles from platelet granules. In addition, PF-
use is known as immune-mediated HIT (formally known as HIT
4 and heparin-like molecules bind to the surface of endothelial cells
type 2).38,100 HIT is a severe pathologic adverse effect of heparin with
resulting in antibody-induced endothelial cell damage and the
a significant potential to cause thrombotic complications (see Table
release of tissue factor. The net result of this cascade of events is an
21–25). The time course and magnitude of thrombocytopenia
increased risk of thrombotic events secondary to platelet activation,
associated with HIT differs from that of HAT. Platelets counts
endothelial damage, and thrombin generation despite moderate to
typically begin to fall days 5 to 10 following initiation of heparin and
severe thrombocytopenia. Antibodies to the heparin/PF-4 complex
reach a nadir by days 7 to 14. The development of thrombocytope-
are transient, and they have been reported to disappear from the
circulation within a median of 85 days.26,38
TABLE 21-25 Presentation of Heparin-Induced Thrombocytopenia
General CLINICAL PRESENTATION AND DIAGNOSIS
Venous thromboembolism is the most common presentation of heparin- OF HIT
induced thrombocytopenia (HIT), although arterial events (e.g., myocardial
infarction, stroke) can occur. HIT should be suspected if a patient develops a Thrombotic complications are the most common clinical sequelae
deep vein thrombosis or pulmonary embolism while or soon after receiving of HIT (see Table 21–25).26,38 The incidence of thrombosis can be as
unfractionated heparin. high as 50% in those patients with laboratory-confirmed immune-
Symptoms and signs
mediated thrombocytopenia. Thrombosis may occur in patients
Thromboembolic events secondary to HIT produce the same signs and symp-
with seemingly mild thrombocytopenia but platelet counts invari-
toms as those of other etiologies (see Presentation of Deep Venous Thrombo-
sis and Pulmonary Embolism). ably have dropped more than 50% from baseline. This syndrome is
Laboratory tests poorly recognized and many, perhaps most, patients diagnosed with
The patient’s platelets count will typically be below 150,000/mm3 or drop more HIT initially presented with thrombosis. Even among those who are
than 50% from baseline. The platelet count usually drops after 5 to 10 days of diagnosed prior to the development of thrombosis, the prognosis is
unfractionated heparin therapy, but may drop sooner if the patient has poor. In patients diagnosed with HIT without thrombosis and
received heparin in the past 3 months. managed only by discontinuation of UFH, the risk of symptomatic
Other diagnostic tests thrombosis is 25% to 50%, and fatal thrombosis is 5%.26,38
An enzyme-linked immunoabsorbent assay (ELISA) for the presence of antibod- The thrombotic risk is 30 times higher in patients with HIT as
ies to the heparin–PF4 complex should be performed to confirm the diagnosis. compared to control populations.101 Venous thrombosis is the most
Functional assays, including the heparin-induced platelet activation assay
common thrombotic complication associated with HIT and the
(HIPAA), the serotonin release assay (SRA), or the platelet-aggregation assay
(PAA), may also be performed to confirm the diagnosis.
majority of patients develop proximal DVT. PE occurs in 25% of
patients with thrombotic complications and contributes signifi-
 365

Heparin PF4

CHAPTER 21
Endothelium

Venous Thromboembolism
4

2
IgG

Platelet

FIGURE 21-11. Pathogenesis of heparin-

induced thrombocytopenia. (IgG, immuno-
globulin G; PF4, platelet factor-4.)

cantly to mortality. Arterial thrombosis occurs less commonly.26,100 than the platelet-aggregation assay but are technically more difficult
Limb artery occlusion, stroke, and myocardial infarction are the to perform. Antigen assays that detect the presence of specific
most commonly reported arterial events. HIT has also been linked antibodies against the heparin–PF-4 complex using enzyme-linked
with atypical manifestations such as skin necrosis, venous limb immunosorbent assays are also available. These tests have reasonably
gangrene, and anaphylactic-type reactions after IV bolus of UFH. high sensitivity and specificity. The optimal test for laboratory
Heparin-induced skin lesions occur in 10% to 20% of patients with confirmation of immune-mediated HIT is unclear. The most readily
HIT. Lesions range from painful, localized erythematous plaques to available test with the greatest sensitivity and specificity should be
widespread dermal necrosis. Amputation in such cases is frequently used. The combined use of functional and enzyme-linked immun-
required. Mortality from HIT may be as high as 50% in patients osorbent assays may reduce false-negative results. When results of
with acute thrombosis. The relatively high frequency of thrombotic one test are negative or indeterminate in patients suspected of HIT,
complications and poor outcomes associated with HIT emphasize another test should be considered.
the need for prompt recognition and diagnosis.26,38
The diagnosis of immune-mediated HIT is made based on GENERAL APPROACHES TO THE TREATMENT
clinical findings supplemented by laboratory tests confirming the OF HIT
presence of antibodies to heparin or platelet activation induced by
heparin.26,38 While thrombocytopenia is the most common initial The goal of therapy in patients with HIT is to reduce the thrombo-
event suggesting the diagnosis of HIT, clinicians should evaluate all sis risk by decreasing thrombin generation and platelet activation.
the potential causes. New thrombosis shortly after the development The ACCP Consensus Conference on Antithrombotic Therapy has
of thrombocytopenia is a distinguishing feature in nearly half of all established recommendations for the treatment of HIT.26 Once the
patients with HIT. The time course and magnitude of thrombocy- diagnosis of HIT is established or strongly suspected, all sources of
topenia are the features distinguishing immune-mediated HIT from heparin, including heparin flushes, should be discontinued and an
HAT. Acute thrombosis and skin lesions may also occur prior to the alternative anticoagulant agent should be initiated (Fig. 21–12).26,38
development of overt thrombocytopenia. HIT should immediately Even in the absence of thrombosis, patients with HIT are at
be suspected when these events occur in any patient on UFH or extremely high risk for developing serious thrombotic complica-
LMWH therapy.26,38 tions without treatment. Because the time required for diagnostic
Laboratory testing must be performed to confirm the diagnosis of laboratory results to be reported can be prolonged, it is crucial that
HIT.26,100,103 Laboratory testing is very helpful in patients with only alternate anticoagulant agents be initiated in a timely fashion to
mild to moderate thrombocytopenia in whom HIT is suspected. prevent new thrombosis. Anticoagulant agents that rapidly inhibit
Two types of assays are available to detect the presence of heparin thrombin activity and are devoid of significant cross-reactivity with
antibodies. Platelet activation assays, also known as functional heparin–PF-4 antibodies are the drugs of choice for the manage-
assays, confirm in vitro platelet activation in the presence of thera- ment of HIT (Table 21–26).26,38 In cases of severe or life-threaten-
peutic heparin levels. Functional assays include the heparin-induced ing thrombosis, surgical extraction of thrombi may be required.
platelet-activation assay, the serotonin release assay, and the platelet- Limited data exists regarding the use of thrombolytic therapy (see
aggregation assay. The heparin-induced platelet-activation assay and Table 21–23) in severe HIT with thrombosis. The use of warfarin
serotonin release assay tests have higher sensitivity and specificity for long-term anticoagulation in patients with HIT and thrombosis
 366

Suspect HIT when all of the following are true:

SECTION 2

• platelet count <150,000 or >50% fall from baseline

• duration of heparin therapy = 5 or more days
• other causes of thrombocytopenia ruled out

*patients who have received heparin within the past 3 months

can develop HIT sooner than 5 days
Cardiovascular Disorders

Discontinue ALL sources of heparin immediately

and
Initiate alternative anticoagulation therapy:
Argatroban, bivalrudin, danaparoid, or lepirudin

Obtain laboratory test to confirm diagnosis:

HIPA assay, Heparin–PF4 ELISA assay, or
14C-serotonin release assay

Postpone warfarin pending platelet

count recovery >150,000; give vitamin
K if warfarin has already been started.

Lab Tests
Positive?

Yes No

Continue anticoagulation therapy 2–10 IF HIT strongly suspected, retest

days until platelet count normalizes with alternate assay
If long-term anticoagulation required, initiate or
warfarin therapy once therapeutic dose of Continue alternate anticoagulant
alternative anticoagulant agent achieved, based on clinical diagnosis
and platelet count has recovered >150,000. or
Overlap until INR >2.0 for at least 2 days. Discontinue alternative anticoagulant

FIGURE 21-12. Treatment of heparin-induced thrombocytopenia (HIT). (HIPA assay, heparin-induced platelet activation assay; ELISA,
enzyme-linked immunosorbent assay; INR, international normalized ratio.)

is recommended, but warfarin should only be initiated after sub- equally suitable for the initial treatment of HIT. Some clinicians
stantial platelet count recovery has been documented (e.g., >150,000/ prefer argatroban because it has a shorter half-life, modest bleeding
mm3) In addition, great care with dosing must be taken when risk, and lower cost when compared to lepirudin.104 Because of a
initiating warfarin in these patients, as the risk of inducing further short-half life, low immunogenicity, minimal effect on INR, and
thrombosis secondary to inhibition of proteins C and S is possible.26 enzymatic metabolism, bivalirudin appears to be a promising alterna-
tive for treatment of HIT. However, to date efficacy data is only based
PHARMACOLOGIC TREATMENT OPTIONS on case series.43 Given fondaparinux is devoid of in vitro cross-
reactivity to HIT antibodies, does not interfere with PT/INR mea-
DTIs are the drugs of choice for the treatment of HIT with or without surement, and has enjoyed favorable experience in HIT in a few case
thrombosis (see Table 21–26).26 Three DTIs are currently available in reports, it is a promising alternative for the management of HIT.105
the United States for the treatment of patients with HIT—lepirudin, Patient-related factors, such as the presence of renal or hepatic
argatroban, and bivalirudin—but only the first two are FDA dysfunction, drug-specific features such as prior exposure to lepiru-
approved for this indication. For the treatment of HIT, lepirudin and din, as well as institutional preference, availability, and cost should be
argatroban are administered by intravenous infusion and should be used to determine the most appropriate agent. The LMWHs are not
titrated based on aPTT testing. The comparative efficacy of these recommended for use in HIT because they have nearly 100% cross
agents has not been formally evaluated, and they are considered reactivity with heparin-antibodies by in vitro testing.26,38
 367

TABLE 21-26 Recommended Dose and Monitoring Parameters for Direct Thrombin Inhibitors to Treat Heparin-Induced Thrombocytopenia

CHAPTER 21
Agent Dose Monitoring Parameters Clinical Considerations
a
Lepirudin 0.4 mg/kg (up to 110 kg) slow IV bolus (can Obtain baseline PT, aPTT, CBC, Scr. Dose must be reduced in patients with renal impair-
also be given without bolus), followed by Check aPTT 2 hours after initiation and each ment; avoiding the bolus dose may reduce the risk of
0.15 mg/kg/h (up to 110 kg) IV infusionb dose change and adjust dose to achieve aPTT accumulation and may reduce the risk of anaphylaxis;
1.5–2.5 times control. Once stabile, monitor antihirudin antibodies can occur in 40%–60% of
aPTT q 12 h. patients and can lead to reduced clearance. Concomi-
tant warfarin requires dose adjustment.
Argatroban 2 mcg/kg/min continuous IV infusion (no Obtain baseline PT, aPTT, CBC. Monitor aPTT 2 Dose reduction is necessary for those patients with
bolus); maximum infusion 10 mcg/kg/min hours after initiation and each dose change hepatic impairment and in critically ill; will cause

Venous Thromboembolism
and adjust dose to achieve aPTT of 1.5–3 significant elevation in PT/INR; concurrent warfarin
times control (maximum 100 s). therapy requires special management (when INR >4,
argatroban therapy should be withheld and the INR
rechecked to determine if it is therapeutic).
Bivalirudin 0.15–0.20 mg/kg/h IV infusion (no bolus); Obtain baseline PT, aPTT, CBC, Scr. Not FDA approved for treatment of HIT.
approved dose for PCI: 0.75 mg IV bolus, Check aPTT 2 hours after initiation and adjust
followed by 1.75 mg/kg/h infusion up to 4 dose to achieve aPTT 1.5–2.5 times control.
hours
aPTT, activated partial thromboplastin time; CBC, complete blood cell count; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; IV, intravenous; PCI, percutaneous coronary
intervention; PT, prothrombin time; Scr, serum creatinine.
a
Bolus dose is not advised in patients with renal impairement.
b
Dose in isolated HIT: no bolus, 0.1 mg/kg/h infusion with aPTT adjusted to 1.5–2.0 times control.

The use of warfarin during the initial treatment of HIT is EVALUATION OF THERAPEUTIC OUTCOMES
potentially dangerous.26,38 The rapid reduction in protein C concen-
trations induced early in the course of warfarin therapy further The appropriate duration of therapy in patients with HIT will
increases the risk thrombosis in patients with HIT. This concern is depend on whether the patient had a thrombotic event. Patients with
supported by the observation that several patients with HIT have HIT without thrombosis should be continued on therapeutic doses
developed venous limb gangrene and warfarin-induced skin necro- of an alternative anticoagulant agent until the platelet counts have
sis when treated with warfarin. Patients with venous limb gangrene normalized. Platelet counts should be monitored frequently, and
had relatively high INRs after the initiation of warfarin therapy and patients should be watched closely for the development of new
presumably had rapid depletion of protein C but persisting throm- thrombosis after starting an alternate anticoagulant. Patients with
bin generation. Therefore, warfarin is contraindicated as monother- thrombosis, either at the time of presentation or following the
apy for the initial treatment of patients diagnosed with HIT. diagnosis of HIT, should receive therapy with an alternative antico-
However, patients with HIT and thrombosis requiring long-term agulant such as lepirudin or argatroban followed by a transition to
anticoagulation can be treated with warfarin if therapy is appropri- warfarin after the platelet count has recovered to >150,000 mm3.
ately timed and carefully initiated. A conservative approach is to Warfarin therapy is usually continued for at least 6 months, or longer
withhold warfarin until the patient is stabilized and platelet counts if indicated. The initial anticoagulant used should be continued until
have substantially recovered at least above 100,000 mm3, and the INR is stable and therapeutic for more than two consecutive
preferably above 150,000 mm3. If warfarin has already been initiated days. In addition, it is important to clearly document the occurrence
when HIT is diagnosed, reversing therapy with vitamin K (5 to 10 of immune-mediated HIT in the patient’s medical record and
mg either IV or oral) is recommended. This may prevent the educate the patient regarding this adverse effect. Future use of UFH,
development of further thrombotic adverse events caused by pro- particularly in the next 3 to 6 months, should be strictly avoided. As
tein C depletion. Warfarin can be reinitiated once platelet counts PF-4–heparin antibodies are transient and usually cleared within 3
have been recovered (>150,000 mm3) but it should be overlapped months, patients with a history of HIT should be tested for HIT
with a direct thrombin inhibitor for a minimum of 5 days and until antibodies prior to any future use of UFH. Although there are few
the full anticoagulant effect of warfarin has been achieved (i.e., INR data regarding the use if UFH in patients with a remote history of
within the therapeutic range for at least 2 consecutive days). Initial HIT, these patients should receive alternative anticoagulant agents
doses of warfarin greater than 5 mg should be strictly avoided in for most indications until more rigorous data are available.26,38
these patients.26,38
The management of pregnant patients with a history of HIT
whom requires anticoagulation therapy presents a challenge. Both NATIONAL QUALITY INITIATIVES
UFH and LMWH are the anticoagulants of choice for pregnant
patients requiring anticoagulation therapy.27 Women who develop Venous thromboembolism is the most common preventable cause of
HIT during pregnancy or who have a recent history of HIT (e.g., less hospital death in the United States and nearly two-thirds of all VTE
than 3 months) cannot use UFH or LMWH safely. Limited evidence events are related to hospitalization.2 Furthermore, PE is the third
exists for the use of DTIs in pregnancy. Lepirudin is known to cross most common cause of hospital-related deaths in the United States
the placenta, however case reports suggest it may be safe for the (300,000 fatalities annually). Survivors of VTE are at-risk for recur-
management of HIT with thrombosis in pregnancy.106 Danaparoid, rence and other serious long-term complications, including post-
a low-molecular-weight heparinoid not available in the United thrombotic syndrome and chronic pulmonary hypertension. The
States, does not cross the placenta and it has also been investigated estimated annual direct medical costs of managing the disease are well
as a potential anticoagulant option in pregnant patients with HIT.27 over $1 billion. Although VTE is often clinically silent, with as many as
Limited case reports suggest that fondaparinux may also be a future 25% of cases presenting as sudden death from PE, needless mortality
potential alternative in pregnant patients.107 and morbidity occur as a result of underdiagnosis and underuse of
 368

TABLE 21-27 Organizations Monitoring Quality Care TABLE 21-28 The Joint Commission’s Proposed Performance
Measures for the Prevention and Treatment of
SECTION 2

The Joint Commission

www.jointcommission.org
Venous Thrombosis
A not-for-profit healthcare accreditation organization that issues performance- Number Description of Proposed Performance Measure
based standards and assesses organizational compliance to improve patient
1 Documentation of Venous Thromboembolism Risk Assessment/Pro-
safety and quality of care.
phylaxis within 24 Hours of Hospital Admission
Leapfrog Group
2 Documentation of Venous Thromboembolism Risk Assessment/Pro-
www.leapfroggroup.org
phylaxis within 24 Hours of Transfer to ICU
An initiative of healthcare purchasing organizations seeking improvements in
3 Documentation of Inferior Vena Cava Filter Indication
safety, quality, and affordability of healthcare, with funding from the Business
4 Venous Thromboembolism Patients with Overlap of Parenteral and
Cardiovascular Disorders

Roundtable, Robert Wood Johnson Foundation, and member organizations.

Warfarin Anticoagulation Therapy
National Quality Forum
5 Venous Thromboembolism Patients Receiving Unfractionated Hep-
www.qualityforum.org
arin with Platelet Count Monitoring
A not-for-profit that develops and implements national strategies for healthcare
6 Venous Thromboembolism Patients with Renal Insufficiency that
quality measurement and reporting.
Received Reduced/Discontinued Anticoagulation Therapy
7 Venous Thromboembolism Patients Receiving Unfractionated Hep-
arin Management by Nomogram/Protocol
prophylaxis. Despite the fact that several clinical interventions are 8 Venous Thromboembolism Discharge Instructions
known to be effective in preventing and treating VTE, only one-third 9 Venous Thromboembolism Patients with International Normalized
of all patients who are at risk for VTE and who are appropriate Ratio >6 After Initiation of Warfarin Therapy
candidates actually receive prophylaxis.108 Although preventing VTE is 10 Incidence of Potentially Preventable Hospital-Acquired Venous
a significant patient safety issue, there is little public awareness of the Thromboembolism
life-threatening nature of DVT and PE. A survey conducted on behalf From The Joint Commission.110
of the American Public Health Association suggests that 75% of
Americans have little or no awareness of DVT, and less than one-half
of respondents could identify any risk factors associated with its
development.109 Recognizing the lack of public awareness, several
organizations have focused on increasing consumer knowledge of the
CLINICAL CONTROVERSY
risks, signs, and symptoms of VTE through increased media visibility. For the treatment of an acute VTE, LMWHs should be dosed
Given the number and variety of clinical conditions or circum- based on the patient’s actual (or total) body weight. Efficacy and
stances that place individuals at risk for VTE, improvements in VTE safety data from clinical trials indicate that obese patients should
prevention and care have the potential to benefit many patients. Over be given full therapeutic doses based on the patient’s actual (or
the past decade, the focus on quality health care has been emphasized total) body weight are used. Dose adjustments or dosing “caps”
by the call to accountability through the Joint Commission’s Agenda are not recommended in obese patients. Despite these data, some
for Change, the Institute of Medicine’s report on medical errors, the clinicians only use LMWH doses up to 150 mg (or 150 interna-
National Quality Forum’s endorsed safe practices, the Leapfrog tional units) per dose even if the patient’s actual body weight is
Group, and the demand for value by healthcare consumers (Table higher then 150 kg.
21–27).108,110 Despite widespread national efforts to educate health-
care professionals about VTE prevention and treatment and the
publication of numerous clinical guidelines, VTE prevention mea-
ABBREVIATIONS
sures are not widely or consistently used. Therefore, wide variation in
ACCP: American College of Chest Physicians
the prevention and treatment of VTE persists. Given the mortality
and morbidity attributed to VTE, the need for standards of care is DTI: direct thrombin inhibitor
compelling. The National Quality Forum (NQF) is developing DVT: deep vein thrombosis
national consensus standards for VTE prevention and treatment that FDA: Food and Drug Administration
will be applicable to a variety of healthcare settings.108 The outcomes
HIT: heparin-induced thrombocytopenia
of this effort will provide a framework for measuring the effective
screening, prevention, and treatment of VTE. NQF’s recommenda- INR: international normalized ratio
tions include developing organizational policies that address staff IPC: Intermittent Pneumatic Compression
education, treatment protocols, and adherence measurements to IV: intravenous
improve VTE prevention in the hospital. The ultimate goal of the
NQF consensus standards is to facilitate early promulgation of VTE LMWH: low-molecular-weight heparin
policies, risk assessment, prophylaxis, diagnosis and treatment ser- aPTT: activated partial thromboplastin time
vices as well as patient education and organizational accountability. PE: pulmonary embolism
To that end, the Joint Commission is developing performance mea-
PF-4: platelet factor-4
sures to enforce the NQF’s recommendations.108,110 Four major
domains have been identified: risk assessment, prevention, diagnosis, PT: prothrombin time
and treatment. Ten proposed measures have been selected for testing SC: subcutaneous
using a multiphased testing approach (Table 21–28). UFH: unfractionated heparin
Hopefully, through the concerted efforts of government and accred-
VTE: venous thromboembolism
iting agencies working with hospitals and other healthcare institutions,
the incidence of DVT and PE will begin to fall. Systematic approaches
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venous thromboembolism after total hip or knee replacement. A bolism in patients with cancer. N Engl J Med 2003;349:677–681.
 371
98. Noble SIR, Finlay IG. Is long-term low-molecular-weight heparin 106. Messmore H, Jeske W, Wehrmacher W, Walenga J. Benefit-risk
acceptable to palliative care patients in the treatment of cancer related assessment of treatments for heparin-induced thrombocytopenia.

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venous thromboembolism? a qualitative study. Palliat Med 2005;19: Drug Saf 2003;26:625–641.
197–201. 107. Mazzolai L, Hohlfeld P, Spertini F, Hayoz D, Schapira M, Duchosal
99. Gould MK, Dembitzer AD, Sanders GD, Garber AM. Low-molecular- MA. Fondaparinux is a safe alternative in case of heparin intolerance
weight heparins compared with unfractionated heparin for treatment during pregnancy. Blood 2006;108:1569–1570.
of acute deep venous thrombosis. A cost-effectiveness analysis. Ann 108. National Quality Forum Project Brief: National Voluntary Consensus
Intern Med 1999;130:789–799. Standards for the Prevention and Care of Venous Thromboembolism,
100. Kelton JG. The pathophysiology of heparin-induced thrombocytope- Including Deep-Vein Thrombosis and Pulmonary Embolism. January
nia: Biological basis for treatment. Chest 2005;127:9S–20S. 2006, www.qualityforum.org/txDVTprojectsummaryFINAL.pdfM.
101. Girolami B, Prandoni P, Stefani PM, et al. The incidence of heparin- 109. American Public Health Association. Deep-Vein Thrombosis: Advanc-

Venous Thromboembolism
induced thrombocytopenia in hospitalized medical patients treated ing Awareness to Protect Patient Lives. White Paper, Public Health
with subcutaneous unfractionated heparin: A prospective cohort Leadership Conference on Deep-Vein Thrombosis. January 2003,
study. Blood 2003;101:2955–2959. www.apha.org/news/press/2003/DVT_whitepaper.pdf.
102. Warkentin TE. Heparin-induced thrombocytopenia: Diagnosis and 110. The Joint Commission. National Consensus Standards on the Preven-
management. Circulation 2004;110:e454–e458. tion and Care of Venous Thromboembolism. http://www.jointcommis-
103. Warkentin TE. New approaches to the diagnosis of heparin-induced sion.org/PerformanceMeasurement/PerformanceMeasurement/VTE.htm.
thrombocytopenia. Chest 2005;127:35S–45S. Published December 5, 2007.
104. Lewis BE, Wallis DE, Hursting MJ, Levine RL, Leya F. Effects of argatroban 111. Federman DG, Kirsner RS. An update on hypercoagulable disorders.
therapy, demographic variables, and platelet count on thrombotic risks in Arch Intern Med 2001;161:1051–1056.
heparin-induced thrombocytopenia. Chest 2006;129:1407–1416. 112. Booth SL, Centurelli MA. Vitamin K. A practical guide to the dietary
105. Efird LE, Kockler DR. Fondaparinux for thromboembolic treatment management of patients on warfarin. Nutr Rev 1999;57:288–296.
and prophylaxis of heparin-induced thrombocytopenia. Ann Pharma- 113. Ginsberg JS, Bates SM. Management of venous thromboembolism
cother 2006;40:1383–1387. during pregnancy. J Thromb Haemost 2003;1:1435–1442.
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 373

C HAP T E R

22 Stroke

SUSAN C. FAGAN AND DAVID C. HESS

EPIDEMIOLOGY
KEY CONCEPTS
 Stroke is one of the leading killers of individuals worldwide. There are currently 4.6 million stroke survivors in the United States,
and stroke is the leading cause of adult disability.1 Approximately 20%
 Stroke can be either ischemic (88%) or hemorrhagic (12%). of patients in nursing homes have had a stroke,2 and stroke is also a
leading diagnosis in inpatient rehabilitation. Owing in part to the need
 Transient ischemic attacks (TIAs) require urgent intervention to for these expensive posthospitalization care environments, stroke is also
reduce the risk of stroke, which is known to be highest in the one of the most expensive diseases in the United States, with annual
first few days after TIA. costs greater than $50 billion.1 Current projections are that death
caused by stroke will increase exponentially in the next 30 years owing
 Carotid endarterectomy should be performed in ischemic
to aging of the population and our inability to control risk factors.3
stroke patients with 70% to 99% stenosis of the ipsilateral ca-
Stroke risk is increased above that of the general population in
rotid artery, provided that it is done in an experienced center.
elderly male individuals and in African Americans.1 In addition,
 Early reperfusion (<3 hours from onset) with tissue plasmino- geographic disparity in stroke incidence exists, such that several
gen activator (t-PA) has been shown to reduce the ultimate areas of the southeastern United States have stroke mortality rates
disability caused by ischemic stroke. more than twice that of the national average.4 This phenomenon,
originally describing areas of the coastal Carolinas and Georgia, has
 Antiplatelet therapy is the cornerstone of antithrombotic thera- been named the “Stroke Belt.”
py for the secondary prevention of ischemic stroke.

 Warfarin is the drug of choice for secondary prevention of car-

ETIOLOGY AND CLASSIFICATION
dioembolic stroke.  Stroke can be either ischemic or hemorrhagic (88% and 12%,
respectively, of all strokes in the 2006 American Heart Association
Blood pressure lowering is effective in both the primary and
report).1 A classification of stroke by mechanism is given in Fig. 22–1.
secondary prevention of both ischemic and hemorrhagic
Hemorrhagic strokes include subarachnoid hemorrhage, intracere-
stroke regardless of blood pressure.
bral hemorrhage, and subdural hematomas. Subarachnoid hemor-

Blood pressure lowering in the acute stroke period (first 7 rhage occurs when blood enters the subarachnoid space (where
days) can result in decreased cerebral blood flow and wors- cerebrospinal fluid is housed) owing to either trauma, rupture of an
ened symptoms. intracranial aneurysm, or rupture of an arteriovenous malformation
(AVM). By contrast, intracerebral hemorrhage occurs when a blood
 Statin therapy is recommended for all ischemic stroke patients, vessel ruptures within the brain parenchyma itself, resulting in the
regardless of baseline cholesterol, to reduce recurrent vascular formation of a hematoma. These types of hemorrhages very often are
events. associated with uncontrolled high blood pressure and sometimes
antithrombotic or thrombolytic therapy. Subdural hematomas refer
to collections of blood below the dura (covering of the brain), and
 Stroke is the second leading killer worldwide and the third leading they are caused most often by trauma. Hemorrhagic stroke, although
cause of death in the United States, behind cardiovascular disease less common, is significantly more lethal than ischemic stroke, with
and all cancers. Despite improvements in the stroke mortality rates 30-day case-fatality rates that are two to six times higher.5,6
in the second half of the 20th century, stroke occurs in more than Ischemic strokes are caused either by local thrombus formation or
700,000 individuals per year and results in 150,000 deaths.1 Recent by embolic phenomenon, resulting in occlusion of a cerebral artery.
advances in our knowledge of the pathophysiology of stroke and Atherosclerosis, particularly of the cerebral vasculature, is a causative
efforts to organize stroke care have led to evidence-based recommen- factor in most cases of ischemic stroke, although 30% are cryptogenic.
dations on the management of the stroke patient. Emboli can arise either from intra- or extracranial arteries (including
the aortic arch) or, as is the case in 20% of all ischemic strokes, the
heart. Cardiogenic embolism is presumed to have occurred if the
patient has concomitant atrial fibrillation, valvular heart disease, or
Learning objectives, review questions, any other condition of the heart that can lead to clot formation.7
and other resources can be found at Distinguishing between cardiogenic embolism and other causes of
www.pharmacotherapyonline.com. ischemic stroke is important in determining long-term pharmaco-
therapy in a given patient.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 374

STROKE
SECTION 2

Primary
12% hemorrhage
88% • Intraparenchymal
• Subarachnoid
Ischemic stroke

20% 25% 20% 30% 5%

Cardiovascular Disorders

Atherosclerotic Penetrating Cardiogenic Cryptogenic Other, unusual

cerebrovascular artery disease embolism stroke causes
disease (“Lacunes”) • Atrial fibrillation • Prothrombic states
• Valve disease • Dissections
• Ventricular thrombi • Arteritis
• Many others • Migraine/vasospasm
• Drug abuse
• Many more
Hypoperfusion Arteriogenic
emboli

FIGURE 22-1. A classification of stroke by mechanism with estimates of the frequency of various categories of abnormalities.
Approximately 30% of ischemic strokes are cryptogenic.

RISK FACTORS An individual’s risk of having a stroke increases substantially as he or

she ages, with a doubling of risk for each decade older than 55 years of
Risk factors for stroke can be subdivided into nonmodifiable, modifi- age. African Americans, Asian-Pacific Islanders, and Hispanics expe-
able, and potentially modifiable. In addition, risk factors can be either rience higher death rates than their Caucasian counterparts.1,4 Men
well documented or less well documented.8 The main risk factors of are at a higher risk of stroke than women when matched for age, but
stroke are listed in Table 22–1. Recommendations for risk factor women who suffer from a stroke are more likely to die from it.1
reduction aggressively target the modifiable, well-documented risk The most common modifiable, well-documented risk factors for
factors, even in individuals with nonmodifiable risk.8 The nonmodifi- stroke include hypertension, cigarette smoking, diabetes, atrial fibril-
able risk factors are age, race, sex, low birth weight, and family history. lation, and dyslipidemia. The treatment of hypertension, beginning in
the mid-20th century, is thought to be primarily responsible for the
TABLE 22-1 Risk Factors for Ischemic Stroke drastic reduction in stroke death rates between 1950 and 1980 in the
Nonmodifiable risk factors or risk markers United States.4 A second very important risk factor for stroke is
Age cardiac disease. Patients with coronary artery disease, congestive heart
Gender failure, left ventricular hypertrophy, and especially atrial fibrillation
Race are at increased risk of stroke.8,9 In fact, the presence of atrial
Family history of stroke fibrillation is one of the most potent risk factors for ischemic stroke,
Low birth weight with stroke rates from 5% to 20% per year depending on the patient’s
Modifiable, well-documented comorbid conditions.10,11 Other known risk factors for atherosclerosis
Hypertension—single most important risk factor for ischemic stroke are also known to place patients at risk of stroke. Diabetes mellitus,
Atrial fibrillation—most important and treatable cardiac cause of stroke
dyslipidemia, and cigarette smoking are known atherogenic states
Other cardiac diseases
that lead to cerebrovascular disease and ischemic stroke.8,9,12
Diabetes—independent risk factor
Dyslipidemia
Cigarette smoking
Alcohol
PATHOPHYSIOLOGY
Sickle cell disease
Asymptomatic carotid stenosis ISCHEMIC STROKE
Postmenopausal hormone therapy
Lifestyle factors—associated with stroke risk In carotid atherosclerosis, progressive accumulation of lipids and
Obesity inflammatory cells in the intima of the affected arteries, combined
Physical inactivity with hypertrophy of arterial smooth muscle cells, results in plaque
Diet formation. Eventually, sheer stress may result in plaque rupture,
Potentially modifiable, less-well documented collagen exposure, platelet aggregation, and clot formation. The clot
Oral contraceptives can remain in the vessel, causing local occlusion, or travel distally as
Migraine an embolism, eventually lodging downstream in a cerebral vessel. In
Drug and alcohol abuse the case of cardiogenic embolism, stasis of blood in the atria or
Hemostatic and inflammatory factors—fibrinogen linked to increased risk ventricles of the heart leads to the formation of local clots that can
Homocysteine
become dislodged and travel directly through the aorta to the
Sleep disordered breathing
cerebral circulation. The final result of both thrombus formation
Adapted from Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: A and embolism is an arterial occlusion, decreasing cerebral blood flow
guideline from the American Heart Association/American Stroke Association Stroke Council: Cospon- and causing ischemia distal to the occlusion.13
sored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovas-
cular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism
Normal cerebral blood flow averages 50 mL/100 g per minute, and
Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Stroke this is maintained over a wide range of blood pressures (mean arterial
2006;37:1583–1633. pressures of 50 to 150 mm Hg) by a process called cerebral autoregu-
 375

CHAPTER 22
Internal
carotid artery
Anterior cerebral
artery (ACA)

Middle cerebral
artery (MCA)

Stroke
Posterior communicating
artery (PCA)

Vertebral arteries leading

to the basilar artery FIGURE 22-2. Main arterial blood supply
to the brain.

lation. Cerebral blood vessels dilate and constrict in response to ucts.5 Approximately 30% of intracerebral hemorrhages continue to
changes in blood pressure, but this process can be impaired by enlarge over the first 24 hours, most within 4 hours, and clot volume
atherosclerosis and acute injury, such as stroke. When local cerebral is the most important predictor of outcome, regardless of location.15
blood flow decreases below 20 mL/100 g per minute, ischemia ensues, Hemorrhage volumes >60 mL are associated with 71% to 93%
and when further reductions below 12 mL/100 g per minute persist, mortality at 30 days.5,6 Much of the early mortality of hemorrhagic
irreversible damage to the brain occurs, and this is called infarction. stroke (up to 50% at 30 days) is caused by the abrupt increase in
Tissue that is ischemic but maintains membrane integrity is referred intracranial pressure that can lead to herniation and death.1 There is
to as the ischemic penumbra because it usually surrounds the infarct also evidence to support that both early and late edema contributes to
core. This penumbra is potentially salvageable through therapeutic worsened outcome after intracerebral hemorrhage.6
intervention.
Reduction in the provision of nutrients to the ischemic cell eventu-
ally leads to depletion of the high-energy phosphates (e.g., adenosine CLINICAL PRESENTATION (INCLUDING
triphosphate [ATP]) necessary for the maintenance of membrane DIAGNOSTIC CONSIDERATIONS)
integrity. Subsequently, extracellular potassium accumulates at the
same time that sodium and water are sequestered intracellularly, Stroke is a term used to describe an abrupt-onset focal neurologic
leading to cell swelling and eventual lysis. Electrolyte imbalance also deficit that lasts at least 24 hours and is of presumed vascular origin.
leads to depolarization of the cell and influx of calcium into the cell. A TIA is the same but lasts less than 24 hours and usually less than 30
The increase in intracellular calcium results in the activation of minutes. The abrupt onset and the duration of the symptoms are
lipases, proteases, and endonucleases and the release of free fatty acids determined through the history. The use of sensitive imaging tech-
from membrane phospholipids. The depolarization of the neuron niques (magnetic resonance imaging [MRI]) has revealed that symp-
leads to the release of excitatory amino acids, such as glutamate and toms lasting more than 1 hour and less than 24 hours, although
aspartate, that perpetuate the neuronal damage when released in technically TIAs, are associated with infarction, making TIA and
excess. The accumulation of free fatty acids, including arachidonic minor stroke clinically indistinguishable. The location of the central
acid, results in the formation of prostaglandins, leukotrienes, and free nervous system injury and its reference to a specific arterial distribu-
radicals. In ischemia, the magnitude of free-radical production over- tion in the brain are determined through the neurologic examination
whelms normal scavenging systems, leaving these reactive molecules and confirmed by imaging studies such as computed tomography
to attack cell membranes and contribute to the mounting intracellu- (CT) scanning and MRI. The main arterial supply to the brain is
lar acidosis. All these events occur within 2 to 3 hours of the onset of illustrated in Fig. 22–2. Further diagnostic tests are performed to
ischemia and contribute to the ultimate cell death.13 identify the cause of the patient’s stroke and to design appropriate
Later targets for intervention in the pathophysiologic process therapeutic strategies to prevent further events.16
involved after cerebral ischemia include the influx of activated inflam-
matory cells, starting from 2 hours after the onset of ischemia and CLINICAL PRESENTATION OF STROKE
lasting for several days. Also, the initiation of apoptosis, or pro- General
grammed cell death, is thought to occur many hours after the acute
■ The patient may not be able to reliably report the history
insult and can interfere with recovery and repair of brain tissue.14
owing to cognitive or language deficits. A reliable history may
have to come from a family member or another witness.
HEMORRHAGIC STROKE
Symptoms
The pathophysiology of hemorrhagic stroke is not as well studied as ■ The patient may complain of weakness on one side of the body,
that of ischemic stroke. However, it is known that the presence of inability to speak, loss of vision, vertigo, or falling. Ischemic
blood in the brain parenchyma causes damage to the surrounding stroke is not usually painful, but patients may complain of
tissue through the mechanical effect it produces (mass effect) and the headache, and with hemorrhagic stroke, it can be very severe.
neurotoxicity of the blood components and their degradation prod-
 376

Signs ■ GENERAL APPROACH TO TREATMENT

■ Patients usually have multiple signs of neurologic dysfunc-
SECTION 2

The initial approach to the patient with a presumed acute stroke is

tion, and the specific deficits are determined by the area of the to ensure that the patient is supported from a respiratory and
brain involved. cardiac standpoint and to quickly determine whether the lesion is
■ Hemi- or monoparesis occurs commonly, as does a hemisen- ischemic or hemorrhagic-based on a CT scan. Ischemic stroke
sory deficit. patients presenting within hours of the onset of their symptoms
should be evaluated for reperfusion therapy.  TIAs also require
■ Patients with vertigo and double vision are likely to have
urgent intervention to reduce the risk of stroke, which is known to
posterior circulation involvement. be highest in the first few days after TIA.20 Patients with elevated
■ Aphasia is seen commonly in patients with anterior circula- blood pressure should remain untreated unless their blood pressure
Cardiovascular Disorders

tion strokes. exceeds 220/120 mm Hg, or they have evidence of aortic dissection,
■ Patients also may suffer from dysarthria, visual field defects, acute myocardial infarction (AMI), pulmonary edema, or hyperten-
and altered levels of consciousness. sive encephalopathy. If blood pressure is treated, short-acting
parenteral agents, such as labetalol, nicardipine, and nitroprusside,
Laboratory Tests
are favored. Current recommendations regarding management of
■ Tests for hypercoagulable states (protein C deficiency, arterial hypertension in stroke patients is given in Table 22–2.17–19
antiphospholipid antibody) should be done only when the In patients with subarachnoid hemorrhage , an immediate assess-
cause of the stroke cannot be determined based on the presence ment of whether the patient has a berry or saccular aneurysm
of well-known risk factors for stroke. Protein C, protein S, and should be made. If an aneurysm is found by angiography, endovas-
antithrombin III are best measured in the “steady state,” not in cular coiling or clipping via a craniotomy should be performed to
the acute stage. Antiphospholipid antibodies as measured by reduce the risk of rebleeding. In intracerebral hemorrhage, patients
anticardiolipin antibodies, β2-glycoprotein I, and lupus antico- may require external ventricular drainage (EVD) if there is intra-
agulant screen are of higher yield than protein C, protein S, and ventricular blood and evolving hydrocephalus (enlargement of the
antithrombin III but should be reserved for patients who are ventricles). Once the patient is out of the hyperacute phase, atten-
young (<50 years of age), have had multiple venous/arterial tion is placed on preventing worsening, minimizing complications,
thrombotic events, or have livedo reticularis (a skin rash). and instituting appropriate secondary prevention strategies. The
Other Diagnostic Tests acute phase of the stroke includes the first week after the event.17
■ CT scan of the head will reveal an area of hyperintensity (white)
in the area of hemorrhage and will be normal or hypointense ■ NONPHARMACOLOGIC THERAPY
(dark) in the area of infarction. The CT scan may take 24 hours
(and rarely longer) to reveal the area of infarction.
Ischemic Stroke
Surgical interventions in the acute ischemic stroke patient are limited.
■ MRI of the head will reveal areas of ischemia with higher
In certain cases of ischemic cerebral edema owing to a large infarc-
resolution and earlier than the CT scan. Diffusion-weighted
tion, craniectomy to release some of the rising pressure has been tried.
imaging (DWI) will reveal an evolving infarct within minutes.
In cases of significant swelling associated with a cerebellar infarction,
■ Carotid Doppler (CD) studies will determine whether the surgical decompression can be lifesaving. Beyond surgical interven-
patient has a high degree of stenosis in the carotid arteries tion, however, the use of an organized, multidisciplinary approach to
supplying blood to the brain (extracranial disease). stroke care that includes early rehabilitation has been shown to be
■ An electrocardiogram (ECG) will determine whether the very effective in reducing the ultimate disability owing to ischemic
patient has atrial fibrillation, a potent etiologic factor for stroke. stroke. In fact, the use of “stroke units” has been associated with
■ Transthoracic echocardiography (TTE) will determine outcomes similar to those achieved with early thrombolysis when
whether valve abnormalities or wall-motion abnormalities are compared with usual care.17
sources of emboli to the brain. A “bubble test” can be done to  In secondary prevention, carotid endarterectomy of an ulcer-
look for an intraatrial shunt indicating an atrial septal defect ated and/or stenotic carotid artery is a very effective way to reduce
or a patent foramen ovale. stroke incidence and recurrence in appropriate patients and in
centers where the operative morbidity and mortality are low. In fact,
■ Transesophageal echocardiography (TEE) is a more sensitive
in ischemic stroke patients with 70% to 99% stenosis of an ipsilat-
test for thrombus in the left atrium. It is effective at examining
eral internal carotid artery, recurrent stroke risk can be reduced by
the aortic arch for atheroma, a potential source of emboli.
up to 48% compared with medical therapy alone when combined
■ Transcranial Doppler (TCD) will determine whether the patient
is likely to have intracranial stenosis (e.g., middle cerebral artery
stenosis). TABLE 22-2 Blood Pressure Treatment Guidelines in Acute
Ischemic Stroke Patients

TREATMENT Treatment Received t-PA Did Not Receive t-PA

None <180/105 <220/120

Stroke Labetalol IVa or

Nicardipine IVb
180–230/105–120 >220/121–140

Nitroprussidec Diastolic >140 Diastolic >140

■ DESIRED OUTCOME t-PA, tissue plasminogen activator.
a
The goals of treatment of acute stroke are (1) to reduce the ongoing Labetalol IV = 10–20 mg, doubled every 10–20 minutes, to a maximum of 300 mg. Also can use an
neurologic injury and decrease mortality and long-term disability, infusion of 2–8 mg/min.
b
Nicardipine IV = infusion starting at 5 mg/h up to 15 mg/h.
(2) prevent complications secondary to immobility and neurologic c
Nitroprusside IV = infusion starting at 0.5 mcg/kg/min, with continuous arterial blood pressure
dysfunction, and (3) prevent stroke recurrence.17–19 Primary preven- monitoring.
tion of stroke is reviewed elsewhere.8 Adapted from Adams HP, del Zoppo G, Alberts MJ, et al. Stroke 2007;38:1655–1711.
 377
21
with aspirin 325 mg daily. In patients in whom the risk of TABLE 22-3 Inclusion and Exclusion Criteria for Alteplase Use in
endarterectomy is thought to be excessive, carotid stenting can be

CHAPTER 22
Acute Ischemic Stroke
effective in reducing recurrent stroke risk but is less invasive.22
Inclusion criteria (all YES boxes must be checked before treatment)
Carotid stenting is still considered investigational, however, and
issues remain regarding the optimal methods and patients for this YES
 Age 18 years or older
procedure.
 Clinical diagnosis of ischemic stroke causing a measurable neurologic deficit
 Time of symptom onset well established to be less than 180 minutes before
Hemorrhagic Stroke treatment would begin
In patients with subarachnoid hemorrhage owing to a ruptured
Exclusion criteria (all NO boxes must be checked before treatment)
intracranial aneurysm or an AVM, surgical intervention to either

Stroke
clip or ablate the offending vascular abnormality substantially NO
 Evidence of intracranial hemorrhage on noncontrast head CT
reduces mortality owing to rebleeding.23 In the case of primary
 Only minor or rapidly improving stroke symptoms
intracerebral hemorrhage, however, the benefits of surgery are less
 High clinical suspicion of subarachnoid hemorrhage even with normal CT
well documented. Although many patients undergo surgical treat-  Active internal bleeding (e.g., GI/GU bleeding within 21 days)
ment of intracerebral hematomas, the procedures have not been  Known bleeding diathesis, including but not limited to platelet count
studied adequately in clinical trials.5,15 Insertion of EVD for hydro- <100,000/mm3
cephalus and subsequent monitoring of intracranial pressure are  Patient has received heparin within 48 hours and had an elevated APTT
done commonly and are the least invasive of the procedures done in  Recent use of anticoagulant (e.g., warfarin) and elevated PT (>15 second)/INR
these patients. Surgical decompression of a hematoma is more  Intracranial surgery, serious head trauma, or previous stroke within 3 months
controversial, except when it is a last option in a life-threatening  Major surgery or serious trauma within 14 days

situation. Guidelines have been developed for the use of surgical  Recent arterial puncture at noncompressible site

intervention in the treatment of intracerebral hemorrhage, but they  Lumbar puncture within 7 days
 History of intracranial hemorrhage, arteriovenous malformation, or aneurysm
are limited in their impact by the lack of clinical trial data to support
 Witnessed seizure at stroke onset
them.15
 Recent acute myocardial infarction
 SBP >185 mm Hg or DBP >110 mm Hg at time of treatment
■ PHARMACOLOGIC THERAPY
APTT, activated partial thromboplastin time; CT, computed tomography; DBP, diastolic blood
pressure; GI, gastrointestinal; GU, genitourinary; INR, international normalized ratio; PT, prothrombin
Ischemic Stroke time; SBP, systolic blood pressure.
Drug Treatments of First Choice: Published Guidelines
The Stroke Council of the American Stroke Association has created
and published guidelines that address the management of acute
ischemic stroke.17 In general, the only two pharmacologic agents TABLE 22-4 Recommendations for Pharmacotherapy of
recommended with a grade A recommendation are intravenous t- Ischemic Stroke
PA within 3 hours of onset and aspirin within 48 hours of onset. Recommendation Evidencea
 Early reperfusion (<3 hours from onset) with intravenous t-PA Acute treatment 7,17
t-PA 0.9 mg/kg IV (maxi- IA
has been shown to reduce the ultimate disability caused by ischemic mum 90 kg) over 1 hour
stroke.24 Caution must be exercised when using this therapy, and in selected patients within
adherence to a strict protocol is essential to achieving positive out- 3 hours of onset
comes.17 The essentials of the treatment protocol can be summarized ASA 160–325 mg daily7,17 IA
as (1) stroke team activation, (2) onset of symptoms within 3 hours, started within 48 hours of
(3) CT scan to rule out hemorrhage, (4) meet inclusion and exclusion onset
criteria (Table 22–3), (5) administer t-PA 0.9 mg/kg over 1 hour, with Secondary prevention
10% given as initial bolus over 1 minute, (6) avoid antithrombotic Noncardioembolic Antiplatelet therapy IA
(anticoagulant or antiplatelet) therapy for 24 hours, and (7) monitor Aspirin 50–325 mg daily7,27 IIa A (all three as ini-
the patient closely for response and hemorrhage.17 tial options)
Early aspirin therapy also has been shown to reduce long-term Clopidogrel 75 mg daily7,27 IIb B (over aspirin)
death and disability25,26 but should never be given within 24 hours Aspirin 25 mg + extended- IIa A (over aspirin)
of the administration of t-PA because it can increase the risk of release dipyridamole 200
bleeding in such patients.17 mg twice daily7,27
The American Heart Association/American Stroke Association Cardioembolic (esp. Warfarin (INR = 2.5)7,27 IA
atrial fibrillation)
(AHA/ASA) guidelines address all pharmacotherapy used in the
All Antihypertensive IA
secondary prevention of ischemic stroke and are updated every 3 treatment 27
years.27 It is clear that antiplatelet therapy is the cornerstone of Previously hypertensive ACE inhibitor + diuretic27 IA
antithrombotic therapy for the secondary prevention of ischemic Previously normotensive ACE inhibitor + diuretic27 IIa B
stroke and should be used in noncardioembolic strokes. All three Dyslipidemic Statin 27 IA
currently used agents, aspirin, clopidogrel, and extended-release Normal lipids Statin 27 IIa B
dipyridamole plus aspirin (ERDP-ASA), are considered first-line
ACE, angiotensin-converting enzymes; ASA, aspirin; INR, international normalized ratio; t-PA, tissue
antiplatelet agents by the American College of Chest Physicians plasminogen activator.
(ACCP). In patients with atrial fibrillation and a presumed cardiac a
Classes and levels of evidence: I—evidence or general agreement that useful and effective; II—
source of embolism, warfarin is the antithrombotic agent of first conflicting evidence about the usefulness; IIa—weight of evidence in favor of the treatment; IIb—
choice. Other pharmacotherapy recommended for secondary pre- usefulness less well established; III—not useful and maybe harmful. Levels of evidence: A—multiple
randomized clinical trials; B—a single randomized trial or nonrandomized studies; C—expert opinion
vention of stroke include blood pressure lowering and statin ther- or case studies.25 (Level A in reference 7—t-PA recommendation—does not require multiple trials, just
apy. Current recommendations regarding the acute treatment and randomized, well-controlled clinical trial.)
secondary prevention of stroke are given in Table 22–4. Data from Albers et al.,7 Adams et al.,17 and Sacco et al.27
 378

■ GENERAL INFORMATION REGARDING this study of more than 19,000 patients with a history of either
SAFETY AND EFFICACY (INCLUDING myocardial infarction (MI), stroke, or peripheral arterial disease
SECTION 2

PIVOTAL CLINICAL TRIALS) (PAD), clopidogrel 75 mg/day was compared with aspirin 325 mg/
day for its ability to decrease MI, stroke, or cardiovascular death. In
t-PA the final analysis, clopidogrel was slightly (8% relative risk reduc-
tion [RRR]) more effective than aspirin (P = 0.043) and had a
The effectiveness of IV t-PA in the treatment of ischemic stroke was
similar incidence of adverse effects. It is not associated with the
demonstrated in the National Institutes of Neurologic Disorders and
blood dyscrasias (neutropenia) common with its congener, ticlopi-
Stroke (NINDS) Recombinant Tissue-Type Plasminogen Activator
dine, and is used widely in patients with atherosclerosis.
(rt-PA) Stroke Trial, published in 1995.24 In 624 patients treated in
In the European Stroke Prevention Study 2 (ESPS-2), aspirin 25
equal numbers with either t-PA 0.9 mg/kg IV or placebo within 3
Cardiovascular Disorders

mg and extended-release dipyridamole (ERDP) 200 mg twice daily

hours of the onset of their neurologic symptoms, 39% of the treated
were compared alone and in combination with placebo for their
patients achieved an “excellent outcome” at 3 months compared
ability to reduce recurrent stroke over a 2-year period.33 In a total of
with 26% of the placebo patients. An “excellent outcome” was
more than 6,600 patients, all three treatment groups were shown to
defined as minimal or no disability by several different neurologic
be superior to placebo—aspirin alone, 18% RRR; ERDP alone, 16%
scales. This beneficial effect was reported despite a 10-fold increase in
RRR; and the combination, 37% RRR. Importantly, this study was
the risk of symptomatic intracerebral hemorrhage in the t-PA-
the first to show a significant benefit of combination antiplatelet
treated patients (0.6% vs. 6.4%). Overall mortality was not different
therapy in stroke prevention, with the combination demonstrating a
between the two groups (17% with t-PA and 21% with placebo).
significant advantage over the aspirin-alone group (23% RRR; P =
Patients with very severe symptoms at baseline (National Institutes
0.006) and the ERDP-alone group (24% RRR; P = 0.002). Headache
of Health Stroke Scale [NIHSS] >20) and early ischemic changes on
resulting in discontinuation occurred in approximately 15% of the
CT scan were shown to be at highest risk for the development of
ERDP groups (four times more common than in the placebo group),
symptomatic intracranial hemorrhage. Even in patients at highest
and the aspirin-treated patients, even at the low dose of 50 mg/day,
risk for bleeding, however, those receiving t-PA had better outcomes
experienced significantly more bleeding than the other groups. The
at 90 days than those who received placebo.24 The publication of the
combination of aspirin 25 mg and ERDP 200 mg twice daily is a
NINDS trial results significantly changed the way in which acute
highly effective treatment to prevent recurrence in patients with
stroke is managed in the community, promoting the development of
stroke or TIA. The European/Australasian Stroke Prevention in
acute stroke teams and emphasis on the early diagnosis and treat-
Reversible Ischemia Trial (ESPRIT) confirmed the results of ESPS-2,
ment of acute stroke. Prospectively collected data, even from the best
in that the combination of dipyridamole (83% extended release) and
centers, report between 3% and 8.5% of ischemic stroke patients in
aspirin (30–325 mg daily) was more effective than aspirin alone in
the United States receive t-PA, primarily owing to failure of patients
reducing recurrent stroke.34 Headache was an important cause of
to present in time to facilities equipped to administer the therapy
discontinuation in the ESPRIT trial, further stressing the importance
safely.28 Hemorrhage rates associated with t-PA use in the commu-
of monitoring and education in these patients. No data exist on the
nity have been reported to be similar to those reported in the NINDS
ability of this combination to reduce MI and/or cardiovascular death
trial (5%),29 but significantly higher rates (up to 15%) have been
in patients with other indications for antiplatelet therapy.
reported when a strict protocol is not followed.30

Aspirin Warfarin
 Warfarin is the most effective treatment for the prevention of
The use of early aspirin to reduce long-term death and disability
stroke in patients with atrial fibrillation.10,11,35,36 In patients with
owing to ischemic stroke is supported by two large, randomized
atrial fibrillation and a recent history of stroke or TIA, the risk of
clinical trials. In the International Stroke Trial (IST),26 aspirin 300
recurrence places these patients in one of the highest risk categories
mg/day significantly reduced stroke recurrence within the first 2
known. In the European Atrial Fibrillation Trial (EAFT), 669
weeks without effect on early mortality, resulting in a significant
patients with nonvalvular atrial fibrillation (NVAF) and a prior
decrease in death and dependency at 6 months. In the Chinese
stroke or TIA were randomized to either warfarin (international
Acute Stroke Trial (CAST),25 aspirin 160 mg/day reduced the risk of
normalized ratio [INR] = 2.5–4), aspirin 300 mg/day, or placebo.
recurrence and death in the first 28 days, but long-term death and
Patients in the placebo group experienced stroke, MI, or vascular
disability were not different than with placebo. In both trials, a small
death at a rate of 17% per year compared with 8% per year in the
but significant increase in hemorrhagic transformation of the
warfarin group and 15% per year in the aspirin group. This
infarction was demonstrated. Overall, the beneficial effects of early
represents a 53% reduction in risk with anticoagulation.10 Subse-
aspirin have been embraced and adopted into clinical guidelines.
quent studies in the primary prevention of stroke in patients with
NVAF have demonstrated that targeting an international normal-
Antiplatelet Agents ization ratio (INR) of 2.5 prevents stroke with the lowest bleeding
All patients who have had an acute ischemic stroke or TIA should risk (Stroke Prevention in Atrial Fibrillation [SPAF III]); therefore,
receive long-term antithrombotic therapy for secondary preven- a target INR of 2.5 is recommended in the secondary prevention of
tion.27  In patients with noncardioembolic stroke, this will be stroke.11,35,36
some form of antiplatelet therapy. In a recent meta-analysis, the Use of warfarin in the secondary prevention of noncardioembolic
overall benefit of antiplatelet therapy in patients with atherothrom- stroke was addressed in the Warfarin Aspirin Recurrent Stroke
botic disorders was estimated to be 22%.31 Aspirin is the best- Study.37 In 2,206 patients with recent stroke, warfarin (INR = 1.4–2.8)
studied of the available agents and, until recently, was considered was not superior to aspirin 325 mg/day in the prevention of recurrent
the sole first-line agent. However, published literature has sup- events. Further data from the Warfarin-Aspirin in Intracranial Dis-
ported the use of clopidogrel and the combination product ERDP- ease (WASID) trial demonstrated that aspirin therapy was as effective
ASA as additional first-line agents in secondary stroke prevention. and safer than warfarin in patients with intracranial stenosis.38 These
The efficacy of clopidogrel as an antiplatelet agent in athero- studies led most clinicians to abandon the practice of using warfarin
thrombotic disorders was demonstrated in the Clopidogrel versus in all but patients with cardioembolic sources of emboli, mainly atrial
Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.32 In fibrillation.
 379

Blood Pressure Lowering rin 75 mg daily was no better than clopidogrel alone in secondary
stroke prevention.48 However, the combination has been studied in

CHAPTER 22
Elevated blood pressure is very common in ischemic stroke
patients with acute coronary syndromes and patients undergoing
patients, and treatment of hypertension in these patients is associ-
percutaneous coronary interventions and shown to be significantly
ated with a decreased risk of stroke recurrence.39 In the Perindopril
more effective than aspirin alone in reducing MI, stroke, and cardio-
pROtection aGainst REcurrent Stroke Study (PROGRESS), a multi-
vascular death.49,50 Also, when clopidogrel was used with aspirin, the
national stroke population (40% Asian) was randomized to receive
risk of life-threatening bleeding increased from 1.3% to 2.6%.48 In the
either blood pressure lowering with the angiotensin-converting
Clopidogrel for High Atherothrombotic Risk and Ischemic Stabiliza-
enzyme (ACE) inhibitor perindopril (with or without the thiazide
tion, Management and Avoidance (CHARISMA) trial, the combina-
diuretic indapamide) or placebo.40 Treated patients achieved an
tion was again found to significantly increase serious bleeding in a
overall 9 points systolic and 4 points diastolic mm Hg blood pressure

Stroke
high risk atherosclerosis population (clinically evident disease or
reduction, and this was associated with a 28% reduction in stroke
multiple risk factors) with no consistent benefit in terms of prevent-
recurrence. In the patients who received the combination treatment
ing vascular events, when compared to aspirin alone.51 This combina-
(clinician’s discretion), the average blood pressure lowering achieved
tion can only be recommended in patients with a recent history of MI
was 12 systolic and 5 diastolic mm Hg, and this was associated with
or coronary stent placement and only with ultra–low-dose aspirin to
an even larger reduction in stroke recurrence (43%). Similar results
minimize bleeding risk.52
were achieved in patients with and without hypertension. Based on
the results of this study and other evidence of the tolerability and
vascular protective properties of the ACE inhibitors, the Seventh Angiotensin II Receptor Blockers
Report of the Joint National Committee on Prevention, Detection, Angiotensin II receptor blockers (ARBs) also have been shown to
Evaluation, and Treatment of High Blood Pressure (JNC7) and the reduce the risk of stroke. In the Losortan Intervention For Endpoint
AHA/ASA guidelines recommend an ACE inhibitor and a diuretic for Reduction in Hypertension (LIFE) study, losartan and metoprolol
the reduction of blood pressure in patients with stroke or TIA.27,41
were compared for their ability to reduce blood pressure and prevent
Blood pressure lowering in the acute stroke period (first 7 days) can cardiovascular events in a group of severely hypertensive patients.53
result in decreased cerebral blood flow and worsened symptoms; Despite similar reductions in blood pressure of approximately 30/16
therefore, recommendations are limited to patients out of the acute mm Hg, the losartan group experienced a 24% reduction in the risk
stroke period.27 of stroke. In a similar study comparing eprosartan to nitrendipine,
the ARB eprosartan was superior to the calcium channel blocker in
Statins reducing recurrent stroke risk, when equal blood pressure lowering
was achieved.54 The ARBs should be considered in patients unable to
 The statins have been shown to reduce the risk of stroke by tolerate ACE inhibitors for blood pressure lowering after acute
approximately 30% in patients with coronary artery disease and ischemic stroke.
elevated plasma lipids.42–44 The National Cholesterol Education Pro-
gram (NCEP) considers ischemic stroke or TIA to be a coronary
“equivalent” and has recommended the use of statins to achieve a low- Heparins
density lipoprotein (LDL) concentration of less than 100 mg/dL.45 The use of full-dose unfractionated heparin in the acute stroke period
When the Heart Protection Study was published, it provided evidence has never been proven to positively affect stroke outcome, and it
that simvastatin 40 mg/day reduced stroke risk in high-risk individuals significantly increases the risk of intracerebral hemorrhage.7,17 Trials of
(including patients with prior stroke) by 25% (P < 0.0001), even in low-molecular-weight heparins or heparinoids have been largely neg-
patients with LDL concentrations of less than 116 mg/dL.46 The ative and do not support their routine use in stroke patients.55–57 Other
investigators also showed that this practice is extremely safe, with an potential but unproven uses for treatment doses of either unfraction-
excess incidence of myopathy of 0.01%. The Stroke Prevention by ated or low-molecular-weight heparins include bridge therapy in
Aggressive Reduction in Cholesterol (SPARCL) study went one step patients being initiated on warfarin, carotid dissection, or continuous
further by demonstrating, in stroke patients, that atorvastatin 80 mg worsening of ischemia despite adequate antiplatelet therapy.7
daily reduced the risk of recurrent stroke by 16% and coronary events
by 42% while causing an increase in liver enzymes, but no increase in ■ DRUG CLASS INFORMATION
myopathy.47 Statin therapy is an effective way to reduce stroke risk and
should be considered in all ischemic stroke patients. Whether high- Aspirin
dose statin therapy is prescribed should be determined in the individ- Aspirin exerts its antiplatelet effect by irreversibly inhibiting cyclo-
ual patient by a careful weighing of the benefits against the potential oxygenase, which, in platelets, prevents conversion of arachidonic acid
increase in adverse events. to thromboxane A2 (TXA2), which is a powerful vasoconstrictor and
stimulator of platelet aggregation. Platelets remain impaired for their
Heparin for Prophylaxis of Deep-Vein life span (5 to 7 days) after exposure to aspirin. Aspirin also inhibits
Thrombosis (DVT) prostacyclin (PGI2) activity in the smooth muscle of vascular walls.
PGI2 inhibits platelet aggregation, and the vascular endothelium can
The use of low-molecular-weight heparins or low-dose subcutane- synthesize prostacyclin such that the platelet antiaggregating effect is
ous unfractionated heparin (5,000 units twice daily) can be recom- maintained. The suppression of PGI2 production by aspirin has been
mended for the prevention of DVT in hospitalized patients with found to be dose- and duration-related; the higher the dose, the longer
decreased mobility owing to their stroke and should be used in all the cyclooxygenase production is suppressed. Therefore, the lower the
but the most minor strokes.7,17 aspirin dose, the less effect on PGI2.7 The optimal dose of aspirin is still
under study, but it should be the dose that inhibits TXA2 with the least
■ ALTERNATIVE DRUG TREATMENTS amount of PGI2 inhibition. It has been shown that an aspirin dose of
325 mg/day will inhibit TXA2 but will not significantly inhibit PGI2
Aspirin Plus Clopidogrel production. There is probably a point at which lower doses of aspirin
In the Management of ATherothrombosis with Clopidogrel in High- do not completely block TXA2, and recent studies indicate that the
risk patients (MATCH) study, clopidogrel in combination with aspi- lowest effective dose may be in the range of 50 mg/day.58 Upper
 380
gastrointestinal (GI) discomfort and bleeding are the most common Clopidogrel is a thienopyridine prodrug and needs to be biotrans-
adverse effects of aspirin and have been shown to be dose-related. The formed by the liver to an active metabolite. Evidence suggests that the
SECTION 2

highest rates of GI bleeding (5%) have been reported in patients enzyme responsible for the conversion is human cytochrome P450
receiving 1,200 mg/day as compared with rates of 2% in patients 3A4 (CYP3A4) and that the platelet effects of clopidogrel can be
taking the more commonly prescribed, 300 mg/day. Upper GI symp- diminished in patients receiving agents that inhibit this enzyme.66
toms are much more common than frank bleeding, however, with Although high doses of the lipophilic statins atorvastatin and simva-
40% of patients affected at 1,200 mg/day and 25% at 300 mg/day.59 In statin can diminish the effectiveness of clopidogrel to inhibit platelet
the ESPS-2 study, even 50 mg/day of aspirin was associated with a aggregation in vitro, there does not appear to be any adverse effect on
twofold increase in bleeding over the placebo group.33 atherothrombotic event rates.67 Concomitant administration of clo-
Low doses (<100 mg) of aspirin quickly inhibit cyclooxygenase in pidogrel with lipophilic statins is often recommended.
Cardiovascular Disorders

all the platelets in the circulation. Therefore, the onset of the

antiplatelet effect of aspirin is less than 60 minutes.60 It has been ■ INVESTIGATIONAL STRATEGIES
reported, however, that some patients either have or develop “aspi-
rin resistance” and can require higher doses to achieve the desired Reperfusion
antiplatelet effect.61 Despite this, routine testing for aspirin resis- Various investigations aimed at shortening the time required to open
tance is not recommended. It was observed recently that adminis- the occluded cerebral artery and preserve its patency are underway in
tration of ibuprofen prior to the administration of a daily aspirin acute ischemic stroke patients.68 Strategies being tried include longer-
dose prohibits the aspirin from binding irreversibly to the cyclooxy- acting fibrinolytic agents, intraarterial fibrinolysis with t-PA and
genase and can decrease its antiplatelet effect.62 Current recommen- other agents, and endovascular clot removal using mechanical and
dations are to administer aspirin at least 2 hours before ibuprofen laser-guided approaches. In addition, investigators are trying to iden-
or to wait at least 4 hours after an ibuprofen dose. tify, using sensitive MRI techniques, which patients benefit from
reperfusion at time points outside the approved 3-hour time window.
Extended-Release Dipyridamole Plus Aspirin Undoubtedly, efforts to reperfuse the ischemic brain will continue to
be explored, so more patients will be eligible for this therapy.
Early studies of the role of dipyridamole in stroke prevention failed to
show a benefit over that realized by aspirin alone. Dipyridamole, in
high doses, is thought to inhibit platelet aggregation by inhibiting Neuroprotection and Neurorestoration
phosphodiesterase, leading to accumulation of cyclic adenosine Although many different neuroprotective agents have been studied in
monophosphate (cAMP) and cyclic guanosine monophosphate clinical trials of acute ischemic stroke, most have been unsuccessful.69
(cGMP) intracellularly, which prevent platelet activation. In addition, A promising nonpharmacologic strategy that has been shown to
dipyridamole also enhances the antithrombotic potential of the vas- provide neuroprotection in patients has been hypothermia.70 Cur-
cular wall.63 The ESPS-2 demonstrated the efficacy of high-dose rently, clinical trials are underway to optimize the mechanism of
extended-release dipyridamole alone and in combination with aspirin cooling the ischemic brain (intravascular coils versus surface cooling)
in secondary stroke prevention.33 This was the first study to demon- and rewarming the patient after hypothermia. Despite discouraging
strate the benefits of combination antiplatelet therapy in stroke results in previous attempts, however, there is still great interest in
prevention (the combination was significantly more effective than developing pharmacologic agents that provide neuroprotection.
either agent alone). The extended-release formulation of dipy- Some of the most promising agents include free-radical scavengers
ridamole is important in that it allows twice-daily administration and (NXY-059),71 anti-inflammatory agents, and agents with multiple
higher doses to be tolerated in patients. The use of immediate-release proposed mechanisms of protection (e.g., albumin infusions).72 In
generic dipyridamole in combination with regular aspirin, in order to addition, hope still exists that clinicians will be able to enhance the
reduce costs, is unproven and should be discouraged. reparative process of the brain (neurorestoration) through targeted
In the ESPS-2, 25% of the patients who received combination neurorehabilitation and the use of neural and cell transplantation.73
dipyridamole and aspirin discontinued the therapy early, and the rate
of discontinuation owing to headache was more than three times as
common (10%) as in the aspirin-alone group (3%). Other reasons for
discontinuation were GI problems. Slow initiation of ERDP-ASA at HEMORRHAGIC STROKE
one capsule at bedtime daily for 2 or 3 days can be tried in order to
There are currently no standard pharmacologic strategies for treat-
lessen headache symptoms. The headache caused by ERDP-ASA is
ing intracerebral hemorrhage (ICH).15 The use of hemostatic agents
mostly self-limiting and decreases after several days.64
(e.g., factor VII) in the hyperacute phase (<4 hours from onset) can
reduce hematoma growth, but no improvement in outcomes has
Clopidogrel been demonstrated.74 Medical guidelines for the management of
Clopidogrel has a unique platelet antiaggregatory effect in that it is an blood pressure, raised intracranial pressure, and other medical
inhibitor of the adenosine diphosphate (ADP) pathway of platelet complications of ICH are those required for the management of any
aggregation and inhibits known stimuli to platelet aggregation.7,32 This acutely ill patient in a neurointensive care unit.
effect causes an alteration of the platelet membrane and interference Subarachnoid hemorrhage (SAH) owing to aneurysm rupture is
with the membrane-fibrinogenic interaction leading to a blocking of associated with a high incidence of delayed cerebral ischemia (DCI)
the platelet glycoprotein IIb/IIIa receptor. A time lag of 3 to 7 days in the 2 weeks following the bleeding episode. Vasospasm of the
before the antiplatelet effect is maximal should be expected. The cerebral vasculature is thought to be responsible for DCI and occurs
tolerability of clopidogrel 75 mg/day is at least as good as medium- between 4 and 21 days after the bleed, peaking at days 5 through 9.23
dose (325 mg/day) aspirin, and GI bleeding is less.32 Clopidogrel is The calcium channel blocker nimodipine is recommended to
associated with an increased risk of diarrhea and rash, but discontinu- reduce the incidence and severity of neurologic deficits owing to
ation rates owing to adverse effects are similar to those with aspirin 325 DCI. Nimodipine at a dose of 60 mg every 4 hours should be
mg/day (5.3% to 6%, respectively).32 There is no excess neutropenia in initiated on diagnosis and continued for 21 days in all SAH patients.
patients taking clopidogrel, and rates of thrombotic thrombocyto- Administration of nimodipine therapy is complicated by a fairly
penic purpura probably are no greater than background rates.65 high incidence of hypotension. This can be managed by reducing
 381
the dosing interval to 30 mg every 2 hours (same daily dose), QALY (adjusted for the acquisition cost) and clopidogrel was $26,580
reducing the total daily dose (30 mg every 4 hours), and maintain- per QALY. Any cost per QALY less than $50,000 is thought to be “cost-

CHAPTER 22
ing intravascular volume and pressor therapy.23 effective.”79 These estimates are extremely dependent on the assump-
tions made in the model. Cost-effectiveness in an individual patient is
much more difficult to discern.
PHARMACOECONOMIC CONSIDERATIONS Primary prevention strategies that address the risk factors for
ischemic stroke can be powerful in reducing the costs of stroke.
Although t-PA is expensive, when the total healthcare costs are Many of the stroke risk factors can be modified and some elimi-
factored in, savings can accrue to the healthcare system as a direct nated at very low costs (lifestyle changes), therefore developing risk-
result of appropriate t-PA therapy.75 It has been estimated that, at a factor-reduction strategies can be the most cost-effective measure of

Stroke
rate of $600 per patient treated, annual cost savings of $15 and $22 all. More research is needed in identifying the cost-effectiveness of
million could be realized by increasing national t-PA use to 4% and other forms of acute stroke treatment.
6%, respectively (from the current 2%).76
In antithrombotic prophylaxis for atrial fibrillation, warfarin therapy
was evaluated using quality-adjusted life-years (QALYs) saved.77 It was
found that in patients with atrial fibrillation and one additional risk CLINICAL CONTROVERSIES
factor, warfarin therapy cost $8,000 per QALY saved. In high-risk The use of full-dose unfractionated heparin in the management
patients, those with atrial fibrillation and two or more risk factors, of acute ischemic stroke remains controversial despite years of
warfarin use was estimated to save $6,200 in costs from stroke and TIA. debate and a lack of evidence supporting its use. Proponents of
Costs of monitoring and hemorrhages from warfarin were estimated to the therapy cite strong anecdotal evidence of positive responses
be $5,500, thus showing a positive savings from warfarin use. Those in selected patients who have never been studied in clinical trials.
without risk factors were much more costly to treat at an estimated The use of intracranial angioplasty and stenting is strongly
$370,000 per QALY saved when compared with aspirin treatment. supported in the few institutions where the technology exists.
Warfarin is cost-effective in high-risk patients, particularly if the hem- Whether these procedures should be attempted in patients
orrhagic side effects are lower relative to the stroke risk. For comparison outside clinical trials remains controversial.
purposes, hypertension screening is estimated to cost $10,000 to
The use of surgical evacuation of intracranial hemorrhage with
$50,000 per QALY saved. A Swedish study reported the cost-effective-
and without instillation of fibrinolytic agents is controversial.
ness of primary stroke prevention in atrial fibrillation patients with oral
Although fervently pursued in select centers and countries,
anticoagulants or aspirin based on four published clinical trials.78 The
indications and outcomes are not known. Results of ongoing
authors found that the total cost per stroke prevented was a $16 savings
clinical trials can assist in settling this controversy.
if the intracerebral bleeding was 0.3% and $43 if the bleeding rate was
2%. At a bleeding complication rate of 1.3%, warfarin would prevent
1,000 strokes per year and save approximately $29 million. The cost- EVALUATION OF THERAPEUTIC OUTCOMES
effectiveness of the various first-line antiplatelet agents have been
compared as well.79 Without a doubt, aspirin, owing to its extremely MONITORING OF THE PHARMACEUTICAL
low acquisition cost (pennies daily), is cost saving. In other words, it CARE PLAN
reduces costs at the same time as saving QALYs. The use of clopidogrel
or ERDP-ASA is associated with higher efficacy but significantly greater Patients with acute stroke should be monitored intensely for the
costs as well (up to $3 daily). Despite this, both options have been development of neurologic worsening (recurrence or extension),
deemed “cost-effective” when administered to a 65-year-old patient complications (thromboembolism or infection), or adverse effects
with a history of stroke or TIA for the prevention of recurrence. In a from pharmacologic or nonpharmacologic interventions. The most
recent analysis, ERDP-ASA was associated with $5,000 to $15,000 per common reasons for deterioration in a stroke patient are (1) exten-

TABLE 22-5 Monitoring the Hospitalized Acute Stroke Patient

Treatment Parameter(s) Frequency Comments
Ischemic stroke t-PA BP, neurologic function, bleeding Every 15 minutes × 1 hour; every 0.5 h × 6 h;
every 1 hour × 17 hour; every shift after
Aspirin Bleeding Daily
Clopidogrel Bleeding Daily
ERDP/ASA Headache, bleeding Daily Headache usually transient (2–3 days) and
may respond to simple analgesics
Warfarin Bleeding, INR, Hb/Hct INR daily × 3 days; weekly until stable;
monthly
Hemorrhagic BP, neurologic function, ICP Every 2 hours in ICU Many patients require intervention with
stroke short-acting agents to reduce BP to <180
mm Hg systolic
Nimodipine (for SAH) BP, neurologic function, fluid status Every 2 hours in ICU
All Temperature, CBC Temp. every 8 hours; CBC daily For infectious complications such as UTI or
pneumonia
Pain (calf or chest) Every 8 hours For DVT, MI, acute headache
Electrolytes and ECG Up to daily For fluid and electrolyte imbalances, cardiac
rhythm abnormalities
Heparins for DVT Bleeding, platelets Bleeding daily, platelets if suspected throm-
prophylaxis bocytopenia
BP, blood pressure; CBC, complete blood count; DVT, deep-vein thrombosis; ECG, electrocardiography, ERDP-ASA, extended-release dipyridamole plus aspirin; Hb/Hct, hemoglobin/hematocrit; ICP, intracranial
pressure; ICU, intensive care unit; MI, myocardial infarction; SAH, subarachnoid hemorrhage.
 382
sion of the original lesion—ischemic or hemorrhagic—in the brain, tion Statistics Committee and Stroke Statistics Subcommittee. Circula-
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SECTION 2

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21. Cina CA, Clase CM, Haynes RB. Carotid endarterectomy for sympto-
RRR: relative risk reduction
matic carotid stenosis (Cochrane Review on CD-ROM). Oxford:
SAH: subarachnoid hemorrhage Cochrane Library Update Software, 2001; issue 1.
TCD: transcranial Doppler 22. Narins CR, Illig KA. Patient selection for carotid stenting versus
endarterectomy: A systemic review. J Vasc Surg 2006;44:661–672.
TIA: transient ischemic attack 23. Miller J, Diringer M. Management of aneurysmal subarachnoid hem-
TXA2: thromboxane A2 orrhage. Neurol Clin 1995;13:451–478.
24. The National Institute of Neurological Disorders and Stroke rt-PA
t-PA: tissue plasminogen activator Stroke Study Group. Tissue plasminogen activator for acute ischemic
stroke. N Engl J Med 1995;333:1581–1587.
25. Chinese Acute Stroke Trial (CAST) Collaborative Group. CAST: A
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arin, both, or neither among 19,435 patients with acute ischemic 48. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel
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CHAPTER 22
27. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke transient ischaemic attack in high-risk patients (MATCH): Random-
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30. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen alone or in combination with clopidogrel in patients with acute coro-
activator for acute ischemic stroke: The Cleveland area experience. nary syndromes: Observations from the clopidogrel in unstable angina
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35. American Society of Health-System Pharmacists. ASHP therapeutics 56. Bath PM, Lidenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic
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Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383– 66. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the
1389. ability of clopidogrel to inhibit platelet aggregation: A new drug-drug
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with pravastatin: The Prospective Pravastatin Pooling (PPP) Project. 67. Saw J, Steinhubl SR, Berger PB, et al. Lack of adverse clopidogrel-
Circulation 2001;103:387–392. atorvastatin clinical interaction from secondary analysis of a randomized,
45. Executive Summary of the Third Report of the National Cholesterol placebo-controlled clopidogrel trial. Circulation 2003;108:921–924.
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and Treatment of High Blood Cholesterol in Adults (Adult Treatment alization strategies. Circulation 2002;106:1563–1569.
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individuals: A randomized, placebo-control trial. Lancet 2002;360:7–22. 70. Broderick JP, Hacke W. Treatment of acute ischemic stroke: II. Neuropro-
47. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels tection and medical management. Circulation 2002;106:1736–1740.
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72. Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: 76. Demaerschalk BM, Yip TR. Economic benefit of increasing utilization
Lessons from neuroprotective stroke trials and new therapeutic direc- of intravenous tissue plasminogen activator for acute ischemic stroke
SECTION 2

tions. Stroke 2002;33:2123–2136. in the United States. Stroke 2005;36:2500–2503.

73. Kondziolka D, Wechsler L, Goldstein S, et al. Transplantation of 77. Gage BF, Cardinalli AB, Albers GW, Owens DK. Cost-effectiveness of
cultured human neuronal cells for patients with stroke. Neurology warfarin and aspirin for prophylaxis of stroke in patients with nonval-
2000;55:565–569. vular atrial fibrillation. JAMA 1995;274:1839–1845.
74. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII 78. Gustafsson C, Asplund K, Britton M, et al. Cost-effectiveness of stroke
for acute intracerebral hemorrhage. N Engl J Med 2005;352:777–785. prevention in atrial fibrillation. BMJ 1992;305:1457–1460.
75. Fagan SC, Morgenstein LB, Peitta A, et al. Cost effectiveness of tissue 79. Sarasin FP, Gaspoz JM, Bournameaux H. Cost-effectiveness of new
plasminogen activate for acute ischemic stroke. Neurology 1998;50:883– antiplatelet regimens used as secondary prevention of stroke or tran-
890. sient ischemic attack. Arch Intern Med 2000;160:2773–2778.
Cardiovascular Disorders
 385

C HAP T E R

23 Hyperlipidemia

ROBERT L. TALBERT

Lipid-lowering therapy is generally considered cost effective,
KEY CONCEPTS particularly in secondary intervention and high-risk patients.

 Hypercholesterolemia, elevated low-density lipoprotein (LDL)  Decreasing elevated total cholesterol and low-density lipopro-
levels, and low high-density lipoprotein (HDL) levels are un- tein cholesterol (LDL-C) levels reduce coronary heart disease
equivocally linked to increased risk for coronary heart disease mortality and total mortality; increasing HDL reduces coronary
and cerebrovascular morbidity and mortality. LDL is the primary heart disease events as well. Aggressive treatment of hyper-
target. cholesterolemia results in fewer patients progressing to myo-
cardial infarction, angina, and stroke and reduces the need for
 Multiple genetic abnormalities and environmental factors are interventions such as coronary artery bypass graft and percuta-
involved in clinical lipid abnormalities, and routinely used clin- neous transluminal coronary angioplasty.
ical laboratory measurements do not define the underlying
abnormalities.
 Initial therapy for any lipoprotein disorder is therapeutic lifestyle Cholesterol, triglycerides, and phospholipids are the major lipids in
changes with restricted intake of total and saturated fat and the body. They are transported as complexes of lipid and proteins
cholesterol and a modest increase in polyunsaturated fat in- known as lipoproteins. Plasma lipoproteins are spherical particles
take along with a program of regular exercise and weight reduc- with surfaces that consist largely of phospholipid, free cholesterol,
tion if needed. and protein and cores composed mostly of triglyceride and choles-
terol ester (Fig. 23–1). The three major classes of lipoproteins in
 If pharmacologic therapy is insufficient after therapeutic life- serum are low-density lipoproteins (LDLs), high-density lipopro-
style changes, lipid-lowering agents should be chosen based teins (HDLs), and very-low-density lipoproteins (VLDLs). VLDL is
on the specific lipoprotein disorder presentation and the sever- carried in the circulation as triglyceride and can be estimated by
ity of the lipid abnormality. dividing the triglyceride concentration by five. Intermediate-density
 Considering compliance, adverse effects, and effectiveness, for lipoprotein (IDL) resides between VLDL and LDL and is included in
patients with hypercholesterolemia statins are the drugs of the LDL measurement in routine clinical measurement. Abnormali-
choice because they are the most potent form of monotherapy ties of plasma lipoproteins can result in a predisposition to coronary,
and are cost effective in patients with known coronary artery cerebrovascular, and peripheral vascular arterial disease and consti-
disease or multiple risk factors and in high-risk primary preven- tutes one of the major risk factors for coronary heart disease (CHD).
tion patients. Accumulating evidence over the last decades had linked elevated
total cholesterol and low-density lipoprotein-cholesterol (LDL-C)
 Patients who do not respond to statin monotherapy can be levels and reduced HDL levels to the development of CHD. Prema-
treated with combination therapy for hypercholesterolemia but ture coronary atherosclerosis, leading to the manifestations of
should be monitored closely because of an increased risk for ischemic heart disease (see Chap. 17), is the most common and
adverse effects and drug interactions. significant consequence of dyslipidemia. The National Cholesterol
 Hypertriglyceridemia usually responds well to niacin, gemfib- Education Program (NCEP) Adult Treatment Panel III (ATP III)
rozil, and fenofibrate. High-dose niacin should be used cau- published its third report summarizing these data and giving recom-
tiously in diabetics because of worsening glycemic control. mendations for the management of hypercholesterolemia in
Statins lower triglycerides to a variable extent depending on adults.1,2 This report and the later update modify earlier recommen-
baseline triglyceride concentration and statin potency. dations and provide a new way of risk-stratifying patients based on
multiple risk factors, the presence of diabetes, and the metabolic
Low high-density lipoprotein-cholesterol (HDL-C) levels are ad- syndrome. The American Heart Association (AHA) also provides
dressed with lifestyle modifications, such as smoking cessation guidelines for primary and secondary prevention of CHD.3,4
and increased exercise. Niacin, gemfibrozil, and fenofibrate can Total cholesterol and LDL-C increase throughout life in men and
significantly increase HDL-C. women, representing an atherogenic pattern characteristic of west-
ernized society diets.5 Based on the National Health and Nutrition
Examination Survey (NHANES 1999–2004) and ATP III guidelines,
slightly more than 50% or nearly 105 million American adults older
Learning objectives, review questions, than 20 years have total cholesterol levels ≥200 mg/dL.6 More than
and other resources can be found at half of individuals at borderline to high risk remain unaware that
www.pharmacotherapyonline.com. they have hypercholesterolemia, and fewer than half of highest-risk
persons (those with symptomatic CHD) are receiving lipid-lowering

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 386
On a positive note, the U.S. mortality rate is midway among the
countries studied. The United States has shown the greatest decline
SECTION 2

in CAD mortality (35%–40%) in men and women over the last 10

Cholesteryl ester years compared to other countries. A decline in the prevalence of
LDL
hypercholesterolemia in certain segments of the U.S. population
parallels these trends in mortality.1 LDL and the ratio of LDL to HDL
also have been used to assess risk, but their use adds little informa-
tion to total cholesterol alone unless HDL is abnormally high or low.
Apoprotein B-100 HDL transports cholesterol from lipid-laden foam cells to the liver.
HDL has been shown to be protective for the occurrence of CHD,
Cardiovascular Disorders

LDL receptor and an inverse relationship exists between CHD and HDL levels.12
VLDL, the major lipoprotein associated with triglycerides, is
enriched with cholesterol esters. It is smaller, denser, and more
atherogenic than less-dense VLDL. Routine measurement of triglyc-
NH2
erides cannot distinguish between the types of VLDL present in
plasma. Elevation of triglyceride-rich lipoproteins is associated with
low HDL, and this ratio predicts increased risk. The 8-year follow-up
of the Copenhagen male study found a clear gradient of risk for
ischemic heart disease with increasing triglyceride levels within each
Plasma level of high-density lipoprotein-cholesterol (HDL-C). Compared to
Cytoplasm membrane
the lowest tertile of triglyceride concentrations, the highest tertile
COOH had 2.2 relative risk for ischemic heart disease, and the relationship
extended across all concentrations of HDL.13 The Helsinki Heart
FIGURE 23-1. Diagrammatic representation of the structure of low- Study showed that hypertriglyceridemia and low HDL are associated
density lipoprotein (LDL), the LDL receptor, and the binding of LDL to the with obesity (body mass index [BMI] >26 kg/m2), smoking, seden-
receptor via apolipoprotein B-100. (From Ganong WF. Review of Medi-
tary lifestyle, blood pressure ≥140/90 mm Hg, and blood glucose
cal Physiology, 22nd ed. New York: McGraw-Hill, 2005:303.)
>4.4 mmol/L, and that the benefit of gemfibrozil (risk reduction
68%, P <0.03) was largely confined to overweight subjects.14 Hyper-
treatment. Approximately one third of treated patients are achieving triglyceridemia in certain instances (e.g., diabetes mellitus, nephrotic
their LDL goal; fewer than 20% of CHD patients are at their LDL syndrome, chronic renal disease, and perhaps in women) is associ-
goal.6,7 Changes in the NCEP guidelines have increased the number ated with increased cardiovascular risk. This is thought to be a
of persons eligible for therapeutic lifestyle changes (TLC) or lipid- consequence of the presence of atherogenic lipoproteins and of
lowering therapy by millions. NCEP estimates that only 26% of hypertriglyceridemia being a marker for them, as triglycerides usu-
patients have an optimal LDL-C (<100 mg/dL) and that large ally are not independently predictive for CHD.15
numbers of patients either are untreated or undertreated.1 Unfortu-
nately, those patients at highest risk are less likely to be treated to
desirable levels of LDL.8 Although these numbers seem staggering in LIPOPROTEIN METABOLISM
their enormity, substantial progress has been made, and the number AND TRANSPORT
of Americans with a desirable blood cholesterol level (<200 mg/dL)
has risen to 49% from 45% from the earlier survey (1976–1980), As the major plasma lipids, cholesterol and triglycerides are essen-
whereas the average total cholesterol in the United States has fallen tial substrates for cell membrane formation and hormone synthesis,
from 220 mg/dL in 1960–1962 to 203 mg/dL in 2002.9 Patients who and they provide a source of free fatty acids.16 Dyslipidemia can be
are at risk but who have not yet experienced their first cardiovascular defined as elevated total cholesterol, LDL-C, or triglycerides level,
or cerebrovascular event (e.g., myocardial infarction [MI]) are low HDL-C concentration, or some combination of these abnor-
termed primary prevention patients, whereas those with manifest malities. Lipids, which are water immiscible, are not present in free
vascular disease are termed secondary intervention patients. form in the plasma but rather circulate as lipoproteins. Hyperlipo-
 Data from the Framingham study and from other studies proteinemia refers to an increased concentration of the lipoprotein
demonstrate that the risk for developing cardiovascular disease is macromolecules that transport lipids in the plasma. The density of
related to the degree of total cholesterol and LDL elevation in a plasma lipoproteins is determined by their relative content of
graded, continuous fashion.10,11 Hypercholesterolemia is additive to protein and lipid. Density, composition, size, and electrophoretic
the other nonlipid risk factors for CHD, including cigarette smok- mobility divide lipoproteins into four classes (Table 23–1).
ing, hypertension, diabetes, low HDL levels, and electrocardio- LDL is further divided into LDL1 (or IDL; density 1.006–1.019 g/
graphic abnormalities. The presence of established CHD or prior mL) and LDL2 (1.019–1.063 g/mL). LDL2 is the major LDL compo-
MI increases the risk of MI five to seven times that seen in men or nent in plasma; it carries 60% to 70% of the total serum cholesterol.
women without CHD, and LDL level is a significant predictor of HDL has been subdivided into HDL2 (density 1.063–1.125 g/mL)
subsequent morbidity and mortality. Approximately 50% of all MIs and HDL3 (1.125–1.21 g/mL). Fluctuations in HDL usually are
and at least 70% of CHD deaths occur in patients with known CHD; caused by alterations in the levels of HDL2. HDL normally carries
therefore, these patients should be targeted for screening, identifica- approximately 20% to 30% of the total cholesterol. VLDL also has
tion, and treatment. Unfortunately, the identification of patients at been subdivided into three classes, and it carries approximately 10%
high risk because of hypercholesterolemia or other lipid disorders is to 15% of serum cholesterol and most of the triglyceride in the
too frequently overlooked because blood lipid levels are not always fasting state. VLDL is the precursor for LDL, and VLDL remnants
evaluated in this population even after an event such as MI. also may be atherogenic. Table 23–2 lists the characteristics of the
A comparison of the United States to other countries shows protein constituent of lipoproteins known as apolipoproteins. The
similar relationships between total cholesterol, LDL, and an inverse structure of LDL, the LDL receptor, and the binding of LDL to the
relationship with HDL to coronary artery disease (CAD) mortality.10 receptor via apolipoprotein B-100 is shown in Fig. 23–1.
 387

TABLE 23-1 Composition of Lipoprotein Isolated from Normal Subjects

CHAPTER 23
Composition (Weight %)
Cholesterol
Lipoprotein Class Density Range (g/mL) Diameter (nm) Protein Triglyceride Free Ester Phospholipid
Chylomicrons <0.94 75–1200 1–2 80–95 1–3 2–4 3–9
VLDL 0.94–1.006 30–80 6–10 55–80 4–8 16–22 10–20
LDL 1.006–1.063 18–25 18–22 5–15 6–8 45–50 18–24
HDL 1.063–1.21 5–12 45–55 5–10 3–5 15–20 20–30
HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

Hyperlipidemia
Chylomicrons are large triglyceride-rich particles that contain up by the liver for catabolism. In patients with homozygous familial
apolipoproteins B-48, B-100, and E. They are formed from dietary hypercholesterolemia, enhanced synthesis of LDL may occur because
fat solubilized by bile salts in intestinal mucosal cells. Chylomicrons LDL clearance is reduced as a consequence of the lack of LDL
normally are not present in the plasma after a fast of 12 to 14 hours. receptors. LDL is catabolized through interaction of cell surface
They are catabolized by lipoprotein lipase (LPL), which is activated receptors found on liver, adrenal, and peripheral cells (including
by apolipoprotein C-II and in the vascular endothelium and hepatic fibroblasts and smooth muscle cells). These cells recognize apolipo-
lipase to form chylomicron remnants. The remnants that contain protein B-100 on LDL, and, after binding to a receptor on the cell
apolipoprotein E (Fig. 23–2) are taken up by the “remnant receptor,” membrane, LDL is internalized and degraded. In the normal fasting
which may be an LDL receptor–related protein, in the liver. Free state, approximately 70% of LDL is cleared through the receptor-
cholesterol is liberated intracellularly after attachment to the rem- dependent mechanism, although this is highly dependent on the
nant receptor. Chylomicrons also function to deliver dietary triglyc- availability and type of saturated and monosaturated or polyunsatu-
eride to skeletal muscle and adipose tissue. During the catabolism of rated fat from dietary sources. Ingestion of cholesterol and saturated
nascent chylomicrons to remnants, triglyceride is converted to free fatty acids such as C12:0, C14:0, and C16:0 is associated with reduced
fatty acids and apolipoproteins A-I, A-II, A-IV (free in plasma), C-I, LDL receptor activity, increased LDL production rate, and elevated
C-II, and C-III, and phospholipids are transferred to HDL. Apolipo- LDL plasma concentration. Receptor-independent mechanisms are
proteins E and C-II are transferred to chylomicrons from HDL and also involved to a lesser extent in the catabolism of LDL, and these
eventually back through these metabolic events. Hepatic VLDL receptors are present in many tissues but are most active in animals
synthesis is regulated in part by diet and hormones and is inhibited in the adrenals and ovary. Increased intracellular cholesterol result-
by uptake of chylomicron remnants in the liver. VLDL is secreted ing from LDL catabolism inhibits the activity of 3-hydroxy-
from the liver and serially converted via LPL to IDL and finally to 3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-
LDL. VLDL receptors are found in adipose tissue and muscle and limiting enzyme for intracellular cholesterol biosynthesis (Fig. 23–3).
bear close homology to the structure of LDL receptors. Additional consequences of increased intracellular cholesterol
LDL, the major cholesterol transport lipoprotein, basically has include reduced synthesis of LDL receptors, which limits subsequent
only apolipoprotein B-100. It is mostly derived from VLDL catabo- cholesterol uptake from the plasma, and accelerated activity of acyl-
lism and cellular synthesis. When normal subjects fast and consume coenzyme A:cholesterol acyltransferase (ACAT) to facilitate choles-
a low-fat diet, most cholesterol is synthesized and used in the terol storage within cells. LDL-C also may be excreted into bile and
extrahepatic organs; most of the cholesterol carried by LDL is taken become part of the enterohepatic pool or may be lost in the stool.

TABLE 23-2 Characteristics and Functions of Apolipoproteins

Approximate Approximate
Lipoprotein Plasma Concentration Molecular Major Site of
Apolipoprotein Density Class (mg/dL) Weight (kDa) Reported Functions Synthesis
A-I Chylomicrons, HDL 120 28 Cofactor with LCAT, structural protein on HDL, ligand Liver, intestine
for HDL receptor
A-II Chylomicrons, HDL 35 17 Structural protein for HDL, ligand for HDL receptor Liver
A-IV Chylomicrons, 1.21B 15 46 Possibly facilitates transfer of other apolipoproteins Intestine
between HDL and chylomicrons
Lp(a) LDL, HDL 10 500± Bound to B-100, high homology with plasminogen, Liver
may prevent LDL uptake by B, E receptor
B-100 VLDL, LDL, IDL 100 540 Necessary for assembly and secretion of VLDL from Liver
liver, structural protein of VLDL, IDL, LDL, ligand for
LDL receptor
B-48 Chylomicrons Trace 264 Necessary for assembly and secretion of chylomicrons Intestine
from small intestine
C-I Chylomicrons, VLDL, HDL 7 6.6 Cofactor with LCAT; may inhibit hepatic uptake of Liver
chylomicron and VLDL remnants
C-II Chylomicrons, VLDL, HDL 4 8.9 Activator of LPL Liver
C-III Chylomicrons, VLDL, HDL 13 8.8 Inhibitor with LPL; may inhibit hepatic uptake of Liver
chylomicron and VLDL remnants
D HDL 6 32 ? ?
E2-E4 Chylomicrons, VLDL, HDL 5 34 Ligand for several lipoproteins to LDL receptor, LRP Liver
and possibly to a separate hepatic apolipoprotein E
receptor
IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LRP, LDL receptor–related protein. Other abbreviations are in Table 23–1.
 388

Exogenous Endogenous
SECTION 2

Dietary Bile
lipids acids
FIGURE 23-2. Simplified diagram of +
Cholesterol
lipoprotein systems for transporting lip-
LDL
ids in humans. In the exogenous sys-
tem, chylomicrons rich in triglycerides of Peripheral
tissues
dietary origin are converted to chylomi- Liver
cron remnants rich in cholesteryl esters Small intestine
by the action of lipoprotein lipase (LPL).
In the endogenous system, very-low-
Cardiovascular Disorders

density lipoproteins (VLDL) rich in tri-

glycerides are secreted by the liver and
converted to intermediate-density lipo-
proteins (IDL) and then to low-density
lipoproteins (LDL) rich in cholesteryl
esters. Some of the LDLs enter the VLDL
IDL
subendothelial space of arteries, are
oxidized, and then are taken up by Chylomicron
Chylomicron
remnant
macrophages, which become foam
cells. The letters on the chylomicrons,
chylomicron remnants, VLDL, IDL, and
LDL identify the primary apoproteins Capillaries Capillaries
LDLR
(ApoB, ApoC, ApoE) found in them. LPL LPL
(LDLR, low-density lipoprotein recep- ApoB
tor.) (From Kasper DL, Braunwald E, FFA
ApoE
FFA
Fauci AS, et al., eds. Harrison’s Princi- ApoC's
ples of Internal Medicine, 16th ed. New
York, McGraw-Hill, 2005, p. 2289.) Muscle Adipose Muscle Adipose

Lipoprotein(a) is a cholesterol-rich lipoprotein similar in composi- marker for inflammation; it may be useful in identifying patients at
tion and density to LDL and with close homology to fibrinogen. It is risk for developing CAD.20 The eventual outcomes of this athero-
reported to be an important independent risk factor for the develop- genic cascade are clinical events such as angina, MI, arrhythmias,
ment of premature cardiovascular disease. stroke, peripheral arterial disease, abdominal aortic aneurysm, and
Nascent HDL is derived from liver and gut synthesis primarily in sudden death. Atherosclerotic lesions are thought to arise from
the form of apolipoprotein A-I phospholipid discs.12 Esterification of transport and retention of plasma LDL-C through the endothelial
free cholesterol in nascent HDL and from peripheral tissues to cell layer into the extracellular matrix of the subendothelial space.
cholesteryl esters by lecithin-cholesterol acyltransferase (LCAT) Once in the artery wall, LDL is chemically modified through oxida-
results in the production of HDL3. Further addition of tissue choles- tion and nonenzymatic glycation. Mildly oxidized LDL then recruits
terol to HDL3 results in the formation of HDL2. HDL2 can also be monocytes into the artery wall, and the monocytes become trans-
formed from remodeling of chylomicrons and VLDL catabolism. formed into macrophages. Macrophages have tremendous potential
HDL2 can be converted back to HDL3 by the action of hepatic lipase for accelerating LDL oxidation and apolipoprotein B accumulation
and by the transfer of cholesteryl esters to the liver, LDL, and VLDL. and altering the receptor-mediated uptake of LDL into the artery
Apolipoprotein A-I production is increased by estrogens, leading to wall from the usual LDL receptor to a “scavenger receptor” not
higher HDL levels in women and in individuals receiving estrogen. regulated by cell content of cholesterol. Oxidized LDL increases
Transfer of excess cholesterol from peripheral tissues by HDL is plasminogen inhibitor levels (promotion of coagulation), induces
called reverse cholesterol transport. Putative HDL receptors in periph- expression of endothelin (vasoconstrictive substance), inhibits
eral cells facilitate the uptake of cholesterol by HDL, which transfers expression of nitric oxide (a vasodilator and platelet inhibitor), and
cholesterol to either VLDL and LDL or to the liver for secretion into is toxic to macrophages if highly oxidized. As oxidation of biologi-
bile or conversion into bile acids. These processes rid peripheral cally active lipids proceeds, other lipids such as lysophosphatidylcho-
tissue (e.g., coronary arteries) of excessive amounts of cholesterol line, hydroperoxides, aldehydic breakdown products of fatty acids,
and account for some of the protective effects noted with increasing and oxysterol are formed and continue the reaction within the tissue.
HDL in women and other factors that elevate HDL levels. Variants These events lead to a massive accumulation of cholesterol. The
of the cholesterol ester transfer protein (CETP) have been demon- cholesterol-laden cells are called foam cells, which are the earliest
strated in humans, and the B1B1 genotype is associated with lower recognized cells of the arterial fatty streak.
HDL and progression of coronary atherosclerosis. Inhibition of Oxidized LDL provokes an inflammatory response that is medi-
CETP leads to elevations in HDL. However, CETP inhibitors tested ated by a number of chemoattractants and cytokines. Examples that
in clinical trials did not induce regression of atherosclerotic plaque appear to be involved at different stages of lesion development
and were associated with higher blood pressure and CHD events.17–19 include monocyte chemoattractant protein 1 (MCP-1); monocyte
The “response-to-injury” hypothesis states that risk factors such as colony stimulating factor (M-CSF); gro; vascular cell adhesion mole-
oxidized LDL, mechanical injury to the endothelium (e.g., percuta- cule (VCAM-1); E-selectin (endothelial-leukocyte adhesion molecule
neous transluminal angioplasty), excessive homocysteine, immuno- [ELAM]-1); intercellular adhesion molecule (ICAM-1); platelet-
logic attack, and infection-induced (e.g., Chlamydia, herpes simplex derived growth factor (PDGF); vascular endothelial growth factor
virus 1) changes in endothelial and intimal function lead to endothe- (VEGF); transforming growth factors (TGF-α and TGF-β); interleu-
lial dysfunction and a series of cellular interactions that culminate in kin (IL)-1 and IL-6; and the ratio of IL-10 and IL-12. Some of these
atherosclerosis. C-reactive protein is an acute phase reactant and a factors (e.g., MCP-1 and M-CSF) appear to participate early in the
 389

TABLE 23-3 Fredrickson-Levy-Lees Classification

CHAPTER 23
of Hyperlipoproteinemia
Type Lipoprotein Elevation
I Chylomicrons
IIa LDL
IIb LDL + VLDL
III IDL (LDL1)
IV VLDL
V VLDL + Chylomicrons

Hyperlipidemia
IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

metalloproteinases can degrade all major constituents of the vascular

extracellular matrix: collagen, elastin, and proteoglycans.23
Lipoprotein disorders are classified into six categories, which are
commonly used for phenotypical description of dyslipidemia (Table
23–3).  Specific genetic defects with disrupted protein, cell, and
organ function give rise to several disorders within each family of
lipoproteins (Table 23–4). An elevated cholesterol level does not
necessarily equate with familial hypercholesterolemia or type IIa, as
cholesterol may be elevated in other lipoprotein disorders and the
lipoprotein pattern does not describe the underlying genetic defect.
The preceding discussion focused on primary or genetic dyslipopro-
teinemia; however, secondary forms exist, and several drugs may
elevate lipid levels (Table 23–5). The secondary forms of hyperlipid-
emia initially should be managed by correcting the underlying abnor-
mality, including modification of drug therapy when appropriate.
Familial hypercholesterolemia is characterized by (a) selective ele-
vation in the plasma level of LDL, (b) deposition of LDL-derived
cholesterol in tendons (xanthomas) and arteries (atheromas), and
(c) inheritance as an autosomal dominant trait with homozygotes
more severely affected than heterozygotes. Homozygotes (prevalence
1:1,000,000) have severe hypercholesterolemia (650–1,000 mg/dL),
FIGURE 23-3. Biosynthetic pathway for cholesterol. The rate-limiting with early appearance of cutaneous xanthomas and fatal CHD gener-
enzyme in this pathway is 3-hydroxy-3-methylglutaryl coenzyme A ally before age 20 years. The primary defect in familial hypercholester-
reductase (HMG-CoA reductase). (CETP, cholesterol ester transfer pro- olemia is the inability to bind LDL to the LDL receptor or, rarely, a
tein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; defect of internalizing the LDL receptor complex into the cell after
LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very-low-
normal binding. Homozygotes have essentially no functional LDL
density lipoprotein.) (Modified from Breslow JL. Genetic basis of lipopro-
tein disorders. J Clin Invest 1989; 84:373.)
receptors. This leads to lack of LDL degradation by cells and unregu-
lated biosynthesis of cholesterol, with total cholesterol and LDL-C
inversely proportional to the deficit in LDL receptors. Heterozygotes
process of monocyte–macrophage attachment and transmigration have only about half the normal number of LDL receptors, total
across the endothelium, whereas others (PDGF and VCAM-1) pro- cholesterol levels in the range from 300 to 600 mg/dL and cardiovas-
mote later lesion growth.18 Based on murine model studies, the cular events beginning in the third and fourth decades of life.
extent of oxidation and the inflammatory response is under genetic Familial LPL deficiency is a rare, autosomal recessive trait charac-
control of a major gene termed Ath-1. The process of aging may lead terized by massive accumulation of chylomicrons and correspond-
to lipoproteins that are more susceptible to oxidation and have ing increase in plasma triglycerides or a type I lipoprotein pattern.
longer resident time in the vascular compartment. Two proteins VLDL concentration is normal. Presenting manifestations include
associated with HDL (apolipoprotein J and paraxonase) appear to repeated attacks of pancreatitis and abdominal pain, eruptive cuta-
play important roles in minimizing oxidation of LDL-C.21,22 neous xanthomatosis, and hepatosplenomegaly beginning in child-
Increased recognition of the role of these growth regulatory mole- hood. Symptom severity is proportional to dietary fat intake and
cules provides the possibility of future directions for antagonists to consequently to the elevation of chylomicrons. LPL is normally
regulatory molecules such as PDGF, TGF-β, and the interleukins. released from vascular endothelium or by heparin and hydrolyzes
Repeated injury and repair within an atherosclerotic plaque eventu- chylomicrons and VLDL (see Fig. 23–2). Diagnosis is based on low
ally leads to the formation of a fibrous cap that protects the underly- or absent enzyme activity with normal human plasma or apolipo-
ing core of lipids, collagen, calcium, and inflammatory cells such as protein C-II, a cofactor of the enzyme. Accelerated atherosclerosis is
T-lymphocytes. Maintenance of the fibrous plaque is critical to not associated with the disease. Abdominal pain, pancreatitis, erup-
preventing plaque rupture and subsequent coronary thrombosis. An tive xanthomas, and peripheral polyneuropathy characterize type V
imbalance between plaque synthesis and degradation may lead to a (VLDL and chylomicrons). Symptoms may occur in childhood, but
weakened or vulnerable plaque prone to rupture. The fibrous cap usually the disorder is expressed at a later age. The risk of athero-
may become weakened through decreased synthesis of the extracellu- sclerosis is increased with the disorder. Patients commonly are
lar matrix or increased degradation of the matrix. The cytokine obese, hyperuricemic, and diabetic, and alcohol intake, exogenous
interferon-γ, produced by T lymphocytes, inhibits the ability of estrogens, and renal insufficiency tend to be exacerbating factors.
smooth muscle cells to synthesize collagen, a structurally important Patients with familial type III hyperlipoproteinemia (also called
component of the fibrous cap. A family of enzymes known as matrix dysbetalipoproteinemia, broad-band, or β-VLDL) develop the fol-
 390

TABLE 23-4 Lipoprotein Disorders

SECTION 2

Lipoproteins
Plasma Lipid Levels
Lipid Phenotype [mmol/L (mg/dL)] Elevated Phenotype Clinical Signs
Isolated hypercholesterolemia
Familial hypercholesterolemia Heterozygotes TC = 7–13 LDL IIa Usually develop xanthomas in adulthood and vascu-
(275–500) lar disease at 30–50 years
Homozygotes TC >13 (>500) LDL IIa Usually develop xanthomas in adulthood and vascu-
lar disease in childhood
Familial defective Apo B-100 Heterozygotes TC = 7–13 LDL IIa
(275–500)
Cardiovascular Disorders

Polygenic hypercholesterolemia TC = 6.5–9 (250–350) LDL IIa Usually asymptomatic until vascular disease devel-
ops; no xanthomas
Isolated hypertriglyceridemia
Familial hypertriglyceridemia TG = 2.8–8.5 (250–750) VLDL IV Asymptomatic; may be associated with increased
risk of vascular disease
Familial LPL deficiency TG >8.5 (750) Chylomicrons, VLDL I, V May be asymptomatic; may be associated with
pancreatitis, abdominal pain, hepatospleno-
megaly
Familial Apo C-II deficiency TG >8.5 (>750) Chylomicrons, VLDL I, V As above
Hypertriglyceridemia and
hypercholesterolemia
Combined hyperlipidemia TG = 2.8–8.5 (250–750) VLDL, LDL IIb Usually asymptomatic until vascular disease devel-
TC = 6.5–13 (250–500) ops; familial form may present as isolated high TG
or isolated high LDL cholesterol
Dysbetalipoproteinemia TG = 2.8–8.5 (250–750); VLDL, IDL; LDL normal III Usually asymptomatic until vascular disease devel-
TC = 6.5–13 (250–500) ops; may have palmar or tuboeruptive xanthomas
Apo, apolipoprotein; LPL, lipoprotein lipase; TC, total cholesterol; TG, triglycerides. Other abbreviations as in Table 23–1.

lowing clinical features after age 20 years: xanthoma striata palmaris TABLE 23-5 Secondary Causes of Lipoprotein Abnormalities
(yellow discolorations of the palmar and digital creases); tuberous
Hypercholesterolemia Hypothyroidism
or tuberoeruptive xanthomas (bulbous cutaneous xanthomas); and
Obstructive liver disease
severe atherosclerosis involving the coronary arteries, internal
Nephrotic syndrome
carotids, and abdominal aorta. A defective structure of apolipopro- Anorexia nervosa
tein E does not allow normal hepatic surface receptor binding of Acute intermittent porphyria
remnant particles derived from chylomicrons and VLDL (known as Drugs: progestins, thiazide diuretics, glucocorticoids,
IDL). Aggravating factors such as obesity, diabetes, and pregnancy β-blockers, isotretinoin, protease inhibitors, cyclo-
may promote overproduction of apolipoprotein B–containing lipo- sporine, mirtazapine, sirolimus
proteins. Although homozygosity for the defective allele (E2/E2) is Hypertriglyceridemia Obesity
common (1:100), only 1 in 10,000 express the full-blown picture, Diabetes mellitus
and interaction with other genetic or environmental factors, or Lipodystrophy
both, is needed to produce clinical disease. Glycogen storage disease
Ileal bypass surgery
Familial combined hyperlipidemia is characterized by elevations in
Sepsis
total cholesterol and triglycerides, decreased HDL, increased apolipo-
Pregnancy
protein B, and small, dense LDL.24 It is associated with premature Acute hepatitis
CHD and may be difficult to diagnose because lipid levels do not Systemic lupus erythematous
consistently display the same pattern. Monoclonal gammopathy: multiple myeloma, lym-
Type IV hyperlipoproteinemia is common and occurs in adults, phoma
primarily in patients who are obese, diabetic, and hyperuricemic and Drugs: Alcohol, estrogens, isotretinoin, β-blockers, glu-
do not have xanthomas. It may be secondary to alcohol ingestion and cocorticoids, bile acid resins, thiazides; asparaginase,
can be aggravated by stress, progestins, oral contraceptives, thiazides, interferons, azole antifungals, mirtazapine, anabolic
or β-blockers. Two genetic patterns that occur in type IV hyperlipo- steroids, sirolimus, bexarotene
proteinemia are familial hypertriglyceridemia, which does not carry a Hypocholesterolemia Malnutrition
Malabsorption
great risk for premature CAD, and familial combined hyperlipidemia,
Myeloproliferative diseases
which is associated with increased risk for cardiovascular disease.
Chronic infectious diseases: acquired immune defi-
Rare forms of lipoprotein disorders include hypobetalipoprotein- ciency syndrome, tuberculosis
emia, abetalipoproteinemia, Tangier disease, LCAT deficiency (fish Monoclonal gammopathy
eye disease), cerebrotendinous xanthomatosis, and sitosterolemia. Chronic liver disease
Most of these rare lipoprotein disorders do not result in premature Low high-density Malnutrition
atherosclerosis, with the exceptions of familial LCAT deficiency, cere- lipoprotein Obesity
brotendinous xanthomatosis, and sitosterolemia with xanthomatosis. Drugs: non-ISA β-blockers, anabolic steroids, probucol,
Treatment consists of dietary restriction of plant sterols (sitosterolemia isotretinoin, progestins
with xanthomatosis) and chenodeoxycholic acid (cerebrotendinous ISA, intrinsic sympathomimic activity.
xanthomatosis), or, potentially, blood transfusion (LCAT deficiency).
 391

CLINICAL PRESENTATION TABLE 23-6 Classification of Total, LDL, and HDL Cholesterol,

CHAPTER 23
and Triglycerides
General
Total cholesterol
■ Most patients are asymptomatic for many years before disease < 200 Desirable
is clinically evident 200–239 Borderline high
■ Patients with the metabolic syndrome may have three or more ≥ 240 High
of the following: abdominal obesity, atherogenic dyslipide- LDL cholesterol
mia, increased blood pressure, insulin resistance with or <100 Optimal
without glucose intolerance, prothrombotic state, or proin- 100–129 Near or above optimal
130–159 Borderline high
flammatory state

Hyperlipidemia
160–189 High
Symptoms ≥190 Very high
■ None to severe chest pain, palpitations, sweating, anxiety, HDL cholesterol
shortness of breath, loss of consciousness or difficulty with <40 Low
≥60 mg/dL High
speech or movement, abdominal pain, sudden death
Triglycerides
Signs <150 Normal
■ None to severe abdominal pain, pancreatitis, eruptive xantho- 150–199 Borderline high
mas, peripheral polyneuropathy, high blood pressure, body 200–499 High
mass index >30 kg/m2 or waist size >40 inches in men (35 ≥500 Very high
inches in women) All values are given in milligrams per deciliters.
HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Laboratory Tests
■ Elevations in total cholesterol, LDL, triglycerides, apolipopro- highest category is known CHD or CHD risk equivalents, which is
tein B, C-reactive protein defined as the risk for major coronary events equal to or greater than
■ Low HDL established CHD, that is, >20% per 10 years (2% per year). The next
Other Diagnostic Tests category is moderately high risk, consisting of patients with multiple
(2+) risk factors in which 10-year risk for CHD is 10% to 20%.
■ Lipoprotein(a), homocysteine, serum amyloid A, small dense
Moderate risk is defined as ≥2 risk factors and a 10-year risk of
LDL (pattern B), HDL subclassification, apolipoprotein E ≥10%. The lowest risk category is persons with a risk factor of 0 to 1.
isoforms, apolipoprotein A-1, fibrinogen, folate, Chlamydia Risk is estimated from Framingham risk scores28 and is estimated
pneumoniae titer, lipoprotein-associated phospholipase A2, based on the patient’s age, LDL-C or total cholesterol level, blood
omega-3 index25 pressure, presence of diabetes, and smoking status (Table 23–7). This
■ Various screening tests for manifestations of vascular disease approach for a single patient is referred to as a case finding or patient-
(ankle–brachial index, exercise testing, magnetic resonance based approach, whereas large-scale screening and recommendations
imaging) and diabetes (fasting glucose, oral glucose tolerance for the general populace, health care providers, and the food industry
test) are called a population-based approach.
Measurement of plasma cholesterol (which is approximately 3%
lower than serum determinations), triglyceride, and HDL-C levels
PATIENT EVALUATION after a fast of 12 hour or longer is important, as triglycerides may be
elevated in nonfasted individuals; total cholesterol is only modestly
A fasting lipoprotein profile including total cholesterol, LDL-C, affected by fasting. Analytic and biologic variability can have a major
HDL-C, and triglycerides should be measured in all adults 20 years impact on the measurement and interpretation of cholesterol level
and older at least once every 5 years.1 If the profile is obtained in the (or any other laboratory test). Analytic variability can be minimized
nonfasted state, only total cholesterol and HDL-C will be usable through the use of adequate quality control procedures, including
because LDL-C usually is a calculated value. If total cholesterol is internal training, routine calibration and monitoring, and external
≥200 mg/dL or HDL-C is <40 mg/dL, a followup fasting lipoprotein proficiency testing. Even with these measures, the coefficient of
profile should be obtained. After a lipid abnormality is confirmed variability in the best procedures can acceptably be up to 5%, and,
(Table 23–6), major components of the evaluation are the history
(including age, gender, and, if female, menstrual and hormone
replacement status), physical examination, and laboratory investiga-
TABLE 23-7 Major Risk Factors (Exclusive of LDL Cholesterol)
tions. A complete history and physical examination should assess
That Modify LDL Goalsa
(a) presence or absence of cardiovascular risk factors (Table 23–7) or
definite cardiovascular disease in the individual; (b) family history of Age
premature cardiovascular disease or lipid disorders; (c) presence or Men: ≥45 years
absence of secondary causes of lipid abnormalities, including con- Women: ≥55 years or premature menopause without estrogen replacement
current medications (see Table 23–5); and (d) presence or absence of therapy
Family history of premature CHD (definite myocardial infarction or sudden death
xanthomas or abdominal pain, or history of pancreatitis, renal or
before age 55 years in father or other male first-degree relative, or before age 65
hepatic disease, peripheral vascular disease, abdominal aortic aneu- years in mother or other female first-degree relative)
rysm, or cerebral vascular disease (carotid bruits, stroke, or transient Cigarette smoking
ischemic attack). In an important change in the ATP III guidelines, Hypertension (≥140/90 mm Hg or taking antihypertensive medication)
diabetes mellitus is regarded as a CHD risk equivalent.1 The presence Low HDL cholesterol (<40 mg/dL)b
of diabetes in patients without known CHD is associated with the
HDL, high-density lipoprotein; LDL, low-density lipoprotein.
same level of risk as in patients without diabetes but with confirmed a
Diabetes is regarded as a coronary heart disease (CHD) risk equivalent.
CHD.26,27 ATP III identifies four categories of risk that modify the b
HDL cholesterol ≥60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor
goals and modalities of LDL-lowering therapy (Table 23–8).2 The from the total count.
 392

TABLE 23-8 LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories
SECTION 2

LDL Level at Which LDL Level at Which to Consider

Risk Category LDL Goal (mg /dL) to Initiate TLC (mg /dL) Drug Therapy (mg /dL)
High risk: CHD or CHD risk equivalents < 100 (optional goal: <70) ≥100 ≥100
(10-year risk >20%) (<100 mg /dL; consider drug options)a
Moderately high risk: 2+ risk factors < 130 ≥130 ≥130
(10-year risk >10%–20%) (100–129: consider drug options)
Moderate risk: 2+ risk factors (10-year risk <10%) < 130 ≥130 ≥160
Lower risk: 0–1 risk factor b < 160 ≥160 ≥190
(160–189: LDL-lowering drug optional)
Cardiovascular Disorders

CHD, coronary heart disease; LDL, low-density lipoprotein.

a
Some authorities recommend use of LDL-lowering drugs in this category if LDL cholesterol <100 mg/dL cannot be achieved by therapeutic lifestyle changes (TLC). Others prefer to use drugs that primarily
modify triglycerides and high-density lipoprotein, e.g., nicotinic acid or fibrates. Clinical judgement also may call for deferring drug therapy in this subcategory.
b
Almost all people with 0–1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0–1 risk factor is not necessary.

when combined with average biologic variability, total variability mg/dL are classified as borderline–high blood cholesterol levels, and
may be as high as approximately 22%. Analytic variability with assessment of risk factors (Table 23–7) is needed to more clearly
desktop equipment generally is greater in the fingerstick capillary define disease risk. Blood cholesterol levels ≥240 mg/dL are classified
blood methods, usually yielding measurements less than those from as high blood cholesterol levels. If total cholesterol is <200 mg/dL and
a clinical laboratory; this technology should be considered for use HDL is >40 mg/dL, no further followup is recommended for
only as a screening method. Reliance on desktop methods can result patients without known CHD who have fewer than two risk factors.
in misclassification of 7% to 14% of patients if capillary blood is In patients with evidence of CHD or other clinical atherosclerotic
used. Two determinations, 1 to 8 weeks apart, with the patient on a disease, the LDL goal is <100 mg/dL, and most patients will require
stable diet and weight and in the absence of acute illness, are diet and/or drug intervention. In patients with very high risk (known
recommended to minimize variability and obtain a reliable baseline.1 CHD and multiple risk factors), the LDL goal may be set <70 mg/dL
If total cholesterol is >200 mg/dL, a second determination is recom- based on evidence from newer studies.29 Decisions regarding classi-
mended, and if the values are more than 30 mg/dL apart, the average fication and management are based on the LDL-C levels listed in
of three values should be used. Familiarity with the method and Table 23–8. An increasing number of persons have the metabolic
quality control procedures used by local laboratories are essential for syndrome, which is characterized by abdominal obesity, atherogenic
interpretation of reported values. If the physical examination and dyslipidemia (elevated triglycerides, small LDL particles, low HDL-
history are insufficient to diagnose a familial disorder, then agarose- C), increased blood pressure, insulin resistance (with or without
gel lipoprotein electrophoresis is useful to determine which class of glucose intolerance), and prothrombotic and proinflammatory
lipoproteins is affected. If triglyceride levels are <400 mg/dL and states. ATP III recognizes the metabolic syndrome as a secondary
neither type III hyperlipidemia nor chylomicrons are detected by target of risk reduction therapy after LDL-C has been addressed, and,
electrophoresis, then VLDL and LDL concentrations can be calcu- if the metabolic syndrome is present, the patient is considered to
lated as follows: VLDL = Triglycerides/5; LDL = Total cholesterol – have a CHD risk equivalent. Other lipid targets include non-HDL
(VLDL + HDL). goals for patients with triglycerides >200 mg/dL. Non-HDL is
Because total cholesterol is composed of cholesterol derived from calculated by subtracting HDL from total cholesterol, and the targets
LDL, VLDL, and HDL, determination of HDL is useful when total are 30 mg/dL greater than for LDL at each risk stratum. Non-HDL
plasma cholesterol is elevated. HDL may be elevated by moderate takes into consideration atherogenic particles such as remnant lipo-
alcohol ingestion (fewer than two drinks per day), physical exercise, proteins and IDL, which are not measured in routine clinical labora-
smoking cessation, weight loss, oral contraceptives, phenytoin, and tory testing.30 HDL raising has potential benefit, but the current
terbutaline. Smoking, obesity, a sedentary lifestyle, and use of drugs guidelines do not set any specific goals, and evidence in support of
such as β-blockers lower HDL. Only exercise and smoking cessa- aggressively increasing HDL levels is modest.31
tion can be recommended as interventions for low HDL concentra- The Expert Panel on Children and Adolescents of the NCEP
tions. Niacin and gemfibrozil increase HDL concentrations. recommends screening of higher-risk children (positive family his-
The range of lipid concentrations represents a population mean tory or parental high blood cholesterol ≥240 mg/dL).32,33 The ratio-
±2 SD and does not define the risk of disease. Reference values for nale for this approach is based partly on the recognition that
plasma total, LDL, and HDL-C concentrations for men and women, atherosclerosis begins in the childhood and adolescent years, as
as well as various ethnic groups, are available from the NHANES documented in the Pathobiologic Determinants of Atherosclerosis in
III.5 Levels of Cholesterol and triglycerides increase throughout life Youth (PDAY) and the Bogalusa studies.34 Similarly, if children with
until about the fifth decade for men and the sixth decade for high blood lipids or lipoprotein levels are identified but the levels in
women. Past these ages, total cholesterol and LDL plateau and fall the parents are unknown, the parents should be screened because
slightly. HDL tends to fall slightly with time and more rapidly after they likely are at high risk. Racial and gender differences do exist in
menopause in women. Institution of a population-based approach the determination of lipoprotein fractions and should be considered
for cholesterol reduction should shift the entire curve to the left, and in screening. Use of the serum cholesterol level alone may be of
the potential reduction in cardiovascular mortality would be pro- insufficient specificity or sensitivity, depending on the cut points
portional to mean reductions at any cholesterol concentration. used in screening, and other discretionary factors, such as hyperten-
Based on a careful review of the experimental pathologic, genetic, sion, smoking, obesity, high-fat diet, and use of cholesterol-raising
and epidemiologic evidence relating to the relationship between medication, may be needed to correctly identify children at risk.
blood cholesterol levels and CHD, the adult treatment panel III of Presently, children older than 10 years are candidates for drug
the NCEP recommends use of a fasting lipoprotein profile and risk therapy if a trial of diet (6 months to 1 year) proves to be inadequate
factor assessment in the initial classification of adults.1,29 If total and LDL-C remains >190 mg/dL, or >160 mg/dL if two or more risk
cholesterol is <200 mg/dL, then the patient has a desirable blood factors or CHD is present in the child or adolescent, or if patient has
cholesterol level (Table 23–6). Cholesterol levels between 200 and 239 a history of premature CHD. The Dietary Intervention Study in
 393
Children (DISC) found that a fat-restricted diet in pubertal children to 450 mg/day, both in excess of a “heart healthy” diet for normal
modestly lowered LDL-C and maintained psychologic well-being, Americans, let alone patients with a lipid disorder. Excessive dietary

CHAPTER 23
and that dietary changes are acceptable to children.35,36 Although bile intake of cholesterol and saturated fatty acids leads to decreased
acid sequestrants have been the recommended drugs for this popu- hepatic clearance of LDL and deposition of LDL and oxidized LDL
lation, clinical trials now demonstrate that statin therapy is effective in peripheral tissues. The targeted saturated fatty acids have carbon
and well tolerated in pediatric populations.37,38 The long-term con- chain lengths of 12 (lauric acid), 14 (myristic acid), and 16 (palmitic
sequences of drug therapy in this population are unknown. In special acid). The rationale for using a nutritionally balanced, low-fat, low-
instances, familial hypercholesterolemia (particularly the homozy- cholesterol diet for treatment of hypercholesterolemia is based on
gous form) or the existence of CHD or two or more risk factors in the following principles: (a) it represents a reasonable extension of
the child prompts earlier institution of drug therapy after a trial of the diet recommended for the general public; (b) it progressively

Hyperlipidemia
dietary intervention. decreases the major cholesterol-raising constituent of the diet; (c) it
precludes large intakes of polyunsaturated fats; and (d) it facilitates
weight reduction by removing foods of high caloric density.41–44
TREATMENT Dietary expertise in providing a wide range of options and sugges-
tions in food preparation can make the difference between a good
■ DESIRED OUTCOMES and an inadequate response to diet. Information on eating out in a
healthy fashion and advice for shopping are important factors for
The goals of therapy expressed as LDL-C levels and the level of success in diet therapy. An example is awareness of products with
initiation of TLC and drug therapy are given in Tables 23–8 and misleading labels, such as coffee creamers that state they contain “no
23–9 for adults and children, respectively. Although these goals are cholesterol” when they may contain hydrogenated (saturated) fats or
surrogate end points, the primary reason for instituting TLC and oils (e.g., palmitic acid, palm kernel oil, or coconut oil), which makes
drug therapy is to reduce the risk of first events or recurrent events them undesirable because of their saturated fat content. Variations in
such as MI, angina, heart failure, ischemic stroke, and other forms polyunsaturated and saturated fat and cholesterol intake influence
of peripheral arterial disease, such as carotid stenosis and abdominal the LDL concentration, but the amount of cholesterol has been
aortic aneurysm. found to have a greater effect than the proportion of polyunsaturated
or saturated fat. There were racial differences in elevation of LDL,
■ GENERAL APPROACH1 with diets high in saturated fat consumed more by whites than by
Establishing targeted changes and outcomes with consistent rein- other racial groups. The isomeric form of fatty acids is important.41
forcement of goals and measures at followup visits to attain goals are Fatty acids with the cis configuration are the preferred substrate for
important to reduce barriers for optimizing TLC and pharmacologic the ACAT reaction and significantly increase hepatic LDL receptor
therapy.  TLC should be implemented in all patients prior to clearance while reducing LDL-C production rate. The trans isomeric
considering drug therapy. The components of TLC include reduced form cannot be used by ACAT and is biologically inactive, with no
intake of saturated fats and cholesterol, dietary options to reduce effect on LDL concentration.
LDL, such as consumption of plant stanols and sterols and soluble Ideally, therapeutic TLC, including reduced intake of saturated
fiber, weight reduction, and increased physical activity. In general, fats and cholesterol, increased stanol/sterol and fiber intake, weight
physical activity of moderate intensity 30 minutes per day for most reduction, and increased physical activity, should be used to attain
days of the week should be encouraged.39,40 Patients with known lower LDL-C and to achieve reductions in CHD risk (Table 23–10).
CAD or who are at high risk should be evaluated before they TLC may obviate the need for drug therapy, augment LDL-lowering
undertake vigorous exercise. Weight and BMI should be determined drug therapy, and allow for lower doses. Weight control plus
at each visit, and lifestyle patterns to induce a weight loss of 10% increased physical activity reduce risk beyond LDL-C lowering, are
should be discussed with persons who are overweight. All patients the primary management approach for the metabolic syndrome,
should be counseled to stop smoking and to meet the Joint National raise HDL, and reduce non-HDL-C.45,46 Many persons should be
Committee VII guidelines for control of hypertension. given a 3-month trial (two visits 6 weeks apart) of dietary therapy
and TLC before advancing to drug therapy unless patients are at
■ NONPHARMACOLOGIC THERAPY very high risk (severe hypercholesterolemia, known CHD, CHD risk
equivalents, multiple risk factors, strong family history). Although
Individualized dietary counseling that provides acceptable substitu- changes in blood lipid levels may change before 3 months, adoption
tions for unhealthy foods and ongoing reinforcement by a registered
dietitian are necessary for maximal effect. The objectives of dietary
therapy are to progressively decrease the intake of total fat, saturated
TABLE 23-10 Macronutrient Recommendations for the
fatty acids (i.e., saturated fat), and cholesterol and to achieve a
Therapeutic Lifestyle Changes Diet
desirable body weight. Typical American diets now include 13% to
20% of total calories from saturated fat and cholesterol intake of 350 Componenta Recommended Intake
Total fat 25%–35% of total calories
Saturated fat Less than 7% of total calories
TABLE 23-9 Classification of Lipid Levels in Children and Polyunsaturated fat Up to 10% of total calories
Adolescents (Age < 20 Years) Monounsaturated fat Up to 20% of total calories
Carbohydratesb 50%–60% of total calories
Desirable Borderline Undesirable
Cholesterol < 200 mg /day
(mg/dL) (mg/dL) (mg/dL)
Dietary fiber 20–30 g /day
Total cholesterol <170 170–199 ≥200 Plant sterols 2 g /day
LDL cholesterol <110 110–129 ≥130 Protein Approximately 15% of total calories
HDL cholesterol >45 25–45 < 35 Total calories To achieve and maintain desirable body weight
Triglycerides <125 NA ≥125 a
Calories from alcohol not included.
b
HDL, high-density lipoprotein; LDL, low-density lipoprotein; NA, not applicable. Carbohydrates should derive from foods rich in complex carbohydrates, such as whole grains, fruits,
From Davis et al.33 and vegetables.
 394
of a different eating pattern may require a longer period of time. solubilize stanol/sterol esters, they usually are available in commer-
It is important to involve all family members, especially if the cial margarines. The presence of plant stanols/sterols is listed on the
SECTION 2

patient is not the primary person preparing food. The NCEP food label. When margarine products are used, persons must be
and AHA both have excellent Internet-based resources to aid advised to adjust caloric intake to account for the calories contained
patients in altering their diet in a culturally sensitive manner in the products. For example, Benecol (McNeil) is a butter-like
(http://www.americanheart.org/presenter.jhtml?identifier=1200009; spread that contains a plant stanol ester, an ingredient that can lower
http://www.nhlbi.nih.gov/health/index.htm). If all of the recom- cholesterol, which is derived from plant stanols found naturally in
mended dietary changes from NCEP were made, the estimated small amounts in foods such as wheat, rye, and corn.52 In August
reduction, on average, in LDL would range from 20% to 30%.1 2007, the FDA issued a warning about the consumption of red yeast
Adherence to diet and interindividual variability in macronutrient rice and products containing red yeast rice/policosonal. These prod-
Cardiovascular Disorders

intake influence the eventual LDL level achieved. Based on the ucts contained lovastatin, which could interact with other drugs and
NHANES data, less than half of patients who should be instructed would have the same toxicity of statins but would not be recognized
on heart healthy diet receive any dietary instructions. by the consumer. The reduction in LDL with their use is minimal.53
Other dietary interventions or diet supplements may be useful in Drug therapy is indicated after an adequate trial of TLC changes
certain patients with lipid disorders. Increased intake of soluble fiber as outlined in Tables 23–8 and 23–9.
in the form of oat bran, pectins, certain gums, and psyllium products
can result in useful adjunctive reductions in total cholesterol and
LDL-C, but these dietary alterations or supplements should not be ■ PHARMACOLOGIC THERAPY
substituted for more active forms of treatment. Total daily fiber Numerous randomized, double-blinded clinical trials have demon-
intake should be about 20–30 g/day, with about 25% or 6 g/day, strated that reduction of LDL reduces CHD event rates in primary
being soluble fiber.1 Studies with psyllium seed in doses of 10 to 15 prevention, secondary intervention, and angiographic trials.54 Gener-
g/day show reductions in total cholesterol and LDL-C ranging from ally speaking, for every 1% reduction in LDL, there is a 1% reduction
approximately 5% to 20%.47,48 They have little or no effect on HDL-C in CHD event rates.1 However, if treatment extends beyond the
or triglyceride concentrations. These products also may be useful in typical duration of a clinical trial (2–5 years), the accumulated benefit
managing constipation associated with the bile acid sequestrants. could be greater. A 1% elevation of HDL results in an approximately
Psyllium binds cholesterol in the gut but also reduces hepatic 2% reduction in CHD events.12,55 Of interest, angiographic trials,
production and clearance. Fish oil supplementation provides an which typically cause small changes in luminal diameter (i.e., approx-
increased amount of the omega-3 polyunsaturated fatty acids, such imately 0.04-mm difference in change between placebo and active
as eicosapentaenoic acid and docosahexaenoic acid. In epidemio- treatment), result in fewer clinical events, such as MI, and a decreased
logic studies, ingestion of large amounts of cold-water oily fish was need for revascularization. These unexpected findings suggest that
associated with a reduction in CHD risk, but whether the same plaque size and luminal encroachment by plaque may be less impor-
advantage is conferred with commercially prepared fish oil products tant than the effects of cholesterol lowering on activity in the plaque
is unclear. Each 20 g/day ingestion of fish lowers CHD risk by 7%, and endothelial dysfunction. These studies provide a strong rationale
and eating fish at least once weekly should reduce CHD mortality.49 for attempting to lower plasma cholesterol and LDL in patients with
Fish oil supplementation has a fairly large effect in reducing triglyc- hypercholesterolemia.
erides and VLDL-C, but it either has no effect on total cholesterol  Although many efficacious lipid-lowering drugs exist, none is
and LDL-C or may cause elevations in these fractions. Other actions effective for all lipoprotein disorders, and all such agents are
of fish oil may account for their protective effects. These effects associated with some adverse effects.56 Lipid-lowering drugs can be
include quantitative and qualitative alterations in the synthesis of broadly divided into agents that decrease the synthesis of VLDL and
prostanoid substances, changes in immune function and cellular LDL, agents that enhance VLDL clearance, agents that enhance LDL
proliferation, and potential antioxidative actions.50 Responses noted catabolism, agents that decrease cholesterol absorption, agents that
with fish oil are discussed in Pharmacologic Therapy below.51 elevate HDL, or some combination of these characteristics (Table
Fat substitutes such as olestra (sucrose polyester, Olean, Procter 23–11). Table 23–12 lists recommended drugs of choice for each
and Gamble), a mixture of hexa-esters, hepta-esters, and octa-esters lipoprotein phenotype and alternate agents. Table 23–13 lists avail-
formed from the reaction of sucrose with long-chain fatty acids, are able products and their doses.
approved by the Food and Drug Administration (FDA) as a nondi- Treatment of type I hyperlipoproteinemia is directed toward
gestible, nonabsorbable, noncaloric fat substitute for snack foods. reducing the levels of chylomicrons derived from dietary fat, with
Olestra is heat stable, so it can be used in the preparation of fried and subsequent reduction in plasma triglycerides. Total daily fat intake
baked foods, an advantage over several other fat substitutes. It is should be no more than 10–25 g/day, or approximately 15% of total
similar in composition to triglycerides, but olestra is not hydrolyzed calories. Secondary causes of hypertriglyceridemia (see Table 23–5)
in the gastrointestinal tract by pancreatic lipase and, consequently, is should be excluded. Any underlying disorder should be treated
not taken up by the intestinal mucosa. The principal adverse effects appropriately. Type V hyperlipoproteinemia also requires stringent
associated with olestra use are bloating, flatulence, diarrhea, and restriction of the fat component of dietary intake; in addition, drug
“anal leakage.” Because of the ability of olestra to solubilize lipophilic therapy is indicated (as outlined in Table 23–12) if the response to
substances, there has been concern over potential drug interactions diet alone is inadequate. Medium-chain triglycerides, which are
in which lipophilic drugs (e.g., digitoxin, cyclosporine, or colchicine) absorbed without chylomicron formation, can be used as a dietary
or vitamins (A, D, E, and K) are solubilized in olestra and excreted in supplement for caloric intake if needed for types I and V. Hepatic
the feces. fibrosis has been reported with medium-chain triglycerides. Omega-3
Studies have demonstrated the LDL-lowering effect of plant ster- fatty acids may be useful for patients with LPL deficiency. In patients
ols, which are isolated from soybean and tall pine-tree oils. Ingestion with apolipoprotein C-II deficiency, infusion of plasma may normal-
of 2 to 3 g/day will reduce LDL by 6% to 15%.1 Plant sterols can be ize plasma triglyceride levels.
esterified to unsaturated fatty acids (creating sterol esters) to increase Primary hypercholesterolemia (familial hypercholesterolemia,
lipid solubility. Hydrogenating sterols produces plant stanols and, familial combined hyperlipidemia, type IIa hyperlipoproteinemia) is
with esterification, stanol esters. The efficacies of plant sterols and treated with bile acid resins (BARs) or sequestrants (colestipol,
stanols are considered comparable. Because lipids are needed to cholestyramine, and colesevelam), HMG-CoA reductase inhibitors
 395

TABLE 23-11 Effects of Drug Therapy on Lipids and Lipoproteins

CHAPTER 23
Effects on Effects on
Drug Mechanism of Action Lipids Lipoproteins Comment
Cholestyramine, colestipol, colesevelam ↑ LDL catabolism ↓ Cholesterol ↓ LDL Problem with compliance; binds many coadminis-
↓ Cholesterol absorption ↑ VLDL tered acidic drugs
Niacin ↓ LDL and VLDL synthesis ↓ Triglyceride ↓ VLDL Problems with patient acceptance; good in combi-
↓ Cholesterol ↓ LDL nation with bile acid resins; extended-release nia-
↑ HDL cin causes less flushing and is less hepatotoxic
than sustained-release form
Gemfibrozil, fenofibrate, clofibrate ↑ VLDL clearance ↓ Triglycercide ↓ VLDL Clofibrate causes cholesterol gallstones; modest LDL

Hyperlipidemia
↓ VLDL synthesis ↓ Cholesterol ↓ LDL lowering; raises HDL; gemfibrozil inhibits glucu-
↑ HDL ronidation of simvastatin, lovastatin, atorvastatin
Lovastatin, pravastatin, simvastatin, flu- ↑ LDL catabolism; inhibit LDL ↓ Cholesterol ↓ LDL Highly effective in heterozygous familial hypercholes-
vastatin, atorvastatin, rosuvastatin synthesis terolemia and in combination with other agents
Ezetimibe Blocks cholesterol absorption across ↓ Cholesterol ↓ LDL Few adverse effects; effects additive to other drugs
the intestinal border
HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

(statins), niacin, or ezetimibe.  Of these choices, statins are first effects more pronounced in nonfamilial than in familial hypercholes-
choice because they are the most potent LDL-lowering agents. Statins terolemia.  Combination therapy with bile acid sequestrants and
interrupt the conversion of HMG-CoA to mevalonate, the rate- lovastatin is rational: LDL receptor numbers are increased, leading to
limiting step in de novo cholesterol biosynthesis, by inhibiting HMG- greater degradation of LDL-C; intracellular synthesis of cholesterol is
CoA reductase (see Fig. 23–3). Currently available products include inhibited; and enterohepatic recycling of bile acids is interrupted.
lovastatin, pravastatin, simvastatin, fluvastatin, and atorvastatin. Combination therapy with a statin pulse ezetimibe also is rational
Rosuvastatin is the most potent statin currently on the market. Table because ezetimibe inhibits cholesterol absorption across the gut
23–14 lists the pharmacokinetic properties of the statins.57 The border and adds 12% to 20% further reduction when combined with
plasma half-lives of all the statins are reported to be short, except for a statin or other drugs.59 Elevation of serum transaminase levels
atorvastatin and rosuvastatin, which may account for their potency. (primarily alanine aminotransferase) to more than three times the
In the Comparative Dose Efficacy Study of Atorvastatin Versus upper limit of normal occurs in approximately 1.3% of patients
Simvastatin, Pravastatin, Lovastatin, and Fluvastatin in Patients with taking moderate to high doses of statins; serious muscle toxicity
Hypercholesterolemia (CURVES), the largest head-to-head compar- occurs in <0.6% of patients.60 Meta-analysis of placebo-controlled
ison of statins, atorvastatin was found to be the most potent drug for studies with statins demonstrated a low risk of abnormal alanine
lowering total cholesterol and LDL-C, with reductions in LDL-C of aminotransferase or creatine kinase (CK) and a low risk of myopathy
38%, 46%, 51%, and 54% for the 10-, 20-, 40-, and 80-mg doses, without or with rhadomyolysis.61 Lens opacities have been reported
respectively.58 Metabolic studies of statin use in normal volunteers with lovastatin. However, in the age groups studied, these abnormal-
and patients with hypercholesterolemia suggest reduced synthesis of ities are common and tend to wax and wane with time irrespective of
LDL-C as well as enhanced catabolism of LDL mediated through drug therapy, and no statistical association is known to exist. As a
LDL receptors as the principal mechanisms for lipid-lowering effects. category of monotherapy, the HMG-CoA reductase inhibitors are the
Total cholesterol and LDL-C are reduced in a dose-related fashion by most potent total cholesterol and LDL-C-lowering agents and are
at least 30% on average when added to dietary therapy, with the among the best tolerated.60,61 In an analysis of more than 75,000
patients allocated to statins in clinical trials, Alsheikh-Ali et al.62
found that risk of statin-associated elevated liver enzymes or rhabdo-
TABLE 23-12 Lipoprotein Phenotype and Recommended
myolysis was not related to the magnitude of LDL-C lowering. A
Drug Treatment
highly significant inverse relationship between achieved LDL-C levels
Lipoprotein Type Drug of Choice Combination Therapy and rates of newly diagnosed cancer was observed (R2 = 0.43, P =
I Not indicated — 0.009). 62 The WHO Foundation Collaborating Centre for Interna-
IIa Statins Niacin or BAR tional Drug Monitoring has issued a report suggesting that a rare
Cholestyramine or colestipol Statins or niacin relationship may exist between statin use and the onset of upper
Niacin Statins or BAR motor neuron diseases such as amyotrophic lateral sclerosis, but this
Ezetimibe association remains uncertain.63 Numerous pharmacokinetic and
IIb Statins BAR, fibrates,b or niacin pharmacodynamic differences among statins and patients give rise to
Fibrates Statins, niacin, BARa variable responses to therapy.64
Niacin Statins or fibrates
The primary action of BAR is binding bile acids in the intestinal
Ezetimibe
lumen, with concurrent interruption of enterohepatic circulation of
III Fibrates Statins or niacin
Niacin Statins or fibrates
bile acids and markedly increased excretion of acidic steroids in the
Ezetimibe feces. This action decreases the bile acid pool size and stimulates
IV Fibrates Niacin hepatic synthesis of bile acids from cholesterol. Depletion of the
Niacin Fibrates hepatic pool of cholesterol results in increased cholesterol biosynthe-
V Fibrates Niacin sis and increased number of LDL receptors on the hepatocyte mem-
Niacin Fish oils brane. The increased number of receptors stimulates catabolism from
a
Bile acid resins (BARs) are not used as first-line therapy if triglycerides are elevated at baseline
plasma and lowers LDL levels. BAR also reduces CETP, which
because hypertriglyceridemia may worsen with BAR alone. correlates with total cholesterol and LDL-C concentrations, perhaps
b
Fibrates includes gemfibrozil or fenofibrate. by interfering with hepatic microsomal cholesterol content; however,
 396

TABLE 23-13 Comparison of Drugs Used in the Treatment of Hyperlipidemia

SECTION 2

Drug Manufacturer Dosage Forms Usual Daily Dose Maximum Daily Dose
Cholestyramine (Questran) BMS Bulk powder/4-g packets 8 g tid 32 g
Cholestyramine (Questran Light) BMS Bulk powder/4-g packets
Cholestyramine (Cholybar) Parke-Davis 4-g resin per bar
Colestipol hydrochloride (Colestid) Upjohn Bulk powder/5-g packets 10 g bid 30 g
Colesevelam (WelChol) Sankyo 625-mg tablets 1,875 mg bid 4,375 mg
Niacin Various 50-, 100-, 250-, 500-mg tablets; 125-, 2 g tid 9g
250-, 500-mg capsules
Extended-release niacin (Niaspan) Kos 500, 750, 1,000 mg tablets 500 mg 2,000 mg
Cardiovascular Disorders

Extended-release niacin + lovastatin Kos Niacin/lovastatin 500-mg/20-mg tablets Niacin/lovastatin 500 mg/20 mg Niacin/lovastatin 1,000 mg/
(Advicor)a Niacin/lovastatin 750-mg/20-mg tablets 20 mg tablets
Niacin/lovastatin 1,000-mg/20-mg
Clofibrate Banner Pharmacaps, 500-mg capsules 1 g bid 2g
USL Pharma
Fenofibrate (TriCor and others) Abbott, various 67-, 134-, 200-mg capsules (micronized); 54 mg or 67 mg 201 mg
54-,160-mg tablets; 40-, 120-mg tablets;
50-, 160-mg tablets
Gemfibrozil (Lopid) Parke-Davis 300-mg capsules 600 mg bid 1.5 g
Lovastatin (Mevacor) MSD 20-, 40-mg tablets 20–40 mg 80 mg
Pravastatin (Pravachol) Bristol-Myers Squibb 10-, 20-mg tablets 10–20 mg 40 mg
Simvastatin (Zocor) MSD 5-, 10-, 20-, 40- and 80-mg tablets 10–20 mg 80 mg
Atorvastatin (Lipitor) Pfizer 10-mg tablets 10 mg 80 mg
Rosuvastatin (Crestor) Astra-Zeneca 5- and 10-mg tablets 5 mg 40 mg
Ezetimibe (Zetia) MSD 10-mg tablets 10 mg 10 mg
Atorvastatin/amlodipine (Caduet) Pfizer Atorvastatin/amlodipine 10 mg/5 mg Atorvastatin/amlodipine Atorvastatin/amlodipine
Atorvastatin/amlodipine 20 mg/5 mg 10 mg/5 mg 80 mg/10 mg
Atorvastatin/amlodipine 40 mg/5 mg
Atorvastatin/amlodipine 80 mg/5 mg
Atorvastatin/amlodipine 10 mg/10 mg
Atorvastatin/amlodipine 20 mg/10 mg
Atorvastatin/amlodipine 40 mg/10 mg
Atorvastatin/amlodipine 80 mg/10 mg
Pravastatin/aspirin (Pravigard PAC) BMS Pravastatin/aspirin 20 mg/81 mg
Pravastatin/aspirin 20 mg/325 mg
Pravastatin/aspirin 40 mg/81 mg
Pravastatin/aspirin 40 mg/325 mg
Pravastatin/aspirin 80 mg/81 mg
Pravastatin/aspirin 80 mg/325 mg
Simvastatin/ezetimibe (Vytorin) Merck/Schering-Plough Simvastatin/ezetimibe 10 mg/10 mg Simvastatin/ezetimibe 20 mg/ Simvastatin/ezetimibe
Simvastatin/ezetimibe 20 mg/10 mg 10 mg 40 mg/10 mg
Simvastatin/ezetimibe 40 mg/10 mg
ω-3 Acid ethyl esters (Lovaza) Reliant Eicosapentaenoic acid (EPA) 465 mg, Four 1-g capsules QD or two Four 1-g capsules QD or
docosahexaenoic acid (DHA) 375 mg 1-g capsules bid two 1-g capsules bid
BMS, Bristol-Myers Squibb; MSD, Merck Sharp & Dohme.
Probucol is no longer on the market in the United States. Gemfibrozil, fenofibrate, and lovastatin are available as generic products.
a
Manufacturer does not recommend use of the fixed combination as initial therapy for primary hypercholesterolemia or mixed dyslipidemia. It is specifically indicated for patients receiving lovastatin alone plus
diet who require an additional reduction in triglyceride levels or increase in HDL-cholesterol levels; it also is indicated for those treated with niacin alone who require additional decreases in LDL cholesterol.

this effect is not as great as with statins.65 BARs are generally ineffec- stipation, bloating, epigastric fullness, nausea, and flatulence are most
tive in patients with homozygous familial hypercholesterolemia commonly reported.1 With intensive education, patients can learn to
because these individuals genetically lack the ability to increase tolerate resins on a long-term basis, as evidenced in clinical trials by
synthesis of LDL receptors. The increase in hepatic cholesterol bio- adherence to active drug regimens. In routine clinical practice, at least
synthesis may be paralleled by increased hepatic VLDL production; 40% of patients discontinue therapy within 1 year, but adherence
consequently, BARs may aggravate hypertriglyceridemia in patients rates can be improved with pharmacist interventions.66,67 Adverse
with combined hyperlipidemia. Gastrointestinal complaints of con- effects can be managed by increasing fluid intake, modifying the diet

TABLE 23-14 Pharmacokinetics of the Statins

Parameter Lovastatin Simvastatin Pravastatin Fluvastatin Atorvastatin Rosuvastatin
Isoenzyme 3A4 3A4 None 2C9 3A4 2C9/2C19
Lipophilic Yes Yes No Yes Yes No
Protein binding (%) >95 95–98 ~50 >90 96 88
Active metabolites Yes Yes No No Yes Yes
Elimination half-life (h) 3 2 1.8 1.2 7–14 13–20
Isoenzyme refers to the specific isoenzyme in the cytochrome P450 system, which is responsible for the metabolism of each drug. Pharmacokinetic parameters in this table are based on studies and reviews
presented in the literature.
 397
to increase bulk, and using stool softeners. The other major limiting release products may minimize these complaints in some patients,
complaint with BARs is their gritty texture and bulk. This problem but controlled trials with regular-release products do not demon-

CHAPTER 23
can be minimized by mixing the powder with orange drink or juice. strate much difference between sustained- and regular-release prod-
Tablet forms of bile acid sequestrants should help to improve compli- ucts. The only legend form of niacin, Niaspan (Kos), is an extended-
ance with this form of therapy, whereas the bar does not improve release form of niacin with pharmacokinetics intermediate between
compliance.68 Other potential adverse effects include impaired instant and sustained-release products, which are sold as food sup-
absorption of fat-soluble vitamins A, D, E, and K; hypernatremia and plements rather than legend products. In controlled trials, Niaspan is
hyperchloremia; gastrointestinal obstruction; and reduced bioavail- reported to have fewer dermatologic reactions and a low risk for
ability of acidic drugs such as coumarin anticoagulants, digitoxin, hepatoxicity. Niaspan in combination with statins produces large
nicotinic acid, thyroxine, acetaminophen, hydrocortisone, hydro- reductions in LDL and increases in HDL.74 Potentially important

Hyperlipidemia
chlorothiazide, loperamide, and possibly iron. Hyperchloremic met- laboratory abnormalities occurring with niacin therapy include ele-
abolic acidosis, hypernatremia, and gastrointestinal obstruction have vated liver function tests, hyperuricemia, and hyperglycemia. Experi-
been reported to occur almost exclusively in children, and malabsorp- ence with niacin in diabetes suggests that some diabetic patients do
tion of fat-soluble vitamins probably is most common with high not have worsened glycemic control with dose-titration and sus-
doses (e.g., 30 g/day of cholestyramine) of the BARs. Drug interac- tained-release products.75 With doses less than 3 g/day, the degree of
tions can be avoided by alternating administration times, with an liver function test elevation generally is not marked and often is
interval of at least 6 hours between the BAR and other drugs. transient, and a temporary reduction in dosage frequently corrects
Colestipol and cholestyramine have comparable side effects; however, the problem. Niacin-associated hepatitis is more common with
colestipol may have better palatability because it is odorless and sustained-release preparations, and their use should be restricted to
tasteless. Colesevelam is the newest BAR, and total and LDL-C patients intolerant of regular-release products.75,76 Sustained-release
reduction are dose related. Adverse effects are qualitatively similar to products often are more expensive and, given the lack of data on
those occurring with the older BARs but may occur less often. reduced adverse effects and increased incidence of hepatitis, regular-
Because of adverse effects that occur commonly with BARs at higher release products should always be used first. Preexisting gout and
doses, BARs are increasingly used in combination with other drugs diabetes may be exacerbated by niacin; patients with these conditions
because low doses are tolerated well, and the BARs work in comple- should be monitored more closely and their medication titrated
mentary fashion with other agents. appropriately. Patients with well-controlled diabetes mellitus type 2
Niacin (nicotinic acid) can be used for treatment of primary do not have significant changes in glycemic control with niacin doses
hypercholesterolemia in combination with bile acid sequestrants or up to 2 g/day.76 Niacin is contraindicated in patients with active liver
as monotherapy for this and other disorders (Table 23–12). Niacin disease. Dry eyes and other ophthalmologic complaints are occasion-
reduces hepatic synthesis of VLDL, which in turn leads to reduced ally noted. Concomitant alcohol and hot drinks may magnify flush-
synthesis of LDL. Factors responsible for decreased VLDL produc- ing and pruritus with niacin and should be avoided at the time of
tion include inhibition of lipolysis with decreased free fatty acids in ingestion. Nicotinamide should not be used for treatment of hyper-
plasma, decreased hepatic esterification of triglycerides, and a possi- lipidemia because it does not effectively lower cholesterol or triglyc-
ble direct effect on hepatic production of apolipoprotein B.69 The eride levels.
complementary action of niacin and bile acid sequestrants in Combined hyperlipoproteinemia (type IIb) can be treated with
increasing catabolism and decreasing LDL synthesis may account for statins, niacin, or gemfibrozil to lower LDL-C without elevating
the additive effects of this combination in patients with hyperlipid- VLDL and triglycerides. Niacin is the most effective agent and can be
emia. Niacin also increases HDL by reducing its catabolism. Niacin combined with a bile acid sequestrant. BARs alone for treatment of
selectively decreases hepatic removal of HDL apolipoprotein A-I but this disorder may elevate VLDL and triglycerides, and their use as
not removal of cholesterol esters, thereby increasing the capacity of single agents for treatment of combined hyperlipoproteinemia
retained apolipoprotein A-I to augment reverse cholesterol transport should be avoided. Fibric acid (gemfibrozil, fenofibrate) monother-
in isolated hepatic cells. Niacin is used principally for treatment of apy is effective in reducing VLDL, but a reciprocal rise in LDL may
mixed hyperlipemia or as a second-line agent in combination ther- occur, and total cholesterol values may remain relatively unchanged.
apy for hypercholesterolemia. It is considered the first-line agent or Gemfibrozil reduces synthesis of VLDL and, to a lesser extent,
an alternative for treatment of hypertriglyceridemia and diabetic apolipoprotein B, with a concurrent increase in the rate of removal
dyslipidemia.70,71 Numerous smaller trials suggest that lower doses of of triglyceride-rich lipoproteins from plasma. Plasma HDL concen-
niacin can be combined with statins or gemfibrozil to minimize trations may rise 10% to 15% or more with fibrates. Ezetimibe also
adverse effects and maximize response. These combinations require can be used in combination therapy for type IIb disease. Gastrointes-
careful monitoring because interactions occur. tinal complaints with fibric acid derivatives occur in 3% to 5% of
Many adverse drug reactions occur commonly with niacin use, but patients, rash in 2%, dizziness in 2.4%, and transient elevations in
most of the symptoms and biochemical abnormalities do not require transaminase levels and alkaline phosphatase in 4.5% and 1.3%,
discontinuation of therapy. Cutaneous flushing and itching appear to respectively.77 Gemfibrozil and fenofibrate may enhance the forma-
be prostaglandin mediated and can be reduced by aspirin 325 mg tion of gallstones associated with an increase in the lithogenic index;
given shortly before niacin ingestion.1,72 Flushing seems to be related however, the rate is low (0.5%–7%) and similar to that seen with
to rising plasma concentrations of niacin; taking the dose with meals placebo in the Helsinki Heart Study.77 Fibric acid derivatives may
and slowly titrating the dose upward may minimize these effects. potentiate the effects of oral anticoagulants, so prothrombin time
Laropiprant is a selective antagonist of the prostaglandin D2 receptor and international normalized ratio should be monitored very closely
subtype 1 (DP1), which may mediate niacin-induced vasodilation. when this combination is used.
Coadministration of laropiprant 30, 100, and 300 mg with extended- Type III hyperlipoproteinemia can be treated with fibric acid
release (ER) niacin significantly lowered flushing symptom scores (by derivatives or niacin. Although fibric acid derivatives have been
at least 50%) and significantly reduced malar skin blood flow meas- suggested as the drugs of choice for treatment of this disorder, the
ured by laser Doppler perfusion imaging.73 Gastrointestinal intoler- lack of data from major studies on hypercholesterolemia supporting
ance and flushing are common problems. Acanthosis nigricans, a their efficacy in altering cardiovascular mortality and the numerous,
darkening of the skin in skinfold areas and an external marker of well-documented serious adverse effects occurring with their use
insulin resistance, may be seen with high doses of niacin. Sustained- make niacin a reasonable consideration. Gemfibrozil increases the
 398
activity of LPL and reduces the synthesis or secretion of VLDL from emia often require combination therapy (two or three drugs) and
the liver into the plasma. A myositis syndrome of myalgia, weak- are managed with surgical therapy (partial ileal bypass), plasma-
SECTION 2

ness, stiffness, malaise, and elevations in creatinine phosphokinase pheresis (LDL apheresis), and liver transplantation (to replace LDL
and aspartate aminotransaminase is seen with the fibric acid deriv- receptors).
atives and seems to be more common in patients with renal
insufficiency.77 Enhanced hypoglycemic effects are reported to
occur when fibric acid derivative are given to patients taking ■ HYPERTRIGLYCERIDEMIA
sulfonylurea compounds, but the mechanisms for these interactions It is important to remember that lipoprotein pattern types I, III, IV,
are not well understood. and V are associated with hypertriglyceridemia, and that these
Three fibric acid derivatives (clofibrate, gemfibrozil, and fenofi- primary lipoprotein disorders and underlying diseases should be
Cardiovascular Disorders

brate) are approved for use in the United States. Gemfibrozil and excluded prior to implementing therapy (see Table 23–5). A family
fenofibrate are used much more commonly than clofibrate. All history positive for CHD is important in identifying patients at risk
reduce LDL-C by 20% to 25% in patients with heterozygous familial for premature atherosclerosis.80,81 If a patient with CHD has ele-
hypercholesterolemia. The response of LDL-C, HDL-C, and triglyc- vated triglycerides, the associated abnormality probably is a contrib-
erides to this category of drug is highly dependent on the specific uting factor to CHD and should be treated.29
lipoprotein type (e.g., type IIa vs IIb) and the baseline triglyceride High serum triglycerides (see Tables 21–6 and 21–12) should be
concentration.78 treated by achieving desirable body weight, consumption of a diet low
As a potential alternative therapy for this phenotype, numerous in saturated fat and cholesterol, regular exercise, smoking cessation,
epidemiologic and normal volunteer studies have found that diets and restriction of alcohol (in selected patients). ATP III identifies the
high in omega-3 polyunsaturated fatty acids (from fish oil), mostly sum of LDL and VLDL (termed non-HDC [total cholesterol – HDL])
commonly eicosapentaenoic acid, reduce cholesterol, triglycerides, as a secondary target of therapy in persons with high triglycerides
LDL-C, and very-low-density lipoprotein cholesterol (VLDLC) and (≥200 mg/dL).1,29 This approach is used when triglycerides are >200
may elevate HDL-C.51 The effects of fish oil on lipoprotein metabo- mg/dL and accounts for atherogenic particles carried in VLDL and
lism are mediated by a reduction in VLDL production and suppres- remnant particles. The goal for non-HDL in persons with high serum
sion of VLDL apolipoprotein B. In patients with hypertriglyceridemia triglycerides can be set 30 mg/dL higher than that for LDL on the
(either phenotype type IIb or V), a diet high in omega-3 fatty acids premise that VLDL ≤30 mg/dL is normal.  In patients with
given for 4 weeks reduced cholesterol 27% and 45% and triglyceride borderline-high triglycerides but accompanying risk factors for estab-
64% and 79% in the type IIb and type V patients, respectively.49 A diet lished CHD disease, family history of premature CHD, concomitant
high in eicosapentaenoic acid given to hyperlipidemic hemodialysis LDL elevation or low HDL, and genetic forms of hypertriglyceridemia
patients resulted in significant decreases in cholesterol and triglycer- associated with CHD (familial dysbetalipoproteinemia, familial com-
ides for as long as 13 weeks. Fish oil supplementation may be most bined hyperlipidemia), drug therapy with niacin should be consid-
useful in patients with hypertriglyceridemia; however, its role in ered. Niacin can be used cautiously in diabetics based on the results of
treatment is not well defined. Potential complications of fish oil the Arterial Disease Multiple Intervention Trial (ADMIT), which
supplementation, such as thrombocytopenia and bleeding disorders, found triglycerides were reduced by 23%, HDL-C increased by 29%,
have been noted, especially with high doses (eicosapentaenoic acid glucose increased only slightly (mean 8.7 mg/dL), and hemoglobin
15–30 g/day). Well-controlled trials are needed to determine if fish A1c did not change.82 Alternative therapies include gemfibrozil, stat-
oils are safe and effective before their use can be broadly recom- ins, and fish oil.81,83,84 Fibrates may increase LDL, and their use in
mended. Based a meta-analysis, fish consumption lowers the risk of borderline–high triglyceridemia requires careful monitoring to detect
CHD, but nutraceuticals have not been adequately tested.49 A pre- this deleterious change in lipid profile. Statins also can be used
scription form of concentrated fish oil, Lovaza, has become avail- because they provide modest reductions in triglycerides and modest
able.51 This product lowers triglycerides by 14% to 30% and raises elevations in HDL. Higher doses of statins may reduce HDL as well as
HDL by approximately 10%, depending on baseline values. LDL and triglycerides, with the amount of reduction related to the
Combination drug therapy may be considered after adequate trials baseline concentration and dose.81,84 In this situation, the goal of
of monotherapy and for patients who are documented as compliant therapy is to lower triglycerides and VLDL particles that may be
to the prescribed regimen. Two or three lipoprotein profiles at 6-week atherogenic, increase HDL, and reduce LDL.
intervals should confirm lack of response prior to initiation of Very high triglycerides are associated with pancreatitis and other
combination therapy. Cholestyramine can be added for patients with consequences of the chylomicron syndrome. At this level of triglyc-
fasting hypertriglyceridemia but should not be used as the initial drug erides elevation, a genetic form of hypertriglyceridemia often coex-
because triglycerides are likely to increase. Contraindications to, and ists with other causes of elevated triglycerides, such as diabetes.
drug interactions with, combined therapy should be carefully Dietary fat restriction (10%–20% of calories as fat), weight loss,
screened. Consideration should be given to the extra cost of drug alcohol restriction, and treatment of the coexisting disorder are the
product and monitoring that may be required. In general, a statin and basic elements of management. Drugs useful for treatment of hyper-
a BAR or niacin with a BAR provide the greatest reduction in total triglyceridemia include gemfibrozil, niacin, and higher-potency stat-
cholesterol and LDL-C. Regimens intended to increase HDL levels ins (atorvastatin, rosuvastatin, and simvastatin). Gemfibrozil is the
should include either gemfibrozil or niacin, bearing in mind that preferred drug in diabetics because of the effect of niacin on glycemic
statins combined with either of these drugs may result in a greater control unless the newer extended-release forms are used. Fenofi-
incidence of hepatotoxicity or myositis. This is particularly important brate may be preferred in combination with statin therapy because it
for statins that are eliminated via cytochrome 3A4 or through glucu- does not impair glucuronidation and minimizes potential drug
ronidation.57 Familial combined hyperlipidemia may respond better interactions. Successful treatment is defined as a reduction in triglyc-
to a fibric acid and a statin than to a fibric acid and a BAR.79 erides <500 mg/dL.1
Severe forms of hypercholesterolemia, such as familial hypercho-
lesterolemia, familial defective apolipoprotein B-100, severe poly-
genic hypercholesterolemia, familial combined hyperlipidemia, and ■ LOW HDL-C
familial dysbetalipoproteinemia (type III), may require more inten- Low HDL is a strong independent risk predictor of CHD. ATP III
sive therapy. In particular, patients with familial hypercholesterol- redefined low HDL-C as <40 mg/dL but specified no goal for HDL-C
 399
1
raising. Low HDL may be a consequence of insulin resistance, ■ SPECIAL CONSIDERATIONS
physical inactivity, type 2 diabetes mellitus, cigarette smoking, very

CHAPTER 23
high carbohydrate intake, and certain drugs (see Table 23–5). In Elderly
low HDL, the primary target remains LDL according to ATP III, but Hypercholesterolemia is an independent risk factor for CHD in the
emphasis shifts to weight reduction, increased physical activity, elderly (>65 years old) as it is in younger patients. The attributable
smoking cessation, and, if drug therapy is required, fibric acid risk, which is the difference in absolute rates of CHD between
derivatives and niacin. Niacin has the potential for the greatest segments of the population with higher or lower serum cholesterol
increase in HDL, and the effect is more pronounced with regular or levels, increases with age. Older patients potentially benefit to a
immediate-release forms than with sustained-release forms.85 greater extent from cholesterol lowering than do younger patients.
Data from studies of elderly men in a variety of settings are consistent
■ DIABETIC DYSLIPIDEMIA

Hyperlipidemia
with a relative risk of at least 1.5 in the highest compared to the lowest
quartile of cholesterol levels.98,99 Treatment of hypercholesterolemia
Diabetic dyslipidemia is characterized by hypertriglyceridemia, low
in the elderly may result in reduction of absolute risk comparable to
HDL, and LDL that is minimally elevated. Small, dense LDL (pattern
that obtained in younger persons.1 Subgroup analyses of the West of
B) in diabetes is more atherogenic than larger, more buoyant forms of
Scotland (primary) and 4S (secondary) intervention studies show that
LDL (pattern A). Routine lipoprotein profiles do not differentiate
elderly patients had lower CHD risk reduction (relative risk reduction
between pattern A and pattern B.86–88 Diabetes in ATP III is a CHD
27% and 29%, respectively) compared to younger patients (relative
risk equivalent. The primary target is LDL, and the goal of treatment is
risk reduction 40% and 39%, respectively).89,100 The Framingham
to lower LDL-C to <100 mg/dL.1 When LDL is >130 mg/dL, most
study suggests that elderly women are at higher risk because of high
patients require simultaneous therapeutic lifestyle changes and drug
blood cholesterol levels, but no other large studies included women,
therapy. When LDL-C is between 100 and 129 mg/dL, intensifying
and the risks or benefits from cholesterol reduction are not well
glycemic control, options include adding drugs for the atherogenic
defined. Primary prevention in younger patients requires approxi-
dyslipidemia (fibric acid derivatives, niacin), and intensifying LDL-C-
mately 2 years before reduction in CHD risk is apparent, and this lag
lowering therapy. Because the primary target is LDL-C in patients with
time should be taken into consideration during patient selection for
diabetic dyslipidemia, statins are considered by many to be the initial
therapy. Relative risk of nonlipid CHD risk factors does not decline
drugs of choice.1,29 The relative risk reduction for CHD in diabetics
with aging, and aggressive management of modifiable nonlipid risk
versus nondiabetics was greater in several trials, including the West of
factors is important in older patients. High-risk elderly patients are
Scotland Coronary Prevention Study (37% vs 20%),89 Air Force/Texas
less likely to be prescribed statins, and their potent benefits are not
Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS; 43%
realized.101 Because most women with CHD are elderly and at risk for
vs 36%),90 Cholesterol and Recurrent Events (CARE) trial (25% vs
osteoporosis, they are logical candidates for diet therapy with consid-
23%),91 and Scandinavian Simvastatin Survival Study (4S; 55% vs
eration of calcium intake consistent with osteoporosis prevention,
32%).92 All statins are fairly comparable in triglyceride lowering, and
exercise, and perhaps estrogen replacement therapy. Evidence sug-
because statins differ in potency for LDL reduction, a ratio of LDL
gests that statins reduce the risk of osteoporosis; however, data from
reduction to triglyceride reduction can be applied. Statin therapy may
various studies are conflicting.102
protect against the development of diabetes.26 The most recent trial of
Drug therapy in principle differs little between older and younger
LDL lowering in type 2 diabetes mellitus is the Collaborative Atorva-
patients, and older patients respond as well as younger patients to
statin Diabetes Study (CARDS).93 This was a randomized, double-
lipid-lowering drugs.103,104 Based on the Heart Protection Study,
blinded placebo comparison of atorvastatin 10 mg/day versus placebo
which comprised more elderly patients than any other trial, simva-
in 2,838 diabetes to reduce first CHD events. Baseline LDL was 118
statin 40 mg/day reduced the CHD event rate in patients older than
mg/dL, and with atorvastatin LDL fell by 46 mg/dL. The primary end
70 years the same as in younger patients.105 The gain in life expectancy
point, a composite of acute CHD death, nonfatal MI, hospitalized
may be small, depending on the patient’s age at the start of treatment
unstable angina, resuscitated cardiac arrest, coronary revasculariza-
and the magnitude of cholesterol reduction.82 Changes in body
tion, or stroke, was reduced by 37%. This study suggests that all
composition, renal function, and other physiologic changes of aging
diabetics should have LDL much lower than 100 mg/dL, and these
may make older patients more susceptible to adverse effects of lipid-
results are consistent with the Heart Protection Study analysis of
lowering drug therapy. In particular, older patients are more likely to
diabetic patients.94
have constipation (BARs), skin and eye changes (niacin), gout (nia-
According to the Diabetes Atherosclerosis Intervention Study
cin), gallstones (fibric acid derivatives), and bone/joint disorders
(DAIS), fenofibrate reduced angiographic progression of CAD in type
(fibric acid derivatives, statins). Therapy should be started with lower
2 diabetics.95 Fewer CHD events were seen with fenofibrate compared
doses and titrated up slowly to minimize adverse effects.
with placebo, but the difference was not significant. Fibric acids
principally lower VLDL and triglycerides while increasing HDL, with
only modest lowering of total cholesterol and LDL-C. Fibric acid Women
derivatives may increase LDL levels. In contrast to niacin, fibric acid Cholesterol is an important determinant of CHD in women, but the
derivatives tend to improve glucose tolerance, with the greatest effect relationship is not as strong as that seen in men. HDL may be a more
seen with bezafibrate. The Helsinki Heart Study found gemfibrozil was important predictor of disease in women.4 LDL and HDL genetic
most effective for diabetic dyslipidemia.96 Although the effect of statins regulation in women and men does not appear to be different. Based
on triglycerides and HDL abnormalities commonly seen in patients on the Nurses’ Health Study, obesity is an important determinant of
with diabetes is less than with fibric acids, the subgroup analyses cited CHD in women, with a relative risk of 3.3 in the highest Quetelet
earlier suggest that these drugs significantly reduce CHD risk. Chole- index (weight in kilograms divided by the square of the height in
styramine in diabetic patients may result in lower LDL levels but may meters) compared to the lowest category (i.e., <21 vs ≥29); low HDL
increase VLDL and triglyceride levels, which already are commonly levels usually accompany obesity.106 No major differences exist in the
elevated in diabetes. Resins may aggravate constipation, which is influence of exercise, alcohol ingestion, and smoking on lipid levels
common in diabetics. As demonstrated in ADMIT and in the Assess- between men and women. Women in the highest tertile of choles-
ment of Diabetes Control and Evaluation of the Efficacy of Niaspan terol appear to be more responsive to dietary therapy than women in
Trial (ADVENT), immediate-release and extended-release niacin are the lower tertiles and more responsive than predicted using formulas
highly effective in raising HDL and lowering triglycerides and LDL.82,97 based on men.
 400
Based on the Heart and Estrogen/Progestin Replacement Study mechanisms, suggesting a potential role for combination therapy in
(HERS)107 and the Women’s Health Initiative (WHI) trial,108–110 optimizing the lowering of small, dense LDL-C and remnant lipo-
SECTION 2

published national guidelines recommended similar types of lifestyle proteins. Statins appear to be safe and effective in renal insufficiency
and risk factor goals and interventions as recommended by NCEP and may alter the natural course of declining renal function.115–119
for the entire population.4 Hormone therapy may continue to have a Renal insufficiency without proteinuria leads to hypertriglyceride-
role for treatment of postmenopausal symptoms; however, a notable mia, slightly elevated total cholesterol and LDL-C (particularly with
exception is hormone replacement therapy and heart protection. chronic ambulatory peritoneal dialysis), and low HDL levels (espe-
Combined estrogen plus progestin hormone therapy for prevention cially during hemodialysis). These abnormalities are thought to be
of cardiovascular disease should not be initiated in postmenopausal caused by a deficiency in apolipoprotein C-II, perhaps as a result of
women. Combined estrogen plus progestin hormone therapy for sustained use of heparin during hemodialysis and depletion of LPL,
Cardiovascular Disorders

prevention of cardiovascular disease should not be continued in carbohydrate-induced obesity and hypertriglyceridemia, loss of car-
postmenopausal women. Other forms of menopausal hormone nitine during hemodialysis, use of acetate buffer (acetate is a precur-
therapy (e.g., unopposed estrogen) for prevention of cardiovascular sor to fatty acid synthesis) during hemodialysis, and decreased LCAT
disease should not be initiated or continued in postmenopausal activity during hemodialysis. Dialysis does not correct the lipid
women pending the results of ongoing trials. Results of the Women’s abnormalities. Renal transplantation may correct lipid abnormalities
International Study of Long Duration Oestrogen after Menopause in some patients; however, use of transplantation-related medica-
(WISDOM) confirm the lack of benefit seen in HERS and WHI.111 tions, such as corticosteroids, cyclosporine, and certain antihyper-
In a post hoc analysis of the WHI, women who initiated hormone tensive agents (see Chaps. 15 and 92), may aggravate the lipid
therapy closer to menopause tended to have a reduced CHD risk abnormalities in other patients. Cyclosporine interferes with the
compared with the increased CHD risk in women more distant from metabolism of statins metabolized by cytochrome P450 3A4 (Table
menopause, but this trend did not meet statistical signifance.108 23–14), and patients must be observed closely for myositis and
Cholesterol and triglyceride levels rise progressively throughout worsening renal function. Of interest, correction of lipid abnormali-
pregnancy, with an average increment in cholesterol of 30 to 40 mg/ ties may improve renal hemodynamics. Pravastatin and fluvastatin
dL occurring around weeks 36 to 39. Triglyceride levels may increase may be safer than other statins, but this must be validated in larger,
by as much as 150 mg/dL. Drug therapy is not instituted, nor is it long-term trials. Diet will modify lipoprotein levels, and polyunsatu-
usually continued during pregnancy. If the patient is very high risk, rated fatty acids may have a role in impeding the progression of renal
a bile acid resin may be considered because no systemic drug disease as well as the cardiovascular complications. Bile acid seques-
exposure occurs.1 Statins are category X and are contraindicated. trants do not correct the lipid abnormalities seen in renal insuffi-
Ezetimibe might be an alternative because it is a category C drug ciency. Lovastatin or its active metabolite may accumulate in renal
(animal studies have shown that the drug exerts teratogenic and insufficiency, and lower doses of reductase inhibitors should be used
embryocidal effects, no adequate and well-controlled studies in to avoid adverse effects. Gemfibrozil can be used with caution; its
pregnant women are available, or no studies are available in either pharmacokinetics are unchanged and it lowers triglycerides and
animals or pregnant women). Dietary therapy is the mainstay of increases HDL.120 Statins (simvastatin, lovastatin and atorvastatin)
treatment, with emphasis on maintaining a nutritionally balanced and fibric acid derivatives may increase the risk of severe myopathy,
diet per the needs of pregnancy. and attention to symptoms of myositis is needed. Niacin may be
useful in nondiabetic patients with renal insufficiency.
Hypertensive patients have a greater-than-expected prevalence of
Children
high blood cholesterol levels; conversely, patients with hypercholes-
Drug therapy in children is not recommended until they are 10 years terolemia have a higher than expected prevalence of hypertension
and older, and the guidelines for institution of therapy and the goals caused by the metabolic syndrome. Recommendations for manage-
of therapy are different from those in adults (see Table 23–9).33 ment of hypertension in patients with hypercholesterolemia include
Younger children are generally managed with therapeutic lifestyle avoiding use of drugs that elevate cholesterol, such as diuretics and
changes until after age 2 years.1,44 In the past bile acid sequestrants β-blockers, and using agents that either are lipid neutral or may
were recommended as first-line therapy, but evidence now shows reduce cholesterol slightly (see Chap. 15).1 Bile acid sequestrants
that statins are safe and effective in children and provide greater lipid may bind to thiazide diuretics and some β-blockers and may
lowering than BAR.38,112,113 Severe forms of hypercholesterolemia interfere with their absorption. Reactions may be avoided by giving
(e.g., familial hypercholesterolemia) may require more aggressive the antihypertensive 1 hour before or 4 hours after the resin. Niacin
treatment. may magnify the hypotensive effects of vasodilators.

■ CONCURRENT DISEASE STATES ■ PHARMACOECONOMIC CONSIDERATIONS

Nephrotic syndrome, end-stage renal disease and nephrotic syn- The clinical benefits of lipid-lowering therapy for primary and
drome, and hypertension compound the risk of dyslipidemia and secondary intervention are well established based on the results of
may present difficult-to-treat lipid abnormalities. Abnormalities of studies showing a reduction in CHD morbidity and mortality.121,122
lipoprotein metabolism in the nephrotic syndrome include elevated The balance of benefits and costs has been examined in a few
total and LDL-C, lipoprotein(a), VLDL, and triglycerides. The ratio studies.82,95 The cost per year of life saved has been estimated to range
of apolipoprotein C-III to apolipoprotein C-II is elevated, consis- from less than $10,000 to more than $1 million dollars, depending
tent with greater LPL inhibitor activity, and the extent of hypoalbu- on the presence or absence of CHD, patient’s age, baseline total or
minemia is correlated with dyslipidemia. The basic abnormality LDL-C level, reduction in cholesterol, and number of risk factors
appears to be overproduction of LDL apolipoprotein B from VLDL present.
Intervention with statin therapy in general is cost effec-
rather than reduced clearance of LDL-C and related proteins. tive in patients with known CHD, with CHD risk equivalents, or
Protein restriction and a “vegan” diet corrects lipid abnormalities to with a 10-year risk of 10% to 20%. Other types of therapy may be
some extent. Statins have been shown to be effective in reducing cost effective if certain assumptions concerning compliance and
elevated total cholesterol and LDL-C in the nephrotic syndrome, efficacy are met. Based on 4S, the range for secondary intervention is
although the levels do not usually return to normal.114 Fibric acid $3,800 for a 70-year-old man with a high cholesterol level to $27,400
derivatives and statins reduce small, dense LDL-C by different per year of life gained for a middle-aged woman with an average
 401
123
cholesterol level. In contrast, primary prevention in men based on combined with niacin was found to reduce plasma cholesterol levels
the West of Scotland trial averages about $35,000 per year of life by approximately 50% over 5 years in patients with homozygous

CHAPTER 23
gained.124 These studies demonstrate that primary and secondary familial hypercholesterolemia, and coronary atherosclerosis did not
intervention are well within the accepted boundary of less than progress as documented by angiography. LDL apheresis (i.e., selec-
$50,000 for a medical intervention to be considered cost effective. tive removal of LDL-C via a filtering system) plus statin therapy is
Based on the specific lipoprotein phenotype, fibric acid derivatives, effective in lowering LDL-C and appears to affect the progression of
niacin, or combination therapy of statins plus BAR may be cost vascular disease. Combined liver and heart transplantation in
effective. Cost effectiveness is maximized by treating high-risk patients with homozygous familial hypercholesterolemia reduced
patients and those with established CHD. total cholesterol and LDL-C concentrations from approximately
Specialty lipid clinics have become increasingly popular, and 1,100 and 900 mg/dL before surgery to approximately 300 and 185

Hyperlipidemia
many use pharmacists to provide direct patient care in this setting. mg/dL after surgery, respectively. Liver transplantation replaced the
An interesting analysis showed that a specialty clinic may be more missing LDL receptors, enhanced catabolism, and reduced lipopro-
expensive ($659 ± $43 vs $477 ± $42 per patient, P < 0.001) than tein synthesis in this patient population.
usual care. However, the overall cost effectiveness is improved when
expressed as program costs per unit (mmol/L) reduction in the ■ SUMMARY OF MAJOR STUDIES
LDL-C, a measure of cost effectiveness that was significantly lower
for specialized care ($758 ± $58 vs $1,058 ± $70, P = 0.002) because  Primary and secondary prevention diet and drug trials have been
more patients achieve their targeted goal.125 Project ImPACT performed to determine whether lowering cholesterol levels will
prevent CHD. These trials are summarized in Tables 23–15 and
(Improve Persistence and Compliance with Therapy) demonstrated
23–16. A number of earlier angiographic studies demonstrated that
that pharmacists, working collaboratively with patients and physi-
cholesterol reduction led to regression of atherosclerosis and plaque
cians, can improve persistence and compliance, and that nearly two
stabilization. Most of the primary and secondary studies were double
thirds of patients achieved their NCEP lipid goal.126 Other programs
blinded, randomized, and placebo controlled, lasted for at least 5
showed similar trends.67,127,128
years, and had sufficient patient numbers to be meaningful. Excep-
tions to these qualifications were seen in the early studies, such as the
■ OTHER THERAPIES Newcastle and Edinburgh trials, which were small and generally did
Partial ileal bypass has been used for treatment of severe heterozygous not show much benefit; and the Coronary Drug Project (CDP), using
and homozygous familial hypercholesterolemia; however, it is inef- dextrothyroxine, which was terminated early because of observed
fective in the latter case. Ileal bypass removes the site of bile acid adverse effects on CHD mortality. The Helsinki Heart Study, using
reabsorption, depleting the bile acid pool and increasing the catabo- gemfibrozil, resulted in a reduction in nonfatal MI, which was the
lism of cholesterol. The Program on the Surgical Control of the primary contributor to reduced CHD incidence (Table 23–15).14
Hyperlipidemias (POSCH), a randomized trial of diet versus surgery, Total cholesterol and LDL-C were reduced an average of 13.4% and
reported that total cholesterol and LDL-C were decreased (23.3% and 20.3%, respectively, by cholestyramine in the Lipid Research Clinics
37.7%, respectively) and HDL increased (4.3%) in patients who had Coronary Primary Prevention Trial (LRC-CPPT). The reduction of
undergone ileal bypass for hypercholesterolemia.97 Surgery delayed lipid levels was related to the amount of drug ingested (5.4% reduction
overall death by nearly 3 years (P = 0.032) and delayed CHD in total cholesterol with 1–2 packets vs 19.0% reduction with ≥5
mortality by nearly 4 years (P = 0.046) compared to the control packets).129 The prescribed dose of cholestyramine was 24 g (or 6
group. Revascularization procedures were delayed by an average of 7 packets) per day. The cholestyramine group experienced a 19% reduc-
years (P < 0.001). Postsurgery diarrhea was more common in the tion in risk (P < 0.05) of the primary end point of definite CHD death
surgical group, as were the rates of kidney stones (4% vs 0.4%), and/or definite nonfatal MI, reflecting a 24% reduction in definite
gallstones (10% vs 2%), and bowel obstruction (13.5% vs 3.6%). CHD death and a 19% reduction in nonfatal MI. Other end points of
Portacaval shunts have been used to decrease the formation of new positive exercise tests, angina, and coronary bypass surgery were
LDL-C, with reported reductions of 10% to 20%. Plasma exchange reduced by 25%, 20%, and 21%, respectively. Death from all causes was

TABLE 23-15 Primary Prevention Trials with Lipid-Lowering Drugs

Followup Control Treatment
Trial (y) N Treatment Events Events P Value RRR ARR NNT
AFCAPS/TexCAPS 5 6,605 Lovastatin 20–40 mg 5.5% 3.5% <0.001 36.4% 2.0% 50
Helsinki 5 4,081 Gemfibrozil 1,200 mg 4.1% 2.7% <0.02 34.0% 1.4% 71
LRC-CPPT 7.4 3,806 Cholestyramine 24 g 9.8% 8.1% <0.05 17.3% 1.7% 59
Oslo 5 1,232 Diet + smoking cessation 4.2% 2.5% 0.03 40.5% 1.7% 59
WOSCOPS 4.9 6,595 Pravastatin 40 mg 7.8% 5.5% <0.001 29.5% 2.3% 43
ALLHAT 4.8 10,355 Usual care 10.4% 9.3% 0.16 9.0% 1.1% 91
Pravastatin 40 mg
WHI 5.2 16,608 Usual care 1.5% 1.9% 0.05 1.29a 0.4% 200b
Diet, CEE 0.625 mg + MPA 2.5 mg
WHI 5.2 16,608 Usual care 3.7% 3.3% NS 9.0% 0.4% 250
Diet, CEE 0.625 mg
CARDS 4 2,838 Atorvastatin 10 mg 9.0% 5.8% 0.001 37.0% 3.2% 32
AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study (Downs et al., 1998); ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; approximately 13%–
15% of patients had a history of coronary heart disease (CHD); events are CHD events only; ARR, absolute risk reduction; CARDS, Collaborative Atorvastatin Diabetes Study (presented at the 2004 American
Diabetes Association meeting); CEE, conjugated equine estrogen; Helsinki, Helsinki Heart Study (Frick et al., 1987); LRC-CPPT, Lipid Research Clinics Coronary Primary Prevention Trial (Insull et al., 1984); MPA,
medroxyprogesterone acetate; NA, not available; NNT, number needed to treat; Oslo, Oslo Study (Hjermann et al., 1988); RRR, relative risk reduction; WHI, Women’s Health Initiative; WOSCOPS, West of
Scotland Coronary Prevention Study (Shepherd et al., 1995).
a
Hazard ratio. Risk of coronary heart disease was increased by 29%.
b
Number needed to harm as CEE + MPA was worse than placebo.
 402

TABLE 23-16 Secondary Prevention Trials with Lipid Lowering Drugs

SECTION 2

Followup Control Treatment

Trial (y) N Treatment Events Events P Value RRR ARR NNT
VA-HIT 5.1 2,531 Gemfibrozil 1,200 mg 23.7% 17.3% 0.006 22% 4.4% 23
AVERT 1.5 341 Atorvastatin 80 mg 21% 13.0% 0.048 38% 8% 12
CARE 5 4,159 Pravastatin 40 mg 13.2% 10.2% 0.003 22.7% 3.0% 33
CDP 5 8,341 Niacin 3 g + clofibrate 1.8 g 20.9% 20.6% NS 1.4% 0.3% 333
HERS 4.1 2,673 Estrogen 0.625 mg + progestin 2.5 mg 12.7% 12.5% 0.91 1.6% 0.2% 500
LIPID 7.4 3,806 Pravastatin 40 mg 9.8% 8.1% <0.05 17.3% 1.7% 59
4S 5 4,444 Simvastatin 20 mg 11.5% 8.2% 0.0003 28.7% 3.3% 30
Cardiovascular Disorders

WHO 5.3 15,745 Clofibrate 1.6 g 3.9% 3.1% <0.005 20.5% 0.8% 125
BIP 6.2 3,090 Placebo 15.0% 13.6% 0.26 9.3% 1.4% 72
Bezafibrate 400 mg
TIMI-22 2 4,162 Pravastatin 40 mg 26.3% (P) 22.4% (A) 0.005 16% 3.9% 26
Atorvastatin 80 mg
HPS 5 20,536 Simvastatin 40 mg 14.7% 12.9% 0.003 13% 1.8% 56
MIRACL 3,086 Atorvastatin 80 mg 17.4% 14.8% 0.048 16% 2.6% 39
PROSPER 3 5,804 Pravastatin 40 mg 16.2% 14.1% 0.014 24% 2.1% 48
SPARCL 4.0 4,731 Atorvastatin 80 mg 13.1% 11.2% 0.03 16% 2.2% 46
TNT 4.9 10,001 Atorvastatin 10 mg vs 80 mg 10.9% 8.7% <0.001 22% 2.2% 46
4S, Scandinavian Simvastatin Survival Study (Pederson et al., 1994); ARR, absolute risk reduction; AVERT, Atorvastatin Versus Revascularization Treatments; BIP, Bezafibrate Infarction Prevention; CARE,
Cholesterol and Recurrent Events (Melendez et al., 1996); CDP, Coronary Drug Project (Berge et al., 1975); HERS, Heart and Estrogen Replacement Study (Hulley et al., 1998); HPS, Heart Protection Study;
results expressed as all-cause mortality (HPS Collaborative Group, 2002); LIPID, Long-Term Intervention with Pravastatin in Ischaemic Disease Study (MacMahon et al., 1995); MIRACL, Myocardial Ischemia
Reduction with Aggressive Cholesterol Lowering (Schwartz et al., 2001); NNT, number needed to treat; PROSPER, prospective study of pravastatin in the elderly at risk; RRR, relative risk reduction; SPARCL, Stroke
Prevention by Aggressive Reduction in Cholesterol Levels; TIMI-22, Thrombolysis in Myocardial Infarction study 22; also known as the PROVE-IT trial (Cannon et al., 2004); TNT, treatment to new targets; VA-
HIT, Veterans Administration-High-Density Lipoprotein Cholestol (HDL-C) Intervention Trial; WHO, World Health Organization (Committee of Principal Investigators, 1978).

not significantly reduced by cholestyramine secondary to more acci- hazard ratio 7.36, 95% confidence interval 2.20–24.60), confirming the
dents and violence in this group. The mean falls in total cholesterol and findings of HERS and WHI. There were no statistically significant
LDL-C in the cholestyramine group were 8% and 12% relative to levels differences in the numbers of breast or other cancers, cerebrovascular
in placebo-treated men, providing evidence that for every 1% reduction events, fractures, and overall death.111
in cholesterol, a 2% decline in CHD mortality can be realized. In the CDP, niacin significantly reduced definite nonfatal MI
AFCAPS/TexCAPS was a primary prevention trial conducted in compared to placebo (10.1% vs 13.9%), whereas clofibrate did not
6,605 men and women aged 57 to 63 years with average total cholesterol reduce death from any cause or nonfatal or fatal MI during the 5-
(<221 mg/dL) and LDL (<150 mg/dL) who were treated with lova- year followup.131
statin 20 to 40 mg/day for 5.2 years. The study showed a 37% One of the most important studies published is 4S, a secondary
reduction (P < 0.001) in the risk for first acute major coronary event intervention trial with a large number of patients.132 Simvastatin 20–
(fatal or nonfatal MI, unstable angina, or sudden cardiac death).90 The 40 mg/day reduced LDL-C by 35% and reduced the risk of death from
need for revascularization procedures was reduced by 33% (P < 0.001). any cause by 30%. Coronary deaths were reduced with simvastatin
The implications of this trial are enormous; based on these results, (relative risk 0.58, confidence interval 0.46–0.73). Therapy was shown
millions of “normal” people potentially could benefit from lipid lower- to be effective in women (18%–19% of patients enrolled) and in the
ing with statins. The number of patients who need to be treated (Table elderly (≥60 years). The relative risk of death or major coronary event
23–15) for primary prevention ranged from 43 in the West of Scotland was reduced to a greater extent in the elderly than in younger patients.
trial to 71 in the Helsinki Heart Study. This range is within the typical Death from noncardiovascular causes was similar for simvastatin and
boundary used for treatment decisions and described previously; cost placebo (2.1% and 2.2%, respectively). The survival curves for simva-
effectiveness is achieved routinely in patients with moderate to high statin and placebo began to separate at 1 year and became more
risk. The Antihypertensive and Lipid-Lowering Treatment to Prevent divergent with additional followup. 4S clearly demonstrates the ben-
Heart Attack Trial—Lipid Lowering Trial (ALLHAT-LLT) tested prav- efit of cholesterol lowering and placates long-held fears of death from
astatin 40 mg/day versus placebo in hypertensive patients with at least non-CHD causes. The Long-Term Intervention with Pravastatin in
one CHD risk factor. Pravastatin did not reduce either all-cause mor- Ischemic Disease (LIPID) study (N = 7,498 men and 1,516 women)
tality or CHD significantly compared with usual care in older partici- investigated the effect of pravastatin therapy over 6 years on CHD
pants with well-controlled hypertension and moderately elevated LDL- mortality in patients with prior MI or unstable angina and mean
C. The results may be due to the modest differential in total cholesterol cholesterol level of 219 mg/dL.133 Pravastatin reduced the risk of CHD
(9.6%) and LDL-C (16.7%) between pravastatin and usual care com- mortality by 24% (8.3% vs 6.4%, P = 0.0004) and total mortality by
pared with prior statin trials supporting cardiovascular disease preven- 23% (14.1% vs 11.0%, P = 0.00002), reduced stroke by 20% (4.3% vs
tion.130 The long-awaited WHI trial proved to be disappointing, 3.5%, P = 0.22), and reduced the need for coronary artery bypass graft
showing no beneficial effects on CHD event reduction in the hormone surgery (11.3% vs 8.9%, P = 0.0001) and percutaneous transluminal
replacement arm (conjugated equine estrogens + medroxyprogester- coronary angioplasty (5.3% vs 4.4%, P = 0.04).
one) or the conjugated equine estrogens alone arm compared to The Veterans Administration High-Density Lipoprotein Intervention
placebo.107,109 Women did experience greater risk for thromboembo- trial (VA-HIT) was a double-blinded trial that compared gemfibrozil
lism, a slight increase in breast cancer, and a reduced risk of hip (1,200 mg/day) with placebo in 2,531 men with CHD, HDL-C level ≤40
fracture. Consequently, hormone replacement therapy can no longer mg/dL, and LDL-C level ≤140 mg/dL.134 The primary study outcome
be recommended for cardiovascular protection.4 In the WISDOM trial, was nonfatal MI or death from coronary causes. Median followup was
comparison of hormone therapy (n = 2,196) versus placebo (n = 2,189) 5.1 years. At 1 year, mean HDL-C level was 6% higher, mean triglycer-
revealed a significant increase in the number of major cardiovascular ide level was 31% lower, and mean total cholesterol level was 4% lower
events (7 vs 0, P = 0.016) and venous thromboembolism (22 vs 3, in the gemfibrozil group than in the placebo group. LDL-C levels did
 403
not differ significantly between groups. A primary event occurred in The enzyme ACAT esterifies cholesterol in a variety of tissues. In
21.7% of the patients assigned to placebo and in 17.3% of the patients some animal models, ACAT inhibitors have antiatherosclerotic

CHAPTER 23
assigned to gemfibrozil. The overall reduction in the risk of an event was effects. However, when tested in clinical trials, ACAT inhibition was
4.4 percentage points, and the reduction in relative risk was 22% (P = not an effective strategy for limiting atherosclerosis and may pro-
0.006). This trial presents the strongest evidence to date that raising mote atherogenesis.141
HDL-C and lowering triglycerides levels reduce risk for CHD. Statins differ in their pharmacokinetic properties and in pleiotro-
The Atorvastatin Versus Revascularization Treatment (AVERT) trial pic effects (i.e., nonlipid lowering). The contribution of lipid lower-
compared atorvastatin 80 mg/day with percutaneous transluminal ing alone (a class effect) versus other effects (antiinflammatory,
coronary angioplasty.135 The followup period was 18 months. Of the antithrombotic) is controversial.
patients who received aggressive lipid-lowering treatment with atorva- Proteinuria has been associated with high-dose rosuvastatin ther-

Hyperlipidemia
statin, 13% had ischemic events compared to 21% of patients who apy (40 mg/day), but a review of a clinical trial database revealed an
underwent angioplasty. Thus, the incidence of ischemic events was 36% increase in the estimated glomerular filtration rate for rosuvastatin-
lower in the atorvastatin group over an 18-month period (P = 0.048, treated patients that was consistent across all major demographic
which was not statistically significant after adjustment for interim and clinical subgroups of interest, including patients with baseline
analyses). This reduction in events was the result of a smaller number proteinuria, patients with baseline estimated glomerular filtration
of angioplasty procedures, coronary artery bypass operations, and rate <60 mL/min/1.73 m2, and patients with hypertension and/or
hospitalizations for worsening angina (the most common end point). diabetes.142
Compared to the patients who were treated with angioplasty and usual The role of nontraditional risk factors (high-sensitivity C-reactive
care, the patients who received atorvastatin had a significantly longer protein, homocysteine) is being studied and may lead to recom-
time to the first ischemic event (P = 0.03). In low-risk patients with mendations for the use of these tests in patient evaluation.
stable CAD, aggressive lipid-lowering therapy is at least as effective as
angioplasty and usual care in reducing the incidence of ischemic events.
The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) EVALUATION OF THERAPEUTIC OUTCOMES
investigates men and women in the age range from 70 to 82 years at
risk for cardiovascular disease and found that pravastatin 40 mg/day Short-term evaluation of therapy for hyperlipidemia is based on
reduced CHD events by 24%, with no effect on cognitive function.136 response to diet and drug treatment as measured in the clinical
The more recent Thrombolysis in Myocardial Infarction 22 laboratory by total cholesterol, LDL-C, HDL-C, and triglycerides
(TIMI-22) study (also known as PROVE-IT [Pravastatin or Atorva- for patients being treated for primary intervention, as well as on
statin Evaluation and Infection Therapy]), enrolled 4,162 patients response to secondary intervention. The followup interval is depen-
who had been hospitalized for an acute coronary syndrome within dent on the severity of illness, and patients with known CAD or
the preceding 10 days and compared pravastatin 40 mg/day (standard multiple risk factors should be monitored more closely. Less com-
therapy) with atorvastatin 80 mg/day (intensive therapy).137 An monly used laboratory measurements include C-reactive protein,
intensive lipid-lowering statin regimen with atorvastatin 80 mg/day homocysteine, apolipoprotein B, and lipoprotein(a) levels. Because
provided greater protection against death or major cardiovascular many patients being treated for primary hyperlipidemia have no
events than did a standard regimen. This study clearly points to symptoms and may not have any clinical manifestations of a genetic
“lower is better” for LDL concentration and likely will lead to revision lipid disorder such as xanthomas or eruptions, monitoring and
in guideline goals to lower LDL levels. The Treating to New Targets outcome are solely laboratory based. In patients treated for second-
(TNT) study assessed the efficacy and safety of lowering LDL-C levels ary intervention, symptoms of atherosclerotic cardiovascular dis-
to <100 mg/dL (2.6 mmol/L) in patients with stable CHD.138,139 ease (e.g., angina or intermittent claudication) may improve over
Intensive lipid-lowering therapy with atorvastatin 80 mg/day in months to years. In patients have xanthomas or other external
patients with stable CHD provided significant clinical benefit beyond manifestations of hyperlipidemia, the lesions should regress with
than treatment with atorvastatin 10 mg/day, providing additional therapy. Lipid measurements should be obtained in the fasted state
evidence that intensive lipid lowering brings greater benefits. to minimize interference from chylomicrons. Once the patient is
Statins reduce the incidence of strokes among patients at increased stable, monitoring is needed at intervals of 6 months to 1 year. The
risk for cardiovascular disease. Whether statins reduce the risk of goals for LDL-C and HDL-C are listed in Tables 23–8 and 23–9.
stroke after a recent stroke or transient ischemic attack (TIA) was Patients with multiple risk factors and established CHD should
addressed by Stroke Prevention by Aggressive Reduction in Choles- be monitored and evaluated for progress in managing their other
terol Levels (SPARCL). During a median followup of 4.9 years, 265 risk factors, such as hypertension, smoking cessation, exercise and
patients (11.2%) who received atorvastatin 80 mg/day and 311 weight control, and glycemic control if diabetic. The goals are to
patients (13.1%) who received placebo had a fatal or nonfatal stroke maintain blood pressure <130/80 mm Hg, especially for patients
(5-year absolute reduction in risk 2.2%, adjusted hazard ratio 0.84, with diabetes or renal insufficiency, stop smoking, maintain an ideal
95% confidence interval 0.71–0.99, P = 0.03; unadjusted P = 0.05).140 body weight, exercise for at least 20 minutes per day at least three
times per week, and keep plasma glucose concentration <100 mg/dL
(threshold for glucose intolerance). Invasive evaluation, such as
CLINICAL CONTROVERSIES cardiac catheterization, is useful in patients with established CHD
and typically is used for planning revascularization rather than
The CETP inhibitor torcetrapib was associated with a substantial monitoring of lipid-lowering therapy.
increase in HDL-C and decrease in LDL-C. It also was associated Evaluation of dietary therapy is part of the outcome evaluation
with an increase in blood pressure and no significant decrease in for treating hyperlipidemia, and the assistance of a dietitian is
the progression of coronary atherosclerosis. The lack of efficacy recommended. Use of diet diaries and recall survey instruments
may be related to the mechanism of action of this drug class or to enables systematic collection of information about diet and may
molecule-specific adverse effects. Other means of raising HDL-C improve patient adherence to dietary recommendations. Patients
(HDL mimetics, which include apolipoprotein A-I mutants and undergoing resin therapy should have a fasting lipoprotein profile
peptide mimetics of apolipoprotein A-I and HDL Milano A, a checked every 4 to 8 weeks until a stable dose is achieved; triglycer-
synthetic form of HDL) still hold hope of HDL modification ides should be checked at stable dose to ensure levels have not
leading to a reduction in clinical events. increased. Niacin requires baseline liver function tests, and uric acid
 404
and glucose concentrations; repeat tests are appropriate at doses of 18. Libby P, Aikawa M, Jain MK. Vascular endothelium and atherosclero-
1,000–1,500 mg/day. Myopathy or diabetes-like symptoms should sis. Handbook Exp Pharmacol 2006;176:285–306.
SECTION 2

be investigated and may require CK or glucose determinations; 19. Miller DT, Ridker PM, Libby P, Kwiatkowski DJ. Atherosclerosis: The path
more frequent monitoring in diabetics may be necessary. A fasting from genomics to therapeutics. J Am Coll Cardiol 2007;49:1589–1599.
20. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and
lipoprotein profile 4 to 8 weeks after the initial dose or after dose
outcomes after statin therapy. N Engl J Med 2005;352:20–28.
changes with statins is appropriate. Liver function tests should be 21. Kujiraoka T, Hattori H, Miwa Y, et al. Serum apolipoprotein j in
obtained at baseline and periodically thereafter based on package health, coronary heart disease and type 2 diabetes mellitus. J Athero-
insert information; recognized experts believe that monitoring for scler Thromb 2006;13:314–322.
hepatotoxicity and myopathy should be symptom triggered.56,61 22. Lavie L, Vishnevsky A, Lavie P. Evidence for lipid peroxidation in
Ezetimibe requires little specific monitoring. obstructive sleep apnea. Sleep 2004;27:123–128.
Cardiovascular Disorders

23. Huang CY, Wu TC, Lin WT, et al. Effects of simvastatin withdrawal on
serum matrix metalloproteinases in hypercholesterolaemic patients.
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CURVES Study). Am J Cardiol 1998;81:582–587. Disease Multiple Intervention Trial. JAMA 2000;284:1263–1270.
59. Robinson JG, Davidson MH. Combination therapy with ezetimibe and 83. McKenney JM, Sica D. Prescription omega-3 fatty acids for the treat-
simvastatin to achieve aggressive LDL reduction. Exp Rev Cardiovasc ment of hypertriglyceridemia. Am J Health Syst Pharm 2007;64:595–
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Lipid Association Statin Safety Assessment Task Force. Final conclu- lipid disorders. Arch Intern Med 2004;164:697–705.
sions and recommendations of the National Lipid Association Statin 86. Gadi R, Samaha FF. Dyslipidemia in type 2 diabetes mellitus. Curr
Safety Assessment Task Force. Am J Cardiol 2006;97:17. Diabetes Rep 2007;7:228–234.
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88. Garg A, Simha V. Update on dyslipidemia. J Clin Endocrinol Metab Women’s Health Initiative randomized controlled trial. JAMA
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89. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart 110. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of
disease with pravastatin in men with hypercholesterolemia. West of estrogen plus progestin on stroke in postmenopausal women: The
Scotland Coronary Prevention Study Group. N Engl J Med Women’s Health Initiative: A randomized trial. JAMA 2003;289:2673–
1995;333:1301–1307. 2684.
90. Downs JRMD, Clearfield MDO, Weis SDO, et al. Primary prevention 111. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities
of acute coronary events with lovastatin in men and women with recorded in the Women’s International Study of Long Duration
average cholesterol levels: Results of AFCAPS/TexCAPS. JAMA May Oestrogen after Menopause (WISDOM): A randomised controlled
1998;279:1615–1622. trial of hormone replacement therapy in postmenopausal women.
91. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on BMJ 2007;335:239.
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coronary events after myocardial infarction in patients with average 112. Clauss SB, Holmes KW, Hopkins P, et al. Efficacy and safety of
cholesterol levels. N Engl J Med 1996;335:1001–1009. lovastatin therapy in adolescent girls with heterozygous familial hyper-
92. Anonymous. Design and baseline results of the Scandinavian Simva- cholesterolemia. Pediatrics 2005;116:682–688.
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93. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention placebo-controlled trial with simvastatin. Circulation 2002;106:2231–
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domised placebo-controlled trial. Lancet 2004;364:685–696. density, intermediate density and low density lipoproteins in hypercho-
94. Collins R, Armitage J, Parish S, Sleight P, Peto R, Heart Protection lesterolemia and combined hyperlipidemia secondary to the nephrotic
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2004;363:757–767. 116. Kwan BC, Kronenberg F, Beddhu S, Cheung AK. Lipoprotein metab-
95. Anonymous. Effect of fenofibrate on progression of coronary-artery olism and lipid management in chronic kidney disease. J Am Soc
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Study, a randomised study. Lancet 2001;357:905–910. 117. Baber U, Toto RD, de Lemos JA. Statins and cardiovascular risk
96. Backes JM, Gibson CA, Ruisinger JF, Moriarty PM. Fibrates: What have reduction in patients with chronic kidney disease and end-stage renal
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97. Grundy SM, Vega GL, McGovern ME, et al. Efficacy, safety, and 118. Ozsoy RC, van Leuven SI, Kastelein JJ, Arisz L, Koopman MG. The
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98. Davidson MH, Kurlandsky SB, Kleinpell RM, Maki KC. Lipid manage- 120. Samuelsson O, Attman PO, Knight-Gibson C, et al. Effect of gemfibrozil
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C HAP T E R

24 Peripheral Arterial Disease

BARBARA J. HOEBEN AND ROBERT L. TALBERT

and PAD should be considered a surrogate marker of subclinical

KEY CONCEPTS coronary artery disease (CAD) and other vascular territories.1,4,5
Treatment of PAD focuses on decreasing the functional impairment
 The prevalence of peripheral arterial disease is dependent caused by symptoms of intermittent claudication through nonphar-
upon patient age and the presence of traditional risk factors for macologic and pharmacologic therapy and minimizing the impact
cardiovascular disease. Many patients are undiagnosed and are of other cardiovascular risk factors.6
at substantial risk for coronary and cerebrovascular events.
 The clinical presentation of peripheral arterial disease is variable
and includes a range of symptoms. The two most common
EPIDEMIOLOGY
characteristics of peripheral arterial disease are intermittent clau-
 Using the definition of an ankle–brachial index (ABI) <0.9 in
dication and pain at rest in the lower extremities.
either leg, the National Health and Nutrition Examination Survey
 The ankle–brachial index (ABI) is a simple, noninvasive, quan- (NHANES) found a 4.3% prevalence of PAD among adults age 40
titative test that has proved to be a highly sensitive and specific years and older in the United States.2 The prevalence of PAD is
tool in the diagnosis of peripheral arterial disease. highly dependent on patient age, being infrequent in younger indi-
viduals and common in older individuals (Fig. 24–1). In age- and
 As with any atherosclerotic condition, several risk factors play an gender-adjusted logistic regression analyses, black race/ethnicity
important role in the morbidity and mortality of peripheral vascular (odds ratio [OR] 2.83), current smoking (OR 4.46), diabetes (OR
disease. Many of these risk factors can be modified with the help 2.71), hypertension (OR 1.75), hypercholesterolemia (OR 1.68), and
of various nonpharmacologic and pharmacologic interventions. impaired renal function (estimated glomerular filtration rate <60
 Nonpharmacologic interventions, such as smoking cessation mL/min/1.73 m2; OR 2.00) were associated with more prevalent
and walking exercise programs, can positively impact several of PAD.2,7 Individuals with PAD are more likely to have a self-reported
the pathophysiologic abnormalities present in patients with pe- history of any CAD or CVD but, interestingly, no association with
ripheral arterial disease. elevated body mass index. The reported relative risk of death from
CVD in patients with PAD ranges from 2 to 5.1 in those with or
 Data proving that antiplatelet therapies can prevent or delay the without CVD and 2.9 to 5.7 in those with known CVD.8 CVD
progression of peripheral arterial disease are unavailable. How- accounts for 75% of all deaths in patients with PAD.9 The risk of
ever, aspirin therapy has repeatedly been proven to significantly death is approximately the same in men and women and is elevated
reduce serious vascular events in these “high-risk” patients and, even in asymptomatic patients. Annual mortality is 25% in patients
in the absence of contraindications, is highly recommended. with critical leg ischemia who have the lowest ABI values.10
 Patients who continue to experience severe intermittent clau- More than five million (estimated range four to seven million) adults
dication even after implementation of appropriate exercise age 40 years and older have PAD. Ninety-five percent of individuals
therapy and therapeutic lifestyle changes may benefit from ad- with PAD have at least one cardiovascular risk factor; the majority
ditional pharmacologic therapy with cilostazol. of patients have multiple risk factors for CVD.2 Based on the
PAD Awareness, Risk, and Treatment: New Resources for Survival

16
Peripheral arterial disease (PAD), the most common form of
peripheral vascular disease, is a manifestation of progressive nar- 14 Male

rowing of the arteries due to atherosclerosis.1 PAD is associated with 12 Female

elevated risk of morbidity and mortality from cardiovascular disease
Prevalence (%)

10
(CVD), even in the absence of a history of acute myocardial
8
infarction, stroke, or other manifestations of CVD.1–3 Patients with
PAD have approximately the same relative risk of death from CVD 6
as do patients with a history of coronary or cerebrovascular disease, 4
2
0
Learning objectives, review questions, 40–49 50–59 60–69 70 and older
and other resources can be found at Age group

www.pharmacotherapyonline.com. FIGURE 24-1. Prevalence of peripheral arterial disease by age and

gender.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 410
(PARTNERS) program, the prevalence of PAD seen in primary care TABLE 24-1 Clinical Presentation of Peripheral Arterial Disease
practices is high, yet physician awareness of the PAD diagnosis is
SECTION 2

General
relatively low.11 In this cross-sectional study, PAD was detected in 29%
• Patients with PAD are likely to be 40 years of age and older with hypertension,
of 6,979 patients. Eighty-three percent of the patients were aware of
hypercholesterolemia, diabetes, impaired renal function, a history of coronary
their diagnosis compared to only 49% of their physicians. The reason artery disease or cardiovascular disease, and/or a history of smoking.
for this observation is that patient self-report of symptoms and use of Signs and symptoms
questionnaires for detecting PAD are not sufficiently sensitive and • The clinical presentation of PAD is variable and includes symptoms ranging from
specific to reproducibly diagnosis PAD, and the cardinal symptom of no symptoms at all (typically early in the disease) to pain and discomfort.
PAD—intermittent claudication—is present in the minority of • The two most common characteristics of PAD are intermittent claudication and
patients (1%–27%).8,12,13 A simple ABI measurement will identify a pain at rest in the lower extremities.
Cardiovascular Disorders

large number of patients with previously unrecognized PAD. Athero- • Intermittent claudication is generally regarded as the primary indicator of PAD. It
sclerosis risk factors were highly prevalent in PAD patients, but these has been described as fatigue, discomfort, cramping, pain, or numbness in the
patients received less intensive treatment for lipid disorders and affected extremities (typically the buttock, thigh, or calf) during exercise and
resolves within a few minutes with rest.
hypertension and were prescribed antiplatelet therapy less frequently
• Physical examination may reveal nonspecific signs of decreased blood flow to the
than were patients with CVD. These results demonstrate that underdi-
extremities (e.g., cool skin temperature, shiny skin, thickened toenails, lack of hair
agnosis of PAD in primary care practice may be a barrier to effective on the calf, feet, and/or toes).
secondary prevention of the high ischemic cardiovascular risk associ- Laboratory tests
ated with PAD.11 Because of the systemic nature of atherosclerosis and • None specific to PAD.
the high risk of ischemic events, patients with PAD should be consid- Other diagnostic tests
ered for secondary prevention strategies, including aggressive modifi- • The ankle–brachial is a simple, noninvasive, quantitative test that has been proven
cation of risk factors and antiplatelet drug therapy.8,14–16 to be a highly sensitive and specific (≥90%) tool in the diagnosis of PAD.
PAD, peripheral arterial disease.
Data from references 2, 7, 12, 19–26, 28, 30, 31, and 78.
ETIOLOGY AND PATHOPHYSIOLOGY
PAD is most commonly a manifestation of systemic atherosclerosis in
As with any good medical encounter, obtaining a detailed patient
which the arterial lumen of the lower extremities becomes progres-
history of symptoms and atherosclerosis risk factors (e.g., smoking,
sively occluded by atherosclerotic plaque.9 The major risk factors for
hypertension, hyperlipidemia, and diabetes) can be helpful in making
development of atherosclerosis are older age (>40 years), cigarette
the diagnosis of PAD. Unfortunately, as illustrated by the PARTNERS
smoking, diabetes mellitus, hypercholesterolemia, hypertension, and
program, providers who rely on a history alone will miss approxi-
hyperhomocysteinemia.8,9,12 The arteries most commonly involved,
mately 85% to 90% of patients with PAD.23 Therefore, physical
in order of occurrence, are the femoropopliteal–tibial, aortoiliac,
examination of the patient is vital to proper diagnosis. Requesting
carotid and vertebral, splenic and renal, and brachiocephalic.17 Famil-
that the patient remove socks and shoes may reveal nonspecific signs
ial hypercholesterolemia leading to hypercholesterolemia and ele-
of decreased blood flow to the extremities (e.g., cool skin tempera-
vated low-density lipoprotein (LDL) levels is associated with
ture, shiny skin, thickened toenails, lack of hair on the calf, feet, and/
accelerated development of atherosclerosis earlier and with more
or toes) or, in severe cases, visible sores or ulcers that are slow to heal
severe symptoms (e.g., intermittent claudication) and abnormal
or even black in appearance.12,20–22,26–28
blood flow studies compared to controls.18 Intima–media thickness
An important criterion for accurate diagnosis of PAD is exclusion
can be used as a surrogate phenotype for cardiovascular risk in
of other conditions having similar signs and symptoms. Differential
familial hypercholesterolemia. Carotid and/or femoral artery athero-
diagnosis should rule out other neurologic conditions (e.g., periph-
sclerosis results in increased intima–media thickness and is correlated
eral neuropathy), musculoskeletal conditions (e.g., restless leg syn-
to cardiovascular risk in patients with familial hypercholesterolemia
drome or spinal stenosis), inflammatory conditions (e.g., arthritis),
compared with normolipidemic individuals.
and vascular conditions (e.g., deep-vein thrombosis or venous
congestion), which may mimic PAD.12,21,25,28,29
CLINICAL PRESENTATION AND DIAGNOSIS  The ABI is a simple, noninvasive, quantitative test that has
proved to be a highly sensitive and specific (≥90%) tool in the
 The clinical presentation of PAD is variable, ranging from no diagnosis of PAD.23,30,31 For measurement of the ABI, the patient lies
symptoms at all (typically early in the disease) to symptoms of pain in the supine position as systolic blood pressure is measured at the
and discomfort (Table 24–1). This finding was illustrated in a study brachial arteries on both arms and the dorsalis pedis and posterior
by Wang et al.,19 who attempted to aid the diagnosis of PAD by tibial arteries of the legs using a standard sphygmomanometer and a
using defined categories of exertional leg pain in patients with and continuous-wave Doppler device. The pressures obtained at the
without PAD. They determined that not one of the five categories of dorsalis pedis and posterior tibial arteries are averaged and divided by
leg pain (no pain, pain on exertion and rest, noncalf pain, atypical the mean measurement taken at the left and right brachial arter-
calf pain, and classic claudication) was sufficiently sensitive or ies.8,26,32,33 ABI = 1 is considered normal, whereas ABI <0.9 is
specific to enable a link to a PAD diagnosis. The two most common consistent with PAD. ABI from 0.7 to 0.9 correlates with mild PAD,
characteristics of PAD are intermittent claudication and pain at rest 0.4 to 0.7 indicates moderate disease, and <0.4 indicates severe
in the lower extremities.19–22 Intermittent claudication is generally PAD.9,24,32 In addition to providing diagnostic information, the ABI
regarded as the primary indicator of PAD. It is described as fatigue, measurement has been shown to be a strong predictor of future
discomfort, cramping, pain, or numbness that occurs in the affected cardiovascular events associated with PAD.34 The ABI can be useful
extremities (typically the buttock, thigh, or calf) during exercise and after an exercise tolerance test (e.g., 5 minutes on a treadmill or 30 to
resolves within a few minutes with rest.20,21,23–25 Resting pain typi- 50 repetitions of heel raises). Patients with PAD will demonstrate a
cally occurs later in the disease when the blood supply is not significant drop in ABI after exercise, but their pain will be normal or
adequate to perfuse the extremity (critical limb ischemia). This unchanged. ABI can rule out PAD and suggest alternate diag-
condition most often is felt at night in the feet (typically the toes or noses.9,12,24,26 Not only is ABI an effective diagnostic tool, but a
heel) while the patient is lying in bed.20–22 systematic review determined that ABI has high specificity for pre-
 411
dicting future cardiovascular outcomes (incident coronary heart American Heart Association Guidelines for the Management of PAD
diseases, incident stroke, and cardiovascular mortality).35 recommend supervised exercise training for patients with intermit-

CHAPTER 24
Other noninvasive tools are available for diagnosis of PAD. One tent claudication, for a minimum of 30–45 minutes, performed at
study has suggested a calculation that takes into consideration the least three times per week.38 A prospective, observational study has
patient’s history of acute myocardial infarction and the number of concluded that PAD patients with higher physical activity (as mea-
auscultated and palpated posterior tibial arteries.36,37 Magnetic res- sured with a vertical accelerometer) have reduced mortality and
onance angiography can be used to examine the presence and cardiovascular events compared to those with low physical activity,
location of significant stenosis, or lack thereof, and is a reasonable regardless of confounders.49 Exercise treadmill walking testing
option in patients who are being considered for surgical revascular- should be repeated at regular intervals (i.e., quarterly to biannually)
ization.38 Similarly, computed tomographic angiography can be to assess improvement or decline in walking duration and distance

Peripheral Arterial Disease

used to determine the presence of significant stenosis and soft-tissue as well as time to pain onset while performing this activity. The type
diagnostic information that may be associated with PAD (e.g., of aerobic activity recommended, as well as the duration and fre-
aneurysms).38 However, because ABI is a sufficient means of diag- quency of the activity, should be individually designed on a patient-
nosis, arteriography is not necessary or encouraged.20,25,31 to-patient basis.

TREATMENT Revascularization Therapy

Various surgical procedures are available for patients with severe,
Peripheral Arterial Disease debilitating claudication who have attempted, and failed, other means
of nonpharmacologic and pharmacologic therapy. The TransAtlantic
■ GOALS OF TREATMENT Inter-Society Consensus (TASC) document on PAD provides clear
recommendations for invasive therapy.27 First, the patient must have
PAD is caused by atherosclerotic plaque formation in the arteries that a lack of adequate response to exercise therapy and risk factor
results in decreased blood flow to the legs. Several of the treatment modification. Second, the patient must have severe disability from
goals for patients with PAD involve the reduction of confounding intermittent claudication resulting in impairment of daily activities.
variables that contribute to the disease process, progress, and eventual Third, a thorough evaluation of the risks versus benefits of an invasive
outcome. Specific goals should include increasing maximal walking intervention must be preformed, including probability of success,
distance, duration of walking, and amount of pain-free walking; and anticipated future course of the disease if intervention is not per-
improving control of comorbid conditions that contribute to mor- formed, and evaluation of concomitant disease states.27 Although the
bidity (e.g., hypertension, hyperlipidemia, and diabetes), resulting in TASC is clear that revascularization is mostly reserved for those who
improvement in overall quality of life and reduction in cardiovascular do not respond to conservative therapy consisting of risk factor
complications and death. modification, exercise, and pharmacologic therapy, revascularization
does have a role in patients with favorable anatomy, whose lifestyle
■ GENERAL APPROACH TO TREATMENT and/or job performance are compromised and who have a favorable
 As with any atherosclerotic condition, several risk factors play an risk-to-benefit ratio based on procedural risk.12 The decision to
important role in the morbidity and mortality of PAD. Many of attempt percutaneous revascularization often is made with the guid-
these risk factors can be modified with the help of various nonphar- ance of diagnostic angiography. Angiography can help to identify the
macologic and pharmacologic interventions. location and size of lesions and provide valuable information regard-
ing the likelihood of success with surgical revascularization.27
■ NONPHARMACOLOGIC THERAPY Percutaneous transluminal angioplasty (PTA) is an example of an
invasive treatment of PAD. A randomized controlled clinical trial by
Smoking Cessation Whyman et al.50 determined that in a 2-year postintervention, PTA
outcomes on maximum walking distance and ABI were not signifi-
 Cigarette smoking not only increases the risk of developing PAD
cantly different than outcomes in patients who had received only daily
and other cardiovascular disorders, but the duration and quantity
low-dose ASA (P >0.05). Nevertheless, patients who had received PTA
smoked can negatively impact disease progression (i.e., increase the
had significantly fewer occluded arteries (P = 0.003), but the true
risk of amputation) and increase mortality.8,29,34,39–43 As a result,
clinical significance of this finding was not realized in the time allotted
providers must advise patients to quit and should offer nonpharma-
for the study. PTA typically is reserved for patients whose lifestyle and/
cologic and pharmacologic means to aid patients in that goal. Numer-
or job performance are compromised secondary to claudication
ous studies have proved the effectiveness of individual or group
despite adequate pharmacologic interventions and exercise.12,38
behavior modification therapy with or without the addition of certain
Stent placement in PAD patients has been an area of study and
antidepressants (e.g., bupropion) or nicotine replacement therapies
controversy. A meta-analysis examining the use of stent placement
(e.g., gum or patches). Reassessment of smoking status and progress
versus PTA for treatment of aortoiliac occlusive disease determined
encouragement at each visit can help reemphasize to the patient the
that although stent placement and PTA yielded similar complication
vital importance of this lifestyle change.
and mortality rates, posttreatment ABI was more improved with
stents (0.87 with PTA and 0.76 with stents, P <0.03) and the risk of
Exercise long-term failure was 39% less with stent placement.51 However,
 Walking exercise programs for patients with PAD have been proven other studies have not demonstrated improvement in patency rates in
to result in increased walking duration and distance, increased pain- peripheral arteries versus PTA alone.20 The TASC document provides
free walking, and delayed onset of claudication by 179%.14,27,29,40,41,44–48 specific recommendations for PTA, with or without stenting, depend-
Walking, or any aerobic exercise program conducted under the ing on the how diffuse the disease process is, the number and size of
supervision of a healthcare provider, can positively impact several of the lesions, and the location of the lesions.27
the pathophysiologic abnormalities present in patients with PAD. For patients with severe intermittent claudication resulting in critical
Benefits of exercise programs include improving diabetes and lipid leg ischemia, physicians may need to discuss alternate surgical interven-
management, reducing weight, improving blood viscosity and flow, tions, including aortofemoral bypass, femoropopliteal bypass, or even
and reducing blood pressure.6 The American College of Cardiology/ amputation.20,21,40
 412

■ PHARMACOLOGIC THERAPY increasing risk of death from cardiovascular events as blood glucose
concentrations increased, with the same relationship observed even at
Hypertension
SECTION 2

levels below the threshold of clinically defined diabetes mellitus. This

Hypertension is a major risk factor for PAD and can lead to acute relationship is just one illustration of the criticality of good glycemic
myocardial infarction, stroke, heart failure, and death.14 Current control. Due to the high prevalence of PAD among diabetic patients,
guidelines recommend that the treatment goal for blood pressure in the American Diabetes Association recommends ABI screening for
patients with PAD mirror those in patients with documented CVD: PAD in all diabetics older than 50 years.59 Because of the presence of
130/85 mm Hg.14,39 Although, the Heart Outcomes Prevention Eval- peripheral neuropathy, patients with diabetes may be less likely to
uation (HOPE) study demonstrated that angiotensin-converting experience or report symptoms of PAD, and the first sign may be as
enzyme inhibitors reduced not only blood pressure but other drastic as the appearance of a gangrenous foot ulcer. Therefore,
Cardiovascular Disorders

cardiovascular events (e.g., acute myocardial infarction, stroke, and although a lack of randomized controlled studies illustrates that the
death) in high-risk patients, including those with PAD, no specific degree of glycemic control is predictive of the extent of PAD present,
class of antihypertensives is recommended over another for treat- it is widely recommended that all patients with concomitant diabetes
ment of hypertension in patients with PAD. Therefore, selection of and PAD maintain good glycemic control, as evidenced by a hemo-
drug therapy for hypertension should be made on the basis of globin A1c level <7%.8,27,29,39,41,59,60 This recommendation is sup-
comorbid disease states, drug costs and availability, drug allergies, ported by a prospective cohort study of 1,894 diabetic patients. The
or other possible limiting factors. For example, patients with docu- study demonstrated that patients with poor glucose control (hemo-
mented CAD may receive a dual benefit by the selection of a β- globin A1c >7.5%) were five times more likely to develop intermittent
blocker, whereas patients with concomitant Raynaud phenomenon claudication and to be hospitalized for PAD compared to patients
may benefit from calcium channel blockers.14,39,52 Dosing, monitor- with hemoglobin A1c <6%.61 Despite this finding, a study by Rehring
ing guidelines, and contraindications for specific agents are dis- et al.62 of 365 patients with known PAD and concomitant diabetes
cussed in Chapter 15. showed that only 45.8% of these patients had hemoglobin A1c <7%.
Oral antidiabetic agents, insulin regimens, and other pharmacologic
Hyperlipidemia and nonpharmacologic strategies for reducing the risk of complica-
tions associated with diabetes mellitus are discussed at length in
Although a reduction in lipid levels can reduce the progression of Chapter 77.
PAD and the severity of claudication, the current recommendations
for management of hyperlipidemia in patients with PAD are based on
only a few small studies and sub hoc analyses from larger trials.8,39,53,54 ■ ANTIPLATELET DRUG
The Expert Panel on Detection, Evaluation, and Treatment of High THERAPY (TABLE 24–2)
Blood Cholesterol in Adults (Adult Treatment Panel III) considers
PAD to be in the category of highest risk, or a coronary heart disease
Aspirin
risk equivalent. Therefore, the Expert Panel recommends that LDL  By far, the most compelling evidence for the use of any pharmaco-
levels be maintained at <100 mg/dL and non–high-density lipopro- logic agent in patients with PAD can be found for aspirin (acetylsali-
tein (HDL) levels (total cholesterol – HDL cholesterol) maintained at cylic acid [ASA]). The Antithrombotic Trialists’ Collaboration (ATC)
<130 mg/dL.53 Results of clinical trials conducted since issuance of the conducted a meta-analysis of 195 randomized trials, composed of
Expert Panel recommendation, specifically the Heart Protection more than 135,000 patients at high risk for occlusive arterial disease.
Study (HPS)55 and the Pravastatin or Atorvastatin Evaluation and The ATC concluded that low-dose ASA (75–160 mg) and medium-
Infection—Thrombolysis in Myocardial Infarction (PROVE IT)56 dose ASA (160–325 mg/day) led to a significant reduction in serious
trial, have led many clinical experts to now recommend an LDL goal vascular events (12%) in “high-risk” patients, such as those with
of <70 mg/dL for additional retardation of atherosclerotic plaque PAD.63 The ATC also noted in this analysis that the risk of major
formation in persons considered to be at very high risk, including extracranial bleed was similar between low-dose and medium-dose
patients with PAD.20 Regardless of the goal LDL level chosen, initia- regimens.
tion of patient therapeutic lifestyle changes (e.g., reduction in con- Tran and Anand64 conducted a systematic review of the literature
sumption of saturated fat, weight reduction, and increased physical in an effort to summarize the best evidence for oral antiplatelet
activity) is vital to achieving these recommendations.16,53 Unfortu- therapy in patients with cerebrovascular disease, CAD, and PAD. This
nately, in many cases, therapeutic lifestyle changes alone will not review included 111 trials (42 of which included patients with PAD,
achieve the desired goals. n = 9,214) and concluded that patients with PAD should use ASA
Several options are available for initiating drug therapy to lower (160–325 mg/day) or clopidogrel (75 mg/day) when ASA is not
LDL levels in patients with PAD. Statins, bile acid sequestrants, and tolerated or contraindicated.64,65 This is in concordance with the
nicotinic acid all are effective treatment options. However, statins are recommendations of the Seventh American College of Chest Physi-
the preferred starting agent in this patient population.23,40,53,55 As cians (ACCP) Conference on Antithrombotic and Thrombolytic
proven in the HPS, simvastatin demonstrated potent action in Therapy, which recommends lifelong ASA (75–325 mg/day) over
reducing LDL and also provided a significant reduction in cardiovas- clopidogrel, ticlopidine, and no antithrombotic therapy in patients
cular events overall (e.g., acute myocardial infarction, stroke, and with PAD.66 Unfortunately, no data from large clinical randomized
death).55 If an increase in HDL levels also is necessary, niacin should trials have yet shown that ASA, or any other antiplatelet therapy,
be considered alone or in combination with a statin without the fear actually can prevent or delay the progression of PAD.66
of worsening glucose metabolism, as previously believed.8,21,29,52,57
Dosing, monitoring guidelines, and contraindications for specific ASA + Dipyridamole
agents are discussed in Chapter 23. Extended-Release (Aggrenox)
The ATC also examined the use of dipyridamole extended-release
Diabetes Mellitus (Aggrenox) in combination with ASA in “high-risk” patients, such as
A meta-analysis of more than 95,000 diabetic patients provided those with PAD. The meta-analysis of 25 trials (which included more
additional support for the accepted premise that glycemic control than 10,000 patients) concluded that the addition of dipyridamole to
serves as a risk factor for CVD.58 The analysis demonstrated an aspirin led to a further reduction in serious vascular events over ASA
 413

TABLE 24-2 Pharmacotherapy Options for Patients with Peripheral Arterial Disease

CHAPTER 24
Daily Dose
Agent (Oral) Mechanism of Action Side Effects Contraindications Level of Evidenceb
Aspirin 81–325 mg Irreversibly inhibits prostaglandin Gastrointestinal upset Active bleeding; hemo- With coronary or cere-
cyclooxygenase in platelets, prevents and/or bleeding philia; thrombocytope- brovascular (grade 1A),
formation of thromboxane A 2 nia without (grade 1C+)
Dipyridamole 400 mg (+ aspirin May act by inhibiting platelet aggrega- Angina, dyspnea, Active bleeding; coronary Recommendation for use
extended-release 50 mg) tion (complete mechanism of action hypotension, headache, artery disease (“coro- not specified in report
(Aggrenox) unknown) dizziness nary steal syndrome”)
Cilostazol (Pletal)a 100 mg bid Phosphodiesterase inhibitor, sup- Fever from infection, All congestive heart fail- With intermittent claudi-

Peripheral Arterial Disease

presses platelet aggregation; direct tachycardia ure patients (decreased cation (grade 2A)
artery vasodilator survival)
Clopidogrel (Plavix) 75 mg Inhibits binding of ADP analogues to its Chest pain, purpura gen- Active pathologic bleed- Recommend clopidogrel
platelet receptor, causing irreversible eralized pain, rash ing (e.g., peptic ulcer, over no antiplatelet
inhibition of platelets intracranial hemor- therapy (grade 1C+)
rhage)
Pentoxifylline (Trental) 1.2 g Alters red blood cell flexibility; decreases Dyspnea, nausea, vomit- Recent retinal or cerebral Not recommended in
platelet adhesion; reduces blood vis- ing, headache, dizziness hemorrhage; active patients with intermittent
cosity; decreases fibrinogen concen- bleeding claudication (grade 1B)
tration
Ticlopidine (Ticlid) 500 mg Inhibits binding of ADP analogues to its Leukopenia; rash; throm- Active bleeding, hemo- Clopidogrel recom-
platelet receptor, causing irreversible bocytopenia; neutrope- philia; thrombocytopenia mended over ticlopi-
inhibition of platelets nia, agranulocytosis; dine (grade 1C+)
aplastic anemia
a
Cilostazol should be used in combination with antiplatelet therapy.
b
Grades of recommendation for antithrombotic and thrombolytic therapy are part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Data from references 5, 22, 29, 30, 63, 65, 66, and 79–83.

alone (6%); however, this reduction did not reach statistical signifi- However, the once promising results seen with ticlopidine therapy
cance (P = 0.32).63,64 Also to be taken into consideration is that most now have been overshadowed by the severe hematologic side effects
of the reduction in nonfatal stroke in this analysis came from one unique to this agent. Ticlopidine has a black box warning from the
trial, and these data have not been replicated in other studies.63,65,67 Food and Drug Administration (FDA) warning providers that use of
The addition of dipyridamole to ASA may cause an increased risk of this agent can cause neutropenia/agranulocytosis, thrombotic throm-
bleeding and gastrointestinal side effects compared to placebo, so the bocytopenic purpura, and aplastic anemia.70 Other agents, namely
combination should not be used in patients with CAD.67 clopidogrel, are now used instead of ticlopidine.8,29,41

Clopidogrel (Plavix) ■ INTERMITTENT CLAUDICATION

The ATC meta-analysis also reviewed the effectiveness of clopidogrel (TABLE 24–2)
75 mg/day in “high-risk” patients, including those with PAD. The
ATC concluded that although clopidogrel was able to reduce serious Cilostazol (Pletal)
vascular events by 10%, this was significantly less than the reduction  In a head-to-head, randomized, placebo-controlled study of 698
seen with ASA (12%, P = 0.03) described previously.63 Included in the patients with moderate-to-severe claudication, Dawson et al.71
meta-analysis was the report from the Clopidogrel versus ASA in assigned patients to cilostazol (100 mg twice daily), pentoxifylline
Patients at Risk of Ischemic Events (CAPRIE) trial, which concluded (400 mg three times daily), or placebo in an effort to improve
that clopidogrel 75 mg/day was more effective than ASA 325 mg/day maximal walking distance. After 24 weeks, the cilostazol group
in preventing vascular events in “high-risk” patients. In comparison to demonstrated a 54% mean increase in distance versus pentoxifylline,
ASA therapy, the clopidogrel regimen resulted in an overall reduction which demonstrated only a 30% mean increase (P <0.001).71 Simi-
in ischemic stroke, myocardial infarction, or vascular death from larly, a meta-analysis of eight randomized, double-blind, placebo-
5.83% to 5.32% (P = 0.043). This difference was even more pro- controlled, parallel-design trials supported this conclusion, with a
nounced in the subgroup analysis of PAD patients, in which clopido- reported increase in maximal walking distance and pain-free walking
grel therapy led to a significant reduction of 4.86% versus 3.71% in the distance with cilostazol at doses of 50 mg and 100 mg twice daily (P
ASA group (P = 0.0028).5,30,34 It must be noted that clopidogrel is <0.05 for all) over placebo.72 Regrettably, improvement in walking
significantly more expensive than ASA therapy, not only in terms of distance has appeared to come with a price (in addition to the high
drug costs but also in cost of physician visits because clopidogrel is a drug cost); cilostazol has a black box warning from the FDA warning
prescription-only medication. For all these reasons, the current rec- providers not to use this medication in patients with PAD and
ommendations list clopidogrel as a first-line agent, but only in cases coexisting heart failure.39 However, the Seventh ACCP Conference on
where ASA therapy is either not tolerated or contraindicated.63,65 Antithrombotic and Thrombolytic Therapy does suggest the use of
this agent in patients with PAD who are not candidates for surgical
Ticlopidine (Ticlid) interventions to improve severe intermittent claudication that persists
even after implementation of appropriate exercise therapy and thera-
Although ticlopidine has the same mechanism of action as clopidogrel
peutic lifestyle changes.66
and possesses a similar molecular structure, the results of clinical trials
investigating the two agents are strikingly different.22 The Swedish
Ticlopidine Multicenter Study (STIMS) had determined that ticlopi- Pentoxifylline (Trental)
dine therapy (500 mg/day) reduced total mortality in patients with Unlike cilostazol, pentoxifylline has produced less promising results
intermittent claudication in comparison to placebo (P = 0.015).22,68,69 in clinical trials, as illustrated by the randomized, placebo-controlled
 414
trial by Dawson et al.71 Not only did cilostazol outperform pentoxifyl- 4. Newman AB, Shemanski L, Manolio TA, et al. Ankle-arm index as a
line with regard to improvement in walking distance, but the predictor of cardiovascular disease and mortality in the Cardiovascular
SECTION 2

improvement seen with pentoxifylline was no different from placebo Health Study. The Cardiovascular Health Study Group. Arterioscler
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5. CAPRIE Steering Committee. A randomised, blinded, trial of clopido-
has been observed in other studies as well.8,73 Meanwhile, other meta-
grel versus aspirin in patients at risk of ischaemic events (CAPRIE).
analyses of pentoxifylline in comparison to placebo for improvement CAPRIE Steering Committee. Lancet 1996;348:1329–1339.
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placebo, but the average effects were relatively small.8,74–77 For these for claudication. N Engl J Med 2002;347:1941–1951.
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Thrombolytic Therapy does not recommend the use of this agent.66 peripheral arterial disease in persons with renal insufficiency: Results
Cardiovascular Disorders

from the National Health and Nutrition Examination Survey 1999–

2000. Circulation 2004;109:320–323.
EVALUATION OF THERAPEUTIC OUTCOMES 8. Hiatt WR. Medical treatment of peripheral arterial disease and claudi-
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It is vital that the physician counsel the patient on the evaluation 9. Mohler ER 3rd. Peripheral arterial disease. Identification and implica-
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15. National Cholesterol Education Program Expert Panel on Detection
their daily quality of life will highlight the physician’s concern for
Evaluation and Treatment of High Blood Cholesterol in Adults. Third
their well-being and aid in the patient’s overall general state of health.
Report of the National Cholesterol Education Program (NCEP) Expert
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46. Langbein WE, Collins EG, Orebaugh C, et al. Increasing exercise 69. Janzon L, Bergqvist D, Boberg J, et al. Prevention of myocardial
tolerance of persons limited by claudication pain using polestriding. J infarction and stroke in patients with intermittent claudication; effects
Vasc Surg 2002;35:887–893. of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicen-
47. Falcone RA, Hirsch AT, Regensteiner JG, et al. Peripheral arterial disease tre Study. [published erratum appears in J Intern Med 1990;228:659].
rehabilitation: A review. J Cardiopulm Rehabil 2003;23:170–175. J Intern Med 1990;227:301–308.
48. Tan KH, De Cossart L, Edwards PR. Exercise training and peripheral 70. Ticlid (ticlopidine hydrochloride) tablets. Roche Laboratories, Nutley,
vascular disease. Br J Surg 2000;87:553–562. NJ, March 2001.
 416
71. Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and 78. Mannava K, Money SR. Current management of peripheral arterial
pentoxifylline for treating intermittent claudication. Am J Med occlusive disease: A review of pharmacologic agents and other inter-
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2000;109:523–530. ventions. Am J Cardio Drugs 2007;7(1);59–66.

72. Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results 79. Plavix package insert. Bristol-Myers Squibb/Sanofi Pharmaceuticals
from eight randomized, placebo-controlled trials on the effect of Partnership, New York, NY, February 2006.
cilostazol on patients with intermittent claudication. Am J Cardiol 80. “S” Monographs; Salicylates (Systemic); Aspirin. In: Group UDE, ed.
2002;90:1314–1319. USP DI® Drug Information for the Health Care Professional, 26th ed.
73. Lindgarde F, Jelnes R, Bjorkman H, et al. Conservative drug treatment Taunton, MA: Micromedex, 2006.
in patients with moderately severe chronic occlusive peripheral arte- 81. “D” Monographs; Dipyridamole (Systemic). In: Group UDE, ed. USP
rial disease. Scandinavian Study Group. Circulation 1989;80:1549– DI® Drug Information for the Health Care Professional, 26th ed.
1556. Taunton, MA: Micromedex, 2006.
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74. Girolami B, Bernardi E, Prins MH, et al. Treatment of intermittent 82. “P” Monographs; Pentoxifylline (Systemic). In: Group UDE, ed. USP
claudication with physical training, smoking cessation, pentoxifylline, DI® Drug Information for the Health Care Professional, 26th ed.
or nafronyl: A meta-analysis. Arch Intern Med 1999;159:337–345. Taunton, MA: Micromedex, 2006.
75. Radack K, Wyderski RJ. Conservative management of intermittent 83. “C” Monographs; Cilostazol (Systemic). In: Group UDE, ed. USP DI®
claudication. Ann Intern Med 1990;113:135–146. Drug Information for the Health Care Professional, 26th ed. Taunton,
76. Ernst E. Pentoxifylline for intermittent claudication. A critical review. MA: Micromedex, 2006.
Angiology 1994;45:339–345. 84. Guyatt G, Schunemann HJ, Cook D, Jaeschke R, Pauker S. Applying
77. Hood SC, Moher D, Barber GG. Management of intermittent claudi- the grades of recommendation for antithrombotic and thrombolytic
cation with pentoxifylline: Meta-analysis of randomized controlled therapy: The Seventh ACCP Conference on Antithrombotic and
trials. CMAJ 1996;155:1053–1059. Thrombolytic Therapy. Chest 2004;126(3 Suppl):179S–187S.
 417

C HAP T E R

25 Use of Vasopressors and Inotropes

in the Pharmacotherapy of Shock

ROBERT MACLAREN, MARIA I. RUDIS, AND JOSEPH F. DASTA

observing for and minimizing evidence of myocardial ischemia

KEY CONCEPTS (e.g., tachydysrhythmias, electrocardiographic changes), renal
(decreased glomerular filtration rate and/or urine production),
 Continuous hemodynamic monitoring with an arterial catheter splanchnic/gastric [low intramucosal pH, bowel ischemia], or
or a central venous catheter capable of measuring mixed venous peripheral (cold extremities) hypoperfusion, and worsening of
oxygen saturation (SvO2) or central venous oxygen saturation partial pressure of arterial oxygen (PaO2), pulmonary artery oc-
(ScvO2) should be used early and throughout the course of sep- clusive pressure, and other hemodynamic variables.
tic shock to assess intravascular fluid status and ventricular filling
pressures, determine cardiac output (CO), and monitor arterial First-line therapy of septic shock is aggressive volume resuscita-
and venous oxygenation. They can be used for monitoring the tion with crystalloid or colloid types of fluids. Dopamine or nor-
response to drug therapy and guiding dosage titration. epinephrine typically is used as the initial vasopressor agent for
hemodynamic support. Dopamine is limited by its ability to in-
 Early goal-directed therapy with aggressive fluid resuscitation in crease CO and complications of tachycardia, tachydysrhythmias,
the emergency department within the first 6 hours of presenta- increase in pulmonary artery occlusive pressure, and decrease
tion improves survival of patients with sepsis and septic shock. in splanchnic oxygen use. Low-dose dopamine should not be
 Derangements in adrenergic receptor sensitivity or activity fre- used to prevent renal failure. Norepinephrine may achieve
quently result in resistance to catecholamine vasopressor and in- greater hemodynamic response than dopamine and is less like-
otropic therapy in critically ill patients. These changes may be a ly to cause tachydysrhythmias and a decrease in splanchnic ox-
function of endogenous catecholamine concentrations, dosage/ ygen utilization.
duration of exposure to and type of exogenously administered
Phenylephrine may be a particularly useful alternative in patients
vasopressors, stage of septic shock, preexisting illness, and other who cannot tolerate tachycardia or tachydysrhythmia with dopa-
factors. mine or norepinephrine or in patients with known underlying
 In refractory septic shock, rational use of vasopressor or inotro- myocardial dysfunction.
pic agents should be guided by receptor activity, pharmacologic  Epinephrine appears to be effective as a single agent and as an
and pharmacokinetic characteristics, and regional and systemic add-on agent. It is particularly useful in the young, in patients
hemodynamic effects of the drug and should be tailored to the with otherwise healthy myocardium, and potentially in patients
patient’s physiologic needs. Pharmacologically sound combina- when used early in the course of treatment. However, because
tions of vasopressor and/or inotrope agents should be initiated epinephrine causes a significant, yet transient, increase in lactate
early to optimize and facilitate rapid response. and worsening of splanchnic oxygen utilization, it is not the agent
 Goals of therapy with vasopressors and inotropes should be of first choice in patients with septic shock. It should be used
predetermined and should optimize regional perfusion to tis- cautiously in patients with a history of coronary artery disease or
sues (e.g., cardiac, renal, mesenteric, and periphery). This can underlying cardiac disturbances.
be accomplished by continuous or intermittent measurements.  Therapy with vasopressors and inotropes is continued until the
SvO2/ScvO2 >70% should be maintained. Arbitrarily targeting myocardial depression and vascular hyporesponsiveness of sep-
vasopressor and inotrope therapy to supranormal values of glo- tic shock improve, usually measured in hours to days. Discontin-
bal oxygen-transport variables cannot be recommended be- uation of vasopressor or inotropic therapy should be executed
cause of lack of clear benefit and possible increased morbidity. slowly; therapy should be “weaned” to avoid a precipitous wors-
 Much higher dosages of all vasopressors and inotropes than tra- ening in regional and systemic hemodynamics.
ditionally recommended are required to improve hemodynamic Vasopressin produces vasoconstriction independent of adren-
and oxygen-transport variables in patients with septic shock. ergic receptors and reduces the doses of catecholamine vaso-
 Dose titration and monitoring of vasopressor and inotropic pressors. Replacement doses of vasopressin (0.01–0.04
therapy should be guided by the “best clinical response” while units/min) can be considered in patients with septic shock re-
fractory to catecholamine vasopressors despite adequate fluid
resuscitation. Vasopressin may enhance urine production. Giv-
en the current data, corticosteroids can be administered to pa-
Learning objectives, review questions, tients with septic shock when adrenal insufficiency is present
and other resources can be found at or when vasopressors have been administered for prolonged
www.pharmacotherapyonline.com. periods without evidence of dose reduction.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 418

TABLE 25-1 Hemodynamic and Oxygen-Transport Shock is an acute, generalized state of inadequate perfusion of critical
Monitoring Parameters organs that can produce serious pathophysiologic consequences,
SECTION 2

Parameter Normal Valuea

including death, when therapy is not optimal. Shock is defined as
systolic blood pressure <90 mm Hg or reduction of at least 40 mm
Blood pressure (systolic/diastolic) 100–130/70–85 mm Hg Hg from baseline with perfusion abnormalities despite adequate
Mean arterial pressure (MAP) 80–100 mm Hg
fluid resuscitation.1 At one time, mortality from septic or cardiogenic
Pulmonary artery pressure (PAP) 25/10 mm Hg
shock exceeded 70%.1 Currently, 10% to 30% of patients with severe
Mean pulmonary artery pressure (MPAP) 12–15 mm Hg
Central venous pressure (CVP) 8–12 mm Hg sepsis are admitted to hospitals, and 8.6% of patients experience
Pulmonary artery occlusive pressure 12–15 mm Hg cardiogenic shock following an acute ST-segment elevation myocar-
(PAOP) dial infarction.1–3 Mortality rates for shock of either cause are at least
Cardiovascular Disorders

Heart rate (HR) 60–80 beats/min 30% to 50% despite enhanced treatment modalities and sophisti-
Cardiac output (CO) 4–7 L/min cated monitoring techniques.1–3 This chapter reviews the theory and
Cardiac index (CI) 2.8–3.6 L/min/m2 current status of hemodynamic monitoring and presents an update
Stroke volume index (SVI) 30–50 mL/m2 on the optimal use of inotropes and vasopressor drugs in shock
Systemic vascular resistance index (SVRI) 1,300–2,100 dyne • s/m2 • cm5 states, specifically septic shock.3–10
Pulmonary vascular resistance index 45–225 dyne • s/m2 • cm5 Hemodynamic and perfusion monitoring can be categorized into
(PVRI)
two broad areas: global and regional monitoring. Global parameters,
Arterial oxygen saturation (SaO2) 97% (range 95%–100%)
such as systemic blood pressure and pulse oximetry, assess perfusion
Mixed venous oxygen saturation (SvO2) 70%–75%
Arterial oxygen content (CaO2) 20.1 vol% (range 19–21) and oxygen utilization of the entire body. Regional monitoring
Venous oxygen content (CvO2) 15.5 vol% (range 11.5–16.5) techniques, such as tonometry, focus on oxygen flow and subsequent
Oxygen content difference (C[a–v]O2) 5 vol% (range 4–6) changes in metabolism of individual organs and tissues. Normal
Oxygen consumption index (VO2) 131 mL/min/m2 (range 100–180) values for commonly monitored parameters are listed in Table 25–1.
Oxygen delivery index (DO2) 578 mL/min/m2 (range 370–730) Evidence-based goals of therapy are listed in Table 25–2.3–10 The
Oxygen extraction ratio (O2ER) 25% (range 22–30) adequacy of regional perfusion can be assessed by indices of specific
Intramucosal pH (pHi) 7.40 (range 7.35–7.45) organ perfusion, although none of these indices alone is a reliable
Index (I) Parameter indexed to body surface indicator of adequate resuscitation. These measurements include
area coagulation abnormalities (disseminated intravascular coagulation),
a
Normal values may not be the same as values needed to optimize the management of a critically ill altered renal function with reduced urine production or increased
patient. serum concentrations of blood urea nitrogen and creatinine, altered

TABLE 25-2 Evidence-Based Treatment Recommendations for Management of Severe Sepsis or Septic Shock
Recommendations Grade
An arterial catheter should be placed as soon as practical to monitor blood pressure in all patients with septic shock requiring vasopressors. E
Resuscitation of tissue hypoperfusion from severe sepsis or septic shock should begin as soon as the syndrome is recognized. An elevated serum lactate concentration B
identifies tissue hypoperfusion in patients at risk who are not hypotensive. During the first 6 hours of resuscitation, goals should include all of the following: (1) CVP
8–12 mm Hg, (2) MAP ≥65 mm Hg, (3) urine production ≥0.5 mL/kg/h, and (4) SvO2 or ScvO2 ≥70%.
Fluid resuscitation should be the initial step in hemodynamic support of septic shock. B
Fluid resuscitation may consist of natural or artificial colloids or crystalloids. No evidence supports one type of fluid over another. C
Fluid challenge in patients with suspected hypovolemia or inadequate arterial circulation can be administered at a rate of 500–1,000 mL of crystalloid or 300–500 mL E
of colloid over 30 minutes and repeated based upon response (blood pressure and/or urine production) and tolerance (intravascular volume overload).
When an appropriate fluid challenge fails to restore adequate blood pressure and organ perfusion, vasopressor therapy should begin. Vasopressor therapy also E
may be required transiently to sustain life and maintain perfusion in the face of life-threatening hypotension, even when a fluid challenge is in progress and
when hypovolemia has not yet been corrected.
Either dopamine or norepinephrine is effective for increasing arterial blood pressure, and either can be used as a first-line vasopressor agent to correct hypotension C
in septic shock. Dopamine raises CO more than norepinephrine, but its use may be limited by tachycardia. Norepinephrine may be the more effective vasopressor.
The combination of norepinephrine and dobutamine is superior to dopamine in the treatment of septic shock. D
Phenylephrine is an alternative for increasing blood pressure, especially in the setting of tachyarrhythmias. D
Epinephrine can be considered for refractory hypotension, but adverse effects, including decreased mesenteric perfusion, are common. D
Low-dose dopamine should not be used for renal protection or to maintain renal function during sepsis. B
Vasopressin can be considered in patients with refractory shock despite adequate fluid resuscitation and administration of high-dose catecholamine vasopressor. C
It should be administered as hormone replacement at doses of 0.01–0.04 units/min.
A strategy of increasing cardiac index to achieve supranormal DO2 is not recommended. A
Dobutamine can be used to increase CO in the presence of low cardiac index or low SvO2 or ScvO2 despite adequate fluid administration. If used in the presence C
of low blood pressure, it should be combined with vasopressor therapy. Dobutamine may cause tachycardia.
Intravenous corticosteroid therapy at hormone replacement doses (200–300 mg/d of hydrocortisone or equivalent corticosteroid dose) for 7 days can be used C
in septic shock when hypotension is present despite adequate fluid resuscitation and vasopressor therapy.
Daily corticosteroid doses >300 mg/d of hydrocortisone (or equivalent corticosteroid dose) should not be used for treating septic shock. A
ACTH–250 mcg stimulation test should be used to identify adrenal insufficiency (≤9 mcg/dL increase in cortisol concentration 30–60 minutes after ACTH). E
Corticosteroid therapy should be initiated before stimulation test results are known. Corticosteroid therapy should be discontinued when adrenal insufficiency
is absent (>9 mcg/dL increase in cortisol concentration 30–60 minutes after ACTH).
Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as significant coronary artery disease or acute hemorrhage, red B
blood cell transfusions should occur when hemoglobin decreases below 7 g/dL.
ACTH, adrenocorticotropic hormone; CO, cardiac output; CVP, central venous pressure; DO2, oxygen delivery; MAP, mean arterial pressure; ScvO2, central-venous oxygen saturation; SvO2, mixed venous oxygen
saturation. Strength of recommendations: A, supported by at least two large, randomized trials with clear-cut results (low risk of false-positive error or false-negative error); B, supported by one large, randomized
trial with clear-cut results (low risk of false-positive error or false-negative error); C, supported by small, randomized trials with uncertain results (moderate-to-high risk of false-positive error or false-negative
error); D, supported by at least one nonrandomized investigation with contemporaneous controls; E, supported by nonrandomized investigations with historical controls, case series, or expert opinion.
Based on data from references 4–7.
 419
hepatic parenchymal function with increased serum concentrations CENTRAL VENOUS CATHETER
of transaminases and bilirubin, altered gastrointestinal perfusion

CHAPTER 25
manifested by ileus and diminished bowel sounds, cardiac ischemia  The central venous catheter is used to measure the central venous
with elevated troponin levels and electrocardiographic changes, and pressure (CVP), to obtain venous blood gas samples, and to admin-
altered sensorium. ister drugs or fluids directly to the central circulation. A triple-lumen
catheter frequently is used, whereby drugs with known incompatibil-
ity can be administered. Blood volume, venous wall compliance,
GLOBAL PERFUSION MONITORING right-sided cardiac function, intraabdominal and intrathoracic pres-
sures, and vasopressor therapy affect CVP. The CVP is not a reliable
ARTERIAL BLOOD PRESSURE MEASUREMENT estimate of blood volume but can be used to qualitatively assess

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

Mean arterial blood pressure (MAP) is the product of cardiac output blood volume changes in patients during the early phases of fluid
(CO) and systemic vascular resistance (SVR). Conditions that may resuscitation. The goal of fluid administration is to maintain the
lower blood pressure in critically ill patients include cardiac failure CVP at 8 to 12 mm Hg, but values of 15 mm Hg may be targeted in
(etiology may be myocardial infarction, arrhythmia, acute heart mechanically ventilated patients to account for increased intratho-
failure, or valvular disease) and hypovolemia (etiology may be racic pressures.5,6 Sustained elevated pressures may be indicative of
hemorrhage, intractable diarrhea, or heat stroke) by lowering CO fluid overloading. Few data support the use of CVP monitoring in
and vasodilation (etiology may be sepsis, drugs, anaphylaxis, acute the ICU. However, initial reports in septic patients suggest that CVP
hepatic failure, or neurotrauma) by lowering SVR. Arterial blood monitoring of fluid therapy during shock was associated with a 50%
pressure is the end point of therapy; however, restoration of ade- reduction in mortality.8
quate pressure is the primary criterion of effectiveness.4 Profound
hypotension (MAP <50 mm Hg) is associated with a pressure- PULMONARY ARTERY CATHETER
dependent decrease in coronary and cerebral blood flow and may
rapidly produce myocardial and cerebral ischemia. Arterial blood  Pulmonary artery catheterization, introduced in 1970, is routinely
pressure can be determined by noninvasive and invasive methods. performed in many ICUs. With this catheter, the practitioner can
All noninvasive blood pressure monitoring techniques depend on obtain multiple cardiovascular parameters, including CVP, pulmo-
the use of an occluding cuff. Systolic and diastolic blood pressures nary artery pressure, pulmonary artery occlusive pressures (PAOP),
are further determined by auscultation, palpation (systolic pressure CO, and SVR. Mixed venous blood samples from the pulmonary
only), oscillometry, or Doppler technique (systolic pressures are artery also can be obtained. In an effort to reduce blood loss from
most reliable). Auscultation is the most commonly used method samples, many clinicians use special pulmonary artery catheters,
outside the intensive care unit (ICU). Its use, however, is limited in called fiberoptic catheters, which measure mixed venous oxygen satu-
patients with hypovolemia, hypothermia, or cardiogenic shock when ration (SvO2). Trends in venous oxygen saturation can be observed
pulses or Korotkoff sounds may be difficult to hear. Similar con- and necessary action taken, if needed. Most important, inflation of
straints exist for the palpation and oscillometric methods. However, the balloon at the catheter tip occludes the pulmonary artery, isolates
oscillometry is preferred in edematous patients. Oscillometry mea- the distal catheter tip from the right side of the heart, and allows the
sures blood pressure by sensing arterial blood pressure changes, or user to measure the PAOP, an approximate measure of the left
oscillations, against an inflated cuff. Rapid changes in oscillation ventricular end-diastolic volume and a major determinant of left
amplitude correspond to systolic and diastolic pressure. It is the only ventricular preload. Some centers use a new pulmonary artery cathe-
noninvasive method to measure MAP even in low-flow states and ter capable of continuously measuring the right ventricular end-
lends itself to automatic cycling and serial measurements (every 1–3 diastolic volume index. The right ventricular end-diastolic volume
minutes) that do not require operator intervention, a key compo- index may be a better predictor of CO than PAOP, but its clinical
nent in ICU monitoring. The use of narrow cuffs or cuffs applied too utility during shock remains to be studied. Ideally, the pulmonary
loosely can result in falsely high readings, whereas wide cuffs may artery catheter should be positioned fluoroscopically; however, satis-
produce falsely low readings.6,8 Fingertip devices offer another ave- factory placement also may be obtained by observing pulmonary
nue for continuous indirect blood pressure measurement, but their artery pressure readings and electrocardiographic waveforms during
accuracy in ICU patients may be significantly diminished by concur- catheter advancement. Proper positioning in the lower lung (zone 3)
rent administration of vasoactive drugs. is essential to measure PAOP and to prevent distal pulmonary artery
 The use of invasive arterial catheters makes possible the collapse. Poor wedging may be caused by catheter migration, patient
continuous measurement of MAP as well as procurement of blood movement, mechanical ventilation, or eccentric balloon inflation.
samples for blood gas monitoring. The radial artery is the most Pulmonary artery catheters equipped with a distal thermistor also
commonly used vessel, but the dorsalis pedis, femoral, brachial, and allow measurement of CO by thermodilution. Rapid injection of
axillary arteries and the umbilical artery in the newborn also can be saline or dextrose solutions via the right atrial port allows complete
accessed. This method of blood pressure monitoring is the standard mixing of blood with injectate, and the resulting change in blood
technique used in the ICU against which all other methods are temperature is measured in the pulmonary artery. From the temper-
compared. Major complications of peripheral artery catheterization ature change, the patient’s CO can be calculated. Newer pulmonary
include infection and distal ischemia. Acute distal ischemia and artery catheters contain a temperature coil that intermittently warms
catheter-related bacteremia occur in <1% of catheter insertions. This the blood in the right ventricle for near-continuous CO measure-
translates to 2.9% of bloodstream infections per 1,000 catheter- ment. Significant tricuspid regurgitation, an intracardiac shunt, and
days.11 Ischemia is most common in patients with multiple or significant positive end-expiratory pressure decrease the validity of
prolonged arterial cannulations, hypertension, or vasopressor ther- CO measurements. The most common complications of pulmonary
apy.6 Invasive techniques are labor intensive, require aseptic tech- artery catheterization include mural thrombus formation (14%–
niques, and offer potential sources of equipment errors, such as 91%), transient ventricular tachydysrhythmias (11%–63%), pulmo-
length and quality of tubing, air bubbles, stopcocks, thrombus nary infarction (1%–7%), pulmonary artery rupture (0.06%–2.0%),
formation, tube kinking, and transducer placement. Hypertension, and sepsis (0.3%–0.5%).12 Most pulmonary artery catheters are hep-
advanced age, and atherosclerosis also may affect the accuracy of arin bonded, and the relative risk (RR) of infection is 2.6 per 1,000
invasive blood pressure readings.7 patient-days, similar to the risk with central venous catheters of 2.3
 420
per 1,000 patient-days.11 Despite its ubiquitous use, much contro- normal values.18,19 Although controversial, many clinicians use these
versy surrounds the utility and safety of the pulmonary artery cathe- measurements interchangeably. Concentrations of ScvO2 <70% reli-
SECTION 2

ter, including issues surrounding correct placement and impact of the ably indicate inadequate oxygenation in shock states and detect
device on patient outcome.13 As a result, recommendations have been subclinical (“cryptic”) shock much earlier than hypotension.18 Target-
made to standardize and monitor clinician education on proper use ing fluid and hemodynamic resuscitation to achieve ScvO2 >70% is a
of the catheter (see www.pacep.org), to conduct clinical trials assessing sensitive indicator and measure of the extent of global tissue hypoxia,
the safety and efficacy of the catheter, and to evaluate new device as well as a determinant of the adequacy of hemodynamic resuscita-
technology on patient outcome.12 The most recent guidelines suggest tion.18 Targeting resuscitation to achieve ScvO2 >70% is associated
a careful evaluation of the indications and the risk of placing a with improved survival in patients with sepsis and septic shock.19
pulmonary artery catheter for resuscitation of critically ill patients.14
 The optimal PAOP needs to be individualized for each patient.
Cardiovascular Disorders

OXYGEN DELIVERY AND CONSUMPTION

Administering a fluid bolus followed by simultaneous PAOP and CO
measurements with the goal of increasing the PAOP until CO does not The concept of tissue oxygen debt as a determinant of organ damage
change can be accomplished and is based on Starling’s law of the heart. in critical illness was proposed in the 1970s. In normal individuals,
However, clinical experience suggests that most patients have an oxygen consumption (VO2 or VO2I, indexed to body surface area)
optimal response to PAOP values in the range from 12 to 15 mm Hg. depends on DO2 (or DO2I) up to a certain critical level (VO2 flow
dependency). At this point, tissue oxygen requirements apparently
are satisfied, and further increases in DO2 will not alter VO2 (VO2 flow
CLINICAL CONTROVERSY: independency). Although animal models of sepsis have substantiated
CVP VERSUS PAOP this relationship, studies in critically ill humans show a continuous,
pathologic dependence relationship of VO2 with DO2. Furthermore,
Limited data are available comparing the use of CVP and PAOP ICU survivors exhibited higher DO2 and VO2 values than did nonsur-
for guiding therapy in patients in shock. The results of a study of vivors. This finding became the basis for targeting supranormal DO2
patients with acute respiratory distress syndrome suggest CVP and VO2 values in the treatment of ICU patients.8 However, a meta-
and PAOP are equivalent in terms of clinical outcomes, includ- analysis of randomized clinical trials involving 1,016 adult ICU
ing mortality.15 Therefore, a pulmonary artery catheter should patients failed to show that achievement of this goal improved patient
be inserted when hemodynamic data are needed that cannot be mortality.20 This may have been due in part to the heterogeneous
obtained from a central venous catheter or when the validity of nature of the ICU patients studied, lack of study blinding, crossover
measurements from the central venous catheter is questionable. patients (control patients who achieve supranormal DO2 and VO2
values by themselves), or lack of adequate control of cointerventions.
OXYGEN TENSION AND The debate continues in more homogeneous patient populations.
SATURATION MONITORING In high-risk surgical patients, supranormal DO2 values decreased
mortality.21,22 Two randomized studies published after the meta-
Partial pressure of arterial oxygen (PaO2) and arterial oxygen satura- analysis further evaluated the effect of increasing DO2I values to >600
tion (SaO2) can be measured subjectively by assessing capillary refill or mL/m2/min in a homogeneous population of elderly surgical patients
invasively by obtaining an arterial blood sample. Arterial blood gases with systemic inflammatory response syndrome, sepsis, severe sepsis,
measured by conventional arterial sampling are considered standard, or septic shock, with conflicting results. In one study, among patients
but their accuracy and usefulness are affected by poor sampling between 50 and 75 years of age the intervention group had a signifi-
techniques, transportation and analysis delays, analyzer accuracy, cant increase in survival at 24 hours (21% vs 52%; P = 0.01) compared
sample cellular metabolism, and inability to trend results. Indwelling with the control group.21 This benefit was not seen in patients older
fiberoptic and electrochemical systems allow continuous monitoring than 75 years. The authors suggested that the combination of increas-
and trend analyses of blood pH, PaO2, and partial pressure of arterial ing DO2 and maintaining the oxygen extraction ratio (O2ER) at <25%
carbon dioxide (PaCO2) while decreasing patient blood loss from less without a changing VO2 may be helpful in maintaining or improving
frequent sampling. Unfortunately, studies evaluating the in vitro the body’s reserve in meeting the oxygen demands. This may be
accuracy of these devices may not apply to the ICU environment. The particularly true in older patients who have a lower baseline VO2. In
indwelling sensors may exhibit lower PaO2, higher PaCO2, and lower the second study, the same intervention revealed a significant reduc-
pH than central arterial blood when peripheral flow is diminished. tion in 60-day survival (15.7% vs 50%; P <0.05) in high-risk elderly
Furthermore, sensor contact with blood vessel wall and vigorous surgical patients randomized to supranormal DO2 goals.22 Thus,
arterial line flushing diminish sensor accuracy. whether supranormal DO2 is beneficial and whether the mechanism of
 SvO2 depends on CO, oxygen demand, hemoglobin, and SaO2. benefit of supranormal DO2 in these patients is prevention and
It can be measured in patients using a pulmonary artery catheter. reversal of tissue hypoxia remain unclear. A review of alternative
Initially, critically ill septic patients may present with a low SvO2 potential mechanisms of beneficial effect of supranormal DO2 suggests
value (<70%) indicating high extraction of oxygen by tissues and that catecholamines exert antiinflammatory actions by modulating
lack of adequate oxygen delivery (DO2, or DO2I, indexed to body cytokine response.23 In general, catecholamines inhibit the production
surface area) to tissues. In patients with sepsis and other conditions of inflammatory cytokines (e.g., interleukin [IL]-6, tumor necrosis
who present with a low SvO2 value, rapid intervention should be factor [TNF]-α) and may enhance synthesis of antiinflammatory
undertaken to increase DO2 to tissues, with the goal of obtaining cytokine (e.g., IL-4 and IL-10).23 The actions of epinephrine on these
SvO2 >70%.16 The length of time SvO2 is <70% is associated with cytokines are blocked by propranolol and thus are mediated by
mortality.17 As sepsis worsens, however, SvO2 often is >70%. This adrenergic β-receptors. These data must be interpreted with caution
occurs because of a maldistribution of blood flow and a lack of because most studies used animal or cell models of sepsis, pretreated
extraction of oxygen in the arteriolar beds. patients with vasopressors prior to endotoxin infusion, and used doses
 Central venous oxygen saturation (ScvO2) is a less invasive that may not always be clinically relevant. Another problem with
measure of venous oxygen saturation because the catheter is placed at therapy directed to achieve supranormal oxygen transport values is
the junction of the inferior and superior venae cavae rather than at the that the apparent linear relationship between DO2 and VO2 has been
pulmonary artery. It is as accurate as SvO2 but provides slightly higher questioned because both share variables, and this mathematical cou-
 421
4,5
pling can produce artifactual relationships between variables. The DO2 hematocrit approximately 21%–27%). Several observational stud-
and VO2 indexed parameters are calculated as follows: ies have shown that improvement of organ function within the first

CHAPTER 25
24 hours of therapy with maintenance of hemodynamic variables for
DO2 = CI × CaO2 at least 48 hours with goals similar to those in the study by Rivers et
al. is associated with improved survival.17,25 The results of several
VO2 = CI × (CaO2 – CvO2),
before and after evaluations of protocols or order sets designed to
where CI = cardiac index, CaO2 = arterial oxygen content deter- achieve the hemodynamic end points of early goal-directed therapy
mined by hemoglobin concentration and SaO2, and CvO2 = mixed show that implementation is easily accomplished, and patient out-
venous oxygen content determined by hemoglobin concentration comes, including survival, are improved.26–28 Therefore, healthcare
and SvO2. facilities should implement strategies to achieve early goal-directed

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

However, variable relationships between DO2 and VO2 have been therapy using the predefined hemodynamic variables of the study by
observed when VO2 was measured independently by indirect calorim- Rivers et al. Directing therapy to increase the goal MAP from 65 to 85
etry. Therefore, a linear relationship between DO2 and VO2 may be the mm Hg with higher doses of vasopressor agents does not confer
result of mathematical coupling or flow-dependent VO2. Currently additional improvement in organ function.29
available data do not support the concept that patient outcome or
survival is altered by treatment measures directed toward achieving BLOOD LACTATE
supranormal DO2 and VO2 values.20 In fact, a consensus conference
Lactate is a metabolic product of pyruvate. Its production is increased
concluded that although pulmonary artery catheterization is useful
under anaerobic conditions, such as may occur during shock. Blood
for guiding therapy, routinely increasing cardiac index to predeter-
lactate concentrations are used as a diagnostic and prognostic tool in
mined supranormal values does not improve outcome.4 Further-
sepsis; they also are used to measure the repayment of oxygen debt to
more, achievement of a supranormal DO2 does not ensure parallel
tissues.16 It is a useful tool in combination with DO2 and VO2 because
improvements in regional organ blood flow and oxygenation.19 The
these measures change independently of one another. Serial lactate
VO2/DO2 ratio, or O2ER, can be used to assess adequacy of perfusion
concentrations may show better correlation with outcome than oxy-
and metabolic response. Patients who are able to increase VO2 when
gen transport parameters and may be superior to hemodynamic
DO2 is increased show improved survival. However, low VO2 and
markers in determining adequacy of restoration of systemic oxygen-
O2ER values are indicative of poor oxygen utilization and lead to
ation.16 However, several caveats guide the use of lactate concentra-
greater mortality.20 Another approach that may decrease the effect of
tions in septic patients.6 First, lactate may accumulate in patients with
mathematical coupling and provide individualized therapy may lie in
other conditions, such as significant hepatic dysfunction or acute
titrated therapy, with sequential measurements of DO2 and VO2 to
respiratory distress syndrome, who are not in shock. Second, both
achieve VO2 flow independency along with normalization of blood
well-perfused and poorly perfused tissues contribute to arterial and
lactate and hemodynamic parameters.
mixed venous lactate concentrations and therefore are not reflective
 The most recent data regarding goal-directed therapy in the
of regional perfusion. Third, although increased lactate concentra-
hemodynamic support of sepsis relates to the importance of achiev-
tions have been correlated with increased mortality, the utility of
ing predetermined parameters early in the management of sepsis. In
blood lactate measurements in guiding therapy has not been clearly
a meta-analysis of early (defined as 8–12 hours postoperatively or
demonstrated. Fourth, elevated lactate concentrations may result
before the development of organ failure) versus late (defined as after
from cellular metabolic failure rather than global hypoperfusion in
onset of organ failure) resuscitative efforts in patients stratified
shock. Serial blood lactate measurements are more useful than single
according to severity of illness (determined by control group mor-
isolated measurements.
tality >20% [12 studies] or <15% [9 studies]) and targeting supra-
normal oxygen-transport variables, the data suggest that timing of
resuscitation matters.24 Early goal-directed therapy reduced mortal- REGIONAL PERFUSION MONITORING
ity and the development of organ failure in patients who were more
severely ill and when therapeutic interventions produced differences GASTROINTESTINAL TONOMETRY
in DO2. Moreover, outcome was not improved significantly in less
severely ill patients (control group mortality <15% and normal DO2 Blood pressures, CO, blood lactate, and global oxygen homeostasis
values as goals) or when therapy did not improve DO2.23 parameters do not offer information about the function of individual
 In a prospective, randomized controlled trial of sepsis, Rivers et organs. Organ-specific hypoxia may be evident by coagulopathy as
al.19 demonstrated a significant reduction in mortality (30.5% versus indicated by thrombocytopenia (platelet count <100,000/L and/or
46.5%; P <0.001) in patients with severe sepsis and septic shock prolonged clotting times [international normalized ratio >1.5 or
randomized to receive therapy based on goal-directed hemodynamic activated partial thromboplastin time at least 1.5-fold the upper limit
end points that were achieved within 6 hours of hospital presentation. of normal]), impaired renal function with urine production <0.5 mL/
They used a strategy of serial administering (1) fluids rapidly to kg/h and/or increased serum concentrations of blood urea nitrogen
achieve CVP 8–12 mm Hg, (2) vasopressor agents to achieve MAP at and creatinine, altered hepatic function with substantially increased
least 65 mm Hg, (3) red blood cell transfusion to maintain hematocrit serum concentrations of transaminases and bilirubin, altered gas-
>30%, and (4) dobutamine to achieve ScvO2 >70%. This approach trointestinal perfusion manifested by ileus and diminished bowel
demonstrates the benefits of initiating therapy early in the course of sounds, cardiac ischemia with elevated troponin levels and electrocar-
sepsis and directs therapy toward clearly defined goals in a consistent diogram changes, and altered sensorium.4–10 Objective measurement
manner. The results of this study cannot delineate which end point or of regional perfusion to detect inadequate tissue oxygenation has
combination of end points was most beneficial, so until proven focused on the splanchnic circulation, which is sensitive to changes in
otherwise, clinicians should direct therapy to achieve all the hemody- blood flow and oxygenation for several reasons. First, the normally
namic goals of this study. In addition, whether these goals must be large majority of blood flow to the gut mucosa is redistributed toward
maintained after resuscitation is unknown. Therefore, after resuscita- the serosa and muscularis. Second, the gut may have a higher critical
tion and assuming patients do not have coronary artery disease, red DO2 threshold than other organs. Third, the tip of the villus has a
blood cell transfusions should be administered in patients with hemo- countercurrent oxygen-exchange mechanism, rendering it highly
globin <7 g/dL to maintain a hemoglobin concentration 7–9 g/dL (or sensitive to alterations in regional blood flow and oxygenation.16
 422
Gastric tonometry measures gut luminal partial pressure of carbon absence of flow-limiting disease, likely due to a loss in membrane
dioxide (PCO2) at equilibrium by placing a saline- or air-filled gas- integrity with subsequent leakage or microvascular thrombosis. Ele-
SECTION 2

permeable balloon in the gastric lumen. Assuming that CO2 perme- vation of cardiac troponin concentrations in patients with sepsis
ates freely among tissues and that the arterial bicarbonate (HCO3–) indicates left ventricular dysfunction and portends a poor progno-
concentration is equal to that of the gut mucosa, the intramucosal pH sis.37 Early recognition of myocardial dysfunction is crucial for
(pHi) may be calculated using the Henderson-Hasselbalch equation: administration of appropriate therapy. In the absence of other mech-
anisms for assessing cardiac function, echocardiographic findings and
pHi = 6.1 log (HCO3–) 0.03 × PCO2 troponin concentrations may help guide and monitor therapy.
Increases in mucosal PCO2 and calculated decreases in pHi are Whereas cardiac troponins may be integrated into the monitoring of
associated with mucosal hypoperfusion and perhaps increased mor- myocardial dysfunction to identify patients requiring aggressive ther-
Cardiovascular Disorders

tality.30 Calculation of pHi can be confounded by increases in apy, natriuretic peptides have not been shown to correlate with LVEF
luminal PCO2, such as may occur when buffering antacids are used. and should not be routinely monitored.37
Histamine2-receptor antagonists or proton pump inhibitors can be
used instead. The presence of respiratory acid–base disorders; sys-
temic bicarbonate administration; arterial blood gas measurement VASOPRESSORS AND INOTROPES
errors; or enteral feeding products, blood, or stool in the gut may
confound pHi determinations.6 As a result, many clinicians believe  Vasopressors and inotropes in patients with septic shock are
that the change in gastric mucosal PCO2 may be more accurate than required when volume resuscitation fails to maintain adequate blood
pHi.6 Furthermore, because mucosal PCO2 is influenced by arterial pressure (MAP 65 mm Hg) and organs and tissues remain hypoper-
PCO2, the consensus is that the mucosal–arterial PCO2 difference fused despite optimizing CVP to 8 to 12 mm Hg or PAOP to 12 to 15
(PCO2 gap) likely is the optimal measurement.30 Gastric tonometry mm Hg. However, vasopressors may be needed temporarily to treat
can be performed using either a saline- or air-filled balloon. The time life-threatening hypotension when filling pressures are inadequate
delay (30 minutes) associated with equilibration of saline inside the despite aggressive fluid resuscitation.4 Inotropes are frequently used
balloon makes this method inconvenient for routine bedside moni- to optimize cardiac function in cases of cardiogenic shock.3 The
toring. An air-filled balloon requires a shorter equilibrium time, is clinician must decide on the choice of agent, therapeutic end points,
simpler to use, and is equally accurate.31 However, the clinical utility and safe and effective doses of vasopressors and inotropes to be used.
of gastric tonometry remains uncertain. Clinical trials of pHi-directed This section reviews adrenergic receptor pharmacology, exogenous
therapy have not shown consistently that gastric tonometry reduces catecholamine use, and alterations in receptor function in critically ill
mortality in critically ill patients.30 In a study of 28 patients with septic patients. It also provides guidelines for the clinical use of adrenergic
shock, gastric tonometry measurements were not beneficial during agents, optimization of pharmacotherapeutic outcomes, and minimi-
initial resuscitation; however, after stabilization, pHi, mucosal PCO2, zation of adverse effects in critically ill patients with septic shock.
and PCO2 gap were independent predictors of hospital mortality.32 Therapies of hypovolemic shock and cardiogenic shock are discussed
Evidence suggests that the most proximal part of the gastrointesti- in other chapters.
nal tract, the sublingual mucosa, may be an acceptable location for Of note, agents other than catecholamines have been used as
monitoring regional perfusion and PCO2. Sublingual capnometry is inotropes and vasopressors in shock states. They include phosphodi-
noninvasive, is not technically complex, and provides results within esterase III inhibitors, naloxone, nitric oxide synthase (NOS) inhibi-
minutes.33 The device consists of a disposable sublingual carbon tors, and calcium sensitizers. This chapter focuses on catecholamines.
dioxide pressure (PslCO2) sensor, a fiberoptic cable that connects the Vasopressin and corticosteroids, as they relate to septic shock, also are
disposable sensor to a blood gas analyzer, and a blood gas monitoring emphasized because they have pharmacologic interactions with cate-
instrument. A small study of 22 critically ill patients with and without cholamines, possess hemodynamic effects, and are frequently used.
sepsis and septic shock attempted to validate the usefulness of sublin-
gual capnography.34 The study measured simultaneous gastric and CATECHOLAMINE RECEPTOR
sublingual PCO2 along with traditional hemodynamic parameters. PHARMACOLOGY
PslCO2 correlated well with mucosal PCO2; however, the initial sublin-
gual-to-arterial PCO2 gap was a better predictor of mortality than the  Comparative receptor activity of endogenous and exogenously
mucosal-to-arterial PCO2 gap. Another small study of 18 patients with administered catecholamines is summarized in Table 25–3.3–10 Endog-
septic shock also found significant correlation between gastric and enous catecholamines are responsible for regulation of vascular and
sublingual PCO2, but enhancement of DO2 with dobutamine better bronchiolar smooth muscle tone and myocardial contractility. These
correlated with the decrease in PslCO2 gap than gastric PCO2 gap.35 effects are mediated by sympathetic adrenergic receptors of the
These pilot studies must be expanded before this technology becomes autonomic nervous system located in the vasculature, myocardium,
part of routine practice, but it offers the possibility of noninvasively and bronchioles. Postsynaptic adrenoceptors are located at or near
measurement of regional perfusion. the synaptic junction. These receptors can be activated by naturally
circulating or exogenous catecholamines (e.g., norepinephrine, epi-
MYOCARDIAL DYSFUNCTION nephrine, and phenylephrine), whereas presynaptic adrenoceptors
are stimulated by locally released neurotransmitters (e.g., norepi-
Although loss of vascular tone is the hallmark of septic shock, nephrine) and are controlled by a negative feedback mechanism.
myocardial dysfunction characterized by transient impairment of The signal transduction pathways associated with catecholamine-
contractility is a recognized complication. The range of left ventricu- and vasopressin-induced effects in the heart and blood vessels are
lar ejection fraction (LVEF) upon presentation is wide, but approxi- illustrated in Fig. 25–1. Agonists of β-adrenoceptors and dopamine
mately 35% of patients with septic shock have left ventricular (D1) receptors stimulate adenylate cyclase by a G-protein (Gs)–
hypokineses (mean ejection fraction 38% ± 17%) and low CO.36 dependent mechanism (Fig. 25–1, top). Adenylate cyclase generates
Because LVEF also is affected by preload and afterload, the low SVR cyclic adenosine monophosphate (cAMP) from adenosine triphos-
of septic shock may mask depressed myocardial contractility that may phate (ATP). cAMP-Dependent protein kinase A, which is activated
be revealed upon restoration of MAP by administration of fluid and by elevations in intracellular cAMP, phosphorylates target proteins to
vasopressors. Cardiac troponin release in septic patients occurs in the modify cellular function. Through these mechanisms, β1-adrenocep-
 423

TABLE 25-3 Adrenergic, Dopaminergic, and Vasopressin Receptor chain kinase is an example of a CaMK. Its action of phosphorylating
myosin light chain leads to vascular smooth muscle contraction.

CHAPTER 25
Pharmacology and Organ Distribution
The normal heart contains primarily postsynaptic β1-receptors,
Effector Organ Receptor Subtype Physiologic Response
which when stimulated cause increased rate and force of contraction.
Heart This effect is mediated by activation of adenylate cyclase and subse-
Sinoatrial node β1, β2 Increased heart rate quent generation and accumulation of cAMP. Stimulation of
Atria β1, β2 Increased contractility postsynaptic cardiac α1-receptors causes a significant increase in
Increased conduction velocity
contractility without an increase in rate, an effect mediated by PLC
Atrioventricular β1, β2 Increased automaticity
rather than adenylate cyclase. The increased contractility is more
node Increased conduction velocity
His-Purkinje β1, β2 Increased automaticity
pronounced at lower heart rates and has a slower onset and longer
duration in comparison with β1-mediated inotropic response. Pre-

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

system Increased conduction velocity
Ventricles β1, β2 Increased contractility synaptic α2-adrenoceptors also are found in the heart and appear to
Increased conduction velocity be activated by norepinephrine released by the sympathetic nerve
Increased automaticity itself. Their activation inhibits further norepinephrine release from
Increased rate idioventricular the nerve terminal.
pacemaker cells Both presynaptic and postsynaptic adrenoceptors are present in the
Arterioles vasculature. Postsynaptic α1- and α2-receptors mediate vasoconstric-
Coronary α1, α2, V1; β2, D1, V2 Constriction; dilation tion, whereas postsynaptic β2-receptors induce vasodilation. Presyn-
(via NO)
aptic α2-receptors inhibit norepinephrine release in the vasculature,
Skin and mucosa α1, α2, V1 Constriction
also promoting vasodilation. Presynaptic β1-adrenoceptors promote
Skeletal muscle α1, V1; β2 Constriction; dilation
Cerebral α1, V1; V2 (via NO) Constriction (slight); dilation
neurotransmitter release. Stimulation of peripheral D1-receptors pro-
Pulmonary α1; β2, V2 (via NO) Constriction; dilation duces renal, coronary, and mesenteric vasodilation and a natriuretic
Abdominal viscera α1, V1; β2, D1 Constriction; dilation response. Stimulation of D2-receptors inhibits norepinephrine release
(mesentery) from sympathetic nerve endings, sequesters prolactin and aldoster-
Renal α1, α2, V1; β1, β2, D1 Constriction; dilation one, and may induce nausea and vomiting. D1- and D2-receptor
Veins (systemic) α1, α2; β2 Constriction; dilation stimulation also suppresses peristalsis and may precipitate ileus.3–9
Lungs
Tracheal/bronchial β2 Relaxation
smooth muscle
ALTERED ADRENOCEPTOR FUNCTION:
Bronchial glands α1; β2 Decreased; increased secretion IMPLICATIONS FOR CRITICALLY ILL PATIENTS
Stomach
 Most of the work describing receptor function and associated
Motility and tone α1, α2, β1, β2 Decreased (usually)
Sphincter α1 Contraction (usually)
clinical pharmacology has been performed in either animal models or
Secretions α2 Inhibition human volunteers. In critically ill septic patients, derangements in
Intestine adrenergic receptor activity may result in resistance to exogenously
Motility and tone α1, α2, β1, β2; V1 Decreased (usually); administered catecholamine.38–43 This “desensitization” frequently is
Increased? characterized by myocardial and vascular hyporesponsiveness to high
Sphincters α1 Contraction dosages of inotropes and vasopressor agents. Prolonged exposure of
Secretions α2 Inhibition vascular endothelial tissue to vasopressor drugs (α-adrenergic agonists)
Kidney or endogenous catecholamines may promote additional receptor
Renin secretion α1; β1 Decreased; Increased downregulation. Increased endogenous catecholamine concentrations
Reabsorption of V2 Increased have been reported in endotoxemic and other critically ill patients,
water
suggesting an acquired adrenergic receptor defect and desensitization of
Skeletal muscle β2 Increased contractility, glyco-
neogenesis, K+ uptake
adrenergic receptors and alteration in voltage-sensitive calcium chan-
Liver α1, β2 Glycogenolysis and gluconeo- nels.38–42 The problem in critically ill patients may be related to
genesis decreased receptor activity or density. However, in patients with septic
Fat cells α1, β1, β2 Lipolysis (thermogenesis) shock, catecholamine concentrations are even higher, so abnormalities
in adrenergic receptor function are greater, with associated reductions
D, dopamine; NO, nitric oxide; V, vasopressin.
Based on data from references 4–7, 42, 45, and 46.
in the concentrations of intracellular signal transduction mediators.
The worsened receptor abnormality may be explained by defects distal
to the receptor site, such as uncoupling of adrenergic receptors from
tor activation exerts positive inotropic and chronotropic effects in the adenylate cyclase or PLC, or dysfunction in the regulatory G-protein
heart, and β2-adrenoceptor and D1-receptor activation induces vascu- unit of signal transduction pathways.38–42
lar smooth muscle relaxation. Agonists of α1-adrenoceptors or vaso- In addition to catecholamines, circulating inflammatory cytokines
pressin (V)1 receptors stimulate phospholipase C-β (PLC-β) through may be partly responsible for distal alterations. Macrophage-derived
a G-protein (Gq)–dependent process (Fig. 25–1, bottom). PLC-β IL-1 and TNF-α produce impaired coupling of β-adrenoceptors to
produces inositol trisphosphate and diacylglycerol from cell mem- adenylate cyclase.38,39 Patients with septic shock have exhibited
brane phosphatidylinositol bisphosphate. Diacylglycerol activates impaired β-adrenergic receptor stimulation of cAMP associated with
protein kinase C, an enzyme that phosphorylates several key proteins myocardial hyporesponsiveness to various vasopressors and ino-
(e.g., extracellular signal-regulated kinases, c-Jun NH2-terminal tropes.38,39 However, increased chronotropic sensitivity to β-adrener-
kinases, and mitogen-activated protein kinases) that modify cellular gic stimulation with hypersensitivity of the adenylate cyclase system
function (e.g., hypertrophy). Inositol trisphosphate elicits the release to isoproterenol stimulation also has been reported in animal models
of calcium from intracellular stores, such as the sarcoplasmic reticu- of bacteremia and endotoxemia. In the presence of intrinsic myocar-
lum. Calcium forms a complex with calmodulin, which then activates dial dysfunction and increased metabolic demands, this dysfunctional
calcium–calmodulin-dependent protein kinases (CaMK). CaMKs adrenergic system is incapable of mobilizing functional cardiac
phosphorylate target proteins to alter cellular function. Myosin light- reserve to maintain adequate myocardial performance.38–40
 424

CCA CCA DA
SECTION 2

1 2 D1
GS
+ GS
AC
+ – ATP
PKA

+
cAMP
Cardiovascular Disorders

ATP

PKA
protein
heart blood vessel

contractility protein PO 4 vasodilation

rate

VP CCA

V1 1
FIGURE 25-1. Signal transduction pathways in PIP2

PLC-
heart and blood vessels. Top. Catecholamine (CCA)- Gq
ATP
+

PKC
induced effects mediated in heart (β1) or vascular protein

smooth muscle (β2, D1). (AC, adenylate cyclase; IP3 DAG

+
ATP, adenosine triphosphate; cAMP, cyclic adeno-
sine monophosphate; PKA, cAMP-dependent pro- + PKC protein PO 4
SR
tein kinase; +, stimulation.) Bottom. CCA (α1) and
Ca++
vasopressin (VP)-induced actions in vascular smooth
muscle. (Ca++, calcium ion; CaMK, calcium/calmod- hypertrophy
ulin-dependent protein kinase; DAG, diacylglycerol; Ca++ calmodulin
IP3, inositol trisphosphate; PIP2, phosphatidylinositol
bisphosphate; PKC, protein kinase C; PLC-β, phos- calmodulin Ca++
pholipase C-β; SR, sarcoplasmic reticulum.) These
+
CaMK

ATP CaMK
pathways have been extensively simplified, and protein
denoted cellular effects represent one of many
produced. (Figure based on data from references
protein PO 4 vasoconstriction
4–6, 10, 42, 44, 45, and 89.)

IL-1 and TNF-α have been shown to suppress gene expression of vary among patients and during the insult. For these reasons, these
α1-adrenoceptors, resulting in fewer receptor proteins.40 Overpro- drugs should be dosed to clinical end points and not to arbitrary
duction of nitric oxide (NO) by inducible nitric oxide synthase maximal doses.
(iNOS) directly contributes to vasodilation by cyclic guanosine
monophosphate–mediated smooth muscle relaxation. NO indi- VASOPRESSIN AND CORTISOL:
rectly produces vasodilation by combining with superoxide to form IMPLICATIONS ON CATECHOLAMINES
peroxynitrite, a highly toxic reactive species that causes endothelial
dysfunction, uncoupling of α1-adrenoceptors to PLC, and deactiva- Endogenous arginine vasopressin, a peptide hormone also
tion of catecholamines.41,42 The result of sepsis-induced inflamma- known as antidiuretic hormone, is important for osmoregulation
tion is a system that promotes adrenergic receptor dysfunction to under normal physiologic conditions. Vasopressin is produced in
accentuate vasodilation and shock. the hypothalamus, stored in the posterior pituitary, and released
 Functional α1-adrenergic receptor changes occur at various from magnocellular neurons of the hypothalamus.44,45 Increased
stages of sepsis; thus, adrenoceptor sensitivity may be time dependent serum osmolality and hypovolemia are the major stimuli for vaso-
during progression of sepsis to septic shock. The findings are not pressin release.44,45 Other stimuli commonly associated with shock
always consistent in various animal models of sepsis and in critically are dopamine, histamine, angiotensin II, prostaglandins, pain,
ill septic patients. Time-dependent alterations in the production of hypoxia, acidosis, hypotension, hypercarbia, and α1-adrenergic
NO, a potent vasodilator, may explain the apparent differences in receptor stimulation. Vasopressin release is inhibited by NO, natri-
vascular reactivity to phenylephrine during the phases of endotox- uretic peptides, γ-aminobutyric acid, β-adrenergic receptor stimu-
emia.43 This finding suggests that the clinical response to vasopressor lation, and α2-adrenergic receptor stimulation.44,45
and possibly inotropic agents is variable during the stages of hemody- Vasopressin has minimal to no inotropic or chronotropic effects.
namic, myocardial, and peripheral vascular derangements of septic Vasopressin-induced vasoconstriction occurs through a variety of
shock. In contrast, in critically ill septic patients in the ICU (24–48 direct and indirect mechanisms.44,45 Stimulation of vascular V1 recep-
hours from hospital admission), β-adrenergic receptor changes tors causes vasoconstriction by receptor-coupled activation of PLC
already were present, although the progression of desensitization of and calcium release from intracellular stores via secondary messen-
receptors earlier in sepsis was not quantified.39 In summary, α- and β- gers similar to α1-adrenergic stimulation. Vasopressin also directly
adrenergic receptor derangements may vary among patients and inhibits vascular potassium-sensitive ATP channels to activate vascu-
during each bacteremic insult; therefore, doses of catecholamines lar calcium channels independent of V1 receptors (Fig. 25–1). V1-
 425
receptor stimulation inhibits the actions of IL-1β and thereby facili- concentrations at baseline is present in 30% to 50% of patients with
tates vasoconstriction. Vasopressin also increases the activity of septic shock and is associated with a poor outcome.46,51

CHAPTER 25
adrenergic receptors. The greatest vasoconstriction occurs in the skin
and soft tissue, skeletal muscle, fat tissue, pancreas, and thyroid gland.
V2 receptors located in the kidneys are responsible for the antidi- CLINICAL CONTROVERSY:
uretic properties of vasopressin.44,45 Stimulation of V2 receptors DIAGNOSING RELATIVE
facilitates integration of aquaporins into the luminal cell membrane ADRENAL INSUFFICIENCY
of distal tubules and collecting duct capillaries to increase permeabil-
ity and thus retain intravascular volume. However, vasopressin stim- The diagnosis of relative adrenal insufficiency in septic shock is
ulation of V1 receptors causes vasoconstriction of efferent arterioles based on serum cortisol concentration(s) rather than clinical
parameters. Some leading experts suggest defining adrenal insuffi-

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

and relative vasodilation of afferent arterioles to increase glomerular
perfusion pressure and filtration rate to enhance urine production. ciency as a random cortisol concentration <15 to 25 mcg/dL,
Vasopressin rapidly increases serum cortisol concentration by irrespective of ACTH testing results because the test dose of ACTH
stimulating V3 receptors in the pituitary gland to enhance the release may cause sufficient cortisol production in patients with mild-to-
of adrenocorticotropic hormone (ACTH).44,45 Cortisol helps regulate moderate adrenal insufficiency. In the only study to correlate
the proinflammatory state associated with sepsis and increases blood mortality with adrenal response, an elevated random cortisol con-
pressure through several mechanisms, including inhibition of iNOS centration (>34 mcg/dL) was an independent predictor of mortal-
to reduce NO production, reversal of adrenergic receptor desensitiza- ity.51 The predictive value of mortality further increased if ACTH
tion, and increased intravascular volume through retention of response was <9 mcg/dL, suggesting that the risk of mortality is
sodium and water. greatest in situations of adrenal gland “fatigue” (i.e., degree of stress
Normal serum vasopressin concentrations are <4 pg/mL.44,45 Serum is not matched by sufficient cortisol production by the adrenal
vasopressin concentrations are elevated with hypotension. Vaso- glands despite operating at maximal functional capacity).
pressin response in septic shock is biphasic. During the first 8 hours of
septic shock requiring catecholamine adrenergic therapy, serum con- CLINICAL PHARMACOLOGY OF
centrations of vasopressin are appropriately high to help maintain VASOPRESSORS AND INOTROPES
blood pressure and organ perfusion. Thereafter, serum vasopressin
concentrations decline dramatically over the next 96 hours to physio-  The receptor selectivity of clinically used, catecholamine-
logically normal but inappropriately low values, resulting in a state of based vasopressors and inotropes and hemodynamic effects are
“relative deficiency.” In contrast, serum vasopressin concentrations listed in Table 25–4. In general, these drugs are rapid acting, with
remain elevated in patients with cardiogenic shock, requiring at least 1 short durations of action. As such, these drugs are given as contin-
day of hemodynamic support with catecholamine agents. Administra- uous infusions and titrated rapidly to predetermined effects. Vaso-
tion of vasopressin at 0.01 to 0.06 units/min produces concentrations pressin is administered as a replacement dose of 0.01 to 0.04 units/
similar to those observed in early septic shock and other hypotensive min and should not be titrated. Careful monitoring and calculation
states; however, vasopressin concentrations do not correlate with of infusion rates are advised for all vasopressors because dosing
blood pressure. adjustments are made frequently, and varying admixtures and
The mechanism of vasopressin insufficiency in septic shock is not concentrations are used in volume-restricted patients.
well understood. Neurohypophyseal stores in the posterior lobe of the Dopamine is often considered a first-line initial therapy in
pituitary gland are depleted during septic shock, likely as a result of patients with septic shock because it increases blood pressure by
excessive and continuous baroreceptor stimulation that eventually increasing myocardial contractility and vasoconstriction.4–10 Dopa-
exhausts the limited vasopressin secretory stores. In addition, secre- mine has been described as having dose-related receptor activity at D1-,
tion of vasopressin is inhibited by enhanced endothelial production D2-, β1-, and α1-receptors (Table 25–4). Unfortunately, this dose–
of NO, high circulating concentrations of adrenergic agonists (both response relationship has not been confirmed in critically ill patients.
endogenous and exogenous), and tonic inhibition by stretch recep- In patients with septic shock, great overlap of hemodynamic effects
tors in response to volume replacement and mechanical ventilation. occurs, even at doses as low as 3 mcg/kg/min.52 Tachydysrhythmias
As with vasopressin, during sepsis a state of “relative adrenal are common due to the release of endogenous norepinephrine by
insufficiency” is produced by continuous activation of the hypotha- dopamine entering the sympathetic nerve terminal. Dopamine may
lamic–pituitary–adrenal axis by IL-1, IL-6, and TNF-α that causes increase PAOP through pulmonary vasoconstriction.6,7 This drug also
depletion of cortisol in the adrenal glands.46 Administration of may depress ventilation and worsen hypoxemia in patients dependent
corticosteroids has been shown to improve arterial pressure while on the hypoxic ventilatory drive.
minimizing the dose of catecholamine vasopressors.47,48 Current Dobutamine, a synthetic catecholamine, is primarily a selective β1-
proposed mechanisms of the vasoconstrictor effect of corticoster- agonist with mild β2- and vascular α1-activity, resulting in strong
oids include increasing the number and stimulating the function of positive inotropic activity without concomitant vasoconstriction. In
α1- and β-adrenergic receptors and attenuating the production of comparison with dopamine, dobutamine produces a larger increase in
inflammatory mediators responsible for vasodilation. CO and is less arrhythmogenic.7,40 α1-Adrenoceptors in the heart are
The use of corticosteroids for treatment of septic shock has been directly stimulated by the (–) isomer of dobutamine, but β1- and β2-
a topic of controversy for many years. Meta-analyses of early studies activity resides in the (+) isomer.7,40 This finding suggests that the
of steroids in patients with sepsis demonstrated a lack of benefit and strong inotropic action of dobutamine is a function of its structure, the
potential harm in sepsis and septic shock.49,50 Interest in corticoster- additive effect of cardiac α1- and β1-agonist activity, and a relatively
oid use is renewed because of the increased awareness of adrenocorti- weak chronotropic effect limited to the (+) isomer action on the β-
cal insufficiency in critically ill patients with septic shock.46 Relative receptors. Clinically, β2-induced vasodilation and the increased myo-
adrenal insufficiency has been defined as a poor adrenal response (<9 cardial contractility with subsequent reflex reduction in sympathetic
mcg/dL [250 nmol/L] irrespective of the initial serum cortisol level) tone lead to a decrease in SVR. Dobutamine is used optimally for
to a dose of synthetic ACTH, indicating a low functional reserve of the patients in low CO states with high filling pressures or in those in
adrenal cortex.51 Although absolute insufficiency is rare, relative cardiogenic shock; however, vasopressors may be needed to counter-
adrenocortical insufficiency in the presence of normal or high cortisol act arterial vasodilation.
 426

TABLE 25-4 Receptor Pharmacology of Selected Inotropic and Vasopressor Agents Used in Septic Shocka
α1 α2 β1 β2
SECTION 2

Agent D V1 V2
Dobutamine (0.5–4 mg /mL D5W or NS)
2–10 mcg/kg/min + 0 ++++ ++ 0 0 0
>10–20 mcg/kg/min ++ 0 ++++ +++ 0 0 0
Dopamine (0.8–3.2 mg /mL D5W or NS)
1–3 mcg/kg/min 0 0 + 0 ++++ 0 0
3–10 mcg/kg/min 0/+ 0 ++++ + ++++ 0 0
>10–20 mcg/kg/min +++ 0 ++++ + 0 0 0
Epinephrine (0.008–0.016 mg /mL D5W or NS)
Cardiovascular Disorders

0.01–0.05 mcg/kg/min ++ ++ ++++ +++ 0 0 0

0.05–3 mcg/kg/min ++++ ++++ +++ + 0 0 0
Norepinephrine (0.016–0.064 mg /mL D5W)
0.02–3 mcg/kg/min +++ +++ +++ +/++ 0 0 0
Phenylephrine (0.1–0.4 mg /mL D5W or NS)
0.5–9 mcg/kg/min +++ + + 0 0 0 0
Vasopressin (0.8 units/mL D5W or NS)
0.01–0.04 units/min 0 0 0 0 0 +++ +++
a
Activity ranges from no activity (0) to maximal (++++) activity.
D, dopamine; D5W, dextrose 5% in water; NS, normal saline; V, vasopressin.
Based on data from references 4–7, 42, 45, and 46.

Norepinephrine is a combined α- and β-agonist that produces CVP of 8 to 12 mm Hg.4–10 Crystalloid fluids (e.g., normal saline,
vasoconstriction primarily via its more prominent α-effects on all Ringer lactate solution) and colloid fluids (e.g., albumin, hetastarch,
vascular beds, thus increasing SVR. Norepinephrine administration dextrans, blood products) are considered equivalent for shock
generally produces either no change or some increase in CO.53,54 In resuscitation. Crystalloid fluids are generally preferred unless
addition to dopamine, norepinephrine is considered an option for patients are at risk for adverse events from redistribution of intrave-
initial vasopressor therapy for septic shock. nous fluids to extravascular tissues and/or are fluid restricted (e.g.,

Phenylephrine is a pure α1-agonist and is believed to increase patients with renal dysfunction, decompensated heart failure, asci-
blood pressure through vasoconstriction. Given the presence of tes compromising diaphragmatic function).
cardiac α1-receptors, phenylephrine also may increase contractility Traditional vasopressors and inotropes used for hemodynamic
and CO.55 It is a therapeutic option in hypotensive patients experi- support of patients with hypotension refractory to fluid administra-
encing a tachyarrhythmia when a vasopressor with minimal to no tion include dopamine, dobutamine, epinephrine, norepinephrine,
β1-agonist activity is indicated. and phenylephrine. Optimizing MAP to 65 mm Hg as the goal of
 Epinephrine exerts combined α- and β-agonist effects. At the vasopressor therapy does not uniformly correlate with decreased
high epinephrine infusion rates used for patients with septic shock, mortality in patients with septic shock.19,20 Historically, significant
predominantly α-adrenergic effects are seen, and SVR and MAP are concerns about the adverse effects of vasopressors limited their use.
increased. Epinephrine traditionally has been reserved as the vaso- The past focus of achieving supranormal oxygen-transport variables
pressor of last resort due to peripheral vasoconstriction, particularly also has yielded poor results in patients with septic shock.20 In fact,
in the splanchnic and renal beds.42,56,57 normalization of systemic DO2 and VO2, whether spontaneously or
Unlike adrenergic receptor agonists, the vasoconstrictive effects with intervention, is associated with improved outcome and is not
of vasopressin are preserved during hypoxia and severe acidosis. Sev- dependent on administration of vasopressor agents. Part of the
eral small studies have evaluated short-term infusions of vasopressin at inability to detect an improvement with vasopressor or inotropic
doses <0.08 units/min as add-on therapy to patients requiring cate- therapies may result from the limited ability to quantify regional
cholamine adrenergic agents.44,45 The results show that initiating vaso- tissue perfusion. However, use of early goal-directed therapy to
pressin in patients with septic shock increases SVR and arterial blood ScvO2 >70% has been shown to reduce mortality in patients with
pressure to reduce the dose requirements of catecholamine adrenergic sepsis and septic shock.19
agents. These effects are rapid and sustained. Vasopressin causes   Dosage titration and monitoring of vasopressor and inotropic
vasodilation in the cerebral, pulmonary, coronary, and selected renal therapy should be guided by the “best clinical response” and the goals
vascular beds by enhancing endothelial NO release through V1-recep- of early goal-directed therapy.4–10,19 Dopamine or norepinephrine is
tor stimulation in these tissues.44 Organ-specific vasodilation reduces considered the agent of choice as initial vasopressor therapy. Norepi-
pulmonary artery pressure and may preserve cardiac and renal func- nephrine may be added in cases where suboptimal response is
tion. Several studies have shown substantial enhancement of urine obtained from dopamine but adding dopamine to norepinephrine
production, likely due to increased glomerular filtration rate. At doses does not provide a hemodynamic benefit. Phenylephrine may be tried
exceeding 0.04 units/min, vasopressin was associated with ischemia of as the initial vasopressor in cases of severe tachydysrhythmias. Regard-
the mesenteric mucosa, skin, and myocardium; elevated hepatic trans- less of which vasopressor is chosen, low doses are initiated and titrated
aminases and bilirubin concentrations; hyponatremia; and thrombo- rapidly (usually every 5–15 minutes) to clinical response. Clinically
cytopenia. Limiting the dose to a maximum of 0.04 units/min may effective dosing of vasopressors and inotropes in septic shock often
minimize the development of adverse effects. requires doses much larger than recommended by most references.
These large infusion rates must be tempered with the development of
CLINICAL APPLICATION adverse effects. The goal is to use the minimally effective infusion rate
while minimizing evidence of myocardial ischemia (e.g., tachydys-
rhythmias, electrocardiographic changes), renal (decreased glomerular
Vasopressors and Inotropes filtration rate and/or urine output), splanchnic/gastric (low pHi,
 Initial hemodynamic therapy for septic shock is administra- bowel ischemia), or peripheral (cold extremities) hypoperfusion, and
tion of intravenous fluid (20–40 mL/kg), with the goal of attaining worsening PaO2, PAOP, and other hemodynamic variables.
 427
 Therapy with catecholamine vasopressors and inotropes is con- studies used moderate physiologic doses (200–300 mg/day) of hydro-
tinued until the myocardial depression and vascular hyporesponsive- cortisone. A meta-analysis of five studies (n = 465) showed that

CHAPTER 25
ness (i.e., blood pressure) of septic shock improve, usually measured in steroid therapy was associated with an overall improvement in sur-
hours to days. Discontinuation of vasopressor or inotropic therapy vival rate (RR 1.23, 95% confidence interval [CI] 1.01–1.50; P = 0.036)
should be executed slowly; therapy should be “weaned” to avoid a and shock reversal (RR 1.71, 95% CI 1.29–2.26; P <0.001).47 These
precipitous worsening in regional and systemic hemodynamics. Care- effects were beneficial in both responders and nonresponders to
ful monitoring of global and regional end points also should be geared ACTH stimulation testing (P = 0.63 and P = 0.75, respectively). These
toward discontinuation of vasopressors and inotropes as soon as the studies also showed that low-dose corticosteroid administration
patient is hemodynamically stable. This requires moment-by-moment improves hemodynamics and reduces the duration of vasopressor
observation. Because vasopressors and inotropes often are started support. All these studies differ from earlier studies in that steroids

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

while the patient is not yet optimally volume resuscitated, clinicians were administered at lower total doses (hydrocortisone equivalents:
should reevaluate intravascular volume status continuously so that the 1,209 mg vs 23,975 mg; P = 0.01) starting later in septic shock (23
patient can be weaned from the vasopressor as soon as possible. Doses hours vs <2 hours; P = 0.02) for longer courses (6 days vs 1 day; P =
should be titrated carefully downward approximately every 10 minutes 0.01) to patients with higher control group mortality rates (mean 57%
to determine if the patient can tolerate gradual withdrawal and vs 34%; P = 0.06) who were more likely to be vasopressor dependent
eventual discontinuation of the vasopressor and/or inotrope. Discon- (100% vs 65%; P = 0.03). The relationship between corticosteroid
tinuation of agents may occur only minutes to hours after their dose and survival was linear, with survival benefit at low doses (P =
initiation, or it may take days to weeks. Septic shock requiring 0.02). Another meta-analysis of 16 trials (n = 2,063) found similar
vasopressor and/or inotropic support usually resolves within 1 week. results with long-term administration of corticosteroids associated
with lower mortality in hospital (RR 0.83, 95% CI 0.70–0.97; P = 0.02)
Vasopressin and at 28 days (RR 0.80, 95% CI 0.67–0.95; P = 0.02) and greater
shock reversal at 7 days (RR 1.22, 95% CI 1.06–1.40; P = 0.006).48
At present, vasopressin therapy should not be initiated as first-line
Combining all corticosteroid studies did not reveal an increased risk
therapy. Lauzier et al. randomized 23 hyperdynamic septic shock
for adverse events, including gastrointestinal hemorrhage (RR 1.16,
patients to initial therapy with vasopressin 0.04 to 0.20 units/min or
95% CI 0.82–0.1.65; P = 0.4), superinfections (RR 0.93, 95% CI 0.73–
norepinephrine 0.1 to 2.8 mcg/kg/min for 48 hours to achieve MAP
1.18; P = 0.54), and hyperglycemia (RR 1.22, 95% CI 0.84–1.78; P =
of 70 mm Hg.58 Both agents increased MAP over 48 hours, but
0.30). Of note, the results of both meta-analyses were heavily driven
norepinephrine achieved the desired MAP significantly faster, and
by data supplied by one study.59 Annane et al.59 randomized 300
norepinephrine was required in 36% of the vasopressin patients. One
patients with septic shock within 8 hours of hypotension to placebo or
patient who received vasopressin developed acute coronary syndrome
a daily combination of hydrocortisone 50 mg IV every 6 hours and
with dose-dependent electrocardiographic changes. Additional stud-
fludrocortisone 0.05 mg enterally for 7 days. Similar to the meta-
ies are needed to determine the optimal dose, duration, and place in
analyses, use of hydrocortisone reduced 28-day mortality (odds ratio
therapy of vasopressin relative to adrenergic agents. In addition, no
[OR] 0.65, 95% CI 0.39–1.07; P = 0.09), but all the benefit was seen in
randomized, blinded, placebo-controlled trials have shown improve-
patients with adrenal insufficiency (OR 0.54, 95% CI 0.31–0.97; P =
ment in long-term outcomes such as mortality and length of hospital
0.04). The placebo group was more likely to continually require
stay. The preliminary results (not yet published at the time this
vasopressor therapy (hazard ratio [HR] 1.54, 95% CI 1.10–12.16; P =
chapter was prepared) of a randomized, double-blind study of 800
0.01), but differences between groups were exhibited only in patients
patients with septic shock requiring catecholamine vasopressors
with adrenal insufficiency (HR 1.91, 95% CI 1.29–2.84; P = 0.001).
showed that 28-day mortality rates were similar when vasopressin
Approximately 76% of patients were deemed adrenally insufficient.
0.01 to 0.03 units/min or norepinephrine was added to traditional
Only one study has been published since the most recent meta-
therapy (see www.utoronto.ca/criticalcare/Research/VASST.shtml). Until
analyses.60 Oppert et al.60 randomized 41 patients with septic shock
further safety data and larger efficacy trials are completed, vasopressin
within 4 hours of hypotension to placebo or continuous infusion
is not recommended as a replacement for norepinephrine or dopa-
hydrocortisone and found that patients treated with hydrocortisone
mine in patients with septic shock but may be considered in patients
required shorter therapy with vasopressors (53 hours vs 120 hours; P
who are refractory to catecholamine vasopressors despite adequate
<0.02). This effect was more pronounced in patients with adrenal
fluid resuscitation. If used, vasopressin should be administered in
insufficiency but still was evident in those with adrenal reserve. Of
doses not exceeding 0.01 to 0.04 units/min.44,45 Use of vasopressin for
note, serum concentrations of the inflammatory cytokine IL-6 were
reducing the dose of adrenergic agents can be considered, but the
significantly reduced with hydrocortisone, and this finding was
risks must be considered prior to initiating therapy.
equally apparent irrespective of adrenal function.
Given the current data, corticosteroids can be administered to
patients with septic shock and adrenal insufficiency.46 In the absence
CLINICAL CONTROVERSY: of adrenal function assessment, corticosteroids can be considered in
VASOPRESSIN cases of refractory shock, as approximately 75% of these patients
have insufficient adrenal reserve.59 Use of vasopressors for prolonged
Adding vasopressin reduces the dose of traditional catechol-
periods without evidence of dose reduction also warrants cortico-
amine therapies and is associated with improved renal function.
steroid administration. Whenever corticosteroids are used for septic
However, the occurrence of ischemic events to digits and
shock, a daily dose equivalent to 200 to 300 mg hydrocortisone
splanchnic circulation may be increased with vasopressin.
should be continued for 7 days. At the time this chapter was
Therefore, the lowest possible dose should be implemented if
prepared, the results of a randomized study of 499 patients with
vasopressin is used.
severe sepsis were released (not yet published) and showed that 28-
day mortality rates were similar amongst patients with and without
Corticosteroids adrenal insufficiency (defined by an ACTH response of less than 9
Since the two meta-analyses reported in 1995,49,50 several random- mcg/dL) and that hydrocortisone did not alter mortality but did
ized controlled trials of low-dose corticosteroids in vasopressor- shorten the length of time patients required vasopressors by 2 to 3
dependent septic shock patients have been published.46–48 These days (see www.esicm.org/PAGE_corticus).
 428
contractility and heart rate, primarily from its β1 effects. It increases
CLINICAL CONTROVERSY: MAP and SVR as a result of both increased CO and, at higher doses
SECTION 2

CORTICOSTEROID THERAPY (>10 mcg/kg/min), its α1 effects.

 The clinical utility of dopamine as a vasopressor in the
Low-dose corticosteroid therapy for 7 days in patients with
setting of septic shock is limited because large doses frequently are
septic shock improves outcomes when adrenal insufficiency is
necessary to maintain CO and MAP. At doses exceeding 20 mcg/kg/
present. Several questions surround the application of cortico-
min, further improvement in cardiac performance and regional
steroid therapy in septic patients, including use in patients with
hemodynamics is limited. Its clinical use frequently is hampered by
sepsis but without shock, use when sufficient adrenal reserve is
tachycardia and tachydysrhythmias, which may lead to myocardial
present, use when patients were taking corticosteroids prior to
ischemia. Although tachydysrhythmias theoretically should not be
ICU admission, most effective dose and duration, use of cortico-
Cardiovascular Disorders

expected to occur until administration of dopamine 5 to 10 mcg/kg/

steroids other than hydrocortisone, and need for coadministra-
min, these β1 effects are observed with doses as low as 3 mcg/kg/
tion of fludrocortisone.
min. They seem to be more prevalent in patients who are inade-
quately resuscitated (hypovolemic), in the elderly, in those with
Adverse Effects preexisting or concurrent cardiac ischemia or dysrhythmias, and in
patients currently receiving other dysrhythmogenic agents, includ-
 Catecholamine vasopressors may result in adverse peripheral
ing vasopressors and inotropes.
vasoconstrictive, metabolic, and dysrhythmogenic effects that limit or
Dopamine increases PAOP and pulmonary shunting to
outweigh their positive effects on the central circulation.8,40,42 Norepi-
decrease PaO2.42 The increase in PAOP may be due to changes in
nephrine, phenylephrine, and epinephrine can produce lactic acidosis
diastolic volumes from decreased cardiac compliance or increased
secondary to excessive constriction in peripheral arterioles or
venous return to the heart by α-adrenergic receptor–mediated
enhanced glycogenolysis, or as a result of mobilization of lactate from
venoconstriction. This may affect gas exchange and decrease PaO2.
peripheral tissues as a result of improved oxygenation. Additionally,
The increase in pulmonary shunting also may result from acute
excessive peripheral vasoconstriction may cause ischemia or necrosis
enhancement of pulmonary blood flow to nonhomogeneous lung
of already poorly perfused tissues such as the skin and the mesenteric
regions. Thus, dopamine should be used with caution in patients
and splanchnic circulations.42,56,57,61 Some of these profound vaso-
with elevated preload because the drug may worsen pulmonary
constrictive effects have been compounded by the use of epinephrine
edema. In the instance of high filling pressures, tachycardia, or
and phenylephrine in patients with septic shock who are significantly
tachydysrhythmias, dopamine should be replaced by another vaso-
hypovolemic. These agents are used in the context of late septic shock,
pressor and/or inotrope such as norepinephrine, dobutamine,
where hypotension is refractory to less selective vasoconstrictors (e.g.,
phenylephrine, or epinephrine, depending on the desired effect.
norepinephrine or dopamine) such that very large doses of epineph-
The effect of dopamine on global oxygen-transport variables paral-
rine or phenylephrine are required but provide little or no benefit.
lels the hemodynamic effects. Although dopamine improves global
Myocardial ischemia and dysrhythmias may occur in patients with
DO2 in septic patients, it may compromise O2ER in the splanchnic
coronary artery disease, atherosclerosis, cardiomyopathies, left ven-
and mesenteric circulations by α1-mediated vasoconstriction.
tricular hypertrophy, congestive heart failure, or underlying dys-
Splanchnic blood flow and DO2 increase with dopamine, but with no
rhythmias because of their inability to tolerate β1 cardiac stimulation
preferential increase in splanchnic perfusion as a fraction of CO and
that mediates increases in CO. However, the effect usually is opposite
systemic increases in DO2.62,63 Indeed, large doses of dopamine
in healthy myocardium and in young patients. β1 Cardiac stimulation
worsen pHi and the PCO2 gap.64,65 This is reflected by a decrease or
is well tolerated, ventricular filling pressures decrease, and CO and
lack of change in regional VO2 and a decrease in tissue O2ER.61
DO2 increase, with a resulting increase in peripheral perfusion. The
Dopamine at low or pressor doses directly impedes gastric motility in
dysrhythmogenic potential of the catecholamine vasopressors
critical illness66 and may aggravate gut ischemia in septic shock.67,68
includes a variety of resulting atrial and ventricular arrhythmias.
Similar to high-dose administration, low-dose dopamine increases
Sympathomimetic vasopressors also have been found to possess
splanchnic blood flow but lowers splanchnic VO2 in sepsis.68 There-
immunomodulatory actions, primarily mediated by β2-adrenergic
fore, dopamine at all doses impairs hepatosplanchnic metabolism
actions (e.g., epinephrine) because almost all immune cells express
despite an increase in regional perfusion. Lastly, immune suppression
this receptor.42 The actions include downregulating expression of
of T-cell proliferation and inhibited secretion of growth and thyroid
proinflammatory cytokines such as TNF-α by neutrophils, suppres-
hormones and prolactin are other potentially clinically significant
sion of oxygen free radical production from neutrophils, and direct
unwanted neuroendocrine effects of dopamine.
proapoptotic effects. Dopamine suppresses prolactin secretion from
Currently, insufficient evidence promotes the use of dopamine
the anterior pituitary gland, which may lead to reduced T-cell respon-
as a first-line agent because regional hemodynamics, oxygen-trans-
siveness.42 These effects may be either beneficial or deleterious by
port variables, and functional parameters of improved organ perfu-
dampening harmful effects of oxygen free radical–mediated tissue
sion are not consistently enhanced in a sustained manner and may be
injury or by reducing neutrophilic defense against bacteria.
negatively impaired. The negative findings of low-dose dopamine use
Vasopressor catecholamines have the potential to cause extrava-
(see Low-Dose Dopamine below) and the deleterious effects of
sation-associated tissue damage if infusions infiltrate during periph-
inotropic and vasopressor doses of dopamine on regional hemody-
eral administration. In the event of infiltration, an α-receptor
namics and oxygen transport raise controversy over whether dopa-
antagonist such as phentolamine (10 mg in 10 mL saline) should be
mine should be considered the first-line vasopressor agent in patients
injected intradermally to reverse local vasoconstriction, with
with severe sepsis or septic shock.4,6–8 The results of an observational
administration of vasopressor drugs into a large central vein.
study found dopamine use was an independent factor associated with
ICU mortality in all 1,058 patients with shock (OR 1.67, 95% CI 1.19–
Dopamine 2.35; P = 0.003) and the subgroup of 462 patients with septic shock
Dopamine frequently is the initial vasopressor used for patients with (OR 2.05, 95% CI 1.25–3.37; P = 0.005).69 Until dopamine is found to
septic shock.4–10 Doses of 5 to 10 mcg/kg/min are initiated to improve have definitive deleterious clinical outcomes compared to other
MAP. Most studies of patients with septic shock have shown that vasopressors, empirical use of dopamine in a hypotensive patient in
dopamine at these doses increases the cardiac index by improving whom a pulmonary arterial catheter has not been inserted and in
 429
whom the cause of hypotension—low CO or vasodilation—is yet available evidence, low-dose dopamine for treatment or prevention of
undetermined still may be reasonable.3,5,9,10 In addition, unlike other acute renal failure cannot be justified and should be eliminated from

CHAPTER 25
vasopressor agents, dopamine is available as premixed ready-to-use routine clinical use.74,75
solutions of various concentrations that can be stored in automated
distribution systems for rapid initiation. Norepinephrine
Norepinephrine was first used 3 decades ago for treatment of
Low-Dose Dopamine hypotensive states prior to the development of the synthetic catechol-
In the critical care setting, low doses (1–3 mcg/kg/min) of dopamine amines dopamine and dobutamine. Traditionally, norepinephrine
once were advocated for use in patients with septic shock receiving was viewed as causing significant peripheral tissue vasoconstriction,
vasopressors with or without oliguria. The goal of this therapy is to which could selectively impair regional blood flow and thus DO2 to the

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

minimize or reverse renal vasoconstriction caused by other pressors, to renal and splanchnic beds. However, clinical studies of norepineph-
prevent oliguric renal failure, or to convert oliguric to nonoliguric rine now support the primary use of norepinephrine to restore blood
renal failure. At low dosages, dopamine has been shown to increase pressure in septic shock.53,79 Several retrospective analyses have dem-
urine production as a result of enhanced renal blood flow from its D1- onstrated improved MAP and mortality in ICU patients with severe
receptor–mediated vasodilation, its D2-receptor–mediated natriuretic hypotension treated with norepinephrine either as first-line therapy or
effects (inhibition of Na +/K + ATP of renal tubular cells), or its β1- after therapeutic failure with fluid resuscitation and dopamine treat-
receptor–mediated increase in cardiac index.70,71 In healthy subjects, ment.6 However, in patients with increased sequential organ failure
the addition of dopamine to incremental doses of norepinephrine may assessment scores and associated multiorgan failure, treatment with
blunt norepinephrine-induced renal vasoconstriction, thereby main- norepinephrine no longer offered an advantage. Early aggressive
taining renal blood flow, natriuresis, urine production, and glomerular vasopressor support may be key to a positive outcome in septic shock.
filtration.52 These effects also have been observed during the course of Use of norepinephrine as first-line therapy may be more rational
dopamine administration in oliguric62 and nonoliguric57,63,70 patients because norepinephrine is more potent than dopamine and is more
with septic shock. For this reason, low doses of dopamine sometimes effective in increasing MAP. It has combined strong α1-activity and
are added to other vasopressors (e.g., norepinephrine). less potent β1-agonist effects while maintaining weak vasodilatory
Tolerance to the vasodilatory effects of dopamine after 24 to 48 effects of β2-receptor stimulation. In clinical practice, however, nor-
hours is evident in nonoliguric patients with sepsis syndrome and has epinephrine often is initiated after vasopressor doses of dopamine (4–
been reported in other conditions.72,73 The lack of response to dopa- 20 mcg/kg/min) alone or in combination with dobutamine (5 mcg/
mine in patients with septic shock receiving vasopressors and the kg/min) fail to achieve desired goals.4–10 Doses of dopamine and
tolerance to low-dose dopamine that develops in responders may be dobutamine are kept constant or stopped; in some instances, dopa-
explained in part by time- and disease-dependent desensitization of mine is kept at low doses for purported renal protection.
the dopamine receptors72,73; this may not occur in patients with sepsis  Norepinephrine infusions can be titrated to preset goals of
syndrome72 or in normal volunteers.52 Furthermore, differences in MAP (usually at least 65 mm Hg), improvement in peripheral
the extent of preexisting vasodilation and the pathophysiology of perfusion (to restore urine production or decrease blood lactate),
renal dysfunction in oliguric and septic shock patients may contribute and/or achievement of desired oxygen-transport variables while not
to the inconsistent responses to administration of low doses of compromising the cardiac index. Norepinephrine 0.01 to 2 mcg/kg/
dopamine. A paucity of evidence suggests that the etiology of acute min reliably and predictably improves hemodynamic parameters to
renal failure from sepsis is due to efferent arteriole vasodilation and “normal” or “supranormal” values in most patients with septic
that potential beneficial outcomes with dopamine, and other vaso- shock. As with  other vasopressors, norepinephrine doses exceed-
pressors, are due to enhanced CO.74,75 Enhanced urine production ing those recommended by most references frequently are needed in
has been shown to occur in hyperdynamic shock with use of agents critically ill patients with septic shock to achieve predetermined
that constrict the efferent arteriole such as vasopressin and norepi- goals. A significant increase in MAP generally is caused by an
nephrine; however, delineating the effects of improved arterial blood increase in SVR. In contrast to dopamine, heart rate generally does
pressure and CO associated with these agents from regional renal not increase significantly with norepinephrine because of dimin-
effects is difficult.44,45,64,65,76 ished stimulation of cardiac β1-receptors in septic shock and reflex
Two studies have settled the debate surrounding low-dose dopa- bradycardia from increased SVR.54,80 In a study of 10 patients with
mine. Friedrich et al.77 performed a meta-analysis to determine if low- septic shock in whom norepinephrine doses were increased to 23,
dose dopamine reduces mortality or the need for dialysis in patients 31, and 47 mcg/min to maintain MAPs of 65, 75, and 85 mm Hg,
with critical illness. Among 61 clinical trials (n = 3,359), low-dose mean heart rates were 95, 101, and 105 beats/min, respectively.54
dopamine had no effect on mortality (RR 0.96, 95% CI 0.78–1.19), The increasing doses of norepinephrine required for the three levels
need for dialysis (RR 0.93, 95% CI 0.76–1.15), or occurrence of of MAP resulted in a progressive increase in the cardiac index (mean
adverse events (RR 1.13, 95% CI 0.90–1.41). Low-dose dopamine values 4.7, 5.3, and 5.5 L/m2/min, respectively).54 Others have
improved urine production by 24% (CI 14%–35%) on the first day of demonstrated no change or a minor increase in the cardiac index
therapy but failed to maintain this effect on days 2 and 3. No with norepinephrine in patients with septic shock.53 In contrast to
improvements in serum creatinine concentration (4% relative dopamine, norepinephrine does not influence PAOP.81
increase, 95% CI 1%–7%) and measured creatinine clearance (6% The effect of norepinephrine on oxygen transport parameters is
relative increase, 95% CI 1%–11%) occurred. One adequately variable and depends on baseline values and concurrently administered
designed prospective, controlled trial has been conducted with low- vasoactive agents. In most studies of norepinephrine alone, either an
dose dopamine in critically ill patients.78 This study was cited in the increase or no change in DO2 is seen with no change in O2ER,
meta-analysis by Friedrich et al. Bellomo et al.78 randomized 328 particularly when mean DO2 values were “supranormal” prior to
critically ill patients with early renal dysfunction to either low-dose therapy.61,64,65 Norepinephrine has demonstrated either no effect or
dopamine (2 mcg/kg/min) or placebo and found no differences in improvement in PCO2 gap and pHi.61,65 Splanchnic blood flow and
peak serum creatinine concentration (245 ± 144 μmol/l vs 249 ± 147 fractional blood flow are higher with norepinephrine than either dopa-
μmol/l), increase in serum creatinine concentration (62 ± 107 μmol/ mine or epinephrine despite higher CO with the two latter agents.61,81,82
L vs 66 ± 108 μmol/L), need for renal replacement therapies (27.7% In a randomized study of 32 septic shock patients unresponsive
vs 24.5%), and urine production at any time point. On the basis of to volume resuscitation, Martin et al.76 found norepinephrine alone
 430
was superior to dopamine in achieving and maintaining preset increase the cardiac index, typically by 25% to 50%. In septic shock,
hemodynamic (MAP of at least 80 mm Hg) and oxygen-transport LVEF and right ventricular function are depressed despite a high
SECTION 2

variables for at least 6 hours (93% vs 31% of patients, P <0.001). Of cardiac index, whereas ventricular volumes and compliance are
the 11 patients who did not respond to dopamine, 10 achieved the increased. Stroke index is maintained by an increased heart rate and
desired hemodynamic goal when norepinephrine was added. The ventricular dilation. In survivors, myocardial depression is reversible
authors suggested that differences between the two agents resulted and normalizes 5 to 10 days after onset of sepsis.7 Dobutamine has
from norepinephrine’s combined increase in VO2 and decrease in been shown to increase stroke index, left ventricular stroke work
lactate concentrations due to reversal of splanchnic ischemia and index, and thus cardiac index and DO2 without increasing PAOP in
efficient hepatic clearance of lactate or a preferential increase in DO2 septic shock in animals, in human volunteers, and in controlled
to areas of greatest oxygen demand, thus optimizing O2ER. studies of human septic shock.7 The ability of dobutamine to enhance
Cardiovascular Disorders

The same investigators showed in a prospective, observational cardiac index and DO2 during septic shock appears to be related to its
cohort study of 97 adult patients with septic shock that use of norepi- chronotropic effect.84
nephrine to provide hemodynamic support was associated with a Most prospective, randomized controlled studies of therapy
significant decrease in mortality (day 7: 28% vs 40%, P <0.005; day 28: directed toward achieving supranormal hemodynamic variables with
55% vs 82%, P <0.001; at hospital discharge: 62% vs 84%, P <0.001).79 dobutamine were performed in surgical and medical ICU patients
Using stepwise logistic regression analysis, norepinephrine was found with septic shock refractory to concurrently administered vasopres-
to be the only factor associated with significantly improved survival (P sors (dopamine and/or norepinephrine).7 The achievement of supra-
= 0.03). Despite the drawback of lack of randomization, this study is normal oxygen transport values with dobutamine is of little value
the first to demonstrate a survival benefit with any vasopressor. In an compared with treatment to normal values. In addition, administra-
interventional study, Martin et al.53 showed that addition of norepi- tion of dobutamine to achieve these high values has resulted in an
nephrine in patients with dobutamine-resistant septic shock resulted in unchanged or increased mortality rate and/or a greater incidence of
significant improvements (40%) in the cardiac index and stroke vol- adverse effects,85 with the exception of a study of older, nonseptic,
ume index during a 4 hour study period. This occurred despite an high-risk surgical patients.22 Results in medical and surgical patients
increase in left ventricular afterload, suggesting that either a positive may differ because of differences in time of starting dobutamine
inotropic effect or the correction of systemic hypotension was respon- infusion, duration of the infusion, and dosages administered. Among
sible. The authors further speculated that older patients may benefit critically ill, high-risk trauma and surgical patients receiving dobuta-
from a combined α- and β-vasopressor versus a pure β-agonist given mine, subgroups of patients with septic shock (6%–34%) have small
the higher incidence of coronary disease and compromised ventricles and insignificant changes in DO2, VO2, O2ER, and cardiac index.86 The
in this patient population. By virtue of restored MAP and hence lack of response may be related to late treatment (>72 hours after
coronary perfusion, cardiac index is increased in older patients, surgery) resulting in irreversible changes due to hypoperfusion and
whereas in younger patients with less coronary artery disease and a hypoxia. In a group of medical patients, the lack of sustained effect
higher cardiac index at baseline, norepinephrine acts primarily as a may have been attributed to the fact that very large doses were needed
vasopressor. In younger patients in this study, norepinephrine did not to achieve the desired effects over a longer treatment period (72
significantly increase the cardiac index or stroke volume index. hours). The requirement for vasopressor support with dopamine may
Whereas the effects of norepinephrine on MAP, SVR, cardiac have decreased O2ER and negated the beneficial effects of increased
index, and heart rate appear to be desirable and more predictable, the delivery with dobutamine. O2ER, mixed venous oxygen tension, and
effect of norepinephrine on urine production may depend on concur- relative changes in SVR were not reported. In populations of medical
rently administered vasoactive agents.6,81 The results of many studies and surgical patients, dobutamine did not increase the likelihood of
are difficult to interpret because of concurrent inotropic support with patients achieving supranormal oxygen-transport variables. Continu-
dobutamine and dopamine or low doses of dopamine precluding the ation of dobutamine until death or resolution of acute illness resulted
attribution of any beneficial effects to norepinephrine alone. In the in increased mortality despite an increase in the mean area under the
randomized study of norepinephrine and dopamine by Martin et DO2 curve.85 This is explained in part by the fact that no change in
al.,76 urine production increased with norepinephrine but not with VO2 was seen, and thus O2ER decreased. Also, much higher doses of
dopamine (22 ± 7 mL/h to 189 ± 52 mL/h vs 24 ± 6 mL/h to 8.2 ± 10 dobutamine were used in this study compared with the previous
mL/h; , P <0.001). Adding norepinephrine to the dopamine group study (5–200 mcg/kg/min vs 5–20 mcg/kg/min). Seventeen of the 50
increased urine production to 107 ± 125 mL/h. An increase in urine patients in the experimental group received dobutamine 50 mcg/kg/
production may be due to increased renal perfusion pressure second- min or more at some time during the study. Despite these high doses,
ary to elevated MAP from improved CO and SVR or the localized 35 (70%) of 50 patients were unable to achieve the predetermined
vasoconstrictive effect of norepinephrine in the kidney (greater vaso- goals. In fact, dose increments of dobutamine were limited by com-
constriction of the efferent arteriole than the afferent arteriole) to plications in half of the dobutamine patients in the treatment group,
increase the glomerular filtration rate. with occurrence of tachycardia, ischemic changes on electrocardio-
Taken together, these data suggest that norepinephrine should be gram, hypertension, and tachydysrhythmias despite the absence of
repositioned as the vasopressor of choice in patients in septic shock preexisting cardiac abnormalities.85
because of its multiple benefits: (1) norepinephrine may decrease Studies have focused on the effects of dobutamine on gastric
mortality in septic shock, (2) it reverses inappropriate vasodilation mucosal flow and the splanchnic circulation. The addition of
and low global oxygen extraction, (3) it attenuates myocardial depres- dobutamine to norepinephrine or epinephrine improves gastric
sion at unchanged or increased CO and increased coronary blood mucosal perfusion without increasing the cardiac index.87,88 This is
flow, (4) it improves renal perfusion pressure and renal filtration, consistent with findings that dobutamine may improve pHi and
(5) it enhances splanchnic perfusion, and (6) it is less likely than other mucosal perfusion in septic patients.89 The addition of dobutamine
vasopressors to cause tachycardias and tachydysrhythmias.79,80,83 to norepinephrine or epinephrine treatment has been shown to
improve gastric mucosal perfusion as measured by improvements
in pHi, arterial lactate concentrations, and PCO2 gap.88,90–92 These
Dobutamine findings likely relate to blood flow redistribution toward gastric
Dobutamine is an inotrope with vasodilatory properties (a “inodila- mucosa.89 This effect may be due to either an increase in the fraction
tor”). It is used for treatment of septic and cardiogenic shock to of CO distributed to the global hepatosplanchnic blood flow87 and/
 431
or a redistribution of blood flow within gastric wall layers toward dynamic, normotensive septic patients but worsens myocardial
mucosal by “stealing” blood away from the muscularis potentially as performance in cardiac controls.94 In sepsis, phenylephrine improves

CHAPTER 25
a result of the greater β2-mediated vasodilation attributable to norepi- MAP by increasing the cardiac index through enhanced venous
nephrine. This hypothesis is supported by four other investiga- return to the heart (increase in CVP and stroke index) and by acting
tions,90–93 including one showing that sublingual microcirculation as a positive inotrope. In cardiac patients, myocardial performance
improved after dobutamine was given to vasopressor-dependent worsens as a result of a decrease in the cardiac index and an increase
septic shock patients.93 The changes in capillary perfusion were in SVR.
unrelated to arterial pressure or cardiac index.93 In septic shock, phenylephrine appears to increase global tissue
In many of these studies, a constant dose of dobutamine (usually oxygen use, although information regarding the relationship of the
5 mcg/kg/min) was added to norepinephrine or epinephrine and oxygen-transport variables with increases in MAP and cardiac index is

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

compared with either vasopressor alone to determine comparative conflicting.55,95 Increases in VO2 appear to be dissociated from DO2,
effects on systemic and regional hemodynamics and oxygen-trans- representing an increase in O2ER as the cardiac index remains
port variables.88,90–92 At the same increase in MAP, no significant unchanged. Increases in VO2 may result from redistribution of blood
difference in the systemic hemodynamic variables was observed flow to previously underperfused areas, improving oxygen use as a
between treatment groups. The combination of dobutamine and result of changes in MAP and SVR. With phenylephrine administra-
norepinephrine results in a lower increase in heart rate compared tion, no organ dysfunction was documented, and evidence of globally
with use of other vasopressors alone. There is no difference in DO2I improved peripheral tissue perfusion was observed as lactic acid
between groups. Arterial lactate concentrations decrease signifi- concentration fell or remained unchanged and urine production
cantly with norepinephrine and dobutamine compared with dopa- increased significantly at increased or maximal VO2. An increased
mine and epinephrine infusions. Norepinephrine and dobutamine O2ER may contribute to improved tissue use.55,95 In one small study,
infusion is associated with a higher pHi compared with epinephrine measured DO2 and VO2 values paralleled MAP in most patients.95 As
infusion, but the differences are not statistically different. The with epinephrine, phenylephrine dosages (1.3–3.7 mcg/kg/min)
difference between gastric and arterial PCO2 with norepinephrine required to achieve goals of therapy were significantly higher than
and dobutamine tends to be lower compared with values obtained dosages traditionally recommended for use. When phenylephrine (0.5
with dopamine, epinephrine, and norepinephrine alone. Therefore, mcg/kg/min) was titrated to a plateau in VO2 or the appearance of
for the same level of MAP as the therapeutic goal in patients with adverse cardiac effects, both DO2 and VO2 increased at least 15%.
septic shock, gastric mucosal perfusion and tissue oxygen utilization When combined with dobutamine, phenylephrine resulted in a more
are most improved with norepinephrine and dobutamine. consistent and statistically significant increase in both DO2 and VO2.
 Dobutamine should be started at dosages ranging from 2.5 to 5 However, these observations may be biased because baseline DO2 and
mcg/kg/min. In a study of early goal-directed therapy, dobutamine VO2 values were somewhat higher in patients who did not require
was administered to 13.7% of patients within 6 hours of resuscitation dobutamine (5/11 patients). In a second study, use of phenylephrine
to achieve ScvO2 >70%.19 Although a dose response may be seen, as a single agent without another cardiotonic agent was evaluated in 10
evidence now suggests that doses >5 mcg/kg/min may provide lim- septic, hyperdynamic surgical ICU patients.55 Eight patients had a
ited beneficial effects on oxygen transport values and hemodynamics clinically significant increase (at least 15%) in VO2 with variable doses
and may increase adverse cardiac effects.93 If given to patients who are of phenylephrine, whereas DO2 increased in only three patients. Phen-
intravascularly depleted, dobutamine will result in hypotension and a ylephrine predictably increased MAP but not VO2 in a dose-dependent
reflexive tachycardia. Pathophysiologic factors influence dosing fashion in the surgical patient population.
requirements and pharmacokinetic parameters over the time course Few data regarding the effect of phenylephrine on regional
of the illness and the duration of the infusion. Decreases in PaO2, as hemodynamics and oxygen-transport variables are available. When
well as myocardial adverse effects such as tachycardia, ischemic phenylephrine replaced norepinephrine in patients with septic
changes on electrocardiogram, tachydysrhythmias, and hypotension, shock, phenylephrine selectively reduced splanchnic blood flow and
are seen.85,89 Thus, infusion rates should be guided by clinical end thus splanchnic DO2 and splanchnic lactate uptake rate without
points and SvO2/ScvO2. Dobutamine, like other inotropes, usually is changing the overall splanchnic VO2.96 Because all these parameters
given until improvement in myocardial function with resolution of normalized when norepinephrine was reinstated, these data suggest
the septic episode or dose-limiting side effects are observed. that exogenous β-adrenergic stimulation (norepinephrine) may
determine hepatosplanchnic perfusion and oxygen availability but
not utilization in septic shock. This study also demonstrated that
Phenylephrine although the phenylephrine-induced reduction in splanchnic DO2
 Despite its purported use in refractory septic shock, little infor- reduced the de novo synthesis of glucose (a highly oxygen-depen-
mation is available regarding the clinical efficacy of phenylephrine. dent pathway in the periportal region), it did not affect the forma-
Nevertheless, it is an attractive agent for use in sepsis because of its tion of monoethylglycinexylidide, a metabolite of lidocaine (a
selective α-agonism with primarily vascular effects. It is generally cytochrome P450–dependent pathway in the perivenous region).
initiated at dosages of 0.5 mcg/kg/min and can be titrated every 5 to This finding demonstrates the heterogeneity of metabolic function
15 minutes to desired effects. in different areas of the liver.
Three clinical trials have evaluated phenylephrine use in 38 patients The available data on hemodynamics, oxygen-transport variables,
with septic shock. Phenylephrine (0.5–9 mcg/kg/min), used alone or and mortality with phenylephrine in septic shock patients may not be
in combination with dobutamine or low doses of dopamine, generalizable because of the small numbers of patients evaluated.
improves blood pressure and myocardial performance in fluid-resus- Adverse effects, such as tachydysrhythmias, are notably infrequent
citated septic patients.94 Incremental doses of phenylephrine admin- with phenylephrine, particularly when it is used as a single agent or at
istered over 3 hours result in linear dose-related increases in MAP, higher doses, because phenylephrine does not exert any activity on β1-
SVR, heart rate, and stroke index when administered alone as a single adrenergic receptors. Whether the beneficial effects can be sustained
agent in stable, nonhypotensive but hyperdynamic, volume-resusci- with longer administrations of phenylephrine is unclear.55 In an
tated surgical ICU patients. In septic shock, phenylephrine did not experimental animal model, however, sustained endotoxemia (48
impair the cardiac index, PAOP, or peripheral perfusion.55,95 Phenyl- hours) did not result in desensitization of α1-adrenergic responsive-
ephrine administration improves myocardial performance in hyper- ness when phenylephrine was used.43 Other mechanisms may be
 432
responsible for the ineffectiveness
of vasopressors during advanced group, in which MAP was <65 mm Hg. After a stable dose of
sepsis. Phenylephrine may be a particularly useful alternative in dopamine, patients were randomized to either norepinephrine or
SECTION 2

patients who cannot tolerate tachycardia or tachydysrhythmias with epinephrine initially and then the other agent after a period of at least
use of dopamine or norepinephrine, in patients with known underly- 45 minutes with each agent. Systemic and regional measurements
ing myocardial dysfunction, and in patients who are refractory to were taken for each drug. Minimal differences between agents were
dopamine or norepinephrine (because of β-adrenergic receptor noted for moderate shock. However, in the severe shock group,
desensitization). As with other vasopressors, phenylephrine is contin- epinephrine resulted in higher DO2 and VO2 but lower absolute and
ued until resolution of the hemodynamic instability associated with fractional splanchnic blood flow. Although the PCO2 gap was not
the septic episode and is weaned when patients are clinically stable. different, indocyanine green clearance was lower with epinephrine
compared with norepinephrine. No detrimental effects on splanchnic
Cardiovascular Disorders

circulation were found with dopamine. This study concluded that

Epinephrine epinephrine titrated to blood pressure in patients with severe septic
 By convention, epinephrine has been reserved as a last-line agent shock causes deterioration in splanchnic circulation and induces
for hemodynamic support of sepsis. Few objective data evaluating its changes in splanchnic metabolism. Given that these changes are likely
comparative efficacy in early sepsis are available; most studies have deleterious, high-dose epinephrine should be avoided in severe septic
examined the effects of epinephrine in refractory septic shock.89 shock patients.61
Despite this lack of data, epinephrine is an acceptable choice as a Four studies have compared epinephrine with either norepineph-
single agent because of its combined vasoconstrictor and inotropic rine alone or norepinephrine in combination with dobutamine to
effects.
Epinephrine infusion rates of 0.04 to 1 mcg/kg/min alone determine their comparative effects on systemic and regional hemody-
increase hemodynamic and oxygen-transport variables to “supranor- namics and oxygen-transport variables.87,90–92 Two randomized stud-
mal” values without adverse effects in septic patients without coro- ies compared the effects of epinephrine with the combination of
nary artery disease. Among 69 patients evaluated in five studies, norepinephrine and dobutamine on gastric perfusion, systemic and
epinephrine alone or combined with either dobutamine or low doses pulmonary hemodynamics, hepatic function, and blood gases in a
of dopamine achieved the desired outcomes.89 Large doses (0.5–1 total of 52 patients with septic shock.90,91 Epinephrine or norepineph-
mcg/kg/min) often were required when epinephrine was added to rine was started at a dose of 0.1 mcg/kg/min and titrated rapidly to
other agents. Smaller doses (0.10–0.50 mcg/kg/min) are effective if achieve MAP of 70 to 80 mm Hg. Dobutamine was infused continu-
dobutamine and dopamine infusions are kept constant, potentially as ously at 5 mcg/kg/min. At the same increase in MAP, no significant
a result of less exposure to β-receptor stimulation and thus less differences in the systemic or pulmonary hemodynamic and blood gas
receptor desensitization. The same holds true when epinephrine is variables were observed between treatment groups. Epinephrine
used as a first-line agent and when it is used in younger patients. A tended to induce greater increases in the cardiac index and oxygen
linear dose–response curve is seen, with rapid improvement of hemo- transport compared with norepinephrine and dobutamine. Epineph-
dynamic variables and DO2. Although DO2 increases mainly as a rine also significantly increased gastric mucosal blood flow compared
function of consistent increases in the cardiac index and a more with norepinephrine and dobutamine without modifying clearance of
variable increase in  SVR, VO2 may not increase, and O2ER may fall. indocyanine green. The effects seen with epinephrine most likely were
A transient fall in pHi may be seen during epinephrine administra- the result of an increase in the cardiac index. In the short term,
tion, and the impairment in gastric mucosal perfusion can be coun- however, epinephrine was associated with increased lactate concentra-
teracted in part by dobutamine. Furthermore, lactate concentrations tions, decreased pHi, and widened PCO2 gap. All these variables
may rise during the first few hours of epinephrine therapy but improved in the group that received norepinephrine and dobutamine.
normalize over the ensuing 24 hours in survivors.89 The increase in The two other studies are prospective, randomized crossover stud-
lactate may be a result of worsened DO2 to the liver (and subsequent ies performed in dopamine-resistant, volume-replete patients with
anaerobic metabolism) or to the hepatosplanchnic circulation or, septic shock.87,92 The design and results of the two studies are similar.
alternately, may be due to a direct increase in calorigenesis and Dopamine, epinephrine, norepinephrine, and norepinephrine plus
breakdown of glycogen and lactate production as a result of epineph- dobutamine were adjusted to a MAP of 70 mm Hg. Epinephrine and
rine. However, evidence suggests that epinephrine, in contrast to the combination of norepinephrine and dobutamine both produced
dopamine, increases the proportion of total CO delivered to the a significant increase in heart rate compared with norepinephrine
splanchnic circulation, although VO2 is not increased sufficiently to alone. Epinephrine also significantly increased the cardiac index and
increase O2ER. In contrast, when epinephrine is compared with a DO2 compared with norepinephrine alone as well as with norepi-
short infusion (2 hours) of a combination of norepinephrine and nephrine and dobutamine. For the same level of MAP, epinephrine
dobutamine, epinephrine preferentially decreases splanchnic DO2, and the combination of norepinephrine and dobutamine induced a
worsens pHi, and increases systemic lactate concentration without greater increase in mucosal perfusion than did norepinephrine alone,
increasing VO2. Methodologic limitations of many of these studies but the same ratio between gastric mucosal perfusion and DO2 was
included nonrandomized crossover periods, potentially leading to observed with norepinephrine and dobutamine and with epinephrine
pharmacologic carryover; failure of patients to achieve a steady state or norepinephrine alone. However, O2ER values were lower with
before crossover; and use of time-dependent response measures. Also epinephrine infusion compared with the other three groups. Arterial
unclear is whether patients were comparable at baseline—that is, lactate concentrations decreased significantly with norepinephrine
whether they had received the same or other vasoactive agents before and dobutamine as compared with dopamine and epinephrine infu-
the study period and for how long.89 sions. In addition, pHi and PCO2 improved more with norepineph-
 Because data on the effects of vasopressors on splanchnic rine and dobutamine than with epinephrine or norepinephrine alone,
circulation in humans are limited and are confounded by the concur- but the differences were not statistically different. These results can be
rent use of multiple agents, De Backer et al.61 conducted a study in explained by the vasodilatory effect of dobutamine on gastric mucosal
which regional hemodynamic effects of three catecholamine vaso- microcirculation resulting in a redistribution of blood flow toward
pressors were evaluated individually in septic shock patients. A the mucosa.87 The results of these studies suggest that epinephrine has
sample of 20 patients with septic shock was divided into two groups: deleterious effects on regional hemodynamics and oxygen utilization.
a moderate shock group, in which the MAP was at least 65 mm Hg Of all the vasopressors, epinephrine exhibits the most pronounced
with dopamine doses between 10 and 20 mcg/kg/min, and a severe capacity to induce hyperglycemia by increased gluconeogenesis and
 433
glycogenolysis with α-mediated suppression of insulin secretion. 42
occurrence rate as high as 30% after vasopressin was added to norepi-
The increase in lactate concentrations with epinephrine may be nephrine-resistant shock.44,101

CHAPTER 25
secondary to exaggerated aerobic glycolysis rather than anaerobic Although vasopressin may have deleterious effects on mesenteric
metabolism from decreased oxygen utilization. and skin perfusion, studies report vasodilation of cerebral, pulmo-
 It is important to note that despite the large doses used in all nary, coronary, and some renal vasculature beds. The clinical
the studies discussed, clinically important dysrhythmias or cardiac outcomes associated with selective vasodilation are not yet deter-
ischemia were reported rarely in patients of any age or underlying mined except for enhanced urine production in patients not anuric
cardiac status. Nevertheless, caution must be exercised before con- at baseline.44,100 Whereas V2 stimulation promotes water retention
sidering epinephrine for managing hypoperfusion in hypodynamic from the distal tubules and collecting ducts, V1 receptors cause
patients with coronary artery disease, in whom ischemia, chest pain, vasoconstriction of efferent arterioles and relative vasodilation of

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

and myocardial infarction may result. Based on the current evi- afferent arterioles to increase glomerular perfusion pressure and
dence, epinephrine should be avoided in septic shock. Although it filtration rate, enhancing urine production. Animal data suggest
effectively increases CO and DO2, it has deleterious effects on the that urine production is not increased with even higher vasopressin
splanchnic circulation. If it is used as a second-line agent in septic doses, likely because of relative vasoconstriction of the afferent
shock, factors that may influence successful therapy with epineph- arteriole to reduce glomerular filtration rate.44 In the studies report-
rine include the time from onset of septic shock to effective therapy ing benefit, the maximum dose used was 0.08 units/min.44
and the age of the population. In order to minimize the potential for adverse events and maximize
the beneficial effects, vasopressin doses should be limited to 0.04 units/
min. Most studies initiated vasopressin as add-on therapy to one or
Vasopressin two catecholamine adrenergic agents rather than as first-line therapy
Studies involving vasopressin infusion for management of septic or salvage therapy. The results of these studies showed that vasopressin
shock show rapid and sustained improvement in hemodynamic markedly reduced the requirements for adrenergic agents, but few
parameters. These effects are evident with administration of doses studies demonstrated complete discontinuation of these therapies.
not exceeding 0.08 units/min. Administration of doses >0.04 units/ Therefore, vasopressin should be used only if response to one or two
min and 0.05 units/min are associated with negative changes in CO adrenergic agents is inadequate or as a method for reducing the dose
and mesenteric mucosal perfusion, respectively. The reduction in of these therapies. Increased arterial pressure should be evident within
CO likely is the result of lowered stroke volume.44 The studies that the first hour of vasopressin therapy, at which time the dose(s) of
reported cardiac function indicate patients had adequate CO prior adrenergic agent(s) should be reduced while maintaining blood pres-
to initiating vasopressin therapy. Therefore, vasopressin use in sure. This method should help limit the degree of ischemia.
septic shock patients with cardiac dysfunction warrants extreme Most studies evaluated vasopressin use for <48 hours, and several
caution. Cardiac ischemia appears to be a rare occurrence and may studies reported difficulty discontinuing vasopressin therapy.
be related to administration of doses >0.05 units/min.44 Whether additional benefits, deleterious effects, or tolerance is
Mesenteric ischemia associated with vasopressin may be clinically observed with longer infusions remains unclear. Because vasopressin
relevant. Two studies demonstrated increased hepatic transaminases is being used to replace a physiologic deficiency, it stands to reason
and total bilirubin concentrations during vasopressin therapy, suggest- that the requirement for vasopressin will subside with reversal of the
ing impaired hepatic blood flow or a direct effect on excretory hepatic septic process. Attempts to discontinue vasopressin should occur
function.42,44 Three prospective studies of a total of 30 patients with when the dose(s) of adrenergic agent(s) has been minimized (e.g.,
septic shock requiring moderate-to-high doses of norepinephrine dopamine ≤5 mcg/kg/min, norepinephrine ≤0.1 mcg/kg/min, phen-
found that pHi and PCO2 gap rapidly worsened after vasopressin at ylephrine ≤1 mcg/kg/min, epinephrine ≤0.15 mcg/kg/min). At
doses of 0.04 to 1.8 units/min was added, despite increased splanchnic present, vasopressin should not be initiated as first-line therapy or
blood flow and fractional blood flow.97–99 Two randomized studies added to existing therapy solely because a patient is septic.
demonstrated contrasting results, likely because of their study
designs.100,101 Dunser et al.100 randomized 48 patients with vasodila-
tory shock to norepinephrine alone or norepinephrine with vaso-
Corticosteroids
pressin 0.07 units/min for 48 hours. The PCO2 gap rose after 1 hour in Corticosteroids can be initiated in cases of septic shock when
the norepinephrine group and then stabilized, whereas the combina- adrenal insufficiency is present or when weaning of vasopressor
tion induced a progressive rise in the PCO2 gap and reached the same therapy proves futile.46 Adverse events are few because corticoster-
values as norepinephrine alone at 48 hours.100 Patel et al. 101 random- oids are administered for a finite period of time, usually 7 days.
ized 24 septic shock patients requiring high-dose norepinephrine to 4 Acutely, elevated serum concentrations of blood urea nitrogen,
hours of additional norepinephrine or vasopressin at a median dose of white blood cell count, and glucose occur. Although long-term
0.06 units/min. The PCO2 gap remained unaltered in both groups. administration of corticosteroids is associated with several chronic
Differences between studies may reflect the time of initiation relative disease states, a meta-analysis did not show an increase in adverse
to onset of shock, the stage of shock, and study duration. It is not events, including gastrointestinal hemorrhage and infections (RR
surprising that even replacement doses of vasopressin in septic shock 0.93, 95% CI 0.73–1.18; P = 0.54), impacting critically ill patients.48
are associated with mesenteric mucosal hypoperfusion because mesen- Therefore, therapy of septic shock with corticosteroids improves
teric vasoconstriction occurs at vasopressin serum concentrations as hemodynamic variables and lowers catecholamine vasopressor dos-
low as 10 pg/dL, and the effect is dose dependent.44 Of concern is the ages with minimal to no effect on patient safety.
additive effective with norepinephrine despite substantially reduced
doses of norepinephrine when vasopressin is initiated.97–99 Although
controversial, the degree of hypoperfusion with vasopressin may be EXPERIMENTAL THERAPIES
greater than with norepinephrine alone44 unless the dose of norepi-
nephrine is markedly increased to maintain adequate arterial blood NITRIC OXIDE SYNTHASE INHIBITORS
pressure. Vasopressin’s strongest vasoconstrictive action occurs in the
skin and soft tissues, skeletal muscles, and fat tissues. As a result, NO is a short-acting, potent vasodilator derived from enzymatic
ischemic skin lesions have been observed in several studies, with an oxidation of arginine. Its production is under control of NOS. This
 434
enzyme is present (expressed) in two forms: a constitutive form DOPEXAMINE AND ISOPROTERENOL
(ecNOS) and an inducible form (iNOS). Small amounts of NO
SECTION 2

normally are produced by the vascular endothelium under the Dopexamine is a structural and synthetic analog of dopamine that
control of ecNOS for physiologic control of vascular tone and blood exerts systemic vasodilation through stimulation of β2-adrenoceptors
flow distribution. Under pathophysiologic conditions such as stim- and peripheral D1 and D2 receptors and weak inotropic properties
ulation by lipopolysaccharide or cytokines, iNOS becomes diffusely through stimulation of β1-adrenoceptors. It has been used in patients
expressed, producing large amounts of NO. The latter has been with acute heart failure and septic shock. Similar to dobutamine,
implicated in the cardiovascular failure of septic shock.102–104 dopexamine is administered in combination with a vasopressor agent
Pharmacologic inhibition of NO production has been investigated in septic shock. In small studies of septic shock, dopexamine pro-
as an adjunct to standard therapies of septic shock. L-Arginine analogs duced a dose-related (range 2–6 mcg/kg/min) increase in cardiac
Cardiovascular Disorders

such as monomethyl-L-arginine (L-NMMA) and L-arginine-methyl- index, stroke volume, and heart rate, as well as a decrease in SVR over
ester (L-NAME) are competitive inhibitors of NOS and have been the course of 0.5 to 1 hour while the dosages of other vasopressors
shown to increase blood pressure, partially restore vascular reactivity, were kept constant.113–118 The increase in myocardial oxygen demand
and reduce vasopressor use.102–104 However, because these arginine is less than with dopamine, but tachycardia and tachydysrhythmia
analogs nonselectively block ecNOS and iNOS, their use has been may lead to myocardial ischemia, especially when ischemic heart
associated with extensive vasoconstriction, decreased CO, and disease is present. Global oxygen-transport variables are similar to
regional hypoperfusion, thus promoting organ failure and mortal- those of dopamine: DO2 increases but VO2 increases insufficiently,
ity.102–104 Some S-substituted thiourea derivatives have demonstrated, resulting in impaired O2ER. The combined β2-adrenoceptors and
both in vitro and in vivo (rodent), dose-dependent selectivity for peripheral D1 agonistic effects of dopexamine should improve distri-
iNOS inhibition, but the clinical application must be evaluated. A bution of blood flow. However, the results of studies of dopexamine
phase I/IIa clinical trial of septic shock patients is underway (see use in septic shock failed to show preferential increase in splanchnic
www.medinox.com). blood flow.115–118 In fact, gastric pHi was lowered. When adminis-
tered over 7 days, dopexamine had no impact on gastrointestinal
METHYLENE BLUE barrier and renal function.118 Therefore, initial data do not support a
role for dopexamine in improving regional hemodynamics and blood
Methylene blue counteracts ecNOS, iNOS, and soluble guanylate flow, but studies continue to investigate dopexamine as an alternative
cyclase to reduce serum concentrations of NO and cyclic guanosine therapy for septic shock.
monophosphate. Despite these effects, methylene blue does not alter Isoproterenol is a synthetic catecholamine that stimulates only β1-
the expression of inflammatory cytokines.105 Clinically, methylene and β2-adrenoceptors to produce vasodilatory and inotropic effects.
blue at doses of 0.25 to 3 mg/kg/h increases SVR, MAP, myocardial Although not thought of as a traditional agent for managing septic
contractility, and DO2 in septic shock patients refractory to vasopres- shock, isoproterenol has received attention because of the concepts of
sors.105–108 Additional studies are needed before methylene blue can early goal-directed therapy.19 The strong β-adrenergic effects of iso-
be recommended; at present it has been used only for salvage therapy. proterenol make it a potential alternative to dobutamine for optimiz-
ing DO2 in patients with low SvO2 despite use of other therapies (e.g.,
TERLIPRESSIN fluid resuscitation, vasopressors, red blood cell transfusion). A study
of 14 patients with septic shock and SvO2 <70% despite volume
Terlipressin, an investigational prodrug that is converted into lysine administration, norepinephrine, and red blood cell transfusion
vasopressin, has been used in septic shock patients.109 This drug has showed that adding isoproterenol over a 12-hour period increased
a half-life of 6 hours and acts via vascular V1 receptors and renal SvO2, cardiac index, and stroke index without increasing heart rate or
tubular V2 receptors.110 In one report, terlipressin 1 mg was given causing myocardial ischemia.119 Although these results are intriguing,
intravenously to 15 patients with norepinephrine-resistant septic additional studies are needed to define the role of isoproterenol,
shock.110 Terlipressin increased MAP at 30 minutes, and the effect especially considering that dobutamine has become standard therapy
lasted for 24 hours. Despite a decrease in CO, terlipressin increased for early goal-directed therapy. At present, isoproterenol is an agent
gastric mucosal perfusion, urine production, and creatinine clear- of last resort.
ance. An open-label study randomized 20 septic shock patients after
fluid resuscitation to terlipressin 1 mg or norepinephrine after fluid OTHER THERAPIES
resuscitation.111 Despite significant decreases in heart rate, cardiac
index, and DO2I with terlipressin, blood pressure was increased to a As with vasopressin and cortisol, critical illness impairs hypotha-
greater extent than with norepinephrine.111 Both agents improved lamic–pituitary function, producing relative deficiencies of tri-
urine production and decreased serum lactate concentration. These iodothyronine (T3) and thyroxine (T4). This condition, referred to as
preliminary findings suggest that a clinical trial evaluating mortality euthyroid sick syndrome, may contribute to hypotension.120 Concen-
as well as hemodynamic effects should be conducted. trations of thyrotropin-releasing hormone and thyroid-stimulating
hormone are inappropriately low. Measured concentrations of free T3
LEVOSIMENDAN and T4 may be low or normal, but synthesis is consistently impaired.
Only scant data regarding the replacement of these hormones in
Levosimendan is a novel inotropic and vasodilator calcium-sensitiz- critically ill patients are available, and the results are variable depend-
ing drug. In acute decompensated heart failure, it improves cardiac ing on the extent of additional hormone replacement (growth hor-
contractility by sensitizing troponin C to calcium. A blinded study mone, gonadotropin-releasing hormone, leptin, insulin, thyrotropin-
randomized 28 septic shock patients with left ventricular dysfunc- releasing hormone, and thyroid-stimulating hormone). Given the
tion despite at least 48 hours of conventional therapy that included data for replacing vasopressin and cortisol in septic shock, it is
dobutamine to levosimendan 0.2 mcg/kg/min or dobutamine 5 reasonable to assume that one day a “thyroid replacement” regimen
mcg/kg/min for 24 hours.112 At the same MAP, levosimendan will be offered as an adjunctive treatment to vasopressors.
decreased PAOP, increased LVEF and cardiac index, improved PCO2 Drotrecogin alfa (activated) or activated protein C has been estab-
gap, and enhanced urine production. Additional clinical trials of lished as a treatment of severe sepsis because it reduces mortality
levosimendan in septic shock are needed. when used early in patients with at least two organ dysfunctions or an
 435
Acute Physiology and Chronic Health Evaluation (APACHE) II score sense of safety resulting from graded doses of dopamine. This dose–
of 25.121 Drotrecogin alfa (activated) promotes fibrinolysis, inhibits response relationship, however, has never been established in criti-

CHAPTER 25
coagulation, and modulates inflammation. Animal studies suggest cally ill patients. In addition, observations of improved outcomes
that inhibition of TNF-α and inactivation of iNOS by drotrecogin alfa with norepinephrine and decreased regional perfusion with dopa-
(activated) prevents endotoxin-induced hypotension. A study of 22 mine are calling into question the use of dopamine as a first-line
septic shock patients treated with drotrecogin alfa (activated) showed agent. Although goal-directed therapies to supranormal values
that the norepinephrine dose decreased 33% over 24 hours.122 In cannot be recommended, developing a strategy to titrate therapy
contrast, the norepinephrine dose increased 38% in the matched early in the course of illness to predetermined values is an acceptable
control group despite MAP values similar to the drotrecogin alfa approach. For all catecholamine vasopressors, doses higher than
(activated) group. Although these results deserve further investiga- recommended traditionally are required for goal-directed therapy

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

tion, drotrecogin alfa (activated) likely will never be administered to MAP and for normalization of oxygen-transport variables, DO2,
solely for hemodynamic support of septic shock patients because it is and VO2. Attainment of supranormal DO2 and VO2 values is difficult
an expensive agent with concerns of hemorrhage as a side effect. in most patients, even when large doses are used. Patients who
Ultimately, patients who “qualify” for drotrecogin alfa (activated) will develop supranormal DO2 and VO2 values have lower mortality, but
receive it irrespective of hemodynamic effect. whether this effect is achieved intrinsically or with exogenous
administration of vasopressors/inotropes appears inconsequential.
Therefore, goal-directed therapy to supranormal oxygen-transport
GENERAL CONCLUSIONS variables cannot be recommended because little or no benefit has
AND RECOMMENDATIONS been demonstrated. Further work is required to better elucidate the
differential effects of vasopressors on regional hemodynamic and
The choice of vasopressor or inotropic agent in septic shock should oxygen-transport values as measures of local tissue perfusion.
be made according to the needs of the patient (Fig. 25–2). The The algorithmic approach (Fig. 25–2) we recommend for use of
traditional algorithm suggests a stepwise approach, first using dopa- vasopressors and inotropes in the hemodynamic support of critically
mine and then norepinephrine. Dobutamine is added for low CO ill septic patients is consistent with the recommendations made in the
states or to optimize SvO2/ScvO2. Occasionally, epinephrine and Surviving Sepsis Campaign5 and the American College of Critical
phenylephrine are used when necessary. Although this approach is Care Medicine’s guidelines to the hemodynamic support of adult
empirical, it is used broadly in clinical practice and has been patients with sepsis (Table 25–2).4,6 Although difficult to demon-
justified by the desire to avoid strong vasoconstriction and by the strate, true differences in clinical outcomes as a result of differences in

Septic Shock

Fluid Resuscitation (order of preference):

1. Crystalloid: 500–1000 mL per 30 minutes or
2. Colloid: 300–500 mL per 30 minutes
Goal:
CVP: 8–12 mm Hg
PAOP: 12–15 mm Hg

MAP ≥ 65 mm Hg?
Yes No

Reevaluate clinical status frequently. 1. Continue uid administration.

2. Initiate norepinephrine 0.02–3 mcg/kg/min or
dopamine 2–20 mcg/kg/min titrated every 5–15 minutes.
If dysrhythmia present, use phenylephrine
0.5–9 mcg/kg/min.
3. ACTH stimulattion test. Consider hydrocortisone
200–300 mg/day x 7 days.
4. If patient meets institutional guidelines, consider
drotrecogin alfa (activated).

ScvO 2 (or SvO 2) ≥ 70 %?

Yes No

CI ≥ 3.0 I/min/m 2? 1. Red blood cell transfusion: Goal Hct ≥30%

2. Dobutamine 2–20 mcg/kg/min titrated.
Yes No FIGURE 25-2. Algorithmic approach to resuscita-
Dobutamine 2–20 tive management of septic shock. Algorithmic
mcg/kg/min titrated approach is intended to be used in conjunction with
clinical judgment, hemodynamic monitoring param-
eters, and therapy end points, as discussed in the
text. (ACTH, adrenocorticotropic hormone; CI, car-
diac index; CVP, central venous pressure; Hct,
MAP ≥ 65 mm Hg? hematocrit; MAP, mean arterial pressure; PAOP,
Yes No pulmonary artery occlusive pressure; Scvo2, central
Re-evaluate clinical status frequently. 1. Add another catecholamine vasopressor.
venous oxygen saturation; Svo2, mixed venous oxy-
2. Initiate vasopressin 0.01–0.04 units/min. gen saturation.) (Figure based on data from refer-
ences 4–6 and 19.)
 436
the pharmacologic activity of vasopressors and inotropes may exist.
For example, evidence suggests that norepinephrine, when used
ABBREVIATIONS
SECTION 2

appropriately with fluid replenishment, is safe and effective in treating

ACTH: adrenocorticotropic hormone
septic shock; it decreases mortality, particularly when started early in
the course of septic shock. It is effective in optimizing hemodynamic APACHE: Acute Physiology and Chronic Health Evaluation
variables and improving systemic and regional (e.g., renal, gastric ATP: adenosine triphosphate
mucosal, and splanchnic) perfusion. Epinephrine causes a greater CaMK: calcium/calmodulin-dependent protein kinase
increase in the cardiac index and DO2 and increases gastric mucosal
cAMP: cyclic adenosine monophosphate
flow but may not preserve splanchnic circulation adequately. Epi-
nephrine may cause a short-lived increase in lactic acid that resolves CaO2: arterial oxygen content
Cardiovascular Disorders

in 24 hours, and no difference in clinical outcome has been docu- CI: confidence interval
mented. Epinephrine may be particularly useful when used earlier in
CO: cardiac output
the course of septic shock in young patients and in those with no
known cardiac abnormalities. Unlike epinephrine, dopamine does CvO2: venous oxygen content
not increase the proportion of CO that preferentially goes to the CVP: central venous pressure
splanchnic circulation. The ability of dopamine to increase CO by no
DO2: oxygen delivery
more than 35% accompanied by a tachycardia or tachydysrhythmias
limits its utility. Dopamine, as opposed to norepinephrine, has been DO2I: oxygen delivery index
shown to worsen splanchnic VO2 and O2ER and is of limited value in ecNOS: constitutive nitric oxide synthase
improving urine production. Low-dose dopamine has not been
HR: hazard ratio
shown consistently to increase the glomerular filtration rate, does not
prevent renal failure, and actually worsens splanchnic tissue oxygen ICU: intensive care unit
utilization. Low-dose dopamine should not be used. Phenylephrine IL: interleukin
should be used when a pure vasoconstrictor is desired in patients who iNOS: inducible nitric oxide synthase
may not require or cannot tolerate the β-effects of dopamine or
L-NAME: L-arginine-methylester
norepinephrine with or without dobutamine. In patients with a high
filling pressure and hypotension, the combination of phenylephrine L-NMMA: monomethyl-L-arginine
and dobutamine may be useful. LVEF: left ventricular ejection fraction
Shortcomings of study methodology prevent the establishment of MAP: mean arterial pressure
definitive conclusions. As a consequence, published guidelines for the
management of severe sepsis and septic shock have many inconclu- NO: nitric oxide
sive recommendations (Table 25–2). Short infusions (not exceeding 2 NOS: nitric oxide synthase
hours) during studies may show differences that are not clinically O2ER: oxygen extraction ratio
significant after 24 hours, as demonstrated for epinephrine and
dobutamine. Clinically, vasopressors and inotropes are used for hours OR: odds ratio
to days. Possible confounding factors are the variable times at which PaCO2: arterial carbon dioxide pressure (tension)
studies are initiated with respect to the stage of sepsis or septic shock, PaO2: arterial oxygen pressure (tension)
the inherent differences in circulating catecholamine concentrations,
changes in receptor activity, as well as differences in prestudy dura- PAOP: pulmonary artery occlusion pressure
tion and type of exogenous catecholamine administration. pHi: intramucosal pH
Initial uncontrolled studies with vasopressin suggest a potential PLC: phospholipase
role in the management of vasopressor-refractory septic shock
PslCO2: sublingual carbon dioxide pressure
patients, although further data are needed. Vasopressin appears to
reduce the requirements of adrenergic agents, but few studies dem- RR: relative risk
onstrate complete discontinuation of these therapies. Therefore, Sao2: arterial oxygen saturation
vasopressin should be used only if response to one or two adrenergic
ScvO2: central venous oxygen saturation
agents is inadequate or as a method for reducing the dose of these
therapies. Close monitoring of ischemic events is needed. Data SvO2: mixed venous oxygen saturation
indicate that moderate doses of hydrocortisone (200–300 mg/day) SVR: systemic vascular resistance
administered over 5 to 7 days may reverse septic shock and depen-
T3: triiodothyronine
dency on vasopressor agents, particularly in patients with relative
adrenal insufficiency. As a result of a recent multicenter study, the T4: thyroxine
presence of adrenal insufficiency to indicate therapy with cortico- TNF: tumor necrosis factor
steroids is controversial and the authors believe testing of adrenal
function will not be recommended in future consensus statements. VO2: oxygen consumption
Data on optimal dosing and definitive outcomes still are needed. VO2I: oxygen consumption index
Further pharmacotherapeutic and outcomes studies are required
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71. Ichai C, Soubielle J, Carles M, et al. Comparison of the renal effects of 95. Gregory JS, Bonfiglio MF, Dasta JF, et al. Experience with phenyleph-
low to high doses of dopamine and dobutamine in critically ill patients: rine as a component of the pharmacologic support of septic shock. Crit
A single-blind randomized study. Crit Care Med 2000;28:921–928. Care Med 1991;19:1395–1400.
72. Lherm T, Troche G, Rossignol M, et al. Renal effects of low-dose 96. Reinelt H, Radermacher P, Kiefer P, et al. Impact of exogenous β-
dopamine in patients with sepsis syndrome or septic shock treated adrenergic receptor stimulation on hepatosplanchnic oxygen kinetics
with catecholamines. Intensive Care Med 1996;22:213–219. and metabolic activity in septic shock. Crit Care Med 1999;27:325–
73. Ichai C, Passeron C, Carles M, et al. Prolonged low-dose dopamine 331.
infusion induces a transient improvement in renal function in hemo- 97. Bracco DC, Revelly JP. Systemic and splanchnic haemodynamic effects
dynamically stable, critically ill patients: A single-blind, prospective, of vasopressin administration in vasodilatory shock. Intensive Care
controlled study. Crit Care Med 2000;28:1329–1335. Med 2001;27:S138.
74. Bellomo R, Bonventre J, Macias W, et al. Management of early acute 98. Klinzing S, Simon M, Reinhart K, et al. High-dose vasopressin is not
renal failure: Focus on post-injury prevention. Curr Opin Crit Care superior to norepinephrine in septic shock. Crit Care Med 2003;31:2646–
2005;11:542–547. 2650.
75. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 99. Van Haren FMP, Rozendaal FW, Van der Hoeven G. The effect of
2004;351:159–169. vasopressin on gastric perfusion in catecholamine-dependent patients
76. Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for in septic shock. Chest 2003;124:2256–2260.
the treatment of hyperdynamic septic shock? Chest 1993;103:1826– 100. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in
1831. advanced vasodilatory shock: A prospective, randomized, controlled
77. Friedrich JO, Adhikari N, Herridge MS, et al. Meta-analysis: Low-dose study. Circulation 2003;107:2313–2319.
dopamine increases urine output but does not prevent renal dysfunc- 101. Patel BM, Chittock DR, Russell JA, et al. Beneficial effects of short-
tion or death. Ann Intern Med 2005;142:510–524. term vasopressin infusion during severe septic shock. Anesthesiol
78. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in 2002;96:576–582.
patients with early renal dysfunction: A placebo-controlled random- 102. Watson D, Grover R, Anzueto A, et al. Cardiovascular effects of the
ized trial. Australian and New Zealand Intensive Care Society nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride
(ANZICS) Clinical Trials Group. Lancet 2000;356:2139–2143. (546C88) in patients with septic shock: Results of a randomized,
79. Martin C, Viviand X, Leone M, Thirion X. Effect of norepinephrine on double-blind, placebo-controlled multicenter study (study no. 144-
the outcome of septic shock. Crit Care Med 2000;28:2758–2765. 002). Crit Care Med 2004;32:13–20.
80. Groeneveld AB, Girbes AR, Thijs LG. Treating septic shock with 103. Lopez A, Lorente JA, Steingrub J, et al. Multiple-center, randomized,
norepinephrine. Crit Care Med 1999;27:2022–2023. placebo-controlled, double-blind study of the nitric oxide synthase
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inhibitor 546C88: Effect on survival in patients with septic shock. Crit 113. Hannemann L, Reinhart K, Meier-Hellmann A, et al. Dopexamine
Care Med 2004;32:21–30. hydrochloride in septic shock. Chest 1996;109:756–760.

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104. Bakker J, Grover R, McLuckie A, et al. Administration of the nitric oxide 114. Smithies M, Yee TH, Jackson L, et al. Protecting the gut and the liver
synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by in the critically ill: Effects of dopexamine. Crit Care Med 1994;22:789–
intravenous infusion for up to 72 hours can promote the resolution of 795.
shock in patients with severe sepsis: Results of a randomized, double- 115. Kiefer P, Tugtekin I, Wiedeck H, et al. Effect of a dopexamine-induced
blind, placebo-controlled multicenter study (study no. 144-002). Crit increase in cardiac index on splanchnic hemodynamics in septic shock.
Care Med 2004;32:1–12. Am J Respir Crit Care Med 2000;161:775–779.
105. Park BK, Shim TS, Lim CM, et al. The effects of methylene blue on 116. Seguin P, Laviolle B, Guinet P, et al. Dopexamine and norepinephrine
hemodynamic parameters and cytokine levels in refractory septic versus epinephrine on gastric perfusion in patients with septic shock:
shock. Korean J Intern Med 2005;20:123–128. A randomized study [NCT00134212]. Crit Care 2006;10:R32.

Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock

106. Kirov MY, Evgenov OV, Evgenov NV, et al. Infusion of methylene blue 117. Meier-Hellmann A, Bredle DL, Specht M, et al. Dopexamine increased
in human septic shock: A pilot, randomized, controlled study. Crit splanchnic blood flow but decreases gastric mucosal pH in severe
Care Med 2001;29:1860–1867. septic patients treated with dobutamine. Crit Care Med 1999;27:2166–
107. Donati A, Conti G, Loggi S, et al. Does methylene blue administration 2171.
to septic shock patients affect vascular permeability and blood volume? 118. Ralph CJ, Tanser SJ, Macnaughton PD, et al. A randomized controlled
Crit Care Med 2002;30:2271–2277. trial investigating the effects of dopexamine on gastrointestinal func-
108. Memis D, Karamanlioglu B, Yuksel M, et al. The influence of methy- tion and organ dysfunction in the critically ill. Intensive Care Med
lene blue infusion on cytokine levels during severe sepsis. Anaesth 2002;28:884–890.
Intensive Care 2002;30:755–762. 119. Leone M, Boyadjiev I, Boulos E, et al. A reappraisal of isoproterenol in
109. O’Brien A, Clapp L, Singer M. Terlipressin for norepinephrine-resis- goal-directed therapy of septic shock. Shock 2006;26:353–357.
tant septic shock. Lancet 2002;359:1209–1210. 120. De Groot LJ. Non-thyroidal illness syndrome is a manifestation of
110. Morelli A, Rocco M, Conti G, et al. Effects of terlipressin on systemic hypothalamic-pituitary dysfunction, and in view of current evidence,
and regional haemodynamics in catecholamine-treated hyperkinetic should be treated with appropriate replacement therapies. Crit Care
septic shock. Intensive Care Med 2004;30:597–604. Clin 2006;22:57–86.
111. Albanese J, Leone M, Delmas A, et al. Terlipressin or norepinephrine 121. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of
in hyperdynamic septic shock: A prospective, randomized study. Crit recombinant human activated protein C for severe sepsis. N Engl J
Care Med 2005;33:1897–1902. Med 2001;344:699–709.
112. Morelli A, De Castro S, Teboul JL, et al. Effects of levosimendan on 122. Monnet X, Lamia B, Anguel N, et al. Rapid and beneficial hemody-
systemic and regional hemodynamics in septic myocardial depression. namic effects of activated protein C in septic shock patients. Intensive
Intensive Care Med 2005;31:628–644. Care Med 2005;31:1573–1576.
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 441

C HAP T E R

26 Hypovolemic Shock

BRIAN L. ERSTAD

resuscitation to maintain circulating blood volume is a common

KEY CONCEPTS principle in managing all forms of shock.

 Plasma does not have to be lost from the body for hypovole-
mic shock to occur. EPIDEMIOLOGY
 Patients may die of hypovolemic shock despite having normal Because shock is not a reportable category by state and federal
serum electrolyte concentrations.
agencies that track causes of death, the incidence is unknown. Esti-
 Although the Starling equation of fluid transport is useful for un- mates of deaths due to shock are complicated by differences in
derstanding the factors involved in fluid shifting between com- definitions and classification systems. Part of the problem is defining
partments, it is not a practical tool for use in the clinical setting. when progressive circulatory insufficiency results in the loss of nor-
mal compensatory responses by the body, which could reverse the
 Patients may have complications and death as a result of re- processes leading to irreversible organ dysfunction. This loss of
perfusion injury as well as the initial insult. appropriate compensation varies from patient to patient and is not
 The clinical presentation of patients with hypovolemic shock always readily apparent during the initial patient presentation. There-
can vary substantially depending on concomitant disease fore, forms of hypovolemic shock, such as hemorrhagic shock, are
states, medications, and cause of hypovolemia. subsumed by more readily identifiable categories of death, such as
accidental injuries and homicides. Crude and conservative estimates
 The initial monitoring of a patient with suspected volume de- of death due to hypovolemic shock are available for some of its forms.
pletion always should include vital signs, urine output, mental At least 100,000 deaths each year in the United States are due to
status, and physical examination. perioperative bleeding,1 and approximately 5,000 deaths are due to
 The need for intravenous (versus oral) rehydration in children hyperthermia and dehydration associated with heat exposure.2 The
often is overestimated. figures are much higher when considered on a global basis. For
example, electrolyte depletion and dehydration due to diarrheal
Crystalloid (sodium-containing) solutions should be used for disease result in approximately two million deaths each year in
most forms of circulatory insufficiency that are associated with children younger than 5 years.3 The most liberal estimates of death
hemodynamic instability. include all causes of circulatory failure (i.e., the last stage of shock).

Crystalloid solutions are preferred over colloid solutions for cir-
culatory insufficiency as a result of decreased plasma volume. ETIOLOGY
 With adequate fluid administration, vasoactive medications
usually are not needed for the patient with circulatory insuffi-  Hypovolemic shock may result from blood loss (plasma and red
ciency as a result of decreased plasma volume. blood cells) due to trauma, surgery, or internal hemorrhage or from
plasma loss due to fluid sequestered within the body or lost from the
body (Table 26–1). In some cases, such as in postoperative patients,
a number of these problems occur at the same time. For example, a
This chapter discusses the assessment and management of hypovo-
patient may have blood loss secondary to trauma or surgery, with
lemic shock. Spinal shock resulting from loss of sympathetic activity
additional fluid being third spaced (e.g., as tissue edema in the
and anaphylactic shock resulting from increased vascular perme-
gastrointestinal tract with a concomitant ileus) and lost through a
ability often are considered separately from hypovolemic shock
because fluid loss from the body is not necessary for their occur-
rence. Although these forms of shock are not discussed in detail, it TABLE 26-1 Causes of Hypovolemic Shock a
is important to note that the initial therapy for both is the same as
Decreased blood (plasma + red blood cells) volume
for hypovolemic shock (i.e., adequate volume replacement) because
External: Surgery or trauma
circulating volume is decreased. In this regard, adequate fluid Internal (e.g., gastrointestinal bleeding)
Decreased plasma volume
External: Losses from urine, gastrointestinal tract (e.g., vomiting, nasogastric
suctioning, fistula, diarrhea), lungs, or skin (including thermal injury)
Learning objectives, review questions, Internal (decreased oncotic pressure or increased capillary permeability): fluid
and other resources can be found at accumulation in bowel, peritoneal or pleural cavities
www.pharmacotherapyonline.com. a
Shock may result from various combinations of blood and plasma volume losses listed (i.e., causes
are not mutually exclusive).

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 442
high-output gastrointestinal fistula postoperatively. As this example immediately to hepatic cells that may function for several hours
of third-spaced fluid indicates, fluid (i.e., plasma) does not have to after injury.4 Left unmitigated, cell death occurs.
SECTION 2

be lost from the body for a person to develop hypovolemic shock, The body attempts to compensate for volume depletion begin-
although the fistula output would clearly aggravate the situation. ning with autoregulatory changes involving smaller blood vessels.
Approximately 20 L of fluid is secreted and reabsorbed daily in the When the cause of circulatory insufficiency continues unabated,
gastrointestinal tract, so it is not surprising that volume loss could local mechanisms eventually fail to provide adequate compensation,
be substantial depending on the location of the fistula and function and macrocirculatory changes ensue. Approximately 75% of blood
of the tract preceding the fistula. volume is contained in venous capacitance vessels, with gravity
Dehydration may result from primary water deficiency, usually being the major impedance to flow back to the heart.4 With
because of decreased intake, but in some instances (e.g., diabetes increasing volume depletion, blood flow to the heart (preload) is
Cardiovascular Disorders

insipidus) may result from increased losses of water. With most forms decreased, with subsequent activation of baroreceptors and
of dehydration, such as those caused by diarrheal disease and heat- chemoreceptors leading to sympathetic discharge. Also, fluid shift-
related illness, a combination of inadequate intake and higher than ing from the interstitial space to the intravascular space occurs
normal losses occurs. In general, the term dehydration implies intra- through a phenomenon known as transcapillary refill, and hor-
cellular and interstitial fluid depletion, in contrast to volume depletion, mones (e.g., adrenocorticotropic hormone, angiotensin, catechol-
which implies extracellular, and particularly intravascular, sodium amines, and vasopressin) that cause sodium and water retention by
and water loss. In the case of primary water deficit, cell dehydration the kidneys are released. The phenomenon of transcapillary refill
occurs. Initially, the patient may be thirsty and possibly have some means that the body can have fluid losses exceeding normal plasma
mental status changes, such as confusion. If cellular dehydration volume. These responses cause alterations in stroke volume, heart
occurs slowly, intracellular substances, referred to as idiogenic osmols, rate, and peripheral vascular resistance so that blood pressure and
develop that limit progressive complications (e.g., cerebral edema or hence tissue perfusion can be maintained.
coma). Death due to primary water deficit, if it occurs, is usually a The microcirculatory changes associated with shock are complex
result of delayed circulatory failure. With combined water and salt and difficult to study. Although some mediators such as endothelin-
deficiencies, such as might occur with gastrointestinal (e.g., diarrhea) 1 cause vasoconstriction, other mediators, such as adenosine and
and skin losses (e.g., heat stroke), interstitial and intravascular deple- nitric oxide, yield vasodilation.5 These changes result in hypoperfu-
tion is an early occurrence. Fortunately, dehydration is relatively easy sion or hyperperfusion depending on the area. As these microcircu-
to prevent with routine vigilance and water replacement compared latory changes fail to maintain adequate organ perfusion, more
with some of the other causes of shock. widespread sympathetic nervous system activation and vasocon-
striction ensue. Failure to respond to sympathetic stimulation and
fluid administration is indicative of the vasodilation that occurs in
PATHOPHYSIOLOGY the final phase of circulatory failure leading to death.
The factors involved in fluid shifting between the intravascular and
 Hypovolemic shock often is described in terms of monitoring interstitial spaces are described by the modified Starling equation:
parameters such as lowered blood pressure, but patients with shock
may die despite normal surrogate markers of circulatory insuffi- JV = Kf,c [(Pc – Pt) – [σ(πc – πt)]
ciency. Therefore, an appropriate definition should mention the
where JV = net transvascular flow rate (cannot be measured in the
underlying problem, which is inadequate tissue perfusion resulting
clinical setting)
from circulatory failure. In the case of hypovolemic shock, the cause
of the altered perfusion is fluid (or volume) depletion resulting Kf,c = capillary filtration coefficient for fluids (cannot be meas-
from trauma, surgery, thermal injury, or some form of dehydration. ured in the clinical setting)
Figure 26–1 provides a simplified view of the pathophysiology of Pc = capillary hydrostatic pressure (indirectly estimated in the
circulatory insufficiency. Cell damage and death may occur from clinical setting, e.g., pulmonary artery occlusive pressure)
the primary insult or from reperfusion injury. The latter problem is
associated most frequently with trauma and blood loss that cause Pt = tissue hydrostatic pressure (cannot be measured in the
the release of a multitude of mediators of inflammation and injury clinical setting)
that have complex interactions. Cells have varying responses to σ = reflection coefficient for proteins (cannot be measured in the
hypoxia, ranging from astrocytes that quit functioning almost clinical setting)

Volume depletion

Recovery Reperfusion Microcirculatory

impairment
with cellular ischemia

Recovery Reperfusion Local ischemia Injury

Delayed recovery Reperfusion Regional ischemia Injury

Inflammation/injury Reperfusion Global ischemia Injury

Death Death

FIGURE 26-1. Pathophysiology of circulatory insufficiency.

 443
πc = plasma colloid osmotic pressure (not usually measured in the

CHAPTER 26
clinical setting, but technology is available) Autoregulation at
πt = tissue colloid osmotic pressure (cannot be measured in the microcirculatory level
clinical setting)
Proteins act as oncotic agents in each of these spaces to attract Activation of baroreceptors
fluid, whereas hydrostatic forces push fluid into or out of the vessels. and chemoreceptors
The equation has distinct permeability values for water and protein causing
sympathetic discharge
because each crosses the vascular membrane at a different rate. The
values for the variables listed in the equation are not the same for +
capillaries in all parts of the body. For example, on a scale from 0 to Transcapillary refill

Hypovolemic Shock
1 with 0 being free passage of protein and 1 being impermeable to +
protein, the typical value for the reflection coefficient in most Renin, vasopressin, ACTH,
capillaries is >0.9. However, in the pulmonary capillaries the value aldosterone release
is closer to 0.7 and approaches 0 in inflammatory states associated
with increased capillary permeability.6 As the value approaches 0, ↑HR
the capillaries are freely permeable not only to the usual fluid and
electrolytes but to plasma proteins such as albumin. Because albu- Further activation of
min accounts for approximately 80% of the plasma oncotic pres- baroreceptor and
sure, its free passage into the interstitial space effectively negates its chemoreceptors
intravascular oncotic benefit.  Although the Starling equation is +
useful to practitioners in terms of understanding the factors Maximization of
involved in fluid shifting between compartments, the rate and transcapillary refill
direction of transvascular flow cannot be calculated accurately in
the clinical setting because most factors cannot be measured directly ↑↑HR,↑PVR, minimal
and the values for the factors vary in different capillaries in the body. change in CO and BP, ↑RR
The body’s compensatory mechanisms may have beneficial and
harmful consequences. For example, cardiac output can be increased
Sympathetic and
substantially by increases in stroke volume or heart rate. Although transcapillary refill
this may be useful for providing blood flow to inadequately perfused effects maximal
tissues, it may cause large increases in oxygen consumption by the
+
heart that could aggravate preexisting ischemia in patients with
Blood flow to heart and
underlying coronary artery disease (CAD). Another example is the
brain prioritized
sympathetic nervous system–mediated vasoconstriction that causes (at the expense of
blood to shift from the skin, skeletal muscle, and some internal organs other organs)
such as the kidneys and gastrointestinal tract to organs (e.g., heart and
brain) that are less tolerant of inadequate flow. If the vasoconstriction
↑↑↑HR, ↑↑PVR,
continues unabated, the hypoperfused organs eventually become
↓CO and ↓BP, ↑↑RR
damaged. Figure 26–2 provides an overview of the compensatory
changes that occur with a loss of circulating blood volume.
 In addition to the more acute implications of hypovolemia Global ischemia with
and attendant complications, reperfusion damage is likely to occur decompensation
particularly after prolonged resuscitation attempts. In addition to Continued decompensation
oxygen free radical damage of cell membranes, a number of cellular
(e.g., white blood cells and platelets) and humoral (e.g., procoagu- Global injury
lants, anticoagulants, complement, and kinins) components are
activated, causing the release of other inflammatory mediators.5 The Death
resulting reperfusion injury may range from readily reversible organ
dysfunction to multiple-organ failure and death.
Although the basic pathophysiology is similar for the various FIGURE 26-2. Activation of compensatory mechanisms with loss of
circulatory volume. Certain stages may be absent depending on a number
causes of hypovolemic shock, there are unique considerations relative
of factors, such as age, preexisting disease states, and cause of circulatory
to each. For example, whereas isolated head injuries associated with
insufficiency. (ACTH, corticotropin; BP, blood pressure; CO, cardiac output;
trauma typically do not result in substantial blood loss or shock, HR, heart rate; PVR, peripheral vascular resistance; RR, respiratory rate.)
pelvic fractures may sequester several liters of blood as hematoma
formation.5 Patients with traumatic or thermal injuries, as well as
postoperative patients, may have substantial fluid accumulation in Packed red blood cell transfusions may be needed to increase the
sites where the fluid cannot be readily transferred back into blood oxygen-carrying capacity of the blood because oxygen transport is a
vessels (i.e., third-spaced fluid) for maintaining pressure. With these function not only of cardiac output but also of hemoglobin concen-
types of injuries, prompt control of compressible bleeding sources tration and saturation and of hemoglobin affinity for oxygen.
with rapid patient transfer to the hospital for definitive treatment may Clotting factors and platelets are also lost in hemorrhage. The
preclude the cascade of events leading to shock. Indeed, with trauma resulting bleeding problems may be aggravated by the dilutional
patients, a “scoop and run” approach that places a priority on rapid effect of fluid resuscitation on clotting factor activity. Fresh-frozen
transport to a hospital is used by most urban hospitals. plasma that contains necessary clotting factors and platelets is often
In the case of hemorrhagic shock, prompt attention must be needed in massive blood loss to restore adequate coagulation. On
given to cell as well as plasma losses. Red blood cells lost during the the other hand, trauma patients are at increased risk for deep vein
bleeding episode may lead to ischemic damage in vital organs. thrombosis and pulmonary embolism caused by multiple factors,
 444
including vessel damage, abnormal blood flow patterns, and the ■ Blood pressure would be decreased (e.g., systolic blood pres-
hypercoagulable state associated with injury. Therefore, some form sure <90 mm Hg).
SECTION 2

of venous thromboembolism prophylaxis usually is indicated in ■ Mental status changes or unconsciousness may occur.
multiple-trauma patients or patients with severe single-system inju-
■ Agitation may be present if the patient is conscious.
ries (e.g., spinal cord damage).
The pathophysiology becomes more complicated if the severity of ■ Body temperature would be low or normal [e.g., 36° to 37°C
shock is sufficient to require admission to the intensive care unit (96.8° to 98.6°F)] in the absence of concomitant infection.
(ICU) after initial resuscitation or surgery. Most patients admitted to Laboratory Tests
the ICU have a systemic inflammatory response syndrome (SIRS), ■ Sodium and chloride concentrations usually are high with
which is the body’s response to injury. This syndrome is defined by a acute depletion but may be low or normal depending on type
Cardiovascular Disorders

number of hypermetabolic changes reflected in the patient’s tempera- of fluid intake.

ture, white blood cell count and differential, and respiratory and heart
rates. The stress response involves complex interactions between the ■ The ratio of blood urea nitrogen (BUN) to creatinine is likely
nervous system and immunomodulating substances and has similar to be elevated initially, but the creatinine level would increase
(if not the same) harmful and helpful consequences described with as renal dysfunction occurs.
reperfusion following shock. If the underlying problems are left ■ The complete blood count should be normal in the absence of
untreated, the patient with SIRS may develop multiple-organ dys- concomitant disease states such as infection; in hemorrhagic
function syndrome (MODS) during the final stages of illness. shock, the red cell count, hemoglobin, and hematocrit would
decrease over time.
■ With more severe volume depletion, other organs may
CLINICAL PRESENTATION become dysfunctional, which may be reflected in laboratory
testing (e.g., elevated transaminase levels with hepatic dys-
 The initial presentation of patients with suspected volume deple-
function).
tion can vary markedly depending on factors such as age, concomi-
tant disease states and medications, and the etiology and rapidity of Other Diagnostic Tests
depletion (see Clinical Presentation box). Intravascular depletion as a ■ Urine output would be decreased to <0.5 to 1 mL/h.
consequence of blood loss is signified by postural vital sign changes,
and such measurements should be performed unless the diagnosis is The diagnosis of dehydration and intravascular depletion in chil-
obvious, as in the case of bleeding associated with trauma. Early signs dren is complicated by difficulties in obtaining an accurate history.
and symptoms of dehydration and intravascular depletion caused by However, some excellent resources are available for healthcare pro-
gastrointestinal or urinary losses often are relatively nonspecific. viders, such as the Centers for Disease Control and Prevention
Plasma volume losses of <10 mL/kg of body weight usually are (CDC) guidelines (www.CDC.gov), which discuss the evaluation and
associated with minor signs and symptoms of distress. Larger losses management of diarrhea in patients of all ages. In younger children,
are not likely to be well tolerated (Table 26–2), particularly in patients parental observations are important for estimating fluid deficits and
older than 65 years. An 18-year-old athlete and a 65-year-old seden- deciding whether hospitalization is necessary. Fortunately, prospec-
tary individual are likely to have much different responses to a similar tive data suggest that parental histories are predictive of acidosis and
amount of fluid loss. The young patient may lose one fourth of his or the need for hospitalization.7  Regardless of patient age or preex-
her circulating blood volume with minimal changes in arterial blood isting conditions, the initial monitoring of a patient with suspected
pressure and a relatively low heart rate. However, the elderly patient volume depletion should include the following noninvasive parame-
may have orthostatic changes in blood pressure that are not well
tolerated by organs such as the kidneys.4 Unfortunately, this same
elderly patient may not have common signs and symptoms of volume TABLE 26-2 Acute Circulatory Insufficiency: Initial Presentation
depletion, such as skin turgor changes or thirst, but instead may have and Therapy a
more subtle changes (e.g., mental status alterations). Mild Severe
Plasma/blood loss 10 mL/kg adult 30 mL/kg adult
CLINICAL PRESENTATION OF 20 mL/kg child 35 mL/kg child
HYPOVOLEMIC SHOCK Mental status/level of None—small changes Marked changes (e.g.,
consciousness (e.g., anxious, irritable) confusion to
General unconsciousness)
■ The initial presentation of adult patients with suspected Vital signs/orthostatic Minor changes Marked changes
volume depletion could vary markedly depending on factors changes
such as age, concomitant disease states and medications, and Therapy 20 mL/kg lactated Ringer Lactated Ringer IV as
IVa over 10–15 min rapidly as possible
the etiology and rapidity of depletion.
Unlikely to need blood until response in adult,
■ Plasma volume losses of <10 mL/kg of body weight usually cell replacement even then decrease rate of
are associated with minor signs and symptoms of distress. if hemorrhagic loss infusion 20 mL/kg lac-
Symptoms tated Ringer IV in child
(repeat quickly if mini-
■ Patients may present with thirst, nausea, anxiousness, weak- mal response); likely
ness, light-headedness, and dizziness. to need blood cell
■ Patients may report scanty urine output and dark-yellow urine. replacement and sur-
gery if hemorrhagic
Signs
a
Patients may have intermediate degrees of volume loss in addition to those listed, but the amount
With more severe volume loss: of loss often is difficult to quantify. The presentations may also vary greatly in patients with similar
amounts of loss (young athlete vs sedentary, elderly person). In patients particularly prone to
■ Patients would have marked increases in heart rate (e.g., >120 complications associated with fluid overload, the fluid can be administered in multiple smaller
beats/min) and respiratory rate (e.g., >30 breaths/min). boluses titrated to clinical response. See text for a more in-depth discussion of some of the guidelines
in this table.
 445

Level of consciousness, return of blood flow to the extremity after removal of compression)
to cold, cyanotic discoloration with impaired refill may not occur.

CHAPTER 26
thirst, vomiting
Also, dry mucous membranes in elderly patients may be caused by
Skin color, capillary Heart rate mouth breathing or medications and not by fluid depletion.
refill, temperature
Urine output (bladder
Ventilation,
respiratory rate
catheter if signs/
symptoms of shock not TREATMENT
readily reversible; can also

Blood pressure
be used for assessing
core body temperature Hypovolemic Shock
(intra-arterial if and presence of hematuria
if trauma patient)
■ DESIRED OUTCOME

Hypovolemic Shock
signs/symptoms of
shock not readily
reversible)
The desired outcomes of therapy for circulatory insufficiency that
Pulse oximetry has led to hypovolemic shock are to prevent further progression of
the disease with subsequent organ damage and, to the extent
FIGURE 26-3. Noninvasive assessment of circulatory insufficiency. possible, to reverse organ dysfunction that has already taken place.

ters: vital signs, urine output, mental status, and physical examina-
tion (Fig. 26–3).
■ GENERAL APPROACH TO TREATMENT
Although the presenting signs and symptoms of circulatory Milder forms of volume depletion may be managed in outpatient
insufficiency are variable, patients usually have decreased blood settings. For example, supplemental fluids can be added to the usual
pressure, increased heart and respiratory rates, and a normal or estimated daily requirements of 30 to 35 mL/kg in patients older
low–normal temperature (e.g., 36° to 37°C [96.8° to 98.6°F]) in the than 12 years with dehydration. Commercially available carbohy-
absence of infection, exposure to extremes of temperature, and drate/electrolyte drinks generally are more palatable than water and
medications that impair thermoregulation. As mentioned earlier, may promote earlier recovery. The rationale for combining carbo-
recordings of vital signs must be interpreted in light of known or hydrates with sodium is based on the cotransport absorption
suspected baseline conditions. For example, alcohol, β-blockers, mechanism in the intestinal tract. With diarrheal states in particu-
butyrophenones such as haloperidol, diuretics, and medications lar, sodium absorption is impaired. Because water follows sodium,
with anticholinergic effects may impair thermoregulation.8 Medica- the diarrhea is likely to continue despite oral crystalloid fluid
tions such as β-blockers and calcium channel blockers may alter administration until the intestinal pathology resolves. However,
resting blood pressure and heart rate, as well as the subsequent when dextrose and sodium are combined in 1:1 equimolar
response to therapeutic interventions. amounts, both are absorbed via the cotransport mechanism, which
Although a blood pressure reading of 110/70 mm Hg (systolic/ also allows for absorption of water. This concept forms the basis for
diastolic) may be acceptable in many patients, it may be inadequate the World Health Organization’s (WHO) oral rehydration solu-
in a patient with preexisting hypertension who normally has a blood tion, which contains 75 mmol/L of dextrose, 75 mmol/L of sodium,
pressure of 170/105 mm Hg. At the other extreme, patients with 20 mmol/L of potassium, 65 mmol/L of chloride, and 10 mmol/L of
very low blood pressure may have inaudible or inaccurate determi- citrate for a total osmolarity of 245 mOsm/L.3 Commercially
nations with cuff (sphygmomanometric) measurements. Chapter available over-the-counter rehydration drinks for children in the
15 details blood pressure measurement (e.g., cuff size, position). In United States also have an osmolarity of approximately 250 mOsm/
this case, intraarterial monitoring is indicated. As a noninvasive L but typically contain 50 mEq/L or less of sodium, and the
tool, the respiratory rate may correlate better than the heart rate dextrose-to-sodium ratio often is 3:1. How these differences
with volume loss, but respiratory rate often is not used.4 The between commercially available formulations and the WHO rehy-
respiratory rate may be elevated because of anxiety or as a compen- dration formula might affect hospitalization rates is unclear, but
satory mechanism for the metabolic acidosis caused by lactic acido- attempts to alter the commercially available products to make them
sis associated with poor tissue perfusion. more consistent with the WHO formula are not recommended.3
Although the kidneys continually produce urine, the bladder Improper home mixing of a previous WHO formulation led to
stores the urine for intermittent elimination. For the initial diagno- cases of hypernatremia.9 Outpatient rehydration of children usually
sis and management of acute circulatory insufficiency, a catheter is recommended for those with uncomplicated (e.g., vomiting less
can be inserted into the bladder for measuring urine output. In than 48 hours) acute gastroenteritis and relatively mild dehydration
contrast to thirst, which is a relatively insensitive indicator of after the exclusion of more severe illnesses such as bowel obstruc-
volume depletion, urine output is generally diminished with inade- tion.  The need for intravenous (IV) rehydration often is overes-
quate fluid administration and increases with appropriate resuscita- timated. Randomized studies conducted in pediatric emergency
tion. This presumes, of course, that acute renal failure or departments have found oral rehydration to be at least as effective
medications such as diuretics are not altering the expected response. as IV rehydration,10,11 and in one study children receiving oral
Adults should produce at least 0.5 to 1 mL/kg/h of urine, whereas rehydration for acute gastroenteritis had shorter lengths of stay
children up to 12 years of age should produce at least 1 mL/kg/h (2 than those receiving IV rehydration (225 versus 358 minutes; P
mL/kg/h if younger than 1 year). <0.01). Furthermore, there was a trend toward decreased hospital
Mental status changes associated with volume depletion, if admissions in the oral compared with the IV rehydration group
present, may range from subtle fluctuations in mood to uncon- (11% versus 25%; P = 0.2).11
sciousness. Although the latter finding typically is indicative of more Hospitalization is indicated for more severe forms of circulatory
severe depletion, less dramatic findings should not be interpreted as insufficiency. If access to the circulatory system for administration
indicating mild fluid deficits. Losses of 4 L of plasma volume may be of fluids and medication was not obtained prior to hospitalization,
associated only with lassitude in an otherwise healthy adult patient.4 this should be a priority. Venous access generally is obtained during
Similar interpretation difficulties must be considered when per- the preliminary examination process that includes the ABCs of life
forming the initial physical examination. An orderly progression support (i.e., airway, breathing, and circulation), assessment of vital
from warm, reddish skin with appropriate capillary refill (rapid signs and mental status, and determination of urine output after
 446

TABLE 26-3 Fluid Distribution and Major Indications a

SECTION 2

Fluid Intracellular Interstitial Intravascular Major Indication

Normal saline or lactated Ringer None 750 mL 250 mL Intravascular repletion in symptomatic patients
3% sodium chloride → 750 mL+ 250 mL+ Small amounts (e.g., 250 mL) by intermittent infusion have been used in
conjunction with normal saline or lactated Ringer for intravascular depletion
in patients with head trauma
5% dextrose/0.45% sodium chloride 333 mL 500 mL 167 mL Maintenance fluid in euvolemic or dehydrated (sodium and water loss)
patients with mild signs/symptoms of volume depletion
5% dextrose 667 mL 250 mL 83 mL Dehydration (primarily water loss) in patients with mild signs/symptoms of
volume depletion
Cardiovascular Disorders

5% albumin None None 1,000 mLb Intravascular repletion in symptomatic patients

25% albumin → → 1,000 mL+++b Usually given by intermittent infusion of small volumes (e.g., 50–100 mL) or
by continuous infusion titrated to response in hypovolemic patients with
excess interstitial fluid accumulation
a
Based on administration of 1 L of each solution for comparative purposes only. This amount of fluid, particularly for 3% saline and 25% albumin, would be inappropriate and likely harmful if given over a
short period of time. Numbers are approximations; arrows indicate direction of fluid shift and plus signs indicate fluid pulled from other compartments.
b
After distribution and attainment of steady-state conditions, 60% of albumin (and associated fluid) is in interstitial compartment and 40% is in intravascular compartment.

catheterization. Whenever large-volume fluid resuscitation is (e.g., varying concentrations of dextrose-in-water or sodium chlo-
expected, as in hemorrhagic shock, at least two IV catheters are ride), respectively.14 Therefore, blood samples for lactate concentra-
desirable. Because flow is a function of tubing length and catheter tion determinations should be drawn from a catheter that has been
diameter, large-bore peripheral IV lines are preferred over longer cleared adequately (e.g., 5 mL) of infusate after temporarily stop-
central lines. Unfortunately, vascular access in some patients may be ping the fluid infusion.
problematic, and other routes (e.g., intraosseous infusion in chil- A number of pharmacologic therapies show promise in animal
dren) may be necessary. One interesting method of fluid adminis- models of shock, but few demonstrate success in subsequent trials
tration that has been investigated in elderly patients is subcutaneous involving patients with shock. In large part this is a result of the lack
infusion, or hypodermoclysis. This route of administration is not of acceptable animal models of shock that mimic the pathophysiol-
used commonly, probably because of concerns of adverse effects ogy of patients.15 In cases in which a relevant animal model is
that were found in early studies that used excessively hypotonic or available, care must be taken when extrapolating the information to
hypertonic solutions. Although alternative methods of fluid admin- forms of shock other than the one under study. This may be the
istration, such as hypodermoclysis, are desirable, well-conducted problem with naloxone, which has been shown to raise blood
trials are needed before such methods can be recommended for pressure in some studies of shock but not in others. In light of the
routine use. lack of other demonstrated pharmaceutical interventions, fluids
remain the mainstay of therapy, although their use is not devoid of
■ PHARMACOLOGIC THERAPY controversy.
Larger-molecular-weight solutions (i.e., >30,000) known as col-
Dextrose-in-water solutions may be appropriate for uncompli- loids have been recommended in conjunction with or as replace-
cated dehydration caused by water deprivation, but crystalloid ments for crystalloid solutions. Examples of colloids used as plasma
(sodium-containing) solutions should be used for forms of circula- expanders include albumin, hetastarch, and dextran. Albumin is
tory insufficiency that are associated with hemodynamic instability. known as a monodisperse colloid because all its molecules are of the
In the latter situation, IV solutions with sodium concentrations same molecular size and weight (~67,000), whereas hetastarch and
approximating normal serum sodium values usually are indicated dextran solutions are polydisperse compounds with molecules of
because they cause more expansion of the intravascular and intersti- varying molecular size that are roughly proportional to molecular
tial spaces compared with dextrose solutions (Table 26–3). Lactated weight [average molecular weights of 450,000 (range 10,000 to 1
Ringer and normal saline solutions are examples of such crystalloid million) for hetastarch, 40,000 (range 10,000 to 90,000) for dextran
solutions, although lactated Ringer solution is typically the preferred 40, or 70,000 to 75,000 (range 20,000 to 200,000) for dextran 70 or
solution for major bleeding because it is unlikely to cause the dextran 75, respectively]. In light of these differences, colloid
hyperchloremic metabolic acidosis that is seen with infusion of large
amounts of normal saline (Table 26–4). A “large” amount of fluid
does not mean a single bolus volume typically used as fluid challenge TABLE 26-4 Adverse Effects of Plasma Expanders: Crystalloids
in a critically ill patient. An isolated bolus (e.g., 250 to 500 mL) in a
young adult trauma patient is unlikely to cause a substantial change Normal saline
Primarily extensions of pharmacologic actions (e.g., fluid overload, dilutional
in blood pressure or acid–base balance.12 Therefore, multiple fluid
coagulopathy)
boluses usually are needed in such patients to achieve hemodynamic Hyperchloremic metabolic acidosis (has 154 mEq/L of chloride)
stability in the perioperative period. Hypernatremia (has 154 mEq/L of sodium)
Although lactated Ringer solution does contain lactate, it does Lactated ringer
not cause substantial elevations in circulating lactate concentrations Primarily extensions of pharmacologic actions (e.g., fluid overload, dilutional
when used as a resuscitation solution.13 Once adequate plasma coagulopathy)
volume has been restored by fluid administration, the body can Hyponatremia (has 130 mEq/L of sodium)
readily clear the blood of the excess lactate that has accumulated Aggravation of preexisting hyperkalemia (has 4 mEq/L of potassium)
from both anaerobic metabolism and from lactated Ringer solution. Hypertonic saline
However, blood samples for lactate determinations drawn through Primarily extensions of pharmacologic actions (e.g., fluid overload, dilutional
coagulopathy; intracellular volume depletion)
catheters (arterial and venous) that have not been cleared appropri-
Hypernatremia (has 513 mEq/L of sodium)
ately may have spurious increases or decreases in lactate concentra- Hyperchloremia (has 513 mEq/L of chloride)
tions because of retained lactated Ringer and nonlactated solutions
 447
comparisons are based on weight-averaged [(number of molecules cardiopulmonary bypass surgery and patients with intracranial
at each weight × particle weight)/total weight of all molecules] or bleeding. Hetastarch may aggravate bleeding through mechanisms

CHAPTER 26
number-averaged (arithmetic mean of all particles weights) molec- specific to this colloid (e.g., decreased factor VIII activity). These
ular weight.16 The size and weight differences of the colloids have mechanisms have not been well elucidated and often are difficult to
important implications for the distribution of the products because distinguish from the dilutional effects on clotting factors caused by
lower-molecular-weight substances are retained in the intravascular all plasma expanders. Hetastarch may cause elevations in serum
space for a shorter period of time as a result of more rapid leakage amylase concentrations but does not cause pancreatitis.
across the vessel membrane. The theoretical usefulness of colloids is Dextran 40, dextran 70, and dextran 75 are available for use as
based on their increased molecular weight (average molecular plasma expanders in the United States. The numbers refer to the
weight in the case of hetastarch and dextran) that corresponds to average molecular weight of the solutions. In general, dextran

Hypovolemic Shock
increased intravascular retention time in the absence of increased solutions are not used as often as albumin or hetastarch solutions
capillary permeability compared with crystalloids. Even in patients for plasma expansion, possibly because of concerns related to
with intact capillary permeability, the colloid molecules eventually aggravation of bleeding (i.e., anticoagulant actions related to inhib-
will leak through the membrane. In the case of albumin with a iting stasis of microcirculation) and anaphylaxis that is more likely
distribution half-life of 15 hours in normal subjects, approximately to occur with the higher-molecular-weight solutions. However,
60% of administered albumin molecules (and associated fluid) both these concerns can be reduced if proper attention is paid to
would be shifted to the interstitial space within 3 to 5 days of patient selection and, in the case of bleeding, published dosing
exogenous administration. In patients with altered permeability guidelines with regard to the amounts of these products that should
(e.g., acute respiratory distress syndrome), the leakage of albumin be infused. There are few comparative trials involving the dextran
from the intravascular to the interstitial space may occur within solutions, but the intravascular expansion within hours after infu-
hours, not days. sion is approximately equal to the amount of dextran infused.
Albumin is available in 5% and 25% concentrations. Plasma The crystalloid versus colloid debate was intensified when a
protein fraction has oncotic actions similar to a 5% albumin solu- metaanalysis by the well-respected Cochrane group found an over-
tion, which is not surprising because albumin is the predominant all increase in mortality associated with albumin using pooled
protein in this product. When given in equipotent amounts, albu- results of randomized investigations.17 The metaanalysis involved
min is much more costly than crystalloid solutions. Additionally, the 30 randomized trials with 1,419 patients (relative risk of death with
5% and 25% albumin solutions typically are priced such that no cost albumin versus no administration or crystalloid administration
savings is associated with dilution of the 25% product to make a 5% 1.68, 95% confidence interval 1.26 to 2.23). For hypovolemia
concentration. In general, dilution should be avoided because of the (caused by blood loss in the majority of studies), the risk of death
possibility of preparation errors; cases of hemolysis and death have associated with albumin administration was not quite statistically
occurred when 25% albumin was inappropriately diluted with sterile significant (relative risk 1.46, 95% confidence interval 0.97 to 2.22).
water for injection, causing a dramatic lowering of effective osmolar- However, with the notable exception of trauma patients, a subse-
ity. The 5% albumin solution is relatively iso-oncotic, which means quent and more comprehensive systematic review did not find
that it does not pull fluid into the compartment in which it is increased mortality attributable to albumin.18 Furthermore, a land-
contained. In contrast, 25% albumin is referred to as hyperoncotic mark investigation involving almost 7,000 critically ill patients
albumin because it tends to pull fluid into the compartment contain- (conducted after the previously mentioned metaanalyses) did not
ing the albumin molecules. In general, the 5% albumin solution is find statistically significant differences in 28-day mortality between
used for hypovolemic states. The 25% solution should not be used patients resuscitated with either normal saline or 4% albumin.19 As
for acute circulatory insufficiency unless it is used in combination in the previous meta-analysis, there was a trend toward increased
with other fluids or it is being used in patients with excess total body mortality in patients with trauma, particularly in a subset of patients
water but intravascular depletion as a means of pulling fluid into the with traumatic brain injury. This multicenter, randomized, double-
intravascular space. An example of the latter condition is cirrhosis blind investigation, referred to as the Saline versus Albumin Fluid
with ascites in which total body water is substantially increased, but Evaluation (SAFE) study, involved a heterogeneous group of ICU
the patient is hypotensive as a consequence of lack of intravascular patients and was not sufficiently powered to look at various subsets,
volume. This use of hyperoncotic albumin presumes that there is so clinicians must be cautious when extrapolating the results to
evidence of adverse effects associated with the excess water (e.g., more specific patient populations. With this caution in mind, this
interstitial fluid accumulation in the lungs) and that the albumin trial provides strong evidence that crystalloid solutions should be
remains in the intravascular space long enough to be of benefit. considered first-line therapy in patients with hypovolemic shock.
Albumin has a variety of other functions, such as binding properties,
inflammatory gene modification, and antioxidant and free radical
scavenging effects, which have been used to justify its administration. ■ SPECIAL POPULATIONS
Although appealing theoretically, improved patient outcomes
related to these properties have not been documented in adequately Trauma/Perioperative Patients
powered, randomized, controlled trials. The need for immediate treatment of hemorrhagic circulatory insuf-
Hetastarch 6% has comparable plasma expansion to a 5% albu- ficiency with plasma expanders (i.e., crystalloids or colloids) seems
min solution but usually is less expensive, which accounts for much obvious, but no large, well-controlled trials conducted in humans
of its use. Most of the trials comparing albumin with hetastarch for have supported this practice. To the contrary, evidence suggests that
volume expansion have found no significant differences in clinically fluid resuscitation beyond minimal levels (i.e., mean arterial pressure
important outcomes (e.g., mortality). Few trials have directly com- >40 to 60 mm Hg) is harmful. One prospective study involving 598
pared hetastarch with crystalloid solutions for intravascular expan- adult patients with gunshot or stab wound injuries to the torso and
sion. Although hetastarch often is stated as being contraindicated in systolic blood pressure measurements of 90 mm Hg or less found
bleeding disorders, it has been most studied in patients with blood that delayed fluid resuscitation until operation was associated with
loss (e.g., trauma and perioperative patients). Hetastarch should be increased survival and discharge from the hospital (P = 0.04).20 Since
avoided in situations where short-term impairments in hemostasis concerns were expressed about the comparability of the immediate
could have dire consequences, such as in patients undergoing and delayed resuscitation groups, particularly because true random-
 448
ization did not take place, a followup randomized trial was con- needed to demonstrate a statistically significant difference in mor-
ducted to verify the findings. There were no differences in survival tality. Until the concerns regarding efficacy and toxicity of these
SECTION 2

(four deaths in each group) in the second trial regardless of whether solutions have been resolved, normal saline could be considered an
systolic blood pressure was titrated to >100 mm Hg or to 70 mm alternative for head-injured patients when a hypertonic solution is
Hg.21 Both studies were conducted in populated urban areas with desirable because it contains 154 mmol/L of both sodium and
approximately 2 hours from the time of injury to operation. There- chloride. Given their relatively poor intravascular expansion and
fore, the results may not be applicable to rural areas with extended association with poor outcome in animal models of closed head
transport times. There also is a concern in applying the results of injury, hypotonic solutions should be avoided in this population.27
these investigations to patients with certain kinds of single-system In addition to crystalloid solutions, colloids have been used for
injuries, particularly head trauma, where cerebral perfusion pressure plasma expansion in patients with hemorrhagic circulatory insuffi-
Cardiovascular Disorders

is of primary importance. Although the applicability of these studies ciency. In the United States, albumin and starch (i.e., hetastarch)
to other populations and settings is debatable, the presumption of derivatives are used most commonly, although dextran solutions
benefits from immediate plasma expansion in all preoperative also are available commercially.
patients with circulatory insufficiency caused by hemorrhage is no
longer valid. Instead, the initial priority should be surgical control of
the bleeding source. CLINICAL CONTROVERSY
Despite the studies suggesting that vigorous prehospital resusci-
Some clinicians believe that colloid solutions have advantages
tation is not helpful and possibly is harmful, hypertonic solutions
beyond crystalloid solutions that justify their use for patients
have several characteristics that make them attractive for acute
with hypovolemic shock.
resuscitation. The intravascular and interstitial expansion resulting
from administration of these solutions is much greater than the
The major theoretical advantage of these compounds is their
volume infused by emergency personnel.
prolonged intravascular retention time compared with crystalloid
solutions. In contrast to isotonic crystalloid solutions that have
substantial interstitial distribution within minutes of IV administra-
CLINICAL CONTROVERSY tion, colloids remain in the intravascular space for hours or days,
Some clinicians believe that hypertonic solutions should be used depending on factors such as capillary permeability.
for resuscitation of patients with head injuries who have con- The colloids, particularly albumin, are expensive solutions. There-
comitant circulatory insufficiency. fore, it is difficult to justify the additional cost of colloidal products
unless the benefit-to-risk ratio is substantially greater than that associ-
By causing redistribution (i.e., pulling fluid) from the intracellu- ated with inexpensive crystalloid solutions. This does not appear to be
lar space, hypertonic solutions cause rapid expansion of the intra- the case based on randomized, controlled studies and metaanalyses
vascular compartment, which is essential for vital organ perfusion. comparing colloid and crystalloid solutions for acute circulatory insuf-
In head-injured patients, it has been postulated that this redistribu- ficiency. Because other colloids, such as hetastarch, almost always have
tion should decrease intracranial pressure because the vessels of the been compared with albumin and not with crystalloid solutions in
brain are more impermeable to sodium ions than are vessels in published clinical studies (with no clinically important differences
other areas of the body. Additionally, hypertonic saline solutions found), there is no reason to suspect that these other colloids have any
have beneficial immunomodulating actions when compared with unique advantages as volume expanders. Adverse effects associated
more isotonic solutions in experiments with animals, although with colloids appear to be uncommon and generally are extensions of
these actions have not always translated into similar beneficial their pharmacologic activity (Table 26–5),
but this is also true of
effects in patients.22 crystalloids. The benefit-to-risk ratio appears to be similar for colloids
Potential dosing and administration errors and related adverse and crystalloids; thus, based on cost, crystalloids are preferred for
events can occur when hypertonic saline is ordered and adminis- initial treatment of circulatory insufficiency.
tered by clinicians relatively unfamiliar with its use. Potential The preceding discussion dealt primarily with acute circulatory
adverse events include cellular crenation and damage caused by the insufficiency, but there are other considerations with regard to fluid
dramatic fluid shifts associated with hypernatremia, hyperchlor- replacement in elective surgical procedures. Preoperative fluid deficits
emic metabolic acidosis from hyperchloremia, and peripheral vein in patients undergoing minor procedures may be associated with
destruction from high osmolality. In the limited number of studies increased perioperative morbidity, some of which (e.g., drowsiness,
conducted in humans to date, such adverse effects have been dizziness) may be reduced by appropriate fluid administration prior
uncommon and apparently of little clinical importance.23,24 to surgery.28 However, care must be taken to avoid overhydration in
Unfortunately, beneficial outcome data attributable to adminis- the perioperative period because excess fluid will lead to weight gain
tration of these hypertonic solutions are lacking. Most of these and decreased pulmonary function. Some evidence suggests that fluid
studies were conducted in prehospital and emergency department restriction on the day of surgery may reduce postoperative morbidity
settings using 250 mL of 7.5% sodium chloride with or without 6% in patients undergoing major surgical procedures. In one random-
dextran 70. A metaanalysis of randomized, controlled trials found ized, multicenter trial, use of a restricted intraoperative and postoper-
no statistical difference between the survival rates of patients receiv- ative IV fluid protocol led to significantly fewer cardiopulmonary
ing the hypertonic saline solutions and those receiving standard (7% versus 24%; P = 0.007) and wound (16% versus 31%; P = 0.04)
isotonic crystalloid solutions.25 Additionally, a subsequent double- complications.29 As the preceding discussion indicates, the benefits
blind, randomized controlled trial involving 229 patients with and risks of fluid administration in the perioperative period are not
hypotension and severe brain injury demonstrated no significant just a function of too little or too much fluid but involve other
differences in neurologic function at 6 months when 250 mL of patient- and procedure-related issues.
7.5% saline or lactated Ringer solution was administered as part of Another consideration in the patient with injuries or surgery is
a prehospital resuscitation regimen.26 Part of the explanation for the potential need for blood product administration (Table 26–6) to
this finding may be related to supplemental crystalloid fluids that replace oxygen-carrying and clotting functions. Although a small
were given routinely to patients in both the treatment and control group of trauma patients respond to the initial fluid bolus and
groups, which probably would increase the number of patients remain stable, most patients respond initially and then deteriorate.
 449

TABLE 26-5 Adverse Effects of Plasma Expanders: Colloids tion of 30% (equivalent to a hemoglobin concentration of 10 Gm/dl)
traditionally has been used as the threshold for transfusion, particu-

CHAPTER 26
Albumin
larly in patients at risk for ischemia, such as those with CAD. Use of a
Primarily extensions of pharmacologic actions (e.g., fluid overload; dilutional
more liberal transfusion strategy has been called into question with
coagulopathy)
Amino acid profile and catabolism alterations (clinical significance?); potential the publication of a randomized, multicenter trial involving critically
protein overload if given with exogenous protein (e.g., parenteral nutrition) ill patients that found 30-day mortality to be similar whether patients
Anaphylactoid/anaphylaxis reactions (life-threatening reactions rare; higher in were transfused at a hemoglobin concentration of 7 or 10 g/dL
patients with immunoglobulin A deficiency) (18.7% versus 23.3%, respectively; P = 0.11).30 The mortality during
Infectious complications (all reported cases have been associated with improper hospitalization was significantly lower in the restrictive group (22.2%
handling by manufacturer or institution; no reported cases of human immu- versus 28.1%; P = 0.05). Although the investigators were cautious
nodeficiency virus or hepatitis transmission)

Hypovolemic Shock
about extrapolating the results of this investigation to patients with
Interactions with medications and nutrients (clinical significance varies) myocardial ischemia, the study does question the use of a liberal
Metal loading, particularly aluminum (long-term administration in patients with
transfusion strategy for critically ill patients.
renal failure)
Blood products are not risk-free. There is the rare but important
Negative inotropic effect; reductions in ionized calcium concentrations (not well
documented) risk of virus transmission [e.g., human immunodeficiency virus
Pyrogenic reactions (not well documented) (HIV), hepatitis]. Citrate that is added to stored blood to prevent
Hetastarch coagulation may bind to calcium, resulting in hypocalcemia,
Primarily extensions of pharmacologic actions (e.g., fluid overload, dilutional although potassium and phosphate concentrations often are ele-
coagulopathy) vated in stored blood, particularly when hemolysis has occurred
Bleeding (decreases factor VIII/C activity; not recommended in patients at high during storage. Other issues that must be considered with blood
risk for bleeding or in patients with severe bleeding conditions such as product administration include monitoring for transfusion-related
subarachnoid hemorrhage) reactions and attention to appropriate warming, particularly when
Macroamylase formation may cause elevation in blood amylase that leads to
large volumes are given to pediatric patients, because hypothermia
inaccurate diagnosis of pancreatitis
is associated with increased fluid requirements and mortality.
Anaphylactoid/anaphylaxis reactions
Pruritus (particularly when large amounts are given; may take months to resolve) The periodic shortages, high costs, and adverse effect concerns
Dextrans related to blood products have prompted investigations of alterna-
Primarily extensions of pharmacologic actions (e.g., fluid overload, dilutional tive “bloodless” strategies. In addition to the use of more restrictive
coagulopathy) transfusion thresholds, as mentioned previously, these strategies
Anaphylactoid/anaphylaxis reactions (increased incidence of anaphylaxis with have included hemoglobin-based oxygen carriers and perfluorocar-
increased molecular weight) bon compounds to deliver oxygen to tissues. Other strategies have
Bleeding (sometimes used for anticoagulant activity, so not recommended for aimed at reducing blood loss through the use of improved proce-
patients with severe bleeding) dural and surgical techniques, as well as the administration of
hemostatic medications.
The latter patients, as well as patients undergoing blood loss
associated with surgery, frequently need blood components such as Patients with Thermal Injuries
packed red blood cells. In the case of the latter component, red
blood cells contain hemoglobin that delivers oxygen to tissues. There are a number of formulas for estimating fluid requirements in
Neither crystalloids nor colloids perform this function. thermally injured patients, but there is little reason to choose one over
Administration of excessive blood products may be counterpro- another based on well-controlled studies. In general, the amount of loss
ductive. In the case of red blood cells, attempts to raise the hematocrit corresponds to the size of the thermal injury. Approximately 3 to 4 mL/
to high–normal or supranormal concentrations may decrease oxygen kg of isotonic fluid (lactated Ringer solution) for each percent burn can
delivery by increasing blood viscosity. Although there is no optimal be used for calculating the expected fluid requirements for the first 24
hematocrit value for all patients, a minimum hematocrit concentra- hours after the burn. For example, a 60-kg person with 30% body
surface area (BSA) burns is expected to require 5,400 to 7,200 mL of
fluid over the initial 24 hours. Regardless of the calculated deficit, fluids
TABLE 26-6 General Indications for Blood Products in Acute should be administered until adequate tissue perfusion has been docu-
Circulatory Insufficiency Due to Hemorrhage a mented or adverse effects (e.g., pulmonary edema) occur. Crystalloids
Packed red blood cells are preferred as initial therapy for burn victims because there is no
Increase oxygen-carrying capacity of blood: Usually indicated in patients with substantial evidence that colloids mobilize edematous fluid, and there is
continued deterioration after volume replacement or obvious exsanguination; a theoretical concern that extravascular fluid accumulation might be
must be warmed, particularly when used in children prolonged by the oncotic actions of albumin and other colloid products
Fresh-frozen plasma that have leaked through vessel walls.31 Additionally, there is no evi-
Replacement of clotting factors: Generally overused; indicated if ongoing dence that colloids reduce mortality in patients with thermal injuries.17
hemorrhage in patients with PT/PTT >1.5 times normal, severe hepatic Some novel therapies for thermal resuscitation are currently under
disease, or other bleeding diathesis study. For example, in a prospective study involving patients with
Platelets
>30% BSA burns, antioxidant therapy with extremely high doses on IV
Used for bleeding due to severe thrombocytopenia (i.e., platelet count <10,000
mcL) or rapidly dropping platelet counts as would occur with massive bleeding
vitamin C (66 mg/kg/h for 24 hours) reduced resuscitation fluid
Other products requirements and wound edema.32 The proposed mechanism is reduc-
With the exception of recombinant activated factor VII, which is currently tion in free radical–induced increases in capillary permeability.
undergoing trials for use in life-threatening hemorrhage unresponsive to
traditional blood product administration, components such as cryoprecipitate
and factor VIII are generally not indicated in acute hemorrhage but rather are CLINICAL CONTROVERSY
used after specific deficiencies are identified
The appropriate use of invasive hemodynamic monitoring tools,
a
Although whole blood can be used for large-volume blood loss, most hospitals use component such as right-sided heart catheterization in patients with hypo-
therapy, and use crystalloids or colloids for plasma expansion.
volemic shock, is controversial.
PT, prothrombin time; PTT, partial thromboplastin time.
 450

■ ONGOING MONITORING metaanalysis (which found a statistically significant reduction in

morbidity using pulmonary artery catheters to guide therapy).36
SECTION 2

One form of monitoring that may take place in the emergency and Ultimately, a large randomized, controlled trial involving pulmonary
operating rooms, as well as in the ICU, requires placement of a central artery catheters was conducted in high-risk surgical patients.37 The
venous pressure (CVP) line. Monitoring of CVP provides the clinician
trial involved 1,994 patients. The mortality was almost identical for
with a somewhat insensitive yet useful estimate of the relationship
the catheter and control groups (7.8% versus 7.7%, 95% confidence
between increased right atrial pressure and cardiac output. A protocol
interval 2.3 to 2.5). There were no episodes of pulmonary embolism
that used a particular type of central catheter to perform continuous
in the catheter group and eight episodes in the control group (P =
monitoring of central venous oxygen saturation in conjunction with
0.004). This trial is important not only because of the implications
so-called goal-directed therapy in the first 6 hours of patient arrival in
for high-risk surgical patients but also because it allows conduction
an urban emergency department resulted in decreased mortality com-
Cardiovascular Disorders

of future trials in other patient populations without some of the

pared to standard monitoring (30.5% vs. 46.5%, P = 0.009).33 However,
ethical issues raised about such trials in the past.
the patients in this study had severe sepsis and septic shock, so the Part of the concern regarding pulmonary artery catheterization
results might not be applicable to other forms of shock with different relates to interpretation of its results by inexperienced practitioners.
pathophysiologic considerations. For example, in hemorrhagic shock Studies in both Europe and the United States found that one of two
due to trauma, the most important intervention is surgical control of physicians incorrectly interpreted a tracing from a pulmonary artery
bleeding, and anything that delays this control is likely to increase, not catheter.38 This could explain some of the results of studies finding
decrease, mortality. Until additional studies have been performed, it
no benefits to pulmonary artery catheterization or, in some cases,
would be premature to recommend goal-directed therapy with the
worse outcomes in the pulmonary artery catheterization group by
associated central venous monitoring in patients with nonseptic forms
actions taken as a result of inaccurate measurements or misinterpre-
of shock, particularly shock due to blood loss. The monitoring of
tation of information obtained from the monitoring process.
patients with various forms of hypovolemic shock becomes more
Complications related to pulmonary artery catheter insertion,
controversial once initial stabilization has been achieved and the patient
maintenance, and removal include damage to vessels and organs
has been transferred to an ICU. This is particularly true with regard to
during insertion, arrhythmias, infections, and thromboembolic dam-
the value of right-sided heart catheterization (also known as pulmonary
age. To avoid the complications associated with pulmonary artery
artery or Swan-Ganz catheterization). Clearly, some form of intensive
catheterization, other less invasive tools were developed to obtain
monitoring is important because patients in the postresuscitation phase
similar information. For example, cardiac output determinations have
of hypovolemic shock are at risk for various complications secondary to
been made by Doppler, bioimpedance, dye, and ionic dilution tech-
ischemia. A more complete discussion of invasive and noninvasive
niques, although such measurements would not provide other data
hemodynamic monitoring is given in Chapter 25.
that are obtained routinely with pulmonary artery catheters (e.g., left-
A number of laboratory tests are indicated for subacute monitoring
sided heart filling pressure). Additionally, advances in pulmonary
of shock in the ICU setting. These include a renal battery for assessing
artery catheter technology that expand the information obtained from
possible electrolyte alterations and kidney perfusion (e.g., BUN and
such monitoring (e.g., mixed venous oxyhemoglobin) are under
creatinine). Among other things, a complete blood count will enable
investigation. However, given the lack of well-defined outcome data
assessment of possible infection (white blood cell count), oxygen-
associated with pulmonary artery catheterization, its use is best
carrying capacity of the blood (hemoglobin, hematocrit), and ongoing
reserved for complicated cases of shock not responding to conven-
bleeding (hemoglobin, hematocrit, and platelet count). The prothrom-
tional fluid and medication therapies.
bin time (PT) and partial thromboplastin time (PTT) will give an
Commonly measured and calculated hemodynamic and oxygen-
indication of the ability of the blood to clot because, in the case of
transport indices associated with invasive monitoring are primarily
hemorrhagic shock, clotting factors are lost and diluted. An increasing
global indicators of tissue perfusion. Attempts have been made to
lactate concentration (arterial, mixed venous, or central venous), an
find regional and local indicators of hypoperfusion so that circula-
increasing arterial base deficit, or a decreasing bicarbonate concentra-
tory insufficiency could be treated before overt shock occurs. One
tion are consistent with inadequate perfusion leading to anaerobic
focus of recent research has been monitoring modalities involving
metabolism with accumulation of lactic acid. Although the value of
the gastrointestinal tract.
these surrogate markers for improving patient outcomes is more con-
Although the literature is fairly consistent concerning low gastric
troversial, they are considered traditional end points of resuscitation in
intramucosal pH (pHi) values being predictive of death, pHi-
certain populations such as trauma patients.34 Other tests may be
guided therapy to decrease mortality has not been demonstrated.39
indicated if organ dysfunction is likely. For example, when blood flow
Additionally, a number of technical considerations remain to be
to the liver is interrupted because of sustained hypotension, a condition
resolved when using pHi or, more recently, capnometry (luminal
known as shock liver may occur. In this condition, the levels of transam-
PCO2 tonometry) for monitoring and therapy. Despite these con-
inases on a liver panel may be markedly elevated in the first couple of
cerns, measures of regional tissue oxygenation continue to be
days after marked hypotension, although the concentrations should
investigated through a variety of novel monitoring techniques.
decrease over time.4 Along with laboratory testing, a more extensive
In addition to regional monitoring of tissue perfusion, local
history can be obtained during the subacute monitoring period. methods of monitoring are being studied. For example, subcutane-
The value of pulmonary artery catheters has been debated hotly ous measurement of tissue oxygen pressure shows promise in
since their introduction. Such catheters are placed to obtain various preliminary investigations. Regional and local measurements likely
oxygen-transport variables, some of which cannot be determined will not replace more global indicators of perfusion; rather, the
reliably from peripheral or other central vessels. The debate was methods will complement each other.
intensified when early studies suggested improved outcomes when
cardiac output and other oxygen-transport variables were raised to
supranormal levels, the monitoring of which required placement of ■ ONGOING MANAGEMENT
a pulmonary artery catheter. Subsequent studies using similar Proper attention to plasma expansion must be continued into the
monitoring parameters associated with pulmonary artery catheter- intraoperative and postoperative periods. A number of neurohor-
ization gave conflicting results.35 monal changes take place that affect urine output, and patients may
The controversy led to consensus conferences and workshops, the have substantial third spacing of fluid depending on the operation
development of organizational guidelines, and the publication of a and preexisting conditions. Furthermore, postoperative patients are
 451
prone to hyponatremia from renal generation of electrolyte-free inotropic or vasoactive agents, assuming that fluid therapy is adequate.
water and from antidiuretic hormone release.40 As in acute resusci- For that matter, there is no evidence that these medications improve

CHAPTER 26
tation, the administration of hypotonic solutions in the periopera- outcome in patients with hypovolemic shock. However, once the
tive period does not prevent the decrease in extracellular volume cause of acute circulatory insufficiency has been stopped or treated and
that often occurs. Therefore, although excess fluid administration is fluids have been optimized, some patients continue to have signs and
to be avoided in the perioperative setting, isotonic crystalloid symptoms of inadequate tissue perfusion. This may be caused by
solutions should be used when fluids are indicated to prevent reperfusion injury. Although the search for a cryptogenic source (e.g.,
intravascular depletion and circulatory insufficiency. intraabdominal bleeding in a trauma patient) should continue, the
Of the randomized studies comparing albumin with crystalloid clinician may need to administer medications to improve perfusion.
solutions in the perioperative period, the majority found no statisti- Pressor agents such as norepinephrine and high-dose dopamine are

Hypovolemic Shock
cally significant differences between groups.41 Any significant differ- to be avoided, if possible, because they may increase blood pressure at
ences found involved isolated hemodynamic or respiratory variables the expense of peripheral tissue ischemia. Some sources use stronger
with no obvious clinical correlates (e.g., duration of mechanical language and state that vasopressors are contraindicated in certain
ventilation). Therefore, albumin and other colloids cannot be recom- forms of shock (e.g., hemorrhagic). This does not help the clinician
mended for the prevention or initial treatment of circulatory insuffi- who is treating a patient with unstable blood pressure despite massive
ciency, although their use may be appropriate in patients who are not fluid replacement and increasing interstitial fluid accumulation. In such
responding to crystalloids and are developing problems such as situations, inotropic agents such as dobutamine are preferred if blood
interstitial fluid accumulation. Practice guidelines published by a pressure is adequate (e.g., systolic blood pressure ≥90 mm Hg) because
consortium of academic medical centers reflect this recommenda- they should not aggravate the existing vasoconstriction. The inotropic
tion, but colloids continue to be used widely.42 agents are justified by presumed inadequate cardiac output for the
In general, medications are not indicated in the initial therapy of specific situation, although the measured values may be in the normal
hypovolemic shock. With hypovolemia, the body’s natural response is range.4
to increase cardiac output and to constrict blood vessels to maintain  When pressure cannot be maintained with inotropic agents or when
blood pressure. There is no reason why most patients should need inotropic agents with vasodilatory properties cannot be used because of

Is inadequate tissue
perfusion suspected?
Yes No

20 mL/kg LR Continue periodic

(or infuse as rapidly as assessment
possible if unmeasurable
pressure or obvious
exsanguination)

Inadequate tissue
perfusion
Yes No

Possible Continue periodic

decompensated CHF assessment
Yes No

Systolic blood pressure <90 Patient >70 years old or

Yes No has interstitial fluid
accumulation
Begin dopamine at Begin dobutamine at
5 mcg/kg/min + consider 2 mcg/kg/min + consider
pulmonary artery catheter pulmonary artery catheter

Yes No

Weight <60 kg 20 mL/kg LR

Yes No (or continue rapid infusion
until adequate perfusion)
Inadequate tissue perfusion
Consider 250 mL 5% Consider 500 mL 5% with evidence of fluid-
albumin + pulmonary albumin + pulmonary related complications?
artery catheter artery catheter
Yes No

Begin dopamine at Continue periodic

5 mcg/kg/min + consider assessment +
pulmonary artery catheter infusions of LR as needed
to maintain adequate
perfusion

FIGURE 26-4. Hypovolemia protocol for adults. This protocol is not intended to replace or delay therapies such as surgical intervention or
blood products for restoring oxygen-carrying capacity or hemostasis. If available, some measurements can be used in addition to those listed
in the algorithm, such as mean arterial pressure or pulmonary artery catheter recordings. The latter can be used to assist in medication choices
(e.g., agents with primary pressor effects may be desirable in patients with normal cardiac outputs, whereas dopamine or dobutamine may
be indicated in patients with suboptimal cardiac outputs). Lower maximal doses of the medications in this algorithm should be considered
when pulmonary artery catheterization is not available. Colloids that can be substituted for albumin are hetastarch 6% and dextran 40. See
text for an in-depth discussion of these and other issues involved in this protocol. (CHF, congestive heart failure; LR, lactated Ringer solution.)
 452
inadequate blood pressure concerns, pressors may be required as a last the standard crystalloid solutions. Although the costs of these solutions
resort. In general, the need for pressors is predictive of the development vary depending on contractual arrangements, as might occur with
SECTION 2

of MODS and increased length of hospital stay.43 Although the purchasing groups, in general, albumin solutions are more expensive
response to pressor agents may be variable in hypovolemic shock, there than hetastarch and dextran products. All these solutions are markedly
does not appear to be resistance as a consequence of altered receptor more costly than crystalloid solutions; in some cases, the differences are
response, as is sometimes seen in patients with septic shock.4 Potent 50- to 100-fold, even when used in equipotent amounts.
vasoconstrictors such as norepinephrine and phenylephrine should be The only trial that investigated albumin use on a large-scale basis
given through central veins because of the possibility of extravasation was an observational study involving 15 academic medical centers
and necrosis with peripheral administration. in the United States. Based on previously published guidelines, 62%
In managing patients with hypovolemic shock, the clinician must of albumin use was defined as inappropriate, at a cost of $124,939.45
Cardiovascular Disorders

be aware of potential adverse effects of medications being used for Presuming equal efficacy and toxicity (as available studies indicate)
supportive care purposes. For example, some patients are particu- between crystalloid and colloid solutions, cost-minimization analy-
larly susceptible to the histamine release associated with morphine sis clearly indicates the economic advantages of the crystalloids.
and may have substantial decreases in blood pressure. Propofol is Because medications are not simply alternatives to crystalloids
commonly used for sedation in the ICU, but it may cause substantial but rather are used when crystalloid therapy has been optimized,
decreases in blood pressure. The initial dose of propofol probably there is little reason to compare medication and fluid therapies from
should be decreased by at least 50% in patients with hemorrhagic an economic perspective. Furthermore, there are no economic
shock who have recently been resuscitated and by at least 80% (if it comparisons of the various inotropic and vasopressor medications
is given at all) in patients who may not be fully resuscitated.44 used in the treatment of hypovolemic shock.
A number of interesting treatments for shock are under investiga-
tion, including autotransfusion for removing harmful cytokines from
the body. Various alternatives to conventional blood components EVALUATION OF THERAPEUTIC OUTCOMES
also are being studied, such as stroma-free hemoglobin and perfluor-
Figure 26–4 is an algorithm that summarizes many of the treatment
ocarbon compounds, as virus-free alternatives to red blood cell
principles discussed in this chapter. The algorithm is an example of
transfusion. Hopefully, these methods will be useful adjuncts to
one approach to the adult patient presenting with hypovolemic
adequate volume replacement, which is the primary therapeutic
shock. It presumes that initial rehydration attempts (i.e., outpatient
intervention in managing acute circulatory insufficiency as a result of
or prehospital) were unsuccessful in restoring circulation. Obvi-
volume depletion.
ously, modifications may be needed for patient-specific forms of
hypovolemic shock. Other limitations of the algorithm should be
PHARMACOECONOMIC CONSIDERATIONS recognized, particularly the decisions to add or to substitute colloid
or medication therapies when crystalloid solutions are not yielding
The primary therapy for hypovolemic shock is fluid replacement. The desired results and when to perform pulmonary artery catheteriza-
institutional cost of 1 L of most crystalloid solutions is less than $1. tion for more invasive monitoring. Medications become more
Assuming that such fluids are used, the associated costs of personnel important for the ongoing management of hypovolemic shock,
and equipment then become the primary economic considerations in particularly when the patient is unresponsive to fluids (Fig. 26–5).
the resuscitation of patients with hypovolemic shock. However, as Medications for more complicated cases of hemorrhagic shock
mentioned, many clinicians recommend that colloid plasma expanders should not detract from the primary effective resuscitative meas-
(e.g., albumin, hetastarch, or dextrans) be used to replace some or all of ure—surgical stabilization of bleeding.

Continued inadequate tissue

perfusion but toleration of
fluid administration
(e.g., no evidence of
pulmonary edema)
Yes No

20 mL/kg LR (or continue rapid infusion Patient receiving

until adequate perfusion) + consider dobutamine
addition of medications if not responding Yes No
to fluid challenges. Norepinephrine
0.1 mcg/kg/min if systolic blood
Increase dose by 5 mcg/kg/min Dobutamine 2 mcg/kg/min
pressure <70; dopamine 5 mcg/kg/min if
at 10-min intervals (if on dopamine, try to
systolic blood pressure 70–90;
until 20 mcg/kg/min, decrease the dopamine to
dobutamine 2 mcg/kg/min (if already on
toxicity or efficacy 3 mcg/kg/min
dobutamine, increase dose by 5 mcg/kg/min)
if systolic blood pressure >90
If systolic blood pressure Inadequate perfusion
<70 ± norepinephrine (or
Inadequate perfusion increase dopamine) Yes No
Yes No

Increase dobutamine by Continue periodic

If systolic blood pressure 3–5 mcg/kg/min at 10-min assessment
<70, add or increase intervals until 20 mcg/kg/min,
dose of norepinephrine toxicity or efficacy
or if systolic blood pressure
≥70, increase dose of Continue periodic
dopamine or dobutamine assessment
at 10-min intervals until
20 mcg/kg/min,
toxicity or efficacy

FIGURE 26-5. Ongoing management of inadequate tissue perfusion. (LR, lactated Ringer solution.)
 453
20. Bickell WH, Wall MJ, Pepe PE, et al. Immediate versus delayed fluid
ABBREVIATIONS resuscitation for hypotensive patients with penetrating torso injuries.

CHAPTER 26
N Engl J Med 1994;331:1105–1109.
BSA: body surface area 21. Dutton RP, Mackenzie CF, Scalea TM. Hypotensive resuscitation
CAD: coronary artery disease during active hemorrhage: Impact on in-hospital mortality. J Trauma
2002;52:1141–1146.
CDC: Centers for Disease Control and Prevention 22. Kolsen-Petersen JA, Nielsen JD, Tonnesen EM. Effect of hypertonic
CVP: central venous pressure saline infusion on postoperative cellular outcome. Anesthesiology
ICU: intensive care unit 2004;100:1108–1118.
23. Vassar MJ, Fischer RP, O’Brien PE, et al. A multicenter trial for
MODS: multiple-organ dysfunction syndrome resuscitation of injured patients with 7.5% sodium chloride: The effect

Hypovolemic Shock
pHi: gastric intramucosal pH of added dextran 70. Arch Surg 1993;128:1003–1013.
24. Suarez JI, Qureshi AI, Bhardwa A, et al. Treatment of refractory intracra-
PT: prothrombin time nial hypertension with 23.4% saline. Crit Care Med 1998;26:1118–1122.
PTT: partial thromboplastin time 25 Wade CE, Kramer GC, Grady JJ, et al. Efficacy of hypertonic 7.5%
SIRS: systemic inflammatory response syndrome saline and 6% dextran-70 in treating trauma: A meta-analysis of
controlled studies. Surgery 1997;122:609–616.
WHO: World Health Organization 26. Cooper DJ, Myles PS, McDermott FT, et al. Prehospital hypertonic
saline resuscitation of patients with hypotension and severe traumatic
brain injury. JAMA 2004;291:1350–1357.
REFERENCES 27. Gurevich B, Talmore D, Artru AA, et al. Brain edema, hemorrhagic
necrosis volume, and neurological status with rapid infusion of 0.45%
1. Dutton RP. Initial resuscitation of the hemorrhaging patient. In: Spiess saline or 5% dextrose in 0.9% saline after closed head trauma in rats.
BD, Spence RK, Shander A, eds. Perioperative Transfusion Medicine, Anesth Analg 1997;84:554–559.
2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2006:289–299. 28. Holte K, Klarskov B, Christensen DS, et al. Liberal versus restrictive
2. Anonymous. Heat-related mortality—Arizona, 1993–2002, and fluid administration to improve recovery after laparoscopic cholecys-
United States, 1979–2002. MMWR Weekly 2005;54:628–630. tectomy. Ann Surg 2004;240:892–899.
3. Duggan C, Fontaine O, Pierce NF, et al. Scientific rationale for a change in 29. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intra-
the composition of oral rehydration solution. JAMA 2004;291:2628–2635. venous fluid restriction on postoperative complications: Comparison
4. Ramsay G, Boom S. Pathophysiology and management of shock. In: of two perioperative fluid regimens. Ann Surg 2003;238:641–648.
Cuschieri A, Giles GR, Moossa AR, eds. Essential Surgical Practice, 3rd 30. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized,
ed. Oxford, UK: Butterworth-Heinemann, 1995:72–89. controlled clinical trial of transfusion requirements in critical care. N
5. Marzi I. Hemorrhagic shock: Update in pathophysiology and therapy. Engl J Med 1999;340:409–417.
Acta Anaesthesiol Scand 1997;111(Suppl):42–44. 31. Zdolsek HJ, Lisander B, Jones AW, Sjoberg F. Albumin supplementa-
6. Vercueil A, Grocott MPW, Mythen MG. Physiology, pharmacology, and tion during the first week after a burn does not mobilise tissue oedema
rationale for colloid administration for the maintenance of effective hemo- in humans. Intensive Care Med 2001;27:844–852.
dynamic stability in critically ill patients. Trans Med Rev 2005;19:93–109. 32. Tanaka J, Matsuda T, Miyagantani Y, et al. Reduction of resuscitation
7. Porter SC, Fleisher GR, Kohane IS, Mandl KD. The value of parental fluid volumes in severely burned patients using ascorbic acid adminis-
report for diagnosis and management of dehydration in the emergency tration. Arch Surg 2000;135:326–331.
department. Ann Emerg Med 2003;41:196–205. 33. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the
8. Anonymous. Prevention and treatment of heat injury. Med Lett treatment of severe sepsis and septic-shock. N Engl J Med
2003;45:58–60. 2001;345:1368–1377.
9. Nalin DR, Hirschhorn N, Greenough W, et al. Clinical concerns about 34. Bilkovski RN, Rivers EP, Horst HM. Targeted resuscitation strategies
reduced-osmolarity oral rehydration solution. JAMA 2004:291:2632–2635. after injury. Curr Opin Crit Care 2004;10:529–538.
10. Spandorfer PR, Alessandrini EA, Joffe MD, et al. Oral versus intrave- 35. Yu M. Oxygen transport optimization. New Horiz 1999;7:46–53.
nous rehydration of moderately dehydrated children: a randomized, 36. Ivanov R, Allen J, Calvin JE. The incidence of major morbidity in
controlled trial. Pediatrics 2005;115:295–301. critically ill patients managed with pulmonary artery catheters: A
11. Atherly-John YC, Cunningham SJ, Crain EF. A randomized trial of meta-analysis. Crit Care Med 2000;28:615–619.
oral vs intravenous rehydration in a pediatric emergency department. 37. Sandham JD, Hull RD, Brant RF, et al. A randomized, controlled trial
Arch Pediatr Adolesc Med 2002;156:1240–1243. of the use of pulmonary-artery catheters in high-risk surgical patients.
12. Axler OA, Tousiganant C, Thompson CR, et al. Small hemodynamic N Engl J Med 2003;348:5–14.
effect of typical rapid volume infusions in critically ill patients. Crit 38. Ginosar Y, Thijs LG, Sprung CL. Raising the standard of hemodynamic
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13. Didwania A, Miller J, Kassel D, et al. Effect of intravenous lactated 1997;25:209–211.
Ringer solution infusion on the circulating lactate concentration: 39. Gomersall CD, Joynt GM, Freebairn RC, et al. Resuscitation of critically ill
Results of a prospective, randomized, double-blind, placebo-controlled patients based on the results of gastric tonometry: A prospective, random-
trial. Crit Care Med 1997;25:1851–1854. ized, controlled trial. Crit Care Med 2000;28:607–614.
14. Jackson EV, Wiese J, Sigal B, et al. Effects of crystalloid solutions on 40. Steele A, Gowrishankar M, Abrahamson S, et al. Postoperative hypo-
circulating lactate concentrations: 1. Implications for the proper han- natremia despite near-isotonic saline infusion: A phenomenon of
dling of blood specimens obtained in critically ill patients. Crit Care desalination. Ann Intern Med 1997;126:20–25.
Med 1996;24:1840–1846. 41. Erstad BL. Concerns with defining appropriate uses of albumin by
15. Deitch EA. Animal models of sepsis and shock: A review and lessons meta-analysis. Am J Health Syst Pharm 1999;56:1451–1454.
learned. Shock 1998;9:1–11. 42. Fox DL, Vermeulen LC. UHC Technology Assessment: Albumin,
16. Grocott MPW, Mythen MG, Gan TJ. Perioperative fluid management Nonprotein Colloid, and Crystalloid Solutions. Oak Brook, IL: Uni-
and clinical outcomes in adults. Anesth Analg 2005;100:1093–1106. versity Health System Consortium, 2000.
17. Cochrane Injuries Group Albumin Reviewers. Human albumin 43. Goncalves JA, Hydo LJ, Barie PS. Factors influencing outcome of
administration in critically ill patients: Systematic review of random- prolonged norepinephrine therapy for shock in critical surgical illness.
ized controlled trials. BMJ 1998;317:235–240. Shock 1998;10:231–236.
18. Choi PTL, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in 44. Shafer SL. Shock values. Anesthesiology 2004;101:567–568.
fluid resuscitation: A systematic review. Crit Care Med 1999;27:200–210. 45. Yim JM, Vermeulen LC, Erstad BL, et al. Albumin and nonprotein
19. The SAFE Study Investigators. A comparison of albumin and saline for fluid colloid solution use in US academic health centers. Arch Intern Med
resuscitation in the intensive care unit. N Engl J Med 2004;350:2247–2256. 1995;155:2450–2455.
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 455

SECTION 3
RESPIRATORY DISORDERS

27
C HAP T E R

Introduction to Pulmonary
Function Testing

JAY I. PETERS AND STEPHANIE M. LEVINE

(PaO2) and arterial pressure of carbon dioxide (PaCO2). To achieve

KEY CONCEPTS this goal, several processes must be accomplished, including alveolar
ventilation, pulmonary perfusion, ventilation–perfusion matching,
 Normal ventilation–perfusion ratio. The function of the lungs and gas transfer across the alveolar–capillary membrane. Alveolar
is to maintain PaO2 and PaCO2 within normal ranges. This goal ventilation is achieved by the cyclic process of air movement in and
is accomplished by matching 1 mL mixed venous blood with out of the lung. During inspiration, the inspiratory muscle contracts
• • •
1 mL fresh air ( V/Q = 1). Normally, ventilation (V) is less than and generates negative pressure in the pleural space. This pressure
• • •
perfusion (Q ), and V/Q ratio is 0.8. gradient between the mouth and the alveoli draws fresh air (tidal
 The air in the lung is divided into four compartments: tidal vol- volume) into the lung. Approximately one third of the inspired gas
ume—air exhaled during quiet breathing; inspiratory reserve vol- stays in the conducting airways (dead space), and two thirds reaches
ume—maximal air inhaled above tidal volume; expiratory reserve the alveoli.
volume—maximum air exhaled below tidal volume; and residual  The human lung contains a series of branching, progressively
volume—air remaining in the lung after maximal exhalation. The tapering airways that originate at the glottis and terminate in a matrix
sum of all four components is the total lung capacity. of thin-walled alveoli. Coursing through this matrix of alveoli is a rich
network of capillaries that originates from the pulmonary arterioles
 Obstructive lung disease is defined as an inability to get air out and terminates in the pulmonary venules. The adequacy of respiration
of the lung. It is identified on spirometry when FEV1/FVC (force in each gas exchange unit depends on the opposition of a thin film of
expiratory volume in the first second of expiration/forced vital mixed venous blood with just the right amount of fresh alveolar gas.
capacity [total amount of air that can be exhaled during a During “ideal” gas exchange, blood flow and ventilation are uniform;
forced exhalation]) is <70% to 75%. accordingly, there is no alveolar–arterial difference (or gradient) in the
 Reversible airway obstruction is common in asthma and chron- partial pressure of oxygen [P(A–a)O2, sometimes called the A–a gradi-
ic obstructive pulmonary disease. An increase in FEV1 of 12% ent]. However, gas exchange is not perfect, even in the normal lung.
(and >0.2 L in adults) after an inhaled β-agonist suggests an Normally, alveolar ventilation is less than pulmonary blood flow, and
acute bronchodilator response. the overall ventilation–perfusion ratio is 0.8 (not 1.0).
Normal expiration is a passive process, and when the inspiratory
 Restrictive lung disease is defined as an inability to get air into muscles end their contraction, the elastic recoil of the lung pulls the
the lung and is best defined as a reduction in total lung capac- lung back to its original size and shape. This process makes the
ity. It is suspected when FVC is low and FEV1/FVC is normal. alveolar pressure positive relative to the pressure at the mouth, and air
 Restrictive lung disease can be produced by a number of de- flows out of the lung. During inspiration, the respiratory muscles
fects, such as increased elastic recoil (interstitial lung disease), must overcome the elastic properties of the lung (elastic recoil) and
respiratory muscle weakness (myasthenia gravis), mechanical the resistance to airflow by the airways. During expiration, the flow of
restrictions (pleural effusion or kyphoscoliosis), and poor effort. air is determined primarily by the elastic recoil and airway resistance.
Different pulmonary function tests (PFTs) are used to evaluate
the physiologic processes of the respiratory system. Physiologic
The primary function of the respiratory system is to maintain nor- abnormalities that can be measured by pulmonary function testing
mality of arterial blood gases, that is, arterial pressure of oxygen include obstruction to airflow, restriction of lung size, and decrease
in transfer of gas across the alveolar–capillary membrane. Abnormal
values on PFTs are outside the range of values obtained from a
Learning objectives, review questions, group of normal individuals matched according to age, height, sex,
and other resources can be found at and race. A PFT is labeled abnormal when the results fall outside the
www.pharmacotherapyonline.com. range in which 95% of people the same age, height, and sex would
be found (95% confidence interval). This definition is arbitrary and

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 456
may misclassify a small percentage of normal individuals as having inspiratory or expiratory muscles and normally is 40% of TLC. Inspira-
lung dysfunction; it also may miss patients with mild pulmonary tory capacity (IC) is the maximal volume of air that can be inhaled from
SECTION 3

disease. Therefore, clinical correlation and serial pulmonary func- the end of a quiet expiration and is the sum of VT and IRV.
tion testing may be necessary for optimal interpretation of PFTs. FVC, which represents the total amount of air that can be exhaled,
Potential uses of pulmonary function testing include evaluation can be expressed as a series of timed volumes. The forced expiratory
of patients with known or suspected lung disease; evaluation of volume in the first second of expiration (FEV1) is the volume of air
symptoms such as chronic cough, dyspnea, or chest tightness; exhaled during the first second of the FVC maneuver. Although FEV1
monitoring of the effects of exposure to dust, chemicals, or pulmo- is a volume, it conveys information on obstruction because it is
nary toxic drugs; risk stratification prior to surgery; monitoring of measured over a known time interval. FEV1 depends on the volume of
the effectiveness of therapeutic interventions; and objective assess- air within the lung and the effort during exhalation; therefore, it can be
Respiratory Disorders

ment of impairment or disability.1 diminished by a decrease in TLC or by a lack of effort. A more sensitive
way to measure obstruction is to express FEV1 as a ratio of FVC. This
ratio is independent of the patient’s size or TLC; therefore, FEV1/FVC
DEFINITIONS OF LUNG VOLUMES is a specific measure of airway obstruction with or without restriction.
AND EXPIRATORY FLOWS Normally, this ratio is ≥75%, and any value <70% to 75% suggests
obstruction.
 The air within the lung at the end of a forced inspiration can be Because flow is defined as the change in volume with time, forced
divided into four compartments or lung volumes (Fig. 27–1). The expiratory flow can be determined graphically by dividing the volume
volume of air exhaled during normal quiet breathing is the tidal change by the time change. The forced expiratory flow (FEF) during
volume (VT). The maximal volume of air inhaled above tidal volume 25% to 75% of FVC (FEF25%–75%) represents the mean flow during the
is the inspiratory reserve volume (IRV), and the maximal air exhaled middle half of the FVC. FEF25%–75%, formerly called the maximal
below tidal volume is the expiratory reserve volume (ERV). The midexpiratory flow, is reported frequently in the assessment of small
residual volume (RV) is the amount of air remaining in the lungs airways. The 95% confidence limit is so wide that FEF25%–75% has
after a maximal exhalation. limited utility in the early diagnosis of small airways disease in an
The combinations or sums of two or more lung volumes are individual subject. The peak expiratory flow (PEF), also called maxi-
termed capacities (Fig. 27–1). Vital capacity (VC) is the maximal mum forced expiratory flow (FEFmax), is the maximum flow obtained
amount of air that can be exhaled after a maximal inspiration. It is during FVC. This measurement is used often in the outpatient man-
equal to the sum of IRV, VT, and ERV. When measured on a forced agement of asthma because it can be measured with inexpensive peak
expiration, it is called the forced vital capacity (FVC). When mea- flowmeters.
sured over an exhalation of at least 30 seconds, it is called the slow All lung volumes and flows are compared to normal values
vital capacity (SVC). The VC is approximately 75% of the total lung obtained from healthy subjects. There are significant ethnic and racial
capacity (TLC), and when the SVC is within the normal range, a variations in normal values, and all PFTs should report that race/
significant restrictive disorder is unlikely. Normally, the values for ethnic adjustment factors have been used. The 2005 American Tho-
SVC and FVC are very similar unless airway obstruction is present. racic Society–European Respiratory Society (ATS–ERS) guidelines
TLC is the volume of air in the lung after the maximal inspiration for interpretation of PFT results recommend that, for spirometry in
and is the sum of the four primary lung volumes (IRV, VT, ERV, the United States, the National Health and Nutrition Examination
and RV). Its measurement is difficult because the amount of air Survey (NHANES) III reference be used for subjects aged 8 to 80 years
remaining in the chest after maximal exhalation (RV) must be and the Wang equation used in subjects younger than 8 years.2
measured by indirect methods. The definition of restrictive lung
disease is based on a reduction in TLC (i.e., an inability to get air SPIROMETRY/FLOW–VOLUME LOOP
into the lung or restriction to air movement on inhalation).
The functional residual capacity (FRC) is the volume of air remaining Spirometry is the most widely available and useful PFT. It takes only
in the lungs at the end of a quiet expiration. FRC is the normal resting 15 to 20 minutes, carries no risks, and provides information about
position of the lung; it occurs when there is no contraction of either obstructive and restrictive disease. Spirometry allows for measure-
ment of all lung volumes and capacities except RV, FRC, and TLC;
it also allows assessment of FEV 1 and FEF 25%–75% . Spirometry
Maximal inspiratory measurements can be reported in two different formats—standard
level
spirometry (Fig. 27–2) and the flow–volume loop (Fig. 27–3). In stan-

IRV 7
1
IC 6
VC 5
Liters (BPTS)

2
TLC 4
VT 3
3
Resting expiratory level 2 4
ERV
1
FRC
Maximal expiratory level 1 2 3 4 5 6
RV RV Seconds

FIGURE 27-2. Standard spirometry. Curve 1 is for a normal subject with

FIGURE 27-1. Lung volumes and capacities. (ERV, expiratory reserve normal FEV1; curve 2 is for a patient with mild airways obstruction; curve
volume; FRC, functional residual capacity; IC, inspiratory capacity; IRV, 3 is for a patient with moderate airways obstruction; curve 4 is for a
inspiratory reserve volume; RV, residual volume; TLC, total lung capacity; patient with severe airways obstruction. (BPTS, body temperature satu-
VC, vital capacity; VT, tidal volume.) rated with water vapor.)
 457
measurement (planimetry). The first two methods are called dilution
techniques and only measure lung volumes in communication with

CHAPTER 27
•
FEF50% (Vmax 50)
the upper airway. In patients with airway obstruction who have
+5 trapped air, dilution techniques will underestimate the actual volume
PEF
Flow (L/s) of the lungs. Planimetry measures the circumference of the lungs on
the posteroanterior view and lateral views of a chest x-ray film and
0 estimates the total lung volume.
TLC FVC RV
Body plethysmography, or body box, is the most accurate tech-
nique for lung volume determinations. It measures all the air in the
−5 PIF
lungs, including trapped air. The principle of the measurement of the

Introduction to Pulmonary Function Testing

body box is Boyle’s gas law (P1V1 = P2V2): A volume of gas in a closed
system varies inversely with the pressure applied to it. The changes in
0 2 4 6
alveolar pressure are measured at the mouth, as well as pressure
Volume (L)
changes in the body box. The volume of the body box is known. Lung
volumes can be determined measuring the changes in pressures
FIGURE 27-3. Normal flow–volume loop. Flows are measured on the caused by panting against a closed shutter.2 Measurement of lung
vertical (y) axis, and lung volumes are measured on the horizontal (x) volumes provides useful information about elastic recoil of the lungs.
axis. Forced vital capacity (FVC) can be read from the tracing as the If elastic recoil is increased (as in interstitial lung disease), lung
•
maximal horizontal deflection. Instantaneous flow ( Vmax ) at any point in
volumes (TLC) are reduced. When elastic recoil is reduced (as in
FVC also can be measured directly. (FEF50%, forced expiratory flow at
50% of forced vital capacity; PEF, peak expiratory flow; PIF, peak
emphysema), lung volumes are increased.
inspiratory flow; RV, residual volume; TLC, total lung capacity.)
CARBON MONOXIDE DIFFUSING CAPACITY
dard spirometry, the volumes are recorded on the vertical (y) axis and
the time on the horizontal (x) axis. In flow–volume loops, volume is The diffusing capacity of the lungs (DL) is a measurement of the
plotted on the horizontal (x) axis, and flow (derived from volume/ ability of a gas to diffuse across the alveolar–capillary membrane.
time) is plotted on the vertical (y) axis. The shape of the flow–volume Carbon monoxide is the usual test gas because normally it is not
loop can be helpful in differentiating obstructive and restrictive present in the lungs and is much more soluble in blood than in lung
defects and in diagnosing upper airway obstruction (Fig. 27–4). This tissue. When the diffusing capacity is determined with carbon
curve gives a visual representation of obstruction because the expira- monoxide, the test is called the diffusing capacity of lung for carbon
tory descent becomes more concave with worsening obstruction. monoxide (DLCO). Because DLCO is directly related to alveolar
volume (VA), it frequently is normalized to the value DL/VA, which
allows for its interpretation in the presence of abnormal lung
LUNG VOLUMES volumes (e.g., after surgical lung resection).
Spirometry measures three of the four basic lung volumes but cannot The diffusing capacity will be reduced in all clinical situations
measure RV. RV must be measured to determine TLC. TLC should where gas transfer from the alveoli to capillary blood is impaired.3
be measured anytime VC is reduced. In the setting of chronic Common conditions that reduce DLCO include lung resection,
obstructive pulmonary disease (COPD) and a low VC, measurement emphysema (loss of functioning alveolar–capillary units), and inter-
of TLC can help to determine the presence of a superimposed stitial lung disease (thickening of the alveolar–capillary membrane).
restrictive disorder. The four methods for measuring TLC are helium Normal PFTs with reduced DLCO should suggest the possibility of
dilution, nitrogen washout, body plethysmography, and chest x-ray pulmonary vascular disease (e.g., pulmonary embolus) but also can
be seen with anemia, early interstitial lung disease, and mild Pneu-
A B
mocystis carinii pneumonia (PCP) infection in patients with acquired
immune deficiency syndrome.
Inspiration

+10 Decreased
overall
+5 RV flows OBSTRUCTIVE LUNG DISEASE
Flow (L/s)

TLC
0 0
 Obstructive lung disease implies a reduced capacity to get air
Expiration

−5 through the conducting airways and out of the lungs. This reduction
in airflow may be caused by a decrease in the diameter of the airways
(bronchospasm), a loss of their integrity (bronchomalacia), or a
reduction in elastic recoil (emphysema) with a resulting decrease in
C D
driving pressure. The most common diseases associated with obstruc-
Decreased Decreased flow with tive pulmonary functions are asthma, emphysema, and chronic bron-
flow at high normal flow–volume
volumes relationship chitis; however, bronchiectasis, infiltration of the bronchial wall by
tumor or granuloma, aspiration of a foreign body, and bronchiolitis
0 0
also cause obstructive PFTs. The standard test used to evaluate airway
obstruction is the forced expiratory spirogram.
Standard spirometry and flow–volume loop measurements include
many variables; however, according to ATS guidelines, the diagnosis
FIGURE 27-4. A. Flow–volume loop depicting mild obstruction charac-
of obstructive and restrictive ventilatory defects should be made using
terized by decrease flow at low lung volumes. B. Moderate airflow
obstruction characterized by a more concave curve. C. Variable intratho- the basic measurements of spirometry.3 A reduction in FEV1 (with
racic obstruction in which peak flow is decreased at higher lung volumes normal FVC) establishes the diagnosis of obstruction. When both
with normalization of curve at lower lung volumes. D. Restrictive lung FEV1 and FVC are reduced, FEV1 cannot be used to assess airway
disease with a curve that is decreased in width but with a normal shape. obstruction because such patients may have either obstruction or
(RV, residual volume; TLC, total lung capacity.) restriction. In restrictive lung disease, the patient has an inability to
 458
get air into the lung, which results in a reduction of all expiratory After the diagnosis of obstructive airways disease is established,
volumes (FEV1, FVC, and SVC). In obstructed patients, a better the course and response to therapy are best followed by serial
SECTION 3

measurement is the ratio FEV1/FVC. Patients with restrictive lung spirometry. The multicenter Lung Health Study demonstrated an
disease have reduced FEV1 and use of reduced FVC, but FEV1/FVC abnormally rapid decline (90–150 mL/y) in patients with COPD
remains normal. Although a normal FEV1/FVC ratio is >70% to 75%, who continue to smoke.5 Smoking cessation often resulted in an
the ratio is age dependent, and slightly lower values may be normal in increase in FEV1 during the first year and a near-normal rate of
older patients. Younger children have increased lung elastic recoil and decline (30–50 mL/y) in subsequent years.
may have higher ratios. Children with asthma often have FEV1/FVC
>90% despite obstructive lung disease. In children, the improvement
in FEV1 after use of an inhaled bronchodilator often is the only way AIRWAY HYPERREACTIVITY
Respiratory Disorders

to document mild-to-moderate obstructive lung disease. Caution

should be used in interpreting obstruction when FEV1/FVC is below  Airway hyperreactivity or hyperresponsiveness is defined as an
normal, but FEV1 and FVC both are within the normal range because exaggerated bronchoconstrictor response to physical, chemical, or
this pattern can be seen with healthy, athletic subjects. In screening pharmacologic stimuli. Individuals with asthma, by definition, have
spirometry performed in office practice, FEV6 (forced expiratory hyperresponsive airways. The Lung Health Study Group observed
volume in 6 seconds) can be used in place of FVC. FEV6 is a more nonspecific hyperresponsiveness in a significant number of patients
reproducible number when obtained by less skilled personnel. The with COPD. This group of patients with airway hyperreactivity
measurement of FEF25%–75% also is abnormal in patients with obstruc- appears to have a worse prognosis and an accelerated rate of decline
tive airways disease. In general, this test has so much variability that it in FEV1.6
adds little to the measurement of FEV1 and FEV1/FVC. FEF25%–75% Some patients with asthma (especially cough-variant asthma)
has been of value in monitoring lung transplant patients for graft present with no history of wheezing and normal PFTs. The diagno-
rejection,4 and a reduced value may be an early indicator of acute sis of asthma still can be established by demonstrating hyperrespon-
rejection. siveness to provocative agents. The two agents used most widely in
Although there is no standardization for interpretation of severity clinical practice are methacholine and histamine. Other agents used
of obstruction, most pulmonary laboratories state that FEV1/FVC for bronchial provocation include distilled water, cold air, and
<70% of the predicted value is diagnostic for obstruction, and the exercise. During a typical bronchoprovocation test, baseline FEV1 is
degree of obstruction then is based on the percent predicted of FEV1. measured after inhalation of isotonic saline, then increasing doses of
FEV1 <60% of the predicted value is moderate obstruction, and methacholine are given at set intervals. Hyperresponsiveness is
<40% of the predicted value is severe obstruction. In patients with defined as a decline in FEV1 ≥20% and reversibility of obstruction
obstruction, a dose of a bronchodilator (e.g., albuterol or isoproter- to bronchodilators. The result can best be expressed as the provoc-
enol) by metered-dose inhaler is given during the initial examina- ative concentration needed to cause a 20% fall in FEV1 (PC20). A test
tion. An increase in FEV1 of >12% and >0.2 L suggests an acute is considered positive if either methacholine or histamine demon-
bronchodilator response.3 Because bronchodilator responsiveness is strates a PC20 for FEV1 ≤8 mg/mL or <60 to 80 cumulative breath
variable over time, the lack of an acute bronchodilator response units.7 This test is used most frequently to establish a diagnosis of
should not preclude a 6- to 8-week trial of bronchodilators and/or asthma in patients with normal PFTs, but it also may be useful in
corticosteroids. following patients with occupational asthma, establishing the sever-
Although all patients with obstructive lung disease of any etiology ity of asthma, and assessing the response to treatment.
will have reduced flow rates on forced exhalation, the pattern on PFTs
may be helpful in differentiating among the various etiologies (Table
27–1). Asthma is characterized by variable obstruction that often
UPPER AIRWAY OBSTRUCTION
improves or resolves with appropriate therapy. Because asthma is an
Obstruction of airflow by abnormalities in the upper airway often
inflammatory disorder of the airways (predominantly large airways),
goes undiagnosed or misdiagnosed because of improper interpreta-
DLCO is normal. Most patients with acute asthma have a bronchodi-
tion of PFTs. Patients have obstructive physiology and often are
lator response >15% to 20%; however, this response is also seen in
misclassified as having asthma or COPD. The shape of the flow–
20% of patients with COPD. These patients are said to have asthmatic
volume loop, which includes inspiratory and expiratory flow–
bronchitis. Chronic bronchitis may be limited to the airways, but the
volume curves, and the ratio of forced expiratory and inspiratory
vast majority of patients with chronic bronchitis and airway obstruc-
flow at 50% of vital capacity (FEF50%/FIF50%) may be useful in the
tion have a mixture of bronchitis and emphysema and have a
diagnosis of upper airway obstruction.8
reduction in DLCO. Therefore, DLCO is the best PFT for separating
The shape of the flow–volume curve differs depending on whether
asthma from COPD.
the obstruction is fixed or variable (Fig. 27–5). Fixed lesions, as in
strictures from previous intubations or tracheostomy, cause a uniform
TABLE 27-1 Specific Patterns of Pulmonary Function in Patients caliber of airway during inspiration and expiration. With variable
with Chronic Obstructive Pulmonary Disease lesions, the airway caliber changes with changes in intrathoracic pres-
COPD sure. Variable lesions are subclassified into variable intrathoracic and
Asthma Chronic Bronchitis Emphysema
variable extrathoracic. If the lesion is intrathoracic, as with tumors of
the trachea, the negative pressure generated during inspiration opens
Decreased FEV1 ++++ ++++ ++++ the obstruction, whereas the positive pressure during expiration wors-
Decreased FEV1/FVC ++++ ++++ ++++
ens the obstruction. If the lesion is a variable extrathoracic obstruction,
Increased airway resistance ++++ ++++ +
Decreased DLCO — —/++a ++++
as with vocal cord dysfunction, the negative pressure within the airways
Response to bronchodilators ++++ +b —b will pull the vocal cord toward the midline and potentiate the obstruc-
tion. In this case, there will be a plateau on the inspiratory limb of the
DLCO, diffusing capacity of carbon monoxide; FEV1, forced expiratory volume in the first second of flow–volume loop, and FEF50%/FIF50% will be >1. Typical flow–volume
expiration; FVC, forced vital capacity.
a
Most smokers with chronic bronchitis have reduced DLCO.
curves from upper airway obstruction are shown in Fig. 27–4.
b
Twenty percent of patients with chronic obstructive pulmonary disease (COPD) have a large (++++) Another test used to distinguish upper airway obstruction from
bronchodilator response. COPD and asthma is FEV1/FEV0.5 (FEV at 0.5 second). This ratio
 459

CHAPTER 27
Expiratory Expiratory Expiratory
flow flow flow

TLC RV RV TLC RV
Inspiratory Inspiratory TLC Inspiratory FIGURE 27-5. Maximum expiratory flow–volume curves
flow flow flow from patients with fixed obstruction, variable extrathoracic
Fixed obstruction Variable extrathoracic Variable intrathoracic obstruction, and variable intrathoracic obstruction. (RV,
obstruction obstruction residual volume; TLC, total lung capacity.)

usually is >1.5 in patients with upper airway obstruction.9 This is so

Introduction to Pulmonary Function Testing

develop a moderately severe restrictive lung disease while maintain-
because FEV0.5 is proportionately more reduced in upper airway ing TLC within the normal range. On flow–volume loop, patients
obstruction because forced expiration measured at 0.5 second better with restrictive disease have normal-shaped curves with a reduction
reflects obstruction at high lung volumes. The abnormality seen on in the height and width of the curve because peak expiratory flow
the flow–volume loop has been referred to as “straightening” of the rate and VC both depend on the amount of air within the lung prior
curve during early expiration. to performance of expiratory maneuvers (Fig. 27–3).
 Restrictive lung function can be produced by increased elastic
recoil of the lung parenchyma (interstitial lung disease), respiratory
RESTRICTIVE LUNG DISEASE muscle weakness, mechanical restrictions (chest wall deformities),
and/or poor effort. Table 27–2 lists common causes of restrictive
 Restrictive lung disease is defined as an inability to get air into the lung disease.
lungs and to maintain normal lung volumes. Restrictive lung disease Restrictive lung function from parenchymal lung disease usually
reduces all the subdivisions of lung volumes (IRV, VT, ERV, and can be differentiated from processes causing mechanical restriction as
RV) without reducing airflow. Patients have normal airway resis- a result of chest bellows malfunction (Table 27–3). Restrictive paren-
tance and FEV1/FVC >75%. chymal diseases are associated with a reduction in alveolar volume
Although restriction could be defined as a reduction in vital and an increase in lung elastic recoil. All lung volumes, as well as
capacity (VC or FVC) with normal FEV1/FVC, poor effort also will DLCO, are reduced. RV/TLC (normal ≤30%) and measurements of
reduce FVC with normal FEV1/FVC. A reduction in TLC is the most maximal inspiratory pressure (normal = –75 cm H2O in males, –50
accurate measurement of restrictive lung function. TLC can be cm H2O in females) remain normal. In addition, patients exhibit mild
measured by various techniques. The gas dilution methods (e.g.,
resting hypoxemia that worsens with exercise. Monitoring gas
helium dilution and nitrogen washout) are unable to measure gas
exchange during exercise may be the most sensitive test for detecting
trapped in cysts or bullae and may underestimate the true lung
progression of interstitial lung disease.10
volume. Therefore, TLC is best measured by plethysmography.
Mechanical restriction caused by chest bellows malfunction may
Most restrictive lung disease is associated with impairment or
result from chest wall or skeletal deformity, loss of neuromuscular
destruction of the alveolar–capillary membrane; therefore, DLCO is
function, fibrosis of the pleural space, and abdominal overdisten-
reduced in most patients with restrictive lung disease. The reduction sion causing upward displacement of the diaphragm, as well as
in DLCO may occur prior to a reduction in lung volumes and is used decreased diaphragm movement. The most common pulmonary
as a marker of early interstitial (restrictive) lung disease. DLCO may function pattern seen in these patients is a decrease in TLC and VC
be abnormal even with a normal chest x-ray film, and thin-cut with only a slight decrease in RV. RV is maintained in these diseases
computed tomographic scans of the chest may be required to because lung compliance remains normal. DLCO is normal or only
diagnose early interstitial lung disease. Because peribronchiolar
minimally reduced, and DLCO/VA (corrected for alveolar volume) is
inflammation and fibrosis occur in patients with restrictive paren-
normal. RV/TLC often is increased in patients with restrictive chest
chymal lung disease, FEF25%–75% may be reduced and fail to respond
bellows disease. Patients with neuromuscular disease have reduced
to bronchodilators. respiratory muscle function with a reduction in maximal inspira-
The severity of restrictive disease has not been standardized; tory pressure.
however, many laboratories classify patients with reduced TLC as
mild (TLC ≤80%), moderate (TLC ≤65%), or severe (TLC ≤50%).
These definitions are completely arbitrary because a patient with PULMONARY GAS EXCHANGE
obstructive lung disease may start with TLC 120% and subsequently
The essential function of the lungs is to maintain blood gas homeo-
stasis. Arterial blood gas measurement plays an important role in
TABLE 27-2 Causes of Restrictive Lung Disease
Interstitial lung diseases Chest wall diseases TABLE 27-3 Patterns of Pulmonary Function
Idiopathic pulmonary fibrosis Kyphoscoliosis Obstructive Restrictive
Sarcoidosis Ankylosing spondylitis Lung Disease Lung Disease
Collagen vascular disease Neuromuscular disease
Pneumoconiosis Miscellaneous causes Parenchymal Chest Bellows
Drug-induced lung disease Obesity Asthma COPD Disease Disease
Pulmonary edema Pregnancy FVC Nl or I Nl or I D D
Infiltrative lung diseases Ascites FEV1 D D D D
Granulomatosis Paralyzed diaphragm FEV1/FVC <75% <75% ≥75% ≥75%
Tumor Lung resection TLC Nl or I Nl or I D D
Pleural diseases RV/TLC Nl or I Nl or I Nl I
Pleural effusion Airway resistance I I Nl Nl
Fibrothorax DLCO Nl D D Nl
Pneumothorax
D, decreased; I, increased; Nl, normal.
 460
the diagnosis and management of patients with pulmonary disease When more formal exercise testing is needed for some of the
and should be ordered whenever hypoxemia, hypercapnia (CO2 indications previously listed (e.g., dyspnea evaluation, evaluation of
SECTION 3

retention), and/or acid–base disorders are suspected clinically. ventilatory or cardiovascular limitations to work, evaluation of
Every time arterial blood gas determinations are ordered, the A–a disability and preoperative assessment before lung resection), exer-
gradient (difference between partial pressure of oxygen in the cise tolerance tests or cardiopulmonary stress testing can be per-
•
alveolus and partial pressure of oxygen in arterial blood) should be formed. Tests include measurement of oxygen consumption (VO2),
• •
calculated. This is accomplished by computer on all automated carbon dioxide production (V CO2), minute volume (V E), VT,
blood gas machines, and a normal P(A–a)O2 can be approximated respiratory rate, SpO2, heart rate, blood pressure, and recording or
•
for sea-level breathing room air by multiplying the age by 0.3. The monitoring of the electrocardiogram. During exercise, VO2 increases
presence of hypoxemia with a normal A–a gradient usually implies with workload in a linear fashion until a maximum oxygen con-
• •
Respiratory Disorders

alveolar hypoventilation (e.g., sedative overdose). Most patients sumption level (VO2max) is reached. Consequently, VO2max is a
11–13
develop hypoxemia secondary to mismatching of ventilation and measure of an individual’s muscular work capacity. Normal
•
perfusion, and P(A–a)O2 will be significantly elevated. VO2max is approximately 1,700 mL/min for a sedentary person and
Oxygen saturation as measured by pulse oximetry (SpO2) is up to 5,800 mL/min for a trained athelete.13 This compares with a
•
widely used in clinical practice for monitoring arterial saturation. A resting VO2 of approximately 250 mL/min. Ventilatory equivalents
pulse oximeter is a small battery-operated device that is placed on for oxygen, carbon dioxide, and O2 pulse are often calculated.
the finger or the earlobe. The device emits and reads the reflected Ventilatory equivalent for oxygen is a measure of the efficiency of
light from capillary blood, and estimates the saturation. Although the ventilatory pump at various workloads11,13,14 and is calculated as
SpO2 is clinically very useful, SpO2 is only an estimate of arterial follows:
saturation. Actual arterial oxygen saturation (SaO2) can be ± 2% to • •
4% of the oximetric reading. The error may be even greater with Ventilatory equivalent for O2 = Ve/Vo2.
saturation <88%. Pulse oximeters do not measure carboxyhemo- A normal ventilatory equivalent for oxygen is 20 to 30.11,13
globin, and SpO2 may be overestimated significantly in patients with O2 pulse is an estimate of oxygen consumption per cardiac cycle
smoke inhalation or in recent smokers. An initial validation of pulse and can be decreased with cardiac problems. O2 pulse can be
oximetry with direct measurement of SaO2 is recommended in any calculated as follows:
critically ill patient.
•
O2 pulse = (VO2 [in L/min] × 1,000)/Heart rate.
EXERCISE TESTING
Cardiopulmonary exercise testing allows for assessment of multiple TABLE 27-4 Indications and Contraindications for Exercise Testing
organs involved in exercise and has benefits over assessment of Indications
either the cardiac system or pulmonary system alone. The major Dyspnea upon exertion
indications for exercise testing are dyspnea on exertion, evaluation Exercise-induced bronchospasm
of exercise-induced bronchospasm, and suspected arterial desatura- Suspected arterial desaturation with exercise
tion during exercise.11–14 Exercise testing also can be useful in the Evaluation of ventilatory limitations to exercise
evaluation of ventilatory or cardiovascular limitations to work, Evaluation of cardiac limitations to exercise
assessment of general fitness or conditioning, evaluation of disabil- Assessment of general fitness or conditioning
ity, establishment of safe levels for exercise, evaluation of drug Evaluation of cardiopulmonary disability
therapy, determining the need and liter flow for supplemental Establishment of safe levels for exercise
oxygen therapy during exercise, assessment of the effects of a Evaluation of drug therapy
Determining appropriate use of supplemental oxygen therapy
rehabilitation program, and preoperative assessment before lung
Establishing an exercise prescription for a rehabilitation program
resection.11–14 Assessment of the effect of a rehabilitation program
Tests for general fitness include the 6-minute walking distance Evaluation of specific disease states or conditions (e.g., asthma, chronic obstructive
and the Harvard step test.11,13–15 For the 6-minute walking distance, pulmonary disease [COPD], interstitial lung disease, pulmonary vascular disor-
the subject simply walks a predetermined route or circuit as fast as ders, coronary artery disease, other vascular disorders, neuromuscular disorders,
possible for 6 minutes. The subject is allowed to stop and rest, but obesity, anxiety-induced hyperventilation)
the clock continues to run. The greater the distance covered, the Assessment before resection
better are the patient’s general fitness and exercise tolerance. For the Assessment before lung volume reduction surgery or lung transplantation
Harvard step test, the subject steps up and down on a 20-inch step Contraindications
at a set rate for 5 minutes. A 1-minute rest period is followed by PaO2 <40 mm Hg on room air
PaCO2 >70 mm Hg
measurement of the subject’s recovery heart rate. The lower the
FEV1 <30% of predicted
recovery heart rate, the better is the subject’s general fitness.
Recent (within 4 weeks) myocardial infarction
Exercise testing sometimes is performed to determine if exercise Unstable angina pectoris
results in arterial oxygen desaturation (SaO2 <90%).12,13 The test Second- or third-degree heart block
may be useful for quantifying the level of exertion the patient can Rapid ventricular/atrial arrhythmias
perform during the activities of daily living as well as determining Orthopedic impairment
appropriate levels of supplemental oxygen therapy. Typically, this Severe aortic stenosis
test is done using a treadmill or cycle ergometer. A baseline mea- Congestive heart failure
surement of arterial blood gas values or pulse oximetry is followed Uncontrolled hypertension
by up to 6 minutes of exercise, during which time the patient is Limiting neurologic disorders
monitored for oxygen desaturation using pulse oximetry. If signifi- Dissecting/ventricular aneurysms
cant desaturation occurs (saturation ≤88%–90%), the test is termi- Severe pulmonary hypertension
Thrombophlebitis or intracardiac thrombi
nated. In the event of oxygen desaturation, the test can be repeated
Recent systemic or pulmonary embolus
to determine the level of supplemental oxygen therapy needed to Acute pericarditis
compensate for the desaturation that otherwise would occur.
 461

TABLE 27-5 Typical Findings during Maximum Exercise with Poor FEV1: forced expiratory volume in first second of expiration

CHAPTER 27
Conditioning, Pulmonary Limitations to Exercise, and FEV6: forced expiratory volume in 6 seconds
Cardiac Limitations to Exercise
FIF50%: forced inspiratory flow at 50% of forced vital capacity
Poor Pulmonary Cardiac
Test Parameter Conditioning Limitation Limitation FRC: functional residual capacity
•
VO2max ↓ ↓ ↓ FVC: forced vital capacity
SpO2 N ↓ N IC: inspiratory capacity
O2 pulse N or ↓ N or ↓ ↓
IRV: inspiratory reserve volume
Anaerobic threshold ↓ or N ↓ or N ↓
Ventilatory reservea N ↓ N or ↑ P1V1 = P2V2: Boyle’s gas law

Introduction to Pulmonary Function Testing

(MVV – VEmax) P(A–a)O2: alveolar–arterial difference in partial pressure of oxygen
a
Ventilatory reserve = Maximum voluntary ventilation (MVV) – Minute volume during maximum PaCO2: arterial partial pressure of carbon dioxide
exercise (VEmax).
N, normal. PaO2: arterial partial pressure of oxygen
Adapted from Madama VE. Pulmonary Function Testing and Cardiopulmonary Stress Testing.
Albany, NY: Delmar, 1993. PC20: provocative concentration needed to cause a 20% fall in FEV1
PCP: Pneumocystis carinii pneumonia
PFT: pulmonary function test
A normal O2 pulse is 2.5 to 4.0 mL per beat at rest and increases to
10 to 15 mL per beat during strenuous exercise.11,13 PO2: partial pressure of oxygen
The anaerobic threshold is the point during strenuous exercise at RV: residual volume
which anaerobic metabolism and lactic acid production begin.11,13,14 SaO2: arterial oxygen saturation
• •
VCO2max increases with exercise at about the same rate as VO2 until
the subject’s anaerobic threshold is reached. From that point on, V
•
SpO2: oxygen saturation as measured by pulse oximetry
•
CO2 increases faster than V O2, and this change can be used to SVC: slow vital capacity
estimate the anaerobic threshold. A breath-by-breath plot of the TLC: total lung capacity
ventilatory equivalents for O2 and CO2 also can be used to deter-
mine the anaerobic threshold. Anaerobic threshold is a measure of VA: alveolar volume
fitness in normal subjects, and aerobic training can delay the anaer- VC: vital capacity
obic threshold.11,13 VT: tidal volume
For exercise tolerance testing, the patient typically is subjected to
either a constant workload (steady-state tests) or an increasing
workload (progressive multistage tests) using a cycle ergometer or REFERENCES
treadmill.11,13 With progressive multistage tests, the patient exer-
cises to exhaustion or the occurrence of an adverse reaction, at 1. Renzessi AA Jr, Bleeker, ER, Eppler, GR, et al. Evaluation of impair-
which point the test is stopped. Safety during exercise testing is of ment/disability secondary to respiratory disorders. Am Rev Respir Dis
major importance, and rigorous guidelines for termination of the 1986;133:1205–1209.
test should be followed. Both types of tests can be used to determine 2. Pelligrino R, Viegi G, Brusasco V, et al. Series ATS/ERS Task Force:
• • Standardization of lung function testing; interpretative strategies for
VO2max. A limit to exercise, as indicated by a decrease in VO2max,
lung function tests. Eur Respir J 2005;26:319–338.
can result from (1) poor conditioning, (2) pulmonary limitation,
3. Crapo RO, Hankinson JL, Irvin C, et al. American Thoracic Society
(3) cardiac limitation, or (4) poor effort. In the case of poor
statement: Standardization of spirometry—1994 update. Am J Respir
conditioning, SpO2 and O2 pulse will be normal. With a pulmonary Crit Care Med 1995;152:1107–1136.
limitation to exercise, SpO2 will be reduced, and O2 pulse will be 4. Levine SM, Peters JI, Jenkinson SG. Lung transplantation and lung
normal. With a cardiac limitation to exercise, SpO2 will be normal, volume reduction surgery. In: George RB, Light RW, Matthaw MA, eds.
and O2 pulse will be reduced. Table 27–4 summarizes the indica- Chest Medicine: Essentials of Pulmonary and Critical Care Medicine,
tions and contraindications for exercise testing. Table 27–5 sum- 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:208–232.
marizes the findings during maximum exercise associated with 5. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking
poor conditioning, pulmonary limitations to exercise, and cardiac intervention and the use of an inhaled anticholinergic bronchodilator
limitations to exercise. on the rate of decline of FEV1: The Lung Health Study. JAMA
1994;272:1497–1505.
6. Tashkin DP, Altose MD, Bleeker ER, et al. The Lung Health Study:
ABBREVIATIONS Airway responsiveness to inhaled methacholine in smokers with mild
to moderate airflow limitation. Am Rev Respir Dis 1992;145:301–310.
7. Crapo RO, Casaburi R, Coates AL, et al. American Thoracic Society
COPD: chronic obstructive pulmonary disease
statement: Guidelines for methacholine and exercise challenge test-
DL: diffusing capacity of lung ing—1999. Am J Respir Crit Care Med 2000;161:309–329.
DLCO: diffusing capacity of lung for carbon monoxide 8. Aboussouan LS, Stoller JK. Diagnosis and management of upper
airway obstruction. Clin Chest Med 1994;15:35–53.
ERV: expiratory reserve volume 9. Bright P, Miller MR, Franklyn JA, et al. The use of a neural network to
FEF: forced expiratory flow detect upper airway obstruction caused by goiter. Am J Respir Crit
Care Med 1998;157:1885–1891.
FEF25%–75%: forced expiratory flow during 25% to 75% of forced
10. Leith DE, Brown R. ERS/ATS Workshop Series: Human lung volumes
vital capacity and the mechanisms that set them. Eur Respir J 1999;13:468–472.
FEF50%: forced expiratory flow at 50% of forced vital capacity 11. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Principles
of Exercise Testing and Interpretation: Including Pathophysiology and
FEFmax: maximum forced expiratory flow Clinical Applications, 4th ed. Philadelphia: Lippincott Williams &
FEV0.5: forced expiratory volume at 0.5 second Wilkins, 2004.
 462
12. Ruppel GE. Manual of Pulmonary Function Testing. St. Louis: Mosby, 14. Weisman IM, Zeballos RJ. Clinical exercise testing. Clin Chest Med
1994. 2001;22:679–701.
SECTION 3

13. ATS/ACCP statement on cardiopulmonary exercise testing. Am J 15. ATS Statement: Guidelines for the six-minute walk test. Am J Respir
Respir Crit Care Med 2003;167:211–277. Crit Care Med 2002;166:111–117.
Respiratory Disorders
 463

C HAP T E R

28 Asthma

H. WILLIAM KELLY AND CHRISTINE A. SORKNESS

mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils,

KEY CONCEPTS and epithelial cells. In susceptible individuals, this inflammation
causes recurrent episodes of wheezing, breathlessness, chest tight-
 Asthma is a disease of increasing prevalence that is a result of ness, and coughing, particularly at night or in the early morning.
genetic predisposition and environmental interactions; it is one These episodes are usually associated with widespread but variable
of the most common chronic diseases of childhood. airflow obstruction that is often reversible either spontaneously or
 Asthma is primarily a chronic inflammatory disease of the air- with treatment. The inflammation also causes an associated increase
ways of the lung for which there is no known cure or primary in the existing bronchial hyperresponsiveness (BHR) to a variety of
prevention; the immunohistopathologic features include cell stimuli. Reversibility of airflow limitation may be incomplete in
infiltration by neutrophils, eosinophils, T-helper type 2 lympho- some patients with asthma.
cytes, mast cells, and epithelial cells. This definition encompasses the important heterogeneity of the
clinical presentation of asthma by describing the scientific and
 Asthma is characterized by either the intermittent or persistent clinically accepted characteristics of asthma.
presence of highly variable degrees of airflow obstruction from
airway wall inflammation and bronchial smooth muscle con-
striction; in some patients, persistent changes in airway struc-
ture occur.
EPIDEMIOLOGY
 The inflammatory process in asthma is treated most effectively  An estimated 20.5 million persons in the United States have
with corticosteroids, with the inhaled corticosteroids having the asthma (approximately 7% of the population).3 Asthma is the most
greatest efficacy and safety profile for long-term management. common chronic disease among children in the United States, with
approximately 6.5 million children affected. The prevalence of
 Bronchial smooth muscle constriction is prevented or treated asthma in the United States and worldwide has continued to
most effectively with inhaled β2-adrenergic receptor agonists. increase. The prevalence rate is highest in children 5–17 years at
 Variability in response to medications requires individualiza- 9.6%.3 In the United States, as in other Western industrialized
tion of therapy within existing evidence-based guidelines for countries, the prevalence of asthma has reached epidemic propor-
management. tions. Asthma accounts for 1.6% of all ambulatory care visits (13.7
million physician office visits and 1.0 million hospital outpatient
 Ongoing patient education, for a partnership in asthma care, is visits) and results in more than 497,000 hospitalizations and 1.8
essential for optimal patient outcomes and includes trigger million emergency department visits per year.3 Although asthma is
avoidance and self-management techniques. the third leading cause of preventable hospitalization in the United
States, hospitalizations for asthma have decreased only slightly over
the past 10 years to 17 per 10,000 population.4 Children younger
Asthma has been known since antiquity, yet it is a disease that still than 15 years of age have the highest rate of hospitalization at 31 per
defies precise definition. The word asthma is of Greek origin and 10,000 population. Asthma accounts for more than 10 million
means “panting.” More than 2,000 years ago, Hippocrates used the missed school days per year.3 The prevalence of disabling asthma in
word asthma to describe episodic shortness of breath; however, the children has increased 232% over the past 20 years compared with
first detailed clinical description of the asthmatic patient was made a 113% increase from all other chronic conditions in childhood.4 In
by Aretaeus in the second century.1 An expert panel of the National young children (0 to 10 years of age), the risk of asthma is greater in
Institutes of Health, the National Asthma Education and Prevention boys than in girls, becomes about equal during puberty, and then is
Program (NAEPP), has provided the following working definition greater in women than in men.3
of asthma2: Ethnic minorities continue to share the burden of asthma dispro-
Asthma is a chronic inflammatory disorder of the airways in portionately. African Americans have a higher prevalence than
which many cells and cellular elements play a role: in particular, whites, but this appears to be a result of urbanization and not race or
socioeconomic status.4 African Americans are three times as likely to
be hospitalized and approximately 2.5 times more likely to die from
asthma.3 In addition, African Americans and Puerto Ricans living in
Learning objectives, review questions, inner cities are four times more likely to experience emergency
and other resources can be found at department visits than whites.3 These patterns are likely a result of
www.pharmacotherapyonline.com. poor access to care as Hispanics in general have a lower prevalence
than African Americans or whites.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 464
The estimated direct medical cost of asthma in the United States but more recent genome-wide searches have found linkages with
in 2004 was $11.5 billion.3 The societal burden of asthma (indirect genes for metalloproteinases (e.g., ADAM33).10,11 Thus, although
SECTION 3

medical expenditures) in the United States was $4.6 billion. Prescrip- genetic predisposition to atopy is a significant risk factor for
tion drugs were the largest single direct medical expenditure at $5 developing asthma, not all atopic individuals develop asthma, nor
billion, however, the combined costs of emergency care of acute do all asthmatics exhibit atopy.
asthma exacerbations makes up 36% of direct medical costs.3 Almost  Environmental risk factors for the development of asthma
$1.5 billion of indirect costs were a result of school days lost, and lost include socioeconomic status, family size, exposure to secondhand
productivity secondary to asthma mortality cost $1.7 billion. tobacco smoke in infancy and in utero, allergen exposure, urbaniza-
The natural history of asthma is still not well defined. Although tion, and decreased exposure to common childhood infectious
asthma can occur at any time, it is principally a pediatric disease, agents.12 The “hygiene hypothesis” proposes that genetically suscep-
Respiratory Disorders

with most patients being diagnosed by 5 years of age and up to 50% tible individuals develop allergies and asthma by allowing the
of children having symptoms by 2 years of age.2 Between 30% and allergic immunologic system (T-helper cell type 2 [TH2]-lympho-
70% of children with asthma will improve markedly or become cytes) to develop instead of the immunologic system used to fight
symptom-free by early adulthood; chronic disease persists in approx- infections (T-helper cell type 1 [TH1]-lymphocytes), and is being
imately 30% to 40% of patients, and generally 20% or less develop used to explain the increase of asthma in Western countries.6,12 The
severe chronic disease.2 Atopic status is the strongest indicator of first 2 years of life appear to be most important for the exposures to
persistence into adulthood, although initial severity also predicts produce an alteration in the immune response system. Support for
severity as an adult.5 Other predictors of persistent adult asthma the hygiene hypothesis for asthma comes from studies demonstrat-
include onset during school age and presence of BHR. Diminished ing a lower risk for asthma in children who live on farms and are
lung growth may occur in children with uncontrolled severe asthma exposed to high levels of bacteria, in those with a large number of
but does not appear to occur in children with mild to moderate siblings, in those with early enrollment into child care, in those with
asthma.6 Most of the deficits in lung function growth occur in exposure to cats and dogs early in life, or in those with exposure to
children whose symptoms begin during the first 3 years of life.6 fewer antibiotics.10,12
In adults, most longitudinal studies have suggested a more rapid Risk factors for early (<3 years of age) recurrent wheezing associ-
rate of decline in lung function in asthmatics than in normal ated with viral infections include low birth weight, male gender, and
volunteers, primarily reflected in forced expiratory volume in 1 parental smoking. However, this early pattern is a result of smaller
second (FEV1).5 However, the annual decline in FEV1 is less than in airways, and these risk factors are not necessarily risk factors for
smokers or in patients with a diagnosis of emphysema. In general, asthma in later life.7 Atopy is the predominant risk factor for children
individuals with less-frequent asthma attacks and normal lung to have continued asthma.7 Asthma can occur in adults later in life.
function on initial assessment have higher remission rates, whereas Occupational asthma in previously healthy individuals emphasizes
smokers have the lowest remission and highest relapse rates.5 The the effect of environment on the development of asthma.13 The
level of BHR tends to predict the rate of decline in FEV1, with a heterogeneity of the asthma phenotype appears most obvious when
greater decline with high levels of BHR.6 Thus airways obstruction listing the diverse triggers of bronchospasm in asthmatic subjects
in asthma not only may become irreversible but also may worsen (Table 28–1).2,6 The various triggers have relative degrees of impor-
over time owing to airway remodeling (see below Remodeling of the tance from patient to patient. This variety should serve as ample
Airway section).7 Many elderly patients with asthma have irrevers- evidence that asthma is likely to be as complex genetically.
ible airways obstruction.5 However, most patients do not die from Environmental exposures are the most important precipitants of
long-term progression of their disease and their life span is not severe asthma exacerbations (see Table 28–1).2,6 Epidemics of severe
different from that of the general population.5 asthma in cities have followed exposures to high concentrations of
Although the prevalence of asthma is increasing in the United aeroallergens.2 Viral respiratory tract infections remain the single
States, measures of significant morbidity (hospital admissions) and most significant precipitant of severe asthma in children, and are an
mortality from acute exacerbations of asthma have reached plateaus important trigger in adults as well.2,6 Other possible factors include
and have been slightly decreasing the past few years.3 Asthma results air pollution, sinusitis, food preservatives, and drugs.
in a little more than 4,000 deaths per year.3 Despite the relatively low
number of asthma deaths, 80% to 90% are preventable.2,8 Most
deaths from asthma occur outside the hospital, and death is rare TABLE 28-1 List of Agents and Events Triggering Asthma
after hospitalization. The most common cause of death from
Respiratory infection
asthma is inadequate assessment of the severity of airways obstruc-
Respiratory syncytial virus (RSV), rhinovirus, influenza, parainfluenza, Myco-
tion by the patient or physician and inadequate therapy. The most
plasma pneumonia
common cause of death in hospitalized patients is also inadequate Allergens
or inappropriate therapy. Thus the key to prevention of death from Airborne pollens (grass, trees, weeds), house-dust mites, animal danders,
asthma, as advocated by the NAEPP, is education.6 cockroaches, fungal spores
Environment
Cold air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke, wood smoke
ETIOLOGY Emotions
Anxiety, stress, laughter
 Asthma is at least a partially heritable complex syndrome that Exercise
requires a gene-by-environment interaction for phenotypic expres- Particularly in cold, dry climate
sion. Epidemiologic studies strongly support the concept of a Drugs/preservatives
genetic predisposition to the development of asthma, yet the picture Aspirin, nonsteroidal antiinflammatory drugs (cyclooxygenase inhibitors),
remains complex and incomplete.9 Genetic factors account for 35% sulfites, benzalkonium chloride, nonselective β-blockers
to 70% of the susceptibility. Asthma represents a complex genetic Occupational stimuli
disorder in that the asthma phenotype is likely a result of polygenic Bakers (flour dust); farmers (hay mold); spice and enzyme workers; printers
(arabic gum); chemical workers (azo dyes, anthraquinone, ethylenediamine,
inheritance or different combinations of genes. Initial searches
toluene diisocyanates, polyvinyl chloride); plastics, rubber, and wood workers
focused on establishing links between atopy (genetically determined
(formaldehyde, western cedar, dimethylethanolamine, anhydrides)
state of hypersensitivity to environmental allergens) and asthma,
 465
Inflammation Normal bronchus The late-phase inflammatory reaction occurs 6 to 9 hours after
allergen provocation and involves the recruitment and activation of

CHAPTER 28
T lymphocytes eosinophils, CD4+ T cells, basophils, neutrophils, and macro-
phages.14 There is selective retention of airway T cells, the expression
Eosinophils of adhesion molecules, and the release of selected proinflammatory
mediators and cytokines involved in the recruitment and activation
Lumen
of inflammatory cells.14 The activation of T cells after allergen
Epithelium challenge leads to the release of TH2-like cytokines that may be a key
Mucous
plug mechanism of the late-phase response.14 The release of preformed
cytokines by mast cells is the likely initial trigger for the early

Asthma
recruitment of cells. This cell type may recruit and induce the more
persistent involvement by T cells.14 The enhancement of nonspecific
BHR usually can be demonstrated after the late-phase reaction but
not after the early phase reaction following allergen or occupational
Smooth
muscle challenge.
Neutrophils

Goblet
cells
CHRONIC INFLAMMATION
Basement
membrane Airway remodeling Airways inflammation has been demonstrated in all forms of asthma,
and an association between the extent of inflammation and the clinical
FIGURE 28-1. Representative illustration of the pathology found in the
asthmatic bronchus compared with a normal bronchus (upper right). severity of asthma has been demonstrated in selected studies.7,15 It is
Each section demonstrates how the lumen is narrowed. Hypertrophy of accepted that both central and peripheral airways are inflamed.
the basement membrane, mucus plugging, smooth muscle hypertrophy, In asthma, all cells of the airways are involved and become activated
and constriction contribute ( lower section). Inflammatory cells infiltrate, (Fig. 28–2). Included are eosinophils, T cells, mast cells, macrophages,
producing submucosal edema, and epithelial desquamation fills the epithelial cells, fibroblasts, and bronchial smooth muscle cells. These
airway lumen with cellular debris and exposes the airway smooth muscle cells also regulate airway inflammation and initiate the process of
to other mediators (upper left). remodeling by the release of cytokines and growth factors.15

Epithelial Cells
PATHOPHYSIOLOGY
Bronchial epithelial cells traditionally have been considered as a
 The major characteristics of asthma include a variable degree of barrier, participating in mucociliary clearance and removal of nox-
airflow obstruction (related to bronchospasm, edema, and hyperse- ious agents. However, epithelial cells also participate in inflamma-
cretion), BHR, and airways inflammation (Fig. 28–1). Evidence of tion by the release of eicosanoids, peptidases, matrix proteins,
inflammation arose from the studies of nonspecific BHR, broncho- cytokines, and nitric oxide (NO). Epithelial cells can be activated by
alveolar lavage, bronchial biopsies, and induced sputum, as well as IgE-dependent mechanisms, viruses, pollutants, or histamine. In
from postmortem observations of patients with asthma who died asthma, especially fatal asthma, extensive epithelial shedding occurs.
from an attack of asthma or from other causes. To understand the The functional consequences of epithelial shedding may include
pathogenetic mechanisms that underlie the many variants of heightened airways responsiveness, altered permeability of the air-
asthma, it is critical to identify factors that initiate, intensify, and way mucosa, depletion of epithelial-derived relaxant factors, and
modulate the inflammatory response of the airways and to deter- loss of enzymes responsible for degrading proinflammatory neu-
mine how these immunologic and biologic processes produce the ropeptides. The integrity of airway epithelium may influence the
characteristic airways abnormalities. Immune responses mediated sensitivity of the airways to various provocative stimuli. Epithelial
by immunoglobulin (Ig) E antibodies are of foremost importance. cells also may be important in the regulation of airway remodeling
and fibrosis.15,16
ACUTE INFLAMMATION
Eosinophils
Inhaled allergen challenge models contribute most to our understand-
Eosinophils play an effector role in asthma by release of proinflamma-
ing of acute inflammation in asthma.14 Inhaled allergen challenge in
tory mediators, cytotoxic mediators, and cytokines.15 Circulating
allergic patients leads to an early phase allergic reaction that, in some
eosinophils migrate to the airways by cell rolling, through interactions
cases, may be followed by a late-phase reaction. The activation of cells
with selectins, and eventually adhere to the endothelium through the
bearing allergen-specific IgE initiates the early phase reaction. It is
binding of integrins to adhesion proteins (vascular cell adhesion
characterized primarily by the rapid activation of airway mast cells
molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-
and macrophages. The activated cells rapidly release proinflammatory
1]). As eosinophils enter the matrix of the membrane, their survival is
mediators such as histamine, eicosanoids, and reactive oxygen species
prolonged by interleukin (IL)-5 and granulocyte-macrophage col-
that induce contraction of airway smooth muscle, mucus secretion,
ony-stimulating factor (GM-CSF). On activation, eosinophils release
and vasodilation.14 The bronchial microcirculation has an essential
inflammatory mediators such as leukotrienes and granule proteins to
role in this inflammatory process. Inflammatory mediators induce
injure airway tissue.15
microvascular leakage with exudation of plasma in the airways.14
Acute plasma protein leakage induces a thickened, engorged, and
Lymphocytes
edematous airway wall and a consequent narrowing of the airway
lumen. Plasma exudation may compromise epithelial integrity, and Mucosal biopsy specimens from patients with asthma contain
the presence of plasma in the lumen may reduce mucus clearance.14 lymphocytes, many of which express surface markers of inflam-
Plasma proteins also may promote the formation of exudative plugs mation. There are two types of T-helper CD4+ cells. TH1 cells
mixed with mucus and inflammatory and epithelial cells. Together produce IL-2 and interferon-γ (INF-γ), both essential for cellular
these effects contribute to airflow obstruction (see Fig. 28–1). defense mechanisms. TH2 cells produce cytokines (IL-4, -5, and -13)
 466
IAR LAR Chronic asthma
SECTION 3

FEV1 (L)

Minutes Hours Days

Respiratory Disorders

Bronchoconstriction Submucosal edema, Epithelial cell damage,

hyperresponsiveness mucus hypersecretion,
hyperresponsiveness

Histamine, PAF, LTC4, MBP,

PGD2, LTC4, ECP, etc.
LTD4, PAF PAF, LTC4, MBP,
cytokines, etc.
LTB4
PAF

IL-5,
FIGURE 28-2. Diagrammatic presentation Mast cell Neutrophil Macrophage GM-CSF Lymphocyte
of the relationship between inflammatory
cells, lipid and preformed mediators, inflam- Antigen
matory cytokines, and proposed pathogene- Eosinophil Eosinophil
sis and clinical presentation in asthma. See
Antigen-presenting cell IL-3,
text for details. (ECP, eosinophil cationic Monocyte GM-CSF
protein; GM-CSF, granulocyte-macrophage IL-8, etc.
colony-stimulating factor; IAR, immediate IL-4, etc.
IFN-γ, etc.
asthmatic reaction; IFN, interferon; IL, inter-
leukin; LAR, late asthmatic response; LT, Preeosinophil
leukotriene; MBP, major basis protein; PAF, (bone marrow)
Lymphocyte Eosinophilopoesis
platelet-activating factor; PG, prostaglandin.)

that mediate allergic inflammation. It is known that TH1 cytokines Mast Cells
inhibit the production of TH2 cytokines, and vice versa. It is
Mast cell degranulation is important in the initiation of immediate
hypothesized that allergic asthmatic inflammation results from a
responses following exposure to allergens.2 Mast cells are found
TH2-mediated mechanism (an imbalance between TH1 and TH2
throughout the walls of the respiratory tract, and increased num-
cells).15
bers of these cells (three- to fivefold) have been described in the
airways of asthmatics with an allergic component. Once binding of
TH1 and TH2 Cell Imbalance allergen to cell-bound IgE occurs, mediators such as histamine;
It has been postulated that the TH1/TH2 imbalance contributes to eosinophil and neutrophil chemotactic factors; leukotrienes (LTs)
the cause and evolution of atopic diseases, including asthma. The C4, D4, and E4; prostaglandins; platelet-activating factor; and others
T-cell population in the cord blood of newborn infants is skewed are released from mast cells (see Fig. 28–2). Histologic examination
toward a TH2 phenotype.7,15 The extent of the imbalance between has revealed decreased numbers of granulated mast cells in the
TH1 and TH2 cells (as indicated by diminished INF-γ production) airways of patients who have died from acute asthma attacks,
during the neonatal phase may predict the subsequent develop- suggesting that mast cell degranulation is a contributing factor in
ment of allergic disease, asthma, or both. It has been suggested that the progression of the disease. Sensitized mast cells also may be
infants at high risk of asthma and allergies should be exposed to activated by osmotic stimuli to account for exercise-induced bron-
stimuli that upregulate TH1-mediated responses in order to restore chospasm (EIB).15
the balance during a critical time in the development of the
immune system and the lung.7 Alveolar Macrophages
The basic premise of the hygiene hypothesis is that the new-
The primary function of alveolar macrophages in the normal airway
born’s immune system is skewed toward TH2 cells and needs timely
is to serve as “scavengers,” engulfing and digesting bacteria and
and appropriate environmental stimuli to create a balanced
other foreign materials. They are found in large and small airways,
immune response. Factors that enhance TH1-mediated responses
ideally located for affecting the asthmatic response. A number of
include infection with Mycobacterium tuberculosis, measles virus,
mediators produced and released by macrophages have been iden-
and hepatitis A virus; increased exposure to infections through
tified, including platelet-activating factor, LTB4, LTC4, and LTD4.15
contact with older siblings; attendance at day care during the first
Additionally, alveolar macrophages are able to produce neutrophil
6 months of life; and a reduction in the production of INF-γ.
chemotactic factor and eosinophil chemotactic factor, which, in
Restoration of the balance between TH1 and TH2 cells may be
turn, amplify the inflammatory process.
impeded by frequent administration of oral antibiotics, with con-
comitant alterations in gastrointestinal flora. Other factors favoring
the TH2 phenotype include Western lifestyle, urban environment,
Neutrophils
diet, and sensitization to house-dust mites and cockroaches. The role of neutrophils in the pathogenesis of asthma remains
Immune “imprinting” may begin in utero by transplacental trans- somewhat unclear because they normally may be present in the
fer of allergens and cytokines. airways and usually do not infiltrate tissues showing chronic allergic
 467
inflammation despite the potential to participate in late-phase Adhesion Molecules
inflammatory reactions. However, high numbers of neutrophils

CHAPTER 28
An important step in the inflammatory process is the adhesion of the
have been reported to be present in the airways of patients who died
various cells to each other and the tissue matrix to facilitate infiltra-
from sudden-onset fatal asthma7 and in those with severe disease.16
tion and migration of these cells to the site of inflammation. To
This suggests that neutrophils may play a pivotal role in the disease
promote this, cell membranes express a number of glycoproteins, or
process, at least in some patients with long-standing or corticoster-
adhesion molecules. Adhesion molecules have additional functions
oid-dependent asthma.16 The neutrophil also can be a source for a
involved in the inflammatory process aside from promoting cell
variety of mediators, including platelet-activating factor, prosta-
adhesion, including activation of cells and cell–cell communication,
glandins, thromboxanes, and leukotrienes, that contribute to BHR
and promoting cellular migration and infiltration.2 The many adhe-
and airway inflammation.
sion molecules are divided into families on the basis of their chemical

Asthma
structure. These families are the integrins, cadherins, immunoglobu-
Fibroblasts and Myofibroblasts lin supergene family, selectins, vascular adressins, and carbohydrate
Fibroblasts are found frequently in connective tissue. Human lung ligands.15 Those thought to be important in inflammation include
fibroblasts may behave as inflammatory cells on activation by IL- the integrins, immunoglobulin supergene family, selectins, and car-
4 and IL-13. The myofibroblast may contribute to the regulation bohydrate ligands, including ICAM-1 and VCAM-1.15 Adhesion
of inflammation via the release of cytokines and to tissue remod- molecules are found on a variety of cells, such as neutrophils,
eling. In asthma, myofibroblasts are increased in numbers beneath monocytes, lymphocytes, basophils, eosinophils, granulocytes, plate-
the reticular basement membrane, and there is an association lets, endothelial cells, and epithelial cells, and can be expressed or
between their numbers and the thickness of the reticular basement activated by the many inflammatory mediators present in asthma.15
membrane.16
CLINICAL CONSEQUENCES OF
Inflammatory Mediators CHRONIC INFLAMMATION
Associated with asthma for many years, histamine is capable of Chronic inflammation is associated with nonspecific BHR and
inducing smooth muscle constriction and bronchospasm and is increases the risk of asthma exacerbations. Exacerbations are char-
thought to play a role in mucosal edema and mucus secretion.2 acterized by increased symptoms and worsening airways obstruc-
Lung mast cells are an important source of histamine. The release of tion over a period of days or even weeks, and rarely hours.
histamine can be stimulated by exposure of the airways to a variety Hyperresponsiveness of the airways to physical, chemical, and
of factors, including physical stimuli (such as exercise) and relevant pharmacologic stimuli is a hallmark of asthma.2 BHR also occurs in
allergens.2 Histamine is involved in acute bronchospasm following some patients with chronic bronchitis and allergic rhinitis.2 Normal
allergen exposure; however, other mediators, such as leukotrienes, healthy subjects also may develop a transient BHR after viral
are also involved. respiratory infections or exposure to ozone. However, the degree of
Besides histamine release, mast cell degranulation releases inter- BHR is quantitatively greater in asthmatic patients than in other
leukins, proteases, and other enzymes that activate the production groups. Bronchial responsiveness of the general population fits a
of other mediators of inflammation. Several classes of important unimodal distribution that is skewed toward increased reactivity.
mediators, including arachidonic acid and its metabolites (i.e., Patients with clinical asthma represent the extreme end of the
prostaglandins, LTs, and platelet-activating factor), are derived distribution. The degree of BHR within asthmatics correlates with
from cell membrane phospholipids. the clinical course of their disease and medication requirement
Once arachidonic acid is released, it can be metabolized by the necessary to control symptoms.2 Patients with mild symptoms or in
enzyme cyclooxygenase to form prostaglandins. Although prosta- remission demonstrate lower levels of responsiveness, although still
glandin D2 is a potent bronchoconstricting agent, it is unlikely to greater than the normal population.
produce sustained effects and its role in asthma remains to be Our current understanding recognizes that the increased BHR
determined. Similarly, prostaglandin F2α is a potent bronchocon- seen in asthma is at least in part owing to an inflammatory response
strictor in patients with asthma and can enhance the effects of within the airways. Early investigations found correlations with
histamine.2 However, its pathophysiologic role in asthma is unclear. inflammatory cells in bronchoalveolar lavage fluids and degree of
Another cyclooxygenase product, prostacyclin (prostaglandin I2), is BHR.2 Newer evidence suggests that airways remodeling, subepithe-
known to be produced in the lung and may contribute to inflamma- lial fibrosis, or collagen deposition also correlates with BHR.16
tion and edema owing to its effects as a vasodilator. Although the precise link is unknown, BHR is in part related to the
Thromboxane A2 is produced by alveolar macrophages, fibro- extent of inflammation in the airways.
blasts, epithelial cells, neutrophils, and platelets within the lung.15
Indirect evidence from animal models suggests that thromboxane REMODELING OF THE AIRWAYS
A2 may have several effects, including bronchoconstriction, involve-
ment in the late asthmatic response, and involvement in the devel- Acute inflammation is a beneficial, nonspecific response of tissues
opment of airway inflammation and BHR. to injury and generally leads to repair and restoration of the normal
The 5-lipoxygenase pathway of arachidonic acid metabolism is structure and function. In contrast, asthma represents a chronic
responsible for the production of the cysteinyl leukotrienes.15 LTC4, inflammatory process of the airways followed by healing. The end
LTD4, and LTE4 are released during inflammatory processes in the result may be an altered structure referred to as a remodeling of the
lung. LTD4 and LTE4 share a common receptor (LTD4 receptor) airways.16 Repair involves replacement of injured tissue by paren-
that, when stimulated, produces bronchospasm, mucus secretion, chymal cells of the same type and replacement by connective tissue
microvascular permeability, and airway edema, whereas LTB4 is and its maturation into scar tissue. In asthma, the repair process can
involved with granulocyte chemotaxis. be followed by complete or altered restitution of airways structure
Thought to be produced by macrophages, eosinophils, and neu- and function, presenting as fibrosis and an increase in smooth
trophils within the lung, platelet-activating factor is involved in the muscle and mucus gland mass.16
mediation of bronchospasm, sustained induction of BHR, edema The precise mechanisms of remodeling of the airways are under
formation, and chemotaxis of eosinophils.15 intense study. Airways remodeling is of concern because it may
 468
represent an irreversible process that can have more serious seque- absent in the small bronchioles. The nonmyelinated C fibers of the
lae such as the development of chronic obstructive pulmonary afferent system lie immediately beneath the tight junctions between
SECTION 3

disease.2 Observations in children with asthma indicate that some epithelial cells lining the airway lumen.15 These endings probably
loss of lung function may occur during the first 5 years of life.7 Of represent the irritant receptors of the airways. Stimulation of these
greatest concern is that no current therapies have been shown to irritant receptors by mechanical stimulation, chemical and particu-
alter either early decreased lung growth or later increased loss of late irritants, and pharmacologic agents such as histamine produces
lung function. reflex bronchoconstriction.15
The nonadrenergic noncholinergic (NANC) nervous system has
MUCUS PRODUCTION been described in the trachea and bronchi. Substance P, neurokinin A,
neurokinin B, and vasoactive intestinal peptide are the best-character-
Respiratory Disorders

The mucociliary system is the lung’s primary defense mechanism ized neurotransmitters in the NANC nervous system.15 Vasoactive
against irritants and infectious agents. Mucus, composed of 95% intestinal peptide is an inhibitory neurotransmitter in the system.
water and 5% glycoproteins, is produced by bronchial epithelial Inflammatory cells in asthma can release peptidases that can degrade
glands and goblet cells.7 The lining of the airways consists of a vasoactive intestinal peptide, producing exaggerated reflex cholinergic
continuous aqueous layer controlled by active ion transport across bronchoconstriction. NANC excitatory neuropeptides such as sub-
the epithelium in which water moves toward the lumen along the stance P and neurokinin A are released by stimulation of C-fiber
concentration gradient. Catecholamines and vagal stimulation sensory nerve endings. The NANC system may play an important role
enhance the ion transport and fluid movement. Mucus transport in amplifying inflammation in asthma by releasing NO.
depends on the viscoelastic properties of the mucus. Mucus that is
either too watery or too viscous will not be transported optimally. The NITRIC OXIDE
exudative inflammatory process and sloughing of epithelial cells into
the airway lumen impair mucociliary transport. The bronchial glands NO is produced by cells within the respiratory tract. It has been
are increased in size and the goblet cells are increased in size and thought to be a neurotransmitter of the NANC nervous system.17
number in asthma. Expectorated mucus from patients with asthma Endogenous NO is generated from the amino acid L-arginine by the
tends to have a high viscosity. The mucus plugs in the airways of enzyme NO synthase.17 There are three isoforms of NO synthase.
patients who died in status asthmaticus are tenacious and tend to be One isoform is induced in response to proinflammatory cytokines,
connected by mucous strands to the goblet cells. Asthmatic airways inducible NO synthase, in airway epithelial cells and inflammatory
also may become plugged with casts consisting of epithelial and cells of asthmatic airways.17 NO produces smooth muscle relaxation
inflammatory cells. Although it is tempting to speculate that death in the vasculature and bronchials; however, it appears to amplify the
from asthma attacks is a result of the mucus plugging resulting in inflammatory process and is unlikely to be of therapeutic benefit.
irreversible obstruction, there is no direct evidence for this. Autopsies Recent investigations measuring the fraction of exhaled NO (FeNO)
of asthmatics who died from other causes have shown similar pathol- concentrations have suggested that it may be a useful measure of
ogy. In addition, some subjects who have died of sudden severe ongoing lower airways inflammation in patients with asthma and
asthma did not show the characteristic mucus plugging on necropsy.7 for guiding asthma therapy.17

AIRWAY SMOOTH MUSCLE CLINICAL PRESENTATION

The smooth muscle of the airways does not form a uniform coat
around the airways but is wrapped around in a connecting network CHRONIC ASTHMA
best described as a spiral arrangement.15 The muscle contraction
 Classic asthma is characterized by episodic dyspnea associated
displays a sphincteric action that is capable of completely occluding with wheezing; however, the clinical presentation of asthma is as
the airway lumen. The airway smooth muscle extends from the diverse as the number of triggering events (see Clinical Presentation:
trachea through the respiratory bronchioles. When expressed as a Chronic Ambulatory Asthma). Although wheezing is the characteris-
percentage of wall thickness, the smooth muscle represents 5% of tic symptom of asthma, the medical literature is replete with the
the large central airways and up to 20% of the wall thickness in the warning that “not all that wheezes is asthma.” A wheeze is a high-
bronchioles. Total smooth muscle mass decreases rapidly past the pitched, whistling sound created by turbulent airflow through an
terminal bronchioles to the alveoli, so the contribution of smooth obstructed airway, so any condition that produces significant
muscle tone to airway diameter in this region is relatively small. In obstruction can result in wheezing as a symptom. In addition, “all of
the large airways of asthmatics, smooth muscle may account for asthma does not wheeze” is an equally justifiable warning. Patients
11% of the wall thickness. It is possible that the increased smooth may present with a chronic persistent cough as their only symptom.2
muscle mass of the asthmatic airways is important in magnifying
and maintaining BHR in chronic asthma. However, it appears that
CLINICAL PRESENTATION: CHRONIC
the hypertrophy and hyperplasia are secondary processes caused by
AMBULATORY ASTHMA
chronic inflammation and are not the primary cause of BHR.7
General
NEURAL CONTROL/NEUROGENIC ■ Asthma is a disease of exacerbation and remission, so the
INFLAMMATION patient may not have any signs or symptoms at the time of
examination.
The airway is innervated by parasympathetic, sympathetic, and Symptoms
nonadrenergic inhibitory nerves.2 Parasympathetic innervation of
the smooth muscle consists of efferent motor fibers in the vagus ■ The patient may complain of episodes of dyspnea, chest
nerves and sensory afferent fibers in the vagus and other nerves.15 tightness, coughing (particularly at night), wheezing, or a
The normal resting tone of human airway smooth muscle is main- whistling sound when breathing. These often occur in associ-
tained by vagal efferent activity. Maximum bronchoconstriction ation with exercise, but also occur spontaneously or in associ-
mediated by vagal stimulation occurs in the small bronchi and is ation with known allergens.
 469

Signs sional use of short-acting inhaled β2-agonists to severe persistent

asthma symptoms despite receiving multiple medications.

CHAPTER 28
■ Expiratory wheezing on auscultation, dry hacking cough, or
signs of atopy (allergic rhinitis and/or eczema) may occur.
SEVERE ACUTE ASTHMA
Laboratory
■ Spirometry demonstrates obstruction (reduced FEV1/FVC) Uncontrolled asthma, with its inherent variability, can progress to an
with reversibility following inhaled β2-agonist administration acute state where inflammation, airways edema, excessive accumula-
(at least a 12% improvement in FEV1). tion of mucus, and severe bronchospasm result in a profound airways
narrowing that is poorly responsive to usual bronchodilator therapy
Other Diagnostic Tests
(see Clinical Presentation: Severe Acute Asthma).2,6 Although this
■ A fall in FEV1 of at least 15% following 6 minutes of near

Asthma
progression is the most common scenario, some patients experience
maximal exercise. Elevated eosinophil count and IgE concen- rapid onset or hyperacute attacks.2,6 Hyperacute attacks are associated
tration in blood. Elevated FeNO (greater than 20 parts per with neutrophilic as opposed to eosinophilic infiltration and resolve
billion in children younger than 12 years of age, and greater rapidly with bronchodilator therapy, suggesting that smooth muscle
than 25 parts per billion in adults). Positive methacholine spasm is the major pathogenic mechanism.6 In most cases, emergency
challenge (PC20 FEV1 less than 12.5 mg/mL). department visits for severe acute asthma represent the failure of an
adequate therapeutic regimen for persistent asthma. Underuse of
There is no single test that can diagnose asthma. The diagnosis is antiinflammatory drugs and excessive reliance on short-acting
based primarily on a good history (Table 28–2).2,6 The patient may inhaled β2-agonists are the major risk factors for severe exacerba-
have a family history of allergy or asthma or have symptoms of tions.2 A blunted perception of airway obstruction may predispose
allergic rhinitis.2 Reversibility of airways obstruction following certain individuals to fatal asthma attacks.2
administration of an inhaled short-acting β2-agonist provides con-
firmation but is not by itself diagnostic. Patients with normal values CLINICAL PRESENTATION:
of spirometry can be challenged by exercise or substances that SEVERE ACUTE ASTHMA
produce bronchoconstriction, such as methacholine, to determine if
they have hyperresponsive airways, but again, positive challenges General
are not diagnostic. Newer tests of inflammation in the airways such ■ An episode can progress over several days or hours (usual
as induced sputum eosinophil counts and FeNO measurements are scenario) or can progress rapidly over 1 to 2 hours.
consistent with but not diagnostic of asthma. Symptoms
Asthma has a widely variable presentation from chronic daily
symptoms to only intermittent symptoms. The intervals between ■ The patient is anxious in acute distress and complains of severe
symptoms can be days, weeks, months, or years. Asthma also can vary dyspnea, shortness of breath, chest tightness, or burning. The
as to its severity, the intrinsic intensity of the disease process. Severity patient is only able to say a few words with each breath.
is most easily and directly measured in a patient who is not currently Symptoms are unresponsive to usual measures (inhaled short-
receiving asthma treatment. The NAEPP has provided a means of acting β2-agonist administration).
classifying asthma severity that is broken down into two domains: Signs
impairment and risk.6 This classification system is individualized for ■ Signs include expiratory and inspiratory wheezing on ausculta-
three age groups (0 to 4 years, 5 to 11 years, and ≥12 years) and tion (breath sounds may be diminished with very severe
summarized in Table 28–3. The intermittent and/or chronic nature of obstruction), dry hacking cough, tachypnea, tachycardia, pale
symptoms does not necessarily determine the severity of symptoms or cyanotic skin, hyperinflated chest with intercostal and supra-
during exacerbations. The severity is determined by lung function, clavicular retractions, and hypoxic seizures if very severe.
symptoms, nighttime awakenings, and interference with normal
Laboratory
activity prior to therapy. Patients can present with a range from
intermittent symptoms that require no medications or only occa- ■ PEF and/or FEV1 less than 50% of normal predicted values.
Decreased arterial oxygen (PaO2), and O2 saturations by pulse
oximetry (SaO2 less than 90% on room air is severe).
TABLE 28-2 Sample Questionsa for the Diagnosis and Initial Decreased arterial or capillary CO2 if mild, but in the normal
Assessment of Asthma range or increased in moderate to severe obstruction.
Other Diagnostic Tests
A “yes” answer to any question suggests that an asthma diagnosis is likely. In the
past 12 months… ■ Blood gases to assess metabolic acidosis (lactic acidosis) in
Have you had a sudden severe episode or recurrent episodes of coughing, severe obstruction. Complete blood count if there are signs of
wheezing (high-pitched whistling sounds when breathing out), chest tightness, infection (fever and purulent sputum). Serum electrolytes as
or shortness of breath? therapy with β2-agonist and corticosteroids can lower serum
Have you had colds that “go to the chest” or that take more than 10 days to get over? potassium and magnesium and increase glucose. Chest radio-
Have you had coughing, wheezing, or shortness of breath during a particular graph if signs of consolidation on auscultation.
season or time of the year?
Have you had coughing, wheezing, or shortness of breath in certain places or
when exposed to certain things (e.g., animals, tobacco smoke, perfumes)? EXERCISE-INDUCED BRONCHOSPASM
Have you used any medications that help you breathe better? How often?
Are your symptoms relieved when the medications are used? During vigorous exercise, pulmonary functions (FEV1 and peak
In the past 4 weeks, have you had coughing, wheezing, or shortness of breath… expiratory flow [PEF]) in patients with asthma increase during the
At night that has awakened you? first few minutes but then begin to decrease after 6 to 8 minutes (Fig.
Upon awakening? 28–3).2 EIB is defined as a drop in FEV1 of greater than 15% of
After running, moderate exercise, or other physical activity? baseline (preexercise value).2 Most studies suggest that many patients
a
These questions are recommended by the National Asthma Education and Prevention Program but with persistent asthma experience EIB.2 The exact pathogenesis of EIB
have not been formally validated. is unknown, but heat loss and/or water loss from the central airways
 470

TABLE 28-3 Classifying Asthma Severity for Patients Who Are Not Currently Taking Long-Term Control Medications
SECTION 3

Children 0–4 Years and 5–11 Years of Age

Persistent
Components Intermittent Mild Moderate Severe
Symptoms ≤2 days/week >2 days/week but not daily Daily Throughout the day
Impairment

Nighttime awakenings (0–4 years) 0 Once or twice per month Three to four times per month > once per week
(5–11 years) ≤ twice per month Three to four times per month > once per week, but not nightly Often seven times per week
SABA use for symptom control ≤2 days/week >2 days/week but not daily Daily Several times per day
Interference with normal activity None Minor limitation Some limitation Extremely limited
Respiratory Disorders

Lung function FEV1 >80% FEV1 >80% FEV1 60%–80% FEV1 <60%
(5–11 years) FEV1/FVC >85% FEV1/FVC >80% FEV1/FVC 75%–80% FEV1/FVC <75%
Exacerbations Intermittent Persistent
Risk

(0–4 years) 0–1/year ≥2 in 6 months or ≥4 wheezing episodes/1 year lasting >1day

(5–11 years) 0–2/year >2 in 1 year →
Recommended step for initiating Step 1 Step 2 Step 3 and consider short course of systemic oral corticosteroids
treatment
Youths ≥12 Years of Age and Adults
Persistent
Components Intermittent Mild Moderate Severe
Symptoms ≤2 days/week >2 days/week but not daily Daily Throughout the day
Impairment

Nighttime awakenings ≤ twice per month Three to four times per month > once per week, but not Often seven times per
nightly week
SABA use for symptom control ≤2 days/week >2 days/week but not > once per Daily Several times per day
day
Interference with normal activity None Minor limitation Some limitation Extremely limited
Lung function (Normal FEV1/FVC: FEV1 >80% FEV1 >80% FEV1 60%–80% FEV1 <60%
age 8–19 y 85%; 20–39 y 80%; FEV1/FVC normal FEV1/FVC normal FEV1/FVC reduced 5% FEV1/FVC reduced >5%
40–59 y 75%; 60–80 y 70%)
Exacerbations Intermittent Persistent
Risk

0–2/year >2 in 1 year →

Recommended step for initiating Step 1 Step 2 Step 3 and consider short Step 4 or 5
treatment course of systemic oral
corticosteroids
FEV1, force expiratory volume in the first second of expiration; FVC, forced vital capacity; SABA, short-acting β-antagonist.

appears to play an important role.18 EIB is provoked more easily in A refractory period following EIB lasts up to 3 hours after
cold, dry air, and warm, humid air can blunt or block it.18 A number exercise. During this period, repeat exercise of the same intensity
of studies have demonstrated increased plasma histamine, cysteinyl produces either no decrease in pulmonary function or a drop of less
leukotrienes, prostaglandins, and tryptase concentrations during EIB, than 50% of the initial response.18 This refractory period is thought
suggesting a role for mast cell degranulation.18 to be caused by an acute depletion of mast cell mediators and time
required for their repletion. Patients with known refractoriness to
300
Normal
exercise will still respond to histamine, so acute hyporesponsiveness
of airway smooth muscle does not appear to be a factor.18
Exercise-induced bronchospasm is believed to be a reflection of the
250
Asthmatic increased BHR of asthmatics. A correlation, though not perfect, exists
between EIB and reactivity to histamine and methacholine.18 Other
200 patient groups with BHR (e.g., after viral infection, cystic fibrosis, or
allergic rhinitis) show bronchoconstriction after exercise to a lesser
PEFR (L/min)

degree (5% to 10% drop) than patients with asthma (20% to 40%
150 drops).18 Patients will not always demonstrate the same sensitivity.
During periods of remission, they often have a decreased sensitivity to
the same degree of exercise. Finally, a number of children and adults
100
with EIB are otherwise normal, without symptoms or abnormal
pulmonary function except in association with exercise.2 Elite athletes
50
have a higher prevalence of EIB than the general population.18
Exercise
NOCTURNAL ASTHMA
0
0 5 10 15 20 25  Worsening of asthma during sleep is referred to as nocturnal
Time (min)
asthma. Patients with nocturnal asthma exhibit significant falls in
FIGURE 28-3. Typical responses to exercise in a normal subject and an pulmonary function between bedtime and awakening.2,8 Typically,
asthmatic subject. Note the initial bronchodilation. (PEFR, peak expiratory their lung function reaches a nadir at 3 to 4 AM. Although the
flow rate.) pathogenesis of this phenomenon is unknown, it is associated with
 471
diurnal patterns of endogenous cortisol secretion and circulating parents that asthma is not an emotional disease; however, coping
epinephrine.8 Direct evidence for an inflammatory component to skills may benefit the patient who becomes emotionally distraught

CHAPTER 28
nocturnal asthma includes increased circulating histamine and during an asthma attack.
activated eosinophils and leukotriene excretion at night associated
with increased hyperresponsiveness to methacholine.8 RHINITIS AND SINUSITIS
Numerous other factors that may affect nocturnal worsening of
asthma, including allergies and improper environmental control, Disorders of the upper respiratory tract, particularly rhinitis and
gastroesophageal reflux, obstructive sleep apnea, and sinusitis, also sinusitis, have been linked with asthma for many years. As many as
must be considered when evaluating these patients.2,6 Most experts 40% to 50% of asthmatics have abnormal sinus radiographs.2
consider nocturnal asthma to be a sign of inadequately treated However, chronic sinusitis may just represent a nonbacterial coex-

Asthma
persistent asthma.2,8 Awakening from nocturnal asthma is a sensi- isting condition with allergic asthmatics because the histologic
tive indicator of both severity and asthma control.6 changes in the paranasal sinuses are similar to those seen in the lung
and nose.2 Treatment of upper airway disease may optimize overall
asthma control. The mechanism by which sinusitis aggravates
FACTORS CONTRIBUTING TO asthma is unknown. The treatment of allergic rhinitis with inhaled
ASTHMA SEVERITY corticosteroids and cromolyn but not antihistamines will reduce
BHR in asthmatic patients.2 It has been postulated that transport of
VIRAL RESPIRATORY INFECTIONS mucus chemotactic factors and inflammatory mediators from nasal
passages during allergic rhinitis into the lung may accentuate BHR.
Viral respiratory infections are primarily responsible for exacerba-
tions of asthma, particularly in children younger than age 10 years.6
Infants are particularly susceptible to airways obstruction and GASTROESOPHAGEAL REFLUX DISEASE
wheezing with viral infections because of their small airways. The Symptoms of gastroesophageal reflux disease are common in both
most common cause of exacerbations in both children and adults is children and adults who have asthma.6 Nocturnal asthma may be
the common rhinovirus.6 Other viruses isolated include respiratory associated with nighttime reflux.8 Reflux of acidic gastric contents
syncytial virus, parainfluenza virus, coronavirus, and influenza into the esophagus is thought to initiate a vagally mediated reflex
viruses. The inflammatory response to viral infection is thought to bronchoconstriction.8 Also of concern is that most medications that
be associated directly with the increasing BHR. Certain viruses decrease airways smooth muscle tone also have a relaxant effect on
(respiratory syncytial virus and parainfluenza virus) are capable of gastroesophageal sphincter tone. Although a systematic review con-
inducing specific IgE antibodies, and rhinovirus can activate eosin- cluded there was no significant improvement in asthma symptoms
ophils directly in asthmatics. The increase in asthma symptoms and from medical management of gastroesophageal reflux disease, the
BHR that occurs may last for days or weeks following resolution of standard approach is to initiate standard antireflux therapy in those
the symptoms of the viral infection. Recent evidence does not patients who are exhibiting symptoms of reflux (particularly with
support a beneficial effect of influenza vaccine for preventing nocturnal asthma) and observe the asthma symptoms.2,20
asthma exacerbations from subsequent influenza infections.19
FEMALE HORMONES AND ASTHMA
ENVIRONMENTAL AND
OCCUPATIONAL FACTORS Premenstrual worsening of asthma has been reported in as many as
30% to 40% of women in some studies, whereas worsening of
Table 28–1 lists the agents, events, and mechanisms that are known pulmonary functions has been reported even in women who are
to trigger asthma.2,8 The general mechanisms are unknown but unaware of worsening symptoms.21 The pathophysiology is uncer-
presumably are the result of epithelial damage and inflammation in tain because estrogen replacement in postmenopausal women wors-
the airway mucosa. Ozone and sulfur dioxide, common compo- ens asthma, whereas estradiol and progesterone administration
nents of air pollution, have been used to induce BHR in animals. have been variably reported to improve or have no effect on asthma
Exposure to 0.2 parts per million ozone for 2 to 3 hours can induce in women with premenstrual asthma.21 The clinical significance of
bronchoconstriction and increase BHR in asthmatics.2,8 Sulfur menstruation-related asthma is still unclear because some studies
dioxide in the ambient atmosphere is highly irritating. It presum- report that up to 50% of emergency department visits by women
ably induces bronchoconstriction through mast cell or irritant- were premenstrual, whereas others report no association with men-
receptor involvement.8 Asthma produced by repeated prolonged strual phase.21,22 Studies indicate that, in general, BHR and symp-
exposure to industrial inhalants is a significant health problem. It toms improve in asthmatics during pregnancy.8,21
has been estimated that occupational asthma accounts for 2% of all
asthmatic persons.13 Persons with occupational asthma have the
typical symptoms of asthma with cough, dyspnea, and wheeze. FOODS, DRUGS, AND ADDITIVES
Typically, the symptoms are related to work and improve on
weekends and during vacations.13 In some instances, symptoms There is no documentation in the literature of food allergens as
may persist even after termination of exposure.13 triggers for asthma.8 However, additives, specifically sulfites used as
preservatives, can trigger life-threatening asthma exacerbations.
STRESS, DEPRESSION, AND PSYCHOSOCIAL Beer, wine, dried fruit, and open salad bars in particular have high
FACTORS IN ASTHMA concentrations of metabisulfites.2 Severe oral corticosteroid-depen-
dent patients should be warned about ingesting foods processed
Observational studies demonstrate an association between increased with sulfites. Another additive producing bronchospasm is benzal-
stress and worsening asthma, but the role is not clearly defined.6 konium chloride, which is found as a preservative in some nebulizer
Bronchoconstriction from psychological factors appears to be solutions of antiasthmatic drugs.23
mediated primarily through excess parasympathetic input. Atropine Aspirin and other nonsteroidal antiinflammatory drugs can pre-
has been shown to block experimental psychogenic bronchocon- cipitate an attack in up to 20% of adults and 5% of children with
striction. It is most important to emphasize to both patients and asthma.24 The mechanism is related to cyclooxygenase inhibition, and
 472
5-lipoxygenase inhibition can alter dose–response but cannot com- powder inhalers (DPIs). The single most important device factor
pletely block the symptoms.24 The prevalence increases with age and determining the site of aerosol deposition is particle size.25 Devices
SECTION 3

severity of asthma.6 The greatest frequency occurs in severe cortico- for delivering therapeutic aerosols generate particles with aerody-
steroid-dependent asthmatics in their fourth and fifth decades who namic diameters from 0.5 to 35 microns.25 Particles larger than 10
also have perennial rhinitis and nasal polyposis (presence of several microns deposit in the oropharynx, particles between 5 and 10
polyps).24 Other drugs that do not precipitate bronchospasm but microns deposit in the trachea and large bronchi, particles 1 to 5
which prevent its reversal are the nonselective β-blocking agents.2,6 microns in size reach the lower airways, and particles smaller than
0.5 microns act as a gas and are exhaled. In asthma, the airways, not
the alveoli, are the target for delivery. Respirable particles are depos-
TREATMENT ited in the airways by three mechanisms: (a) inertial impaction, (b)
Respiratory Disorders

gravitational sedimentation, and (c) Brownian diffusion.25 The first

Asthma two mechanisms are the most important for therapeutic aerosols and
probably are the only factors that can be manipulated by patients.
■ AEROSOL THERAPY FOR ASTHMA Each delivery device within a classification generates specific
  Aerosol delivery of drugs for asthma has the advantage of aerosol characteristics, so extrapolation of delivery data from one
being site-specific and thus enhancing the therapeutic ratio.2,25 device cannot be done for the other devices in the class. For
Inhalation of short-acting β2-agonists provides more rapid bron- instance, MDIs can deliver 5% to 50% of the actuated dose; DPIs,
chodilation than either parenteral or oral administration, as well as 10% to 30% of the labeled dose; and nebulizers, 2% to 15% of the
the greatest degree of protection against EIB and other challenges.2 starting dose.25 Unlike nebulizers, MDIs and DPIs are portable and
Inhaled corticosteroids have been developed with rapid oral and convenient. MDIs consist of a pressurized canister with a metering
systemic clearance to enhance lung activity and reduce systemic valve; the canister contains active drug, low-vapor-pressure propel-
activity. Specific agents (e.g., cromolyn, nedocromil, formoterol, lants such as chlorofluorocarbon or hydrofluoroalkane (HFA),
salmeterol, and ipratropium) are only effective by inhalation.25 The cosolvents, and/or surfactants.25 With any change in these compo-
international ban on the production and use of chlorofluorocar- nents, the Food and Drug Administration (FDA) considers it to be
bons, has resulted in the ongoing development of new devices for a new drug that requires stability, safety, and efficacy studies prior
delivering topically active medication.2,25 Consequently, an under- to approval. The drug is either in solution or a suspended micron-
standing of aerosol drug delivery is essential to optimal asthma ized powder. To disperse the suspension for accurate delivery, the
therapy. Table 28–4 lists the factors determining lung deposition of canister must be shaken. The metering chamber measures a liquid
therapeutic aerosols. volume; consequently, the device must be held with the valve stem
facing downward so that the chamber is covered with liquid (Fig.
Device Determinants of Delivery 28–4).25 When the canister is actuated, the device releases the
propellant and drug in a forceful spray whose particles are large
Devices used to generate therapeutic aerosols include jet nebuliz- (mass median aerodynamic diameter [MMAD] = 45 microns; Fig.
ers, ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry- 28–4).25As evaporation occurs, the particle size is reduced to a final
MMAD of 0.5 to 5.5 microns depending on the MDI. The aerosol
cloud of a chlorofluorocarbon-propelled MDI extends at least 10
TABLE 28-4 Factors Determining Lung Deposition of Aerosols
inches beyond the MDI at the lowest MMAD, and that of an HFA-
Device Device Factors Patient Factors propelled MDI extends about 6 inches.25
Metered- Canister held inverted Inspiratory flow (slow, deep) The breath-actuated MDI Autohaler, is cocked with a lever to
dose Formulation (CFC, HFA, solu- Breath-holding “load” the dose of medication, a baffle is opened by inspiratory
inhaler tion, suspension) Coordinating actuation with pressure, and the dose is expelled from the canister metering
(MDI) Actuator cleanliness inhalation chamber.25 Although the need for hand–lung coordination for
Addition of a spacer device Priming and shaking the device proper actuation is reduced significantly with breath-actuated
Dry-powder Device cleanliness Inspiratory flow (deep, forceful) MDIs, these devices do not allow the use of a spacer device.
inhaler Resistance to inhalation Tilting head back Spacer devices are used frequently with a MDI to decrease
(DPI) Humidity Maintaining parallel to ground oropharyngeal deposition and enhance lung delivery.2,6 However,
once activated
not all spacer devices produce similar effects. The design of spacers
Jet nebulizer Volume fill (3–6 mL) Inspiratory flow (slow, deep)
(small Gas flow (6–12 L/min) Breath-holding
varies from simple, open-ended tubes that separate the MDI from
volume) Dead-space volume Tapping nebulizer the mouth to holding chambers with one-way valves (valved hold-
Open versus closed system
Thumb-activating valve Canister
Mouthpiece versus face mask
Ultrasonic Volume fill Inspiratory flow (slow, deep)
nebulizer Not effective for suspensions Breath-holding
Mouthpiece versus face mask Tapping nebulizer Mouthpiece
Spacer Volume (≥650 mL) Inspiratory flow (slow, deep) Metering
device One-way valves Time between actuation and valve
Holding chamber versus inhalation (<5 s)
open-ended Cleaning with detergent to
Metal versus plastic reduce static
Mouthpiece versus face mask Multiple actuations decrease Actuator orifice
delivery
Coordination of actuation and Hollow tube
inhalation for the simple Slower velocity
open-tube spacers
FIGURE 28-4. Illustration of a metered-dose inhaler demonstrating the
CFC, chlorofluorocarbon; HFA, hydrofluoroalkane. particle size difference as the aerosol cloud extends outward.
 473
25
ing chambers [VHCs]) that open during inhalation (the preferred above a transducer at speeds of about 1 mHz. Both produce similar
system). A VHC allows evaporation of the propellant prior to degrees of lung deposition, with the exception that ultrasonic nebu-

CHAPTER 28
inhalation permitting a greater number of drug particles to achieve lizers are ineffective for nebulizing micronized suspensions.25 The
a respirable droplet size. It also allows inhalation after actuation of aerosol output and lung delivery vary significantly among the com-
the device, obviating the need for good hand–lung coordination.25 mercially available jet nebulizers even when operated in the same
Additionally, the large particles that normally would deposit in the manner.25 Increasing fill volume will increase the total amount of
oropharynx “rain out” in the spacer.25 All the available spacers drug delivered; however, it also will take longer for the patient to
significantly reduce oropharyngeal deposition from MDIs, with the nebulize the dose.25 The MMAD of the droplets is related directly to
VHCs being superior to the open-ended tubes.25 This reduction in the gas flow, with flows of 5 to 12 L/min providing an aerosol cloud
oropharyngeal deposition is an important factor in reducing local with a MMAD of 4 to 8 microns for most jet nebulizers.25 Each jet

Asthma
adverse effects (i.e., hoarseness and thrush) from inhaled cortico- nebulizer comes with its optimal operating instructions.
steroids.25 The change in lung delivery depends on both the MDI
and the drug, where one spacer device may enhance delivery with
one MDI preparation and decrease delivery with others.25 The use
Patient Determinants of Delivery
of VHCs is less likely to enhance delivery from HFA propelled (See Table 28–4)
MDIs. Finally, over time, holding chambers can build up static   The most important patient factor determining aerosol depo-
electricity that attracts small particles to the sides of the chamber, sition is inspiratory flow.2,25 High inspiratory flows increase the
significantly reducing aerosol availability. It is recommended that degree of deposition owing to impaction of particles of any size,
some spacers be washed weekly with household detergent, with a thereby increasing deposition centrally (i.e., throat and large air-
single rinse, and allowed to drip dry.25 ways) and decreasing peripheral deposition. Use of a VHC will
Dry, micronized powders can be inhaled directly into the lung. A enhance the clinical efficacy in patients with poor hand–lung coordi-
number of DPIs are now available for use in the United States, and nation but may offer no advantage in patients who can use an MDI
others are under development.25 Currently, there are no generic DPIs optimally alone.25 Optimal inspiratory flow for most MDIs is slow
as each drug plus device has its own patent. Each DPI has unique and deep (approximately 30 L/min or 5 seconds for a full inhala-
characteristics with advantages and disadvantages (Table 28–5). The tion).2 In general, DPIs require higher inspiratory flows (≥60 L/min)
primary advantage of DPIs is that they are breath-actuated and and a change in inhalation technique (i.e., deep, forceful inspiration)
require minimal hand–lung coordination, making it easier to teach for optimal dispersion of the powder, which, in turn, increases the
patients proper technique.25 Some DPIs are more flow-dependent amount of drug delivered to the larger central airways.25 However,
than others.25 Thus, similar to MDIs and spacers, delivery data from this difference in delivery may not produce clinically significant
one DPI cannot be extrapolated to another. differences.25 Patients should be cautioned not to exhale into DPIs
Nebulizers come in two basic types: the jet nebulizer and the because this causes loss of dose and moistens the dry powder,
ultrasonic nebulizer. Jet nebulizers produce an aerosol from a liquid causing aggregation into larger particles. Patient factors that cannot
solution or suspension placed in a cup. A tube connected to a stream be controlled include interpatient variability in airway geometry
of compressed air or oxygen flows up through the bottom and draws (particularly the differences between children and adults)25 and the
the liquid up an adjacent open-ended tube.25 The air and liquid effects of bronchospasm, edema, and mucus hypersecretion. Mild
strike a baffle, creating a droplet cloud that is then inhaled.25 obstruction increases aerosol deposition; however, severe obstruc-
Ultrasonic nebulizers produce an aerosol by vibrating liquid lying tion probably leads to increased central deposition from impac-

TABLE 28-5 Characteristics of Various Inhalation Devices

Breath- Dose
Device Drugs Activated Counter Other Excipients Disadvantages
CFC MDI All classes No No Propellants, surfactants Requires coordination of actuation and inhalation
Large pharyngeal deposition
Difficult to teach
HFA MDI Albuterol No No/Yes Propellants, surfactants, Same as CFC MDI
Levalbuterol No No cosolvents
Corticosteroids No No
Autohaler MDI Pirbuterol Yes No CFC propellant, surfactant Requires rapid inhalation to activate
MDI plus hold- All classes No No More expensive than MDI alone; less portable; some
ing chamber payers will not pay; inconsistent effect on delivery
Jet nebulizers All classes No — Preservatives in some Significant interbrand variability; expensive and time-
solutions consuming; less efficient than MDIs; contamination
possible; preparations may be light- and temperature-
sensitive (short shelf-life)
Ultrasonic Cromolyn solution short- No — Preservatives in some Same as for jet nebulizers plus cannot be used for
nebulizer acting β2-agonist solutions suspensions
solutions
Turbuhaler Budesonide Yes Indicator for last No Requires high inspiratory flow (60 L/min). Pharyngeal
20 doses deposition; not approved for <6 years of age
Diskus Fluticasone Yes Yes Lactose filler Not approved for <4 years of age
Salmeterol
Fluticasone/salmeterol
Aerolizer Formoterol Yes — Lactose filler Single-dose capsules; not approved for <5 years of age
Requires high inspiratory flow (≥60 L/min)
Twisthaler Mometasone Yes Yes Lactose filler Not approved for <12 years of age
CFC, chlorofluorocarbon; HFA, hydrofluoroalkane; MDI, metered-dose inhaler.
 474

Steps for Using Your Inhaler

SECTION 3

Please demonstrate your inhaler technique at every visit.

1. Remove the cap and hold inhaler upright.
2. Shake the inhaler.
3. Tilt your head back slightly and breathe out slowly.
4. Position the inhaler in one of the following ways (A or B is optimal, but C is acceptable for those who have difficulty with A or B.
C is required for breath-activated inhalers):
Respiratory Disorders

A Open mouth with inhaler 1 to B Use spacer/holding chamber (that is C In the mouth. Do not use for D NOTE: Inhaled dry powder capsules
2 inches away. recommended especially for young children corticosteroids. require a different inhalation technique.
and for people using corticosteroids). To use a dry powder inhaler, it is im-
portant to close the mouth tightly around
the mouthpiece of the inhaler and to
inhale rapidly.
5. Press down on the inhaler to release medication as you start to breathe in slowly.
6. Breathe in slowly (3 to 5 seconds).
7. Hold your breath for 10 seconds to allow the medicine to reach deeply into your lungs.
8. Repeat puff as directed. Waiting 1 minute between puffs may permit second puff to penetrate your lungs better.
9. Spacers/holding chambers are useful for all patients. They are particularly recommended for young children and
older adults and for use with corticosteroids.
Avoid common inhaler mistakes. Follow these inhaler tips:
• Breathe out before pressing your inhaler.
• Inhale slowly.
• Breathe in through your mouth, not your nose.
• Press down on your inhaler at the start of inhalation (or within the first second of inhalation).
• Keep inhaling as you press down on inhaler.
• Press your inhaler only once while you are inhaling (one breath for each puff).
• Make sure you breathe in evenly and deeply.
NOTE: Other inhalers are becoming available in addition to those illustrated above. Different types of inhalers require different techniques.

FIGURE 28-5. Instructions for inhaler use from the National Asthma Education and Prevention Program Expert Panel Report 2. (Adapted from reference 2.)

tion.25 The absolute delivery to the lung is not as important as elderly adults, will have more variability in delivery from high-
consistency of delivery, assuming that a sufficient dose to produce resistance devices.25 Most children who are younger than 4 years of
the desired therapeutic effect is achieved. No single inhalation device age cannot generate a sufficient inspiratory flow to use DPIs. Young
is the best for all patients. Table 28–5 lists the differing characteristics children (age <4 years) and infants generally require the use of a face
of inhalation devices. mask attached to either an MDI plus VHC or to a nebulizer. The use
Appropriate inhalation technique is essential to achieve optimal of a face mask results in a reduction in lung delivery because of the
drug delivery and therapeutic effect.2,8 Figure 28–5 illustrates the portion of the aerosol inhaled nasally so the doses of drugs used in
components of appropriate technique. Approximately 50% to 80% these patients is often not decreased from that of older children.
of a dose from MDIs and DPIs impacts on the oropharynx and is
then swallowed; the rest is either left in the device or exhaled.25 It is
important that actuation occurs during inhalation, although the TREATMENT
time during inspiration is unimportant.2,25 Although radiolabeled
studies with chlorofluorocarbon-propelled MDIs indicate improved
delivery by holding the actuator 2 to 3 cm in front of an open mouth Severe Acute Asthma
to allow more evaporation and less impaction, physiologic studies The primary goal is prevention of life-threatening asthma by early
with bronchodilators have failed to document an advantage for this recognition of signs of deterioration and early intervention. As such,
method.2,25 Many patients do not use their MDIs optimally, and the principal goals of treatment include2
patient instruction with demonstration is the most effective means of
improving inhaler technique.2,25 Even with instruction, up to 30% of • Correction of significant hypoxemia
patients, particularly young children and the elderly, cannot master • Rapid reversal of airflow obstruction
the use of an MDI. For these patients, attachment of a VHC to the • Reduction of the likelihood of relapse of the exacerbation or
MDI or use of a breath-actuated MDI can improve efficacy signifi- future recurrence of severe airflow obstruction
cantly.2,25 Mouth rinsing following treatment with MDI- and DPI-
• Development of a written asthma action plan in case of a
inhaled corticosteroids is important to minimize local effects and
further exacerbation
oral absorption.2,25
Delivery from high-resistance DPIs is more flow-dependent than These goals are best achieved by early initiation or intensification
from low-resistance DPIs. Thus younger children, and possibly of treatment and close monitoring of objective measures of oxygen-
 475
2
ation and lung function. Early response to treatment as measured by inhaled or systemic β2-agonists are to be used because they can
the improvement in FEV1 at 30 minutes following inhaled β2-agonists produce transient decreases in potassium, magnesium, and phos-

CHAPTER 28
is the best predictor of outcome.2,8 Providing adequate oxygen sup- phate.26 Measurement of serum electrolytes is also prudent in patients
plementation to maintain oxygen (O2) saturations above 90% (or who take diuretics regularly, and in patients with coexistent cardio-
above 95% in pregnant women and those who have coexistent heart vascular disease. The combination of high-dose β2-agonists and
disease) is essential. In children younger than 6 years of age, in whom systemic corticosteroids occasionally may result in excessive eleva-
lung function measures are difficult to obtain, a combination of tions of glucose.26
objective (e.g., oxygen saturation, capillary CO2, respiratory rate, and Initial response should be achieved within minutes, and most
heart rate) and subjective measures may be used to assess severity.2,8 patients experience significant improvement within the first 30 to 60
The primary therapy of acute exacerbations is pharmacologic, minutes of therapy, with most patients doubling their FEV1 or PEF.27
which includes inhaled short-acting β2-agonists and, depending on

Asthma
In patients ultimately admitted to the hospital, only a 10% to 20%
the severity, systemic corticosteroids, inhaled ipratropium and O2 predicted improvement is seen within the first 2 hours. Hypoxemia,
(Figs. 28–6 and 28–7).6 It is important that therapy not be delayed, primarily a result of ventilation–perfusion mismatch, is immediately
so the history and physical examination should be obtained while correctable by low-flow oxygen.2 While reversal of lung function into
initial therapy is being provided. Patients at risk for life-threatening the normal range may take 12 to 24 hours, complete restoration takes
exacerbations require special attention. Risk factors include a his- much longer—up to 3 to 7 days.8,26 A strategy to prevent recurrence,
tory of previous severe asthma exacerbations (e.g., hospitalizations, such as systemic corticosteroids and symptom or PEF monitoring,
intubations, or hypoxic seizures); difficulty perceiving asthma should be used.2,8 It is essential to provide the patient with a self-
symptoms or severity of exacerbations; comorbidities (e.g., cardiac management plan that includes a written action plan for dealing with
disease, other chronic lung disease, illicit drug use, or major psycho- exacerbations. Patients who are at risk for severe exacerbations should
social/psychiatric history); use of more than two canisters per be taught how to use a peak-flow meter and to monitor morning peak
month of short-acting inhaled β2-agonists; and current intake of flows at home.2,8 In young children, an increased respiratory rate,
oral corticosteroids or recent withdrawal from oral corticosteroids.6 increased heart rate, and inability to speak more than one or two
A complete blood count may be appropriate for patients with fever words between breaths are signs of severe obstruction.2 Oxygen
or purulent sputum, but modest leukocytosis is common in asthma saturations by pulse oximetry and peak flows should be measured in
exacerbations as a consequence of viral infection or secondary to all patients who are not completely responding to initial intensive
corticosteroid administration. Chest radiography is not recom- inhaled β2-agonist therapy. Initially, on admission, the peak flows or
mended for routine assessment but should be obtained for patients clinical symptoms should be monitored every 2 to 4 hours. Prior to
suspected of a complicating cardiopulmonary process or another discharge from the emergency department or hospital, the patient
pulmonary process (pneumothorax or pulmonary consolidation).2 should be given a sufficient supply of prednisone, taught the purpose
Serum electrolytes should be monitored if high-dose continuous- of the medications and proper inhaler technique, and referred to

Assess severity
Measure PEF: Value <50% personal
best or predicted suggests severe
exacerbation.

Note signs and symptoms: Degrees of

cough, breathlessness, wheeze, and
chest tightness correlate imperfectly
with severity of exacerbation.
Accessory muscle use and
suprasternal retractions suggest
severe exacerbation.

Initial treatment
• Inhaled short-acting ȕ2-agonist:
Up to three treatments of 2–4
puffs by MDI at 20-min
intervals or single nebulizer
treatment.

Good response Incomplete response Poor response

Mild Exacerbation Moderate Exacerbation Severe Exacerbation
PEF > 80% predicted or personal best PEF 50%–80% predicted or personal PEF <50% predicted or personal best
No wheezing or shortness of breath best Marked wheezing and shortness of
Response to ȕ2-agonist sustained for Persistent wheezing and shortness breath
4h of breath • Add oral corticosteroid.
• May continue ȕ2-agonist every • Add oral corticosteroid. • Repeat ȕ2-agonist immediately.
3–4 h for 24–48 h. • Continue ȕ2-agonist. • If distress is severe and non-
• For patients on inhaled responsive, call your doctor and
corticosteroids, double dose for proceed to emergency
7–10 days. Contact clinician urgently (this department; consider calling
day) for instructions. ambulance or 911.

Contact clinician for followup

instructions. Proceed to emergency department.

FIGURE 28-6. Home management of acute asthma exacerbation. Patients at risk for asthma-related death should
receive immediate clinical attention after initial treatment. Additional therapy may be required. (MDI, metered-dose
inhaler; PEF, peak expiratory flow.) (Adapted from reference 2.)
 476

Initial assessment
SECTION 3

History, physical examination (auscultation, use of accessory muscles, heart rate,

respiratory rate), PEF or FEV1, oxygen saturation, and other tests as indicated

FEV1 or PEF >50% FEV1 or PEF <50% (severe exacerbation) Impending or actual respiratory arrest
• Inhaled ȕ2-agonist by metered-dose inhaler or • Inhaled high-dose ȕ2-agonist and anticho- • Intubation and mechanical ventilation with 100%
nebulizer, up to three doses in first h linergic by nebulization every 20 min or O2
• Oxygen to achieve O2 saturation ≥90% continuously for 1 h • Nebulized ȕ2-agonist and anticholinergic
• Oral systemic corticosteroids if no immediate
• Oxygen to achieve O2 saturation ≥90% • Intravenous corticosteroid
response or if patient recently took oral systemic
Respiratory Disorders

corticosteroid • Oral systemic corticosteroid

Admit to hospital intensive care (see
Repeat assessment box below)
Symptoms, physical examination, PEF, O2
saturation, other tests as needed

Moderate exacerbation Severe exacerbation

FEV1 or PEF 50%–80% predicted/personal best FEV1 or PEF <50% predicted/personal best
Physical exam: moderate symptoms Physical exam: severe symptoms at rest, accessory
• Inhaled short-acting ȕ2-agonist every 60 min muscle use, chest retraction
History: high-risk patient
• Systemic corticosteroid
No improvement after initial treatment
• Continue treatment 1–3 h, provided there
is improvement • Inhaled short-acting ȕ2-agonist, hourly or
continuous + inhaled anticholinergic
• Oxygen
• Systemic corticosteroid

Good response Poor response

• FEV1 or PEF ≥70% Incomplete response • FEV1 or PEF <50%
• Response sustained 60 min after last treatment • FEV1 or PEF ≥50% but <70% • PCO2 ≥42 mm Hg
• No distress • Mild-to-moderate symptoms • Physical exam: symptoms severe, drowsiness,
• Physical exam: normal confusion
Individualized decision re:
hospitalization (see text)

Admit to hospital ward

• Inhaled ȕ2-agonist + inhaled
anticholinergic
Discharge home • Systemic (oral or intravenous)
corticosteroid Admit to hospital intensive care
• Continue treatment with inhaled ȕ2-agonist
• Continue course of oral systemic corticosteroid • Oxygen • Inhaled ȕ2-agonist hourly or continuously
• Patient education • Monitor FEV1 or PEF, O2 + inhaled anticholinergic
— Review medicine use saturation, pulse • Intravenous corticosteroid
— Review/initiate action plan • Oxygen
Improve
— Recommend close medical followup • Possible intubation and mechanical ventilation
Discharge home
• Continue treatment with inhaled
ȕ2-agonist
• Continue course of oral systemic
corticosteroid
• Patient education
— Review medicine use
— Review/initiate action plan
— Recommend close medical
followup

FIGURE 28-7. Emergency department and hospital care of acute asthma exacerbations. (FEV1, forced expiratory volume in the first second of expiration;
PEF, peak expiratory flow.) (Adapted from reference 2.)

followup asthma care within 1 to 4 weeks; initiation of inhaled encouraged to communicate promptly with their asthma care pro-
corticosteroids (ICSs) should also be considered.6 vider during an exacerbation. Systemic corticosteroids and aggres-
 Early recognition of deterioration and aggressive treatment are sive use of inhaled β2-agonists continue to be the cornerstones of
the keys to successful treatment of acute asthma exacerbations. therapy for severe acute asthma exacerbations.2,6
Thus patient and/or parent education teaching self-management Figures 28–6 and 28–7 illustrate the recommended therapies for
skills and written action plans for early institution of therapy for the treatment of acute asthma exacerbations in home and emer-
acute exacerbations improve outcomes.2,6,8 For more moderate to gency department/hospital settings, respectively.2 Table 28–6 lists
severe patients, this therapeutic plan also may include the availabil- the dosages of the drugs for acute severe asthma.2,6 Institutions
ity of oral prednisone to begin at home.2 Easy access by telephone to should strongly consider developing critical pathways/treatment
healthcare providers is also needed. Because of the rapid progres- algorithms for their emergency departments because their imple-
sion to severe asthma that can occur, patients and parents should be mentation improves outcomes and decreases the cost of care.28
 477

TABLE 28-6 Dosages of Drugs of Acute Severe Exacerbations of Asthma in the Emergency Department or Hospital

CHAPTER 28
Dosages
Medications >6 Years Old ≤6 Years Old Comments
Inhaled β-agonists
Albuterol nebulizer solution 2.5–5 mg every 20 min for 3 doses, then 0.15 mg/kg (minimum dose 2.5 mg) every 20 min Only selective β2-agonists are recommended;
(5 mg/mL) 2.5–10 mg every 1–4 h as needed, or for 3 doses, then 0.15–0.3 mg/kg up to 10 mg for optimal delivery, dilute aerosols to mini-
10–15 mg/h continuously every 1–4 h as needed, or 0.5 mg/kg/h by mum of 4 mL at gas flow of 6–8 L/min
continuous nebulization
Albuterol MDI (90 mcg/puff) 4–8 puffs every 30 min up to 4 h, then 4–8 puffs every 20 min for 3 doses, then every In patients in severe distress, nebulization is
every 1–4 h as needed 1–4 h as needed preferred; use holding-chamber-type spacer

Asthma
Levalbuterol nebulizer Give at one-half the mg dose of Give at one-half the mg dose of albuterol above The single isomer of albuterol is likely to be
solution albuterol above twice as potent on a mg basis
Levalbuterol MDI (45 mcg/ Give at one-half the mg dose of Give at one-half the mg dose of albuterol above
puff) albuterol above
Pirbuterol MDI (200 mcg/ See albuterol dose See albuterol dose; one-half as potent as albuterol Has not been studied in acute severe asthma
puff) on a mcg basis
Systemic β-agonists
Epinephrine 1:1000 (1 mg/ 0.3–0.5 mg every 20 min for 3 doses 0.01 mg/kg up to 0.5 mg every 20 min for 3 doses No proven advantage of systemic therapy over
mL) subcutaneously subcutaneously aerosol
Terbutaline (1 mg/mL) 0.25 mg every 20 min for 3 doses 0.01 mg/kg every 20 min for 3 doses, then every Not recommended
subcutaneously 2–6 h as needed subcutaneously
Anticholinergics
Ipratropium bromide nebu- 500 mcg every 30 min for 3 doses, 250 mcg every 20 min for 3 doses, then 250 mcg May mix in same nebulizer with albuterol; do
lizer solution (0.25 mg/mL) then every 2–4 h as needed every 2–4 h not use as first-line therapy; only add to β2-
agonist therapy
Ipratropium bromide MDI 4–8 puffs as needed every 2–4 h 4–8 puffs as needed every 2–4 h Not recommended because dose in inhaler is
(17 mcg/puff) low and has not been studied in acute asthma
Corticosteroids
Prednisone, methylprednis- 60–80 mg in 3 or 4 divided doses for 1 mg/kg every 6 h for 48 h, then 1–2 mg/kg/day For outpatient “burst” use 1–2 mg/kg/day, max-
olone, prednisolone 48 h, then 30–40 mg/day until PEF in 2 divided doses until PEF is 70% of normal imum 60 mg, for 3–7 days; it is unnecessary
reaches 70% of personal best predicted to taper course
FEV1, forced expiratory volume in the first second of expiration; MDI, metered-dose inhaler; PEF, peak expiratory flow.
Note: No advantage has been found for very-high-dose corticosteroids in acute severe asthma, nor is there any advantage for intravenous administration over oral therapy. The usual regimen is to continue the
frequent multiple daily dosing until the patient achieves an FEV1 or PEF of 50% of personal best or normal predicted value and then lower the dose to twice-daily dosing. This usually occurs within 48 hours.
The final duration of therapy following a hospitalization or emergency department visit may be from 7 to 14 days. If patient is then started on inhaled corticosteroids, studies indicate there is no need to taper
the systemic steroid dose. If the followup therapy is to be given once daily, studies indicate there may be an advantage to giving the single daily dose in the afternoon at around 3 pm.

■ NONPHARMACOLOGIC AND ■ PHARMACOTHERAPY

ANCILLARY THERAPY
Infants and young children may be mildly dehydrated owing to β2-Agonists
increased insensible loss, vomiting, and decreased intake.2 Unless  The short-acting inhaled β2-agonists are the most effective bron-
dehydration has occurred, increased fluid therapy is not indicated in chodilators and the treatment of first choice for the management of
acute asthma management because the capillary leak from cytokines severe acute asthma.2,8,26 Up to 66% of adults presenting to an emer-
and increased negative intrathoracic pressures may promote edema in gency department require only three doses of 2.5-mg nebulized
the airways.2 Correction of significant dehydration is always indi- albuterol to be discharged.27 Most well-controlled clinical trials have
cated, and the urine specific gravity may help to guide therapy in demonstrated equal to greater efficacy and greater safety of aerosolized
young children, in whom the state of hydration may be difficult to β2-agonists over systemic administration regardless of the severity of
determine.2 Chest physical therapy and mucolytics are not recom- obstruction.2,26 Systemic adverse effects, hypokalemia, hyperglycemia,
mended in the therapy of acute asthma.6 Sedatives should not be tachycardia, and cardiac dysrhythmias are more pronounced in patients
given because anxiety may be a sign of hypoxemia, which could be receiving systemic β2-agonist therapy. Children younger than 2 years of
worsened by central nervous system depressants. Antibiotics also are age achieve clinically significant responses from nebulized albuterol.2,29
not indicated routinely because viral respiratory tract infections are Effective doses of aerosolized β2-agonists can be delivered successfully
the primary cause of asthma exacerbations.2,8 Antibiotics should be through mechanical ventilator circuits to infants, children, and adults in
reserved for patients who have signs and symptoms of pneumonia respiratory failure secondary to severe airways obstruction.29
(e.g., fever, pulmonary consolidation, and purulent sputum from Frequent administration of inhaled β2-agonists (every 20 minutes
polymorphonuclear leukocytes). Mycoplasma and Chlamydia are or continuous nebulization) is superior to the same dosage adminis-
infrequent causes of severe asthma exacerbations but should be tered at 1-hour intervals.30 In the subset of more severely obstructed
considered in patients with high oxygen requirements.8 patients, continuous nebulization decreases the hospital admission
Respiratory failure or impending respiratory failure as measured by rate, provides greater improvement in the FEV1 and PEF, and reduces
rising PaCO2 (>45 mm Hg) or failure to correct hypoxemia with duration of hospitalization when compared with intermittent
supplemental oxygen therapy is treated with intubation and mechan- (hourly) nebulized albuterol in the same total dose.30 Thus continu-
ical ventilation. To prevent barotrauma and pneumothoraces from ous nebulization is recommended for patients having an unsatisfac-
excess positive pressure, it is recommended that controlled hypoven- tory response (achieving less than 50% of normal FEV1 or PEF)
tilation or permissive hypercapnia be used (correcting the hypox- following the initial three doses (every 20 minutes) of aerosolized β2-
emia, PaO2 >60 mm Hg, but allowing the PaCO2 to rise to the high 60 agonists and potentially for patients presenting initially with PEF or
mm Hg range). FEV1 values of less than 30% of predicted normal.2,30
 478
The doses of inhaled β2-agonists for severe acute asthma (see Table a reasonable recommendation because inflammation is the underly-
28–6) have been derived empirically. The β2-agonists follow a log- ing cause of deterioration in most cases.6
SECTION 3

linear dose–response curve.31 In addition, the dose–response curve is

shifted to the right by more severe bronchospasm or by increased
Anticholinergics
concentrations of bronchospastic mediators, which is characteristic of
functional antagonists.31 The ability to increase the dose of the short- Inhaled ipratropium bromide produces a further improvement in
acting aerosolized β2-agonists by as much as 5- to 10-fold over doses lung function of 10% to 15% over inhaled β2-agonists alone. In
producing adequate bronchodilation in chronic stable asthmatics is children and adults, multiple-dose ipratropium bromide added to
what contributes to their efficacy in reversing the bronchospasm of initial therapy also produced a reduced hospitalization rate in the
acute severe asthma. The nebulizer dose of inhaled β2-agonists for subset of patients with an FEV1 of less than 30% of predicted at
baseline.33 Ipratropium bromide, a quaternary amine, is poorly
Respiratory Disorders

children often is listed on a weight basis (milligrams per kilogram).

However, a fixed minimal dose (2.5 mg albuterol or equivalent), as absorbed and produces minimal or no systemic effects. Care should
opposed to a weight-adjusted dose, is more appropriate in younger be used when administering ipratropium bromide by nebulizer. If a
children because children younger than 5 years of age receive a tight mask or mouthpiece is not used, the ipratropium bromide that
lower lung dose.25 Adults dosed on a weight basis demonstrate deposits in the eyes may produce pupillary dilation and difficulty in
excessive cardiac stimulation, so they have fixed maximal doses (see accommodation. Ipratropium bromide is not a vasodilator, so unlike
Table 28–6).29 Initial doses of inhaled β2-agonists can produce vaso- β2-agonists it will not worsen ventilation–perfusion mismatch.26
dilation, worsening ventilation–perfusion mismatch, slightly lower-
ing oxygen saturation or PaO2.26 High-doses of inhaled β2-agonists Alternative Therapies
can produce a decrease in serum potassium concentration, an
The emergency department use of aminophylline, a moderate
increase in heart rate, and an increase in serum glucose concentration.
bronchodilator, for acute asthma has not been recommended for a
However, both children and adults receiving continuously nebulized
number of years.2 Clinical trials of aminophylline in adults and
β2-agonists have demonstrated decreased heart rates as their lung
children hospitalized with acute asthma have not reported sufficient
function improves.30 Thus, an elevated heart rate is not an indication
evidence of efficacy (improvement in lung function and reduced
to use lower doses or to avoid using inhaled β2-agonists.
hospital stay) but have reported an increased risk of adverse
Some controversy exists concerning the most cost-effective deliv-
effects.34 Adverse effects of theophylline include nausea and vomit-
ery system (MDI plus VHC vs. nebulization) to be used in treating
ing and potentiation of the cardiac effects of the inhaled β2-agonists.
severe acute asthma in the emergency department and hospital (see
Magnesium sulfate is a moderately potent bronchodilator, pro-
Clinical Controversies below).25,29 The DPIs are currently not indi-
ducing relaxation of smooth muscle and central nervous system
cated for the treatment of severe acute asthma exacerbations because
depression.35 The use of intravenous magnesium sulfate in patients
of the higher inspiratory flows required for adequate delivery.25
presenting to the emergency department is controversial (see Clini-
cal Controversies below).35,36 The adverse effects of magnesium
Corticosteroids sulfate include hypotension, facial flushing, sweating, nausea, loss of
Systemic corticosteroids are indicated in all patients with acute severe deep tendon reflexes, and respiratory depression.35 Some patients
asthma not responding completely to initial inhaled β2-agonist have required dopamine to treat the hypotension.
administration (every 20 minutes for three to four doses).2 Intrave- Helium is an inert gas of low density with no pharmacologic
nous therapy offers no therapeutic advantage over oral administra- properties that can lower resistance to gas flow and increase ventila-
tion.26,32 This therapy usually is continued until hospital discharge. tion because the low density decreases the pressure gradient needed
Tapering the dose in acute asthma following discharge from the to achieve a given level of turbulent flow, converting turbulent flow
hospital appears unnecessary, provided that patients are prescribed to laminar flow.2 Helium is given as a mixture of helium and oxygen
inhaled corticosteroids for outpatient therapy.2 Most patients achieve (heliox), usually 60% to 70% helium with 30% to 40% oxygen.37 As
70% of predicted normal FEV1 within 48 hours and 80% of predicted with a number of experimental approaches, heliox was reported to
by 6 days after plateauing by day 3. Thus maintaining systemic be efficacious in initial nonrandomized clinical trials. However, the
corticosteroid courses for 10 to 14 days may be unnecessarily long in small number of randomized, controlled trials completed to date
some patients. Indeed, many patients not admitted to the hospital have failed to document efficacy.37 Although heliox is free of adverse
respond to 3- to 5-day courses of systemic corticosteroids. Short effects, its use is limited to patients with a low inspired oxygen
courses of oral prednisone (3 to 10 days) have been effective in requirement because the decrease in density generally is insignifi-
preventing hospitalizations in infants and young children.2 It is rec- cant clinically with less than 60% helium.37
ommended that a full dose of the corticosteroid be continued until the The inhalational anesthetics halothane, isoflurane, and enflurane
patient’s peak flow reaches 70% of predicted normal or personal best.2 all have been reported to have a positive effect in children and adults
Multiple daily dosing of systemic corticosteroids for the initial with severe asthma that is unresponsive to standard medical therapy.2
therapy of acute asthma exacerbations appears warranted because The proposed mechanisms for inhalational anesthetics include direct
receptor-binding affinities of lung corticosteroid receptors are action on bronchial smooth muscle, inhibition of airway reflexes,
decreased in the face of airway inflammation.32 However, patients attenuation of histamine-induced bronchospasm, and interaction
with less-severe exacerbations may be treated adequately with once- with β2-adrenergic receptors.2 Well-controlled trials with these agents
daily administration. High-dose and very-high-pulse-dose cortico- have not been completed. Potential adverse effects include myocar-
steroid regimens do not enhance the outcomes in severe acute dial depression, vasodilation, arrhythmias, and depression of muco-
asthma but are associated with a higher likelihood of side effects.32 ciliary function. In addition, the practical problem of delivery and
Studies of ICSs in acute exacerbations of asthma have provided scavenging these agents in the intensive care environment as opposed
conflicting results. Studies have demonstrated both greater and lesser to the operating room is a concern. The use of volatile anesthetics
efficacy than standard doses of oral corticosteroids.32 Currently, there cannot be recommended based on insufficient evidence of efficacy.
is insufficient evidence supporting efficacy in the emergency depart- Ketamine has been recommended for rapid induction of anesthe-
ment setting, although continued research appears warranted.32 sia in patients with asthma who require intubation and mechanical
There is evidence that prescribing ICSs on discharge from the emer- ventilation.2 Ketamine is thought to produce bronchodilation from
gency department reduces the risk of relapse.32 This policy seems like a combination of an increase in circulating catecholamines, direct
 479

TABLE 28-7 Pharmacologic Responses to sisting of clusters of seven helices of amino acids that form the
ligand-binding core.31 The human β2-adrenergic receptors are poly-

CHAPTER 28
Sympathomimetic Agonists
morphic in structure, with the most common polymorphisms in the
Receptor
amino terminus of the receptor at amino acid positions 16 (encoding
Tissue Type Response
either arginine [Arg] or glycine [Gly]) and 27 (encoding either
Airways β2 Smooth muscle relaxation (bronchodilation), glutamine [Gln] or glutamic acid [Glu]).38 Some of the polymor-
increased ciliary beat, increased serous secretion, phisms determine responsiveness to β2-agonists, whereas others may
and inhibition of mast cell degranulation
act as disease modifiers (see Treatment section on Chronic Asthma,
α Smooth muscle contraction (bronchoconstriction?)
Clinical Controversy below).38 Stimulation of β2-adrenergic receptor
Heart β1 Inotropic and chronotropic
β2 Chronotropic activates cytoplasmic G proteins, which, in turn, activate adenylyl

Asthma
Vasculature β2 Vasodilation, decrease microvascular leakage cyclase to produce cyclic adenosine monophosphate (cAMP), gener-
α Vasoconstriction ally thought to be responsible for the bulk of activity through
Skeletal β2 Increased neuromuscular transmission (tremor and activation of various proteins by cAMP-dependent protein kinase
increased strength of contraction) A.31 This activation, in turn, decreases unbound intracellular cal-
Uterus β2 Relaxation (tocolysis) cium, producing smooth muscle relaxation, mast cell membrane
Metabolic α, β1 Glycogenolysis, lipolysis stabilization, and skeletal muscle stimulation.31 Despite the fact that
β2 Gluconeogenesis, hypokalemia, increased lactate β2-agonists are potent inhibitors of mast cell degranulation in vitro,
production they do not inhibit the late asthmatic response to allergen challenge
or the subsequent bronchial hyperresponsiveness.2,31 Long-term
smooth muscle relaxation, and inhibition of vagal flow.2 Anecdotal administration of β2-agonists does not reduce BHR, confirming a
reports have suggested that ketamine is useful as a short-term lack of significant antiinflammatory activity.31 β2-Adrenergic stimu-
adjunct in severe acute asthma; controlled trials have not provided lation also activates Na+-K+-ATPase, produces gluconeogenesis, and
sufficient evidence of efficacy, however. Ketamine has several signif- enhances insulin secretion, resulting in a mild to moderate decrease
icant adverse effects, including the anesthesia emergence reaction, in serum potassium concentration by driving potassium intracellu-
which can alter mood and cause delirium. These emergence phe- larly.31 The chronotropic response to β2-agonists is mediated in part
nomena occur in at least 25% of patients older than 16 years of age; by baroreceptor reflex mechanisms as a result of the drop in blood
the incidence seems to be much lower in younger patients.2 Other pressure from vascular smooth muscle relaxation, as well as by direct
risks include an increase in heart rate, arterial blood pressure, and stimulation of cardiac β2-receptors and some β1 stimulation at high
cerebral blood flow because of its sympathetic effects.26 concentrations.31 Table 28–7 lists the pharmacologic effects of adre-
nergic receptor stimulation. Because β1-receptor stimulation pro-
duces excessive cardiac stimulation, resulting in cardiac arrhythmias,
■ SPECIAL POPULATIONS and because the inotropic effect enhancing myocardial oxygen con-
 Infants and children younger than 4 years of age may be at greater sumption leads to myocardial necrosis, there is no rationale for using
risk of respiratory failure than older children and adults. Although non–β2-selective agonists in the treatment of asthma.31
treated with the same drugs, these younger children require the use of Table 28–8 compares the various β-adrenergic agonists used in
a facemask as opposed to a mouthpiece for delivery of aerosolized asthma in terms of selectivity, potency, oral activity, and duration of
medication. Use of the facemask reduces delivery of drug to the lung action. The β2-agonists are functional or physiologic antagonists in
by one-half so that a minimal dose is recommended as opposed to a that they relax airway smooth muscle regardless of the mechanism
weight-adjusted dose.25,29 The facemask should be sized appropriately for constriction.31 When administered in equipotent doses, all the
and should fit snugly over the nose and mouth. Use of the “blow-by” short-acting drugs produce the same intensity of response; the only
method, where the respiratory therapist or parent places the mask or differences are in duration of action and cardiac toxicity.2,31 The
extension tubing near the child’s nose and mouth, should be discour- catecholamine derivatives all have the disadvantage of rapid inacti-
aged because holding the mask as few as 2 cm from the patient’s face vation of their 3,4-hydroxyl catechol group from catechol-O-meth-
reduces lung delivery of the aerosol by 80%.25 yltransferase found in the gastrointestinal tract, rendering them
orally inactive. In addition, catecholamines are taken up rapidly
■ DRUG CLASS INFORMATION into tissues by secondary uptake mechanisms that limit their recep-
tor occupancy and thus have a shorter duration of action.31 All the
Short-Acting β2-Agonists β2-agonists are more bronchoselective when administered by the
  The β2-agonists are the most effective bronchodilators avail- aerosol route. Aerosol administration of the short-acting β2-ago-
able. The β2-adrenergic receptors are transmembrane proteins con- nists provides more rapid response and greater protection against

TABLE 28-8 Relative Selectivity, Potency, and Duration of Action of the β-Adrenergic Agonists
Selectivity Duration of Actionb
Agent β1 β2 Potency, β2a Bronchodilation (h) Protection (h)c Oral Activity
Isoproterenol ++++ ++++ 1 0.5–2 0.5–1 No
Metaproterenol +++ +++ 15 3–4 1–2 Yes
Albuterol + ++++ 2 4–8 2–4 Yes
Pirbuterol + ++++ 5 4–8 2–4 Yes
Terbutaline + ++++ 4 4–8 2–4 Yes
Formoterol + ++++ 0.12 ≥12 6–12 Yes
Salmeterol + ++++ 0.5 ≥12 6–12 No
a
Relative molar potency to isoproterenol: 15 = lowest potency.
b
Median durations with the highest value after a single dose and lowest after chronic administration.
c
Protection refers to the prevention of bronchoconstriction induced by exercise or nonspecific bronchial challenges.
 480
provocations that induce bronchospasm such as exercise and aller- regular administration and does not worsen with continued admin-
gen challenges than does systemic administration.25 Differences in istration. As would be expected from a receptor phenomenon,
SECTION 3

myocardial effects are discernible between selective and nonselective tolerance is a cross-tolerance to all β2-agonists.31 Whether or not
agents even when administered as aerosols, particularly at the regular use of short-acting inhaled β2-agonists produces worsening
higher doses used for severe acute asthma. The β2-agonists also of asthma in a subset of patients remains controversial (see Treat-
differ in efficacy or ability to activate the β2-adrenergic receptors. ment section on Chronic Asthma, Clinical Controversy below), but
Full agonists include the catecholamines, metaproterenol, and for- it does not appear to occur in the entire population.38 Regular
moterol.31 Partial agonists include albuterol, terbutaline, pirbuterol, treatment with short-acting β2-agonists can increase BHR and in
and salmeterol.31 The principal differences between full and partial homozygous Arg-16 patients reduced morning PEF and increased
agonists are that full agonists require a lower fraction of receptor exacerbations.38 Regular treatment (four times daily) does not
Respiratory Disorders

occupancy to produce their maximum effect and more easily improve symptom control over as-needed use.2,8
produce receptor desensitization.38 However, these differences have In conclusion, the inhaled short-acting selective β2-agonists are
not been proven to be clinically significant. indicated for the treatment of intermittent episodes of broncho-
All synthetic β2-agonists are 1:1 racemic mixtures of two mirror spasm. They are the first treatment of choice for acute severe asthma
images (enantiomers) owing to an asymmetric or chiral carbon.38 and exercise-induced bronchospasm.2,8,31 They inhibit EIB in a
Because most physiologic functions (receptor occupancy and activa- dose-dependent fashion and provide complete protection for a 2-
tion and enzymatic metabolism) are stereoselective, the (R)-enanti- hour period following inhalation with varying levels of patient-
omers of the β2-agonists are the most pharmacologically active dependent protection over 4 hours.31 Although the regular admin-
isomer.38 Although it was initially thought that the (S)-enantiomers istration of β2-agonists slightly decreases the effect, two inhalations
were essentially inactive owing to the 100- to 1,000-fold potency prior to exercise still essentially blocks exercise-induced broncho-
difference between the enantiomers, studies in animal models and spasm completely (1% versus 5% drop in FEV1).38
isolated in vitro tissue preparations have suggested that the (S)-
enantiomer of albuterol may be proinflammatory and could induce
BHR.38 However, evidence that this occurs consistently in humans or Systemic Corticosteroids
is clinically relevant is lacking.38 The pharmacokinetics also are  The corticosteroids are the most effective antiinflammatories
stereoselective, although not predictable. (R)-Albuterol is metabo- available to treat asthma.2,6,8 Actions useful in treating asthma
lized more rapidly than (S)-albuterol, which could lead to accumu- include (a) increasing the number of β2-adrenergic receptors and
lation of (S)-albuterol with continued dosing.38 This accumulation is improving the receptor responsiveness to β2-adrenergic stimulation,
more exaggerated with oral dosing, as would be expected from a (b) reducing mucus production and hypersecretion, (c) reducing
drug with a high first-pass effect.31 On the other hand, (S)-terbuta- BHR, and (d) reducing airway edema and exudation.7,8 The gluco-
line is eliminated more rapidly than (R)-terbutaline.38 corticoid receptor is found in the cytoplasm of most cells throughout
Both the intensity and duration of response are dose-dependent, the body, explaining the multiple effects of systemic corticosteroids.
and more importantly, the dose–response relationship is dynamic.31 Although there is no difference between the glucocorticoid receptors
At increasing levels of baseline bronchoconstriction (irrespective of found throughout the body, genetic differences between glucocorti-
the stimulus), the dose-response curve is shifted to the right, and the coid receptors from different individuals may determine some of the
duration of bronchodilation is decreased.31 This shift is reflected in variations in response.39 The corticosteroids are lipophilic, readily
the need for higher, more frequent doses in acute asthma exacerba- cross the cell membrane, and combine with the glucocorticoid
tions; the duration of protection against significant provocation is receptor. The activated complex then enters the nucleus, where it
much less than the duration of bronchodilation in chronic stable acts as a transcription factor leading to gene activation or suppres-
asthma (see Table 28–8).31 sion.40 This leads to specific messenger ribonucleic acid (mRNA)
Chronic administration of β2-agonists leads to downregulation production, resulting in increased production of antiinflammatory
(decreased number of β2-receptors) and a decreased binding affinity mediators; suppression of several proinflammatory cytokines such as
for these receptors.31 Systemic corticosteroid therapy can both pre- IL-1, GM-CSF, IL-3, IL-4, IL-5, IL-6, and IL-8, reducing inflamma-
vent and partially reverse this phenomenon.2,31 However, the use of tory cell activation, recruitment, and infiltration; and decreasing
inhaled corticosteroids appears to have minimal ability to prevent vascular permeability.40 In addition, the activated glucocorticoid
tolerance to β2-agonists.31 The homozygous Gly-16 form of the receptor complex can act directly with cytoplasmic transcription
receptor downregulates to a much greater extent compared with the factors, nuclear factor κB, and activating protein 1 to prevent the
homozygous Arg-16 form of the receptor with heterozygous Arg-16/ action of proinflammatory cytokines on the cell.40
Gly-16 intermediately desensitized.38 On the other hand, glutamate Owing to the mechanism that modifies gene expression, the time
substitution at codon 27 (Glu-27) protects against downregulation required to see the particular effect depends on the time required for
compared with the glutamine form (Gln-27) of the receptor.38 new protein synthesis, decreased formation of the particular medi-
However, the Gly-16 overcomes any protective effect of Glu-27.38 ator, and resolution of the inflammatory response.40 Generally, the
Tolerance primarily reduces duration of bronchodilation as opposed cellular and biochemical effects are immediate, but varying amounts
to peak response although that can occur as well. A significantly of time are required to produce a clinical response. β2-Receptor
greater tolerance develops in other tissues (e.g., lymphocytes and density increases within 4 hours of corticosteroid administration.40
cardiac and skeletal muscle) compared with the lung primarily as a Improved responsiveness to β2-agonists occurs within 2 hours.40 In
result of the surplus β2 receptors found in respiratory smooth severe acute asthma, 4 to 12 hours may be required before any
muscle.31 Tolerance to the extrapulmonary effects (cardiac stimula- clinical response is noted.32,40 Reversal of seasonally increased BHR
tion and hypokalemia) may account for a lack of significant cardiac requires at least 1 week of therapy.40 The chronic use of corticoster-
effects with retention of the bronchodilator response despite chronic oids does not induce a state of corticosteroid dependence. Nor is
inhaled β2-agonist therapy, whereas tolerance to mast cell stabiliza- there evidence of tolerance produced by chronic administration.
tion may be a drawback to chronic use.31 Thus, chronic β2-agonist Table 28–9 compares the corticosteroids used in asthma.39–41 Besides
administration produces a tolerance of minimal clinical significance acute severe asthma, systemic corticosteroids are also recommended
that is overcome easily by increasing the dose or by administering for the treatment of impending episodes of severe asthma unresponsive
corticosteroids.2,31,38 Most of the tolerance occurs within a week of to bronchodilator therapy.2,6,8 The effects of corticosteroids in asthma
 481

TABLE 28-9 Pharmacodynamic/Pharmacokinetic Comparison of the Corticosteroids

CHAPTER 28
Antiinflammatory Mineralcorticoid
Systemic Potency Potency Duration of Biologic Activity (h) Elimination Half-Life (h)
Hydrocortisone 1 1.0 8–12 1.5–2.0
Prednisone 4 0.8 12–36 2.5–3.5
Methylprednisolone 5 0.5 12–36 3.3
Dexamethasone 25 0 36–54 3.4–4.0
Receptor Binding Topical Skin Oral Bioavailability Systemic Half-Life (h) IV/
ICS Affinity Blanching (%) Clearance (L/h) Inhaled

Asthma
BDP/BMPb 0.4/13.5 600/400 15–20 UK 0.5/1.5–6.5
BUD 9.4 980 11 55–84 2.8/2.0
CIC/des-CICb 0.12/12.0 UK <1/<1 152/228 (0.36/3.4)/UK
FLU 1.8 330 20 58 1.6/1.6
FP 18 1200 ≤1 66 7.8/14.4
MF 27a UK <1 53 5.8/UK
TAA 3.6 330 23 45–69 2.0/3.6
BDP, beclomethasone dipropionate; BMP, beclomethasone 17-monopropionate; BUD, budesonide; CIC, ciclesonide; des-CIC, des-ciclesonide; FLU, flunisolide; FP, fluticasone propionate; MF, mometasone
furoate; TAA, triamcinolone acetonide; UK, unknown.
Note: Receptor binding affinities and topical skin blanching are relative to dexamethasone equal to 1.
a
MF studied in a different receptor system. Value estimated from relative values of BDP, TAA, and FP in that system.
b
BDP and CIC are prodrugs that are activated in the lung to their active metabolites BMP and des-CIC respectively.

are dose and duration dependent. This pattern is true for the adverse cholinergics are competitive inhibitors of muscarinic receptors.42
effects as well (Table 28–10). The clinician must continually balance Unlike β2-agonists, they are not functional antagonists; they only
the toxicity of chronic systemic corticosteroid therapy with control of reverse cholinergic-mediated bronchoconstriction. Normal bronchial
asthma symptoms. Because short-term (1 to 2 weeks) high-dose tone is maintained through parasympathetic innervation of the air-
corticosteroids (1 to 2 mg/kg per day of prednisone) do not produce ways via the vagus nerve.42 A number of the triggers and mediators of
serious toxicities, the ideal use is to administer the systemic corticoster- asthma (i.e., histamine, prostaglandins, sulfur dioxide, exercise, and
oids in a short “burst” and then to maintain the patient on appropriate allergens) produce bronchoconstriction in part through vagal reflex
long-term control therapy with ICSs (discussed below under Inhaled mechanisms.42 Studies of asthmatics consistently demonstrate that
Corticosteroids).2,8 In general, therapy for more than 5 days at doses anticholinergics are effective bronchodilators, although not as effec-
that exceed the usual physiologic endogenous cortisol production will tive as β2-agonists. Anticholinergics attenuate but do not block
cause temporary aberration in adrenal cortisol release.39 However, this allergen-induced asthma in a dose-dependent fashion and have no
hypothalamic–pituitary–adrenal axis suppression is short-lived (1 to 3 effect on BHR.42 Anticholinergics attenuate but do not block EIB.43
days) and readily reversible following short bursts (10 days or less) of Ipratropium bromide is a nonselective muscarinic receptor
pharmacologic doses.40 A maximum number of short bursts that a blocker, and blockade of inhibitory muscarinic receptors theoreti-
patient can receive probably exists, after which chronic corticosteroid cally could result in an increased release of acetylcholine and over-
side effects occur. Patients receiving at least eight bursts (≥10 days each) come the block on the smooth muscle receptors (M3).42 Only the
have a similar decrease in trabecular bone density as patients on daily quaternary ammonium derivatives such as ipratropium bromide
or alternate-day corticosteroids over 1 year.40 Children who received should be used because they have the advantage of poor absorption
four or more bursts of prednisone exhibited a subnormal response to across mucosae and the blood–brain barrier. This results in negligi-
hypoglycemic stress or adrenocorticotropic hormone administration.40 ble systemic effects with a prolonged local effect (i.e., bronchodila-
Very short courses (3 to 5 days) have been effective in reducing tion). In addition, the quaternary compounds do not appear to
hospitalization from acute exacerbations.2,8 Use of the shorter-acting produce a decrease in mucociliary clearance.42 Ipratropium bromide
corticosteroids, such as prednisone, produces less adrenal suppression has a duration of action of 4 to 8 hours. Both intensity and duration
than the longer-acting dexamethasone.40 of action are dose-dependent. Tiotropium bromide, a new long-
acting inhaled anticholinergic, has a duration of 24 hours. Time to
Anticholinergics reach maximum bronchodilation for ipratropium is considerably
slower than from aerosolized short-acting β2-agonists (30 to 60
The anticholinergic agents have a long history of use for asthma, but
minutes vs. 5 to 10 minutes). However, this is of little clinical
they do not have an FDA-approved indication for asthma.2,42 Anti-
consequence because some bronchodilation is seen within 30 sec-
onds, 50% of maximum response occurs within 3 minutes.42 Ipratro-
TABLE 28-10 Adverse Effects of Chronic Systemic pium bromide is only indicated as adjunctive therapy in severe acute
Glucocorticoid Administration
asthma not completely responsive to β2-agonists alone because it
Hypothalamic–pituitary–adrenal Hypertension does not improve outcomes in chronic asthma.2,8 Tiotropium has
suppression Skin striae not been studied in asthma.
Growth retardation Impaired wound healing
Skeletal muscle myopathy Inhibition of leukocyte and monocyte
Osteoporosis/fractures function PHARMACOECONOMICS
Aseptic necrosis of bone Subcutaneous tissue atrophy
Pancreatitis Glaucoma The number of emergency department visits for asthma exceeds the
Pseudotumor cerebri Posterior subcapsular cataracts number of hospitalizations by approximately four times, yet the
Psychiatric disturbances Moon facies
annual expenditure for emergency department visits ($518 million)
Sodium and water retention Central redistribution of fat
is significantly less than the estimated $2.7 billion spent on inpatient
Hypokalemia/hyperglycemia
hospital services for patients with acute severe asthma.3 Thus,
 482
reducing the number of patients requiring hospitalizations is a
primary goal of therapy. Because the primary drugs used to treat TREATMENT
SECTION 3

severe acute asthma are available generically, drug costs account for
only a small portion of the overall costs of care. Few of the therapies Chronic Asthma
used in the management of acute severe asthma have been evaluated
The diagnosis of chronic asthma is made primarily by history and
formally for their pharmacoeconomic impact. One evaluation based
confirmatory spirometry (see Clinical Presentation above).2,6 The
on a meta-analysis of inhaled anticholinergics added to short-acting
NAEPP has provided a list of questions that would lead to the diagnosis
inhaled β2-agonists in children with acute severe asthma suggested
of asthma (see Table 28–2).2,6 In the older child and adult patient in
that this approach was cost-effective and would reduce overall costs
whom spirometric evaluations can be performed, failure of pulmonary
by reducing hospitalizations.44 In children with acute severe asthma
functions to improve acutely does not necessarily rule out asthma.
Respiratory Disorders

admitted to an intensive care unit, the use of continuously nebu-

Patients with long-standing disease or substantial inflammation may
lized albuterol resulted in a decreased cost of care compared with
require an intensive, prolonged course of bronchodilators and gluco-
intermittent nebulization.30
corticoids before reversibility is detected.2,8 If baseline spirometry is
normal, challenge testing with exercise, histamine, or methacholine
can be used to elicit BHR.2 Patients with significant symptoms and/or
CLINICAL CONTROVERSIES an FEV1 of less than 65% of predicted normal should not be chal-
Some clinicians believe that intravenous magnesium sulfate is lenged. Studies for atopy, such as serum IgE and sputum and blood
effective for the treatment of severe acute asthma unresponsive eosinophil determinations, are unnecessary to make the diagnosis of
to standard doses of inhaled β2-agonists in the emergency asthma, but they may help differentiate asthma from chronic bronchi-
department. This is based on subset analyses of two studies tis in adults. Clinically, this distinction is often difficult to make. Some
showing that patients with the most severe obstruction following patients with chronic bronchitis may have a reversible component, and
initial inhaled β2-agonists decreased hospitalizations with mag- some patients with long-standing severe chronic asthma may have
nesium treatment compared with placebo.35 However, the sub- significant irreversible damage and obstruction. Very high peripheral
set with severe obstruction is the one demonstrating an blood eosinophil counts may point to the diagnosis of allergic bron-
improved response to the addition of ipratropium bromide and chopulmonary aspergillosis or other hypereosinophilic syndromes.8
continuous nebulization of inhaled β2-agonists. In addition a Skin testing is of no value in diagnosing asthma but is useful in
large, randomized trial failed to confirm a decreased hospitaliza- identifying triggers.2 In small infants unable to perform spirometry, the
tion even in the severe group. The new NAEPP6 and the Global diagnosis is more difficult. They may demonstrate hyperinflation on
Initiative for Asthma guidelines state that it can be considered the chest roentgenogram.2 Radiologic examination is helpful in ruling
for use in patients with severe episodes with a poor response to out other causes of wheezing (e.g., foreign-body aspiration, parenchy-
initial inhaled β2-agonists.8 mal lung disease, cardiac disease, and congenital anomalies).2 In place
Numerous studies show that the inhaled β2-agonists adminis- of pulmonary functions, the parents should be given a diary card to
tered by MDI plus VHC provide a similar outcome in severe record symptoms and precipitating events.
acute asthma as administration by jet nebulizers.29 Proponents
of administration by MDI plus VHC argue that it is more cost- ■ GOALS FOR MANAGING
effective and so should replace nebulizer therapy. However, ASTHMA LONG TERM
appropriate cost analyses have yet to be performed.25 Nor have
The NAEPP has provided key points for managing asthma long
there been comparisons in the most severe subsets, where
term.6 The goal for therapy is to control asthma by:
combination therapy and continuous nebulization are recom-
mended.25 Current practice should be based on the comfort level Reducing impairment
of the clinical staff until sufficient data are available to warrant a
1. Prevent chronic and troublesome symptoms (e.g., coughing or
wholesale recommendation of one method.29
breathlessness in the daytime, in the night, or after exertion)
2. Require infrequent use (≤2 days a week) of inhaled short-
EVALUATION OF THERAPEUTIC OUTCOMES acting β2-agonist for quick relief of symptoms2 (not including
prevention of EIB)
Figures 28–6 and 28–7 provide the monitoring parameters for 3. Maintain (near-) normal pulmonary function
severe acute asthma. Lung function, either spirometry or peak 4. Maintain normal activity levels (including exercise and other
flows, should be monitored 5 to 10 minutes after each treatment.2 activity and attendance at work or school)
Oxygen saturations can be easily monitored continuously with
pulse oximetry. For young children and infants, pulse oximetry, 5. Meet patients’ and families’ expectations of and satisfaction
lung auscultation, and observation of the presence of supraclavicu- with care
lar retractions is useful.2,26 The majority of patients will respond Reducing risk
within the first hour of initial inhaled β2-agonists regardless of
history of home administration of drug.26 Patients not achieving an 1. Prevent recurrent exacerbations of asthma and minimize the
initial response should be monitored every 0.5 to 1 hour. Depend- need for visits or hospitalizations
ing on whether there is a standard emergency department or a 2. Prevent loss of lung function; for children, prevent reduced
special unit for severe acute asthma, the decision to admit to the lung growth
hospital should be made within 4 to 6 hours of entry to the 3. Minimal or no adverse effects of therapy
emergency department.26 The mean duration of hospitalization
following admission is 2 to 3 days. Frequency of monitoring
depends on the severity of the exacerbation. With mild exacerba-
■ NONPHARMACOLOGIC THERAPY
tions, monitor lung function every 2 to 3 hours; with severe Although the mainstay of the management of asthma is pharma-
exacerbations, monitor every 30 minutes to 1 hour. cologic therapy, it is likely to fail without concurrent attention to
 483
relevant environmental control and management of comorbid give primary healthcare providers a framework with which to
conditions. Figure 28–8 depicts the stepwise approach for manag- develop the proper approach to the individualized therapy of

CHAPTER 28
ing asthma recommended in the newest update by the NAEPP.6 It patients. The heterogeneity of asthma demands an individualized
is important to note that the nonpharmacologic aspects of therapy approach to therapy with the basic goals of therapy as primary
are incorporated into the steps. The guidelines were designed to outcome measures.2,6

Children 0–4 Years of Age

Intermittent
Persistent Asthma: Daily Medication
Asthma

Asthma
Step 6 Step up if
Step 5 needed
Preferred:
Preferred: (first, check
Step 4 High-dose ICS adherence and
High-dose ICS environmental
Preferred: AND control)
Step 3 AND
Medium-dose Either:
Preferred: Either: Montelukast or Assess
Step 2 ICS
Montelukast or LABA control
Preferred: Medium-dose AND
ICS LABA
Step 1 Low-dose ICS AND Step down if
Either:
Preferred: Montelukast or possible
Oral
Alternative: LABA (and asthma is
SABA PRN corticosteroids
well controlled
Montelukast or at least
Cromolyn 3 months)

Patient Education and Environmental Control at Each Step

Persistent Asthma : Daily Medication

Intermittent
Consult with asthma specialist if step 4 care or higher is required.
Asthma
Consider consultation at step 3.

Step 6
5–11 year olds Step 5 Preferred: Step up if
Preferred: needed
Step 4 High-dose ICS
High-dose ICS + LABA + oral (first, check
Preferred: corticosteroid
Step 3 + LABA adherence and
Medium-dose environmental
Preferred: Alternative: Alternative: control and
ICS + LABA
High-dose ICS comorbid
Step 2 Medium-dose Alternative: High-dose ICS
conditions)
ICS + either LTRA + either LTRA
Preferred: Medium-dose or Theophylline
or Theophylline
OR + oral Assess
Step 1 Low-dose ICS ICS + either
control
Low-dose ICS + LTRA or corticosteroid
Preferred: Alternative: Theophylline
either LABA,
Step down if
SABA PRN LTRA LTRA, or
possible
Cromolyn, Theophyline
Nedocromil, or (and asthma is
Theophylline well controlled
at least
3 months)
Patient Education and Environmental Control at Each Step
Steps 2-4: Consider SQ allergen immunotherapy for allergic patients

Quick-Relief Medication for All Patients

• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at
20-minute intervals as needed. Short course of systemic oral corticosteroids may be needed.
• Caution: Increasing use of beta-agonist or use >2 times a week for symptom control (not prevention of EIB)
indicates inadequate control and the need to step up treatment.

FIGURE 28-8. Stepwise approach for managing asthma in adults and children. (ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LTRA,
leukotriene receptor antagonist; PRN, as needed; SABA, short-acting β-agonist.) (Adapted from reference 6.)
 484
SECTION 3

Persistent Asthma : Daily Medication

Intermittent
Consult with asthma specialist if step 4 care or higher is required.
Asthma
Consider consultation at step 3.

Step 6 Step up if
Step 5 needed
Preferred:
Preferred: (first, check
Step 4 High-dose adherence,
High-dose ICS + LABA +
Respiratory Disorders

Step 3 Preferred: ICS + LABA

environmental
oral control, and
Preferred: Medium-dose corticosteroid comorbid
AND
Step 2 Medium-dose
ICS + LABA conditions)
Consider AND
Preferred: ICS Alternative:
Omalizumab for Consider Assess
Step 1 Low-dose ICS OR Medium-dose patients who Omalizumab for control
Preferred: Low-dose ICS + either have allergies patients who
Alternative: ICS + LABA LTRA, have allergies Step down if
SABA PRN Cromolyn, Theophylline
Alternative: possible
Nedocromil, or Zileuton (and asthma is
LTRA, or Low-dose ICS + well controlled
Theophylline either LTRA, at least
Theophylline 3 months)
or Zileuton

Patient Education and Environmental Control at Each Step

Step 2-4: Consider SQ allergen immunotherapy for allergic patients

Quick-Relief Medication for All Patients

• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3

treatments at 20-minute intervals as needed. Short course of systemic oral corticosteroids may be needed.
• Use of beta2-agonist >2 days a week for symptom control (not prevention of EIB) indicates inadequate
control and the need to step up treatment.

FIGURE 28-8. (continued)

The knowledge that inflammation plays a primary role in the The NAEPP advocates the use of PEF monitoring only for
pathogenesis of asthma has led to the conviction that the focus of patients with severe persistent asthma who have difficulty perceiv-
therapy is the prevention and suppression of the underlying inflam- ing airway obstruction.2 The NAEPP also has recommended a
mation.2,6,8 Thus current therapeutic options in asthma consist of system based on a traffic light scenario (based on percentage of
acute reliever medications used for acute exacerbations and long- normal predicted values or personal best values): the green zone is
term control medications used for the prevention of symptoms and
exacerbations and the suppression of inflammation.2 The currently
accepted approach is to use drugs that suppress the inflammatory TABLE 28-11 Key Educational Messages for Patients
response as primary long-term control therapy, thereby reducing Basic facts about asthma
the degree of BHR and improving long-term control and outcomes • The contrast between asthmatic and normal airways
in asthma.2,6,8 • What happens to the airways in an asthma attack
 The development of a partnership in care through patient Roles of medications
education and the teaching of patient self-management skills should • How medications work
be the cornerstone of any treatment program.2,6,8 There are a • Long-term control: medications that prevent symptoms, often by reducing
number of published self-management programs for children and inflammation
adults available through local American Lung Association chapters, • Quick relief: short-acting bronchodilator relaxes muscles around airways
• Stress importance of long-term-control medications and not to expect quick
as well as asthma treatment centers, and nationally through the
relief from them
NAEPP and the Asthma and Allergy Foundation of America.2,6,8
Skills
Asthma self-management programs have been shown to improve • Inhaler use (patient demonstrate)
patient adherence to medication regimens, improve self-manage- • Spacer and holding chamber use
ment skills, and improve use of healthcare services.2,6,8 The objective • Use of the nebulizer
of these programs is to develop a partnership relationship between • Symptom monitoring, peak flow monitoring, and recognizing early signs of
the patient and the healthcare provider. Table 28–11 lists the key deterioration
educational messages recommended by the NAEPP.6 • How to assess asthma control after therapy has begun
Self-management programs instruct patients in the pathogenesis Environmental control measures
of asthma and the appropriate use of their medications but focus • Identifying and avoiding environmental precipitants or exposures, including
principally on teaching patients to recognize triggers for their tobacco smoke
When and how to adjust treatment
asthma and how to recognize early signs of deterioration. Home
• Using written action plan
PEF monitoring is part of some programs.2,8 However, routine PEF
• Responding to changes in asthma control
monitoring in and of itself does not improve patient outcomes.6
 485
equal to 80% to 100%, the yellow zone is equal to 50% to 79%, and control status of the patient (refer to Evaluation of Asthma Control
the red zone is less than 50%. The yellow zone is cautionary and section). Regardless of the long-term therapy, all patients need to have

CHAPTER 28
requires increasing as-needed bronchodilator use and possibly quick-relief medication in the form of short-acting inhaled β2-agonists
beginning prednisone if not improved, whereas the red zone war- available for acute symptoms. The ICSs are considered the preferred
rants contacting the patient’s healthcare provider.2 long-term control therapy for persistent asthma in all patients because
Patient education is essential before monitoring can be effective. of their potency and consistent effectiveness.6,8 Low- to medium-dose
Patient education has proved successful regardless of the health profes- ICSs reduce BHR, improve lung function, and reduce severe exacerba-
sional who provided the information (physician, nurse, or pharma- tions leading to emergency department visits and hospitalizations.
cist). The NAEPP advocates significant involvement of all points of They are more effective than cromolyn, nedocromil, theophylline, or
patient care in the educational process. The provision of written action the leukotriene receptor antagonists.6 In addition, the ICSs are the only

Asthma
plans enhances the success of education and is considered an essential therapy that reduces the risk of dying from asthma.45 In the low to
component of care.2,6 Samples of clinically tested written action plans medium doses recommended by the NAEPP guidelines (Table 28–12),
are available from the NAEPP guidelines and other sources.2,6 ICSs are safe for long-term administration (see Drug Class Informa-
In patients with known allergic triggers for their asthma, allergen tion, Inhaled Corticosteroids below).6,39 The ICSs do not appear to
avoidance has resulted in an improvement in symptoms, a reduction reduce airway remodeling and loss of lung function found in some
in medication use, and a decrease in BHR.2,6 A comprehensive patients with persistent asthma. The ICSs do not enhance lung growth
approach to environmental control is advocated. For example, for in children with asthma, prevent the development of asthma in high
patients with house-dust mite allergy, removing carpeting from bed- risk infants, or induce remission of asthma as BHR and other measures
rooms, washing sheets in hot water (>54.4°C [130°F]), and using of inflammation return to pretreatment levels on discontinuation of
special dust-proof pillow and mattress covers can reduce symptoms therapy.46,47 The sensitivity and consequent clinical response to ICSs
and need for medications.2,6 Obvious environmental triggers (e.g., can vary among patients.6
animal dander, cockroaches), if the patient is sensitive, should be Although studies of the alternative long-term control therapies
avoided. Evidence for home air-filtering systems and chemicals for (e.g., cromolyn, leukotriene receptor antagonists, nedocromil, and
killing house-dust mites is limited.6 Immunotherapy (allergy shots) theophylline) demonstrate improvement in symptoms, lung func-
with single antigens particularly, has been beneficial and may be tion, and as-needed short-acting inhaled β2-agonist use, they do not
considered in patients with persistent asthma with documented sensi- reduce BHR, suggesting minimal antiinflammatory activity.6 The
tivity.6 Immunotherapy with multiple antigens has been less effective. evidence suggests minimal to no differences in efficacy between
Patients who smoke should be encouraged to stop. Parents of these alternatives. Consequently, the NAEPP lists them in alphabet-
children with asthma should stop or at least not smoke around their ical order to show no preference for one over the other.6
children.2,6,8 For those patients who are inadequately controlled on low-dose
ICSs, either an increased dose of the ICS or the combination of ICS
and long-acting inhaled β2-agonist (LABA) is the next step to gain
■ PHARMACOLOGIC THERAPY control of more moderate persistent asthma.6,8 Alternatives could be
Figure 28–8 illustrates the current NAEPP recommendations for the addition of leukotriene modifiers or theophylline to ICSs.6,8 The
therapy of persistent asthma.6 Therapy should be adjusted based on addition of theophylline or leukotriene modifiers to ICSs is no more

TABLE 28-12 Available Inhaled Corticosteroid Products, Lung Delivery, and Comparative Daily Dosages
Inhaled Corticosteroids Product Lung Delivery a
Beclomethasone dipropionate (BDP) 40 and 80 mcg/actuation HFA MDI, 120 actuations 55–60%
Budesonide (BUD) 200 mcg/dose DPI, Turbuhaler, 200 doses 32% (16–59%)
200 and 500-mcg ampules, 2 mL each 6%
Flunisolide (FLU) 250 mcg/actuation CFC MDI, 100 actuations 20%
80 mcg/actuation HFA MDI, 120 actuations 68%
Fluticasone propionate (FP) 44, 110, and 220 mcg/actuation HFA MDI, 120 actuations 20–25%
50 mcg/dose DPI, Diskus, 60 doses 15%
Mometasone furoate (MF) 200 and 400 mcg/dose DPI, Twisthaler, 14, 30, 60, and 120 doses 11%
Triamcinolone acetonide (TAA) 75 mcg/actuation CFC MDI, 240 actuations with spacer 22%
Comparative Daily Dosages (mcg) of Inhaled Corticosteroids
b
Low Daily Dose Child /Adult Medium DailyDose Child b/Adult High Daily Dose Child b/Adult
BDP
HFA MDI 80–160/80–240 >160–320/>240–480 >320/>480
BUD
DPI 200–400/200–600 >400–800/>600–1,200 >800/>1,200
Nebules 500/UK 1,000/UK 2,000/UK
FLU
CFC MDI 500–750/500–1,000 1,000–1,250/1,000–2,000 >1,250/>2,000
HFA MDI 160/320 320/320–640 ≥640/>640
FP
HFA MDI 88–176/88–264 176–352/264–440 >352/>440
DPIs 100–200/100–300 200–400/300–500 >400/>500
MF, DPI UK/200 UK/400 UK/>400
TAA, CFC MDI 300–600/300–750 600–900/750–1,500 >900/>1,500
a
Lung delivery from in vivo radiolabel scintigraphy or pharmacokinetic studies.
b
5–11 years of age.
CFC, chlorofluorocarbon; DPI, dry-powder inhaler; HFA, hydrofluoroalkane; MDI, metered-dose inhaler; UK, unknown.
 486
effective than doubling the dose of the ICS.6 The combination of ICS/ a LABA if not adequately controlled.52 Budesonide is considered the
LABA is more effective at reducing severe asthma exacerbations than preferred ICS to initiate because it has the greatest amount of safety
SECTION 3

doubling the dose of ICS in moderate persistent asthma; increasing data.52 Albuterol is considered the preferred rescue therapy.52
the dose of ICSs fourfold also will result in a significant reduction in
exacerbations.48–50 However, doses of ICSs in the high range signifi- ■ DRUG CLASS INFORMATION
cantly enhance the risk of toxicity. Thus, high doses of ICSs plus
LABA are reserved for patients with severe persistent asthma.6 Inhaled Corticosteroids
Although the addition of a third controller medication is often
used clinically in patients with severe, persistent asthma uncon- The mechanism of action of the corticosteroids was reviewed under
trolled on high-dose ICS/LABA, there are few studies evaluating this Systemic Corticosteroids above. The principal advantage of the ICSs
is their high topical potency to reduce inflammation in the lung and
Respiratory Disorders

practice.6 Leukotriene receptor antagonists or theophylline added to

low systemic activity.39–41 The ICSs have high antiinflammatory
high-dose combination ICS/LABA do not improve outcomes.6
potency, approximately 1,000-fold greater than endogenous cortisol,
Omalizumab, a recombinant anti-IgE has demonstrated significant
and differ from each other by as much as 4- to 6-fold.41 However,
activity in these severe, uncontrolled patients.51 Thus adult patients
potency differences, which are simply a measure of binding affinity
with severe, persistent, uncontrolled asthma and atopy would be
to the receptor, can be overcome simply by giving different micro-
candidates for omalizumab therapy.
gram dosages of drug. Aerosol delivery of the preparations is remark-
ably variable, ranging from 10% to 60% of the nominal dose (i.e.,
■ SPECIAL POPULATIONS that dose which leaves an actuator for an MDI or, in the case of a
 Children 4 years of age and younger have not been studied DPI, that which is released on actuation of the inhaler).25,41 Different
adequately. Thus, many of the recommendations in this age group devices for the same chemical entity may result in twofold differences
are based on extrapolation of data from older children and adults.6 in delivery, such as with fluticasone propionate and budesonide, or
The studies of ICSs in this younger group demonstrate improvement as much as eightfold with beclomethasone dipropionate prepara-
in symptoms, as needed bronchodilator use and exacerbations. The tions.39 Thus the delivery method can make a significant difference
nebulized suspension of budesonide gained FDA approval from in the relative comparable dose.2,6
three pivotal efficacy and safety trials.6 The FDA approval for Table 28–12 lists and compares the ICSs, beclomethasone dipropio-
montelukast in children younger than age 6 years was based on safety nate, budesonide, flunisolide, fluticasone propionate, mometasone
and pharmacokinetic studies establishing doses but not on efficacy furoate, and triamcinolone acetonide, which are currently available for
although improvement in symptoms and as needed bronchodilators use, and ciclesonide, which is undergoing clinical trials. The ICSs have
was noted.6 Cromolyn nebulizer solution was approved down to 2 pharmacokinetic differences that result in different topical/systemic
years based upon efficacy, however, not all trials of cromolyn, activity.44,45 Most evidence is consistent with log-linear dose–response
particularly when administered by MDI plus VHC, in this younger curves for both indirect and direct responses.39 The log-linear nature
group have demonstrated efficacy.6 Theophylline has not been eval- of the dose–response curve for corticosteroid activity raises the issue of
uated adequately, except for pharmacokinetics.6 Combination ther- how much of a difference in dose (or lung delivery) or potency is
apy of any kind has not been studied except for a small number of detectable. The measures used to assess efficacy (lung function, BHR,
patients down to 4 years of age on ICS/LABA.6 symptoms, and as-needed, short-acting, inhaled β2-agonist use) are
The FDA approval of the fluticasone/salmeterol DPI 100/50 in downstream events from the antiinflammatory activity.39 In general, it
patients 4 to 11 years of age was largely based on extrapolation of takes a fourfold difference in potency or dose to detect clinically
efficacy data from patients older than 12 years of age and by a single significant differences in efficacy. The table of comparable doses (see
safety and efficacy study in children with asthma aged 4 to 11 years. Table 28–12) is based on extensive clinical trial data.6 Clinically
In children 5 to 11 years old, the ICS/LABA combination has not comparable doses take into consideration drug potency differences as
been shown to decrease exacerbations compared to medium-dose well as device delivery differences.
ICS as in adults although impairment domains improved. The only Because the glucocorticoid receptors within the various tissues are
study of the addition of montelukast to ICS showed minimal the same, differences in the pharmacokinetic profile are required to
improvement in PEF and as-needed albuterol use. Thus combina- produce differences in the topical–systemic effect ratio (therapeutic
tion therapy has been inadequately studied in this population. index).39 Pharmacokinetic properties that enhance improved topical
Owing to the increased risk of osteoporosis in the elderly, patients selectivity include rapid systemic clearance, poor oral bioavailability,
requiring high doses of ICSs should have their bone mineral density and long residence time in the lung.39,41 Owing to their high lipophi-
determinations followed and appropriate therapies for prevention licity, systemic clearance of the available ICSs is very rapid, approach-
of osteoporosis instituted.39 ing the rate of liver blood flow, with the exception of ciclesonide,
Asthma affects 7% of pregnant women, making it potentially the which is inactivated by blood esterases.41 However, the ICSs differ
most common serious medical condition to complicate preg- markedly in their oral bioavailability, although they all undergo rather
nancy.52 Maternal asthma has been reported to increase the risk of extensive first-pass metabolism to less active substances when
perinatal mortality, preeclampsia, preterm birth, and low-birth- absorbed (see Table 28–9).41 The ICSs produce dose-dependent
weight infants.52 More severe asthma is associated with increased systemic effects from a combination of the orally absorbed fraction
risks, whereas better-controlled asthma is associated with decreased and the fraction absorbed from the lung (Table 28–13).39,41 Essentially
risks. A systematic review of the evidence on the safety of asthma all the drug that reaches the lung is absorbed systemically; thus a slow
medications has been conducted by drug class.52 This review con- absorption from the lung results in an apparent long elimination half-
cluded that it is safer for pregnant women with asthma to be treated life and enhances topical selectivity by lowering the systemic concen-
with effective medications than for them to have exacerbations.52 tration.41 The potential advantage of the drugs with low oral bioavail-
Proper monitoring and control of asthma should enable a woman ability is obviated by using a spacer device with the MDI for the drugs
with asthma to maintain a normal pregnancy with little or no risk with higher oral bioavailability because appropriate spacers reduce
to mother or her fetus. the oral dose by 80%.25 The use of VHCs also can increase systemic
A stepwise approach to managing asthma during pregnancy and activity by increasing lung delivery of drugs not absorbed significantly
lactation has been published, with low-dose ICSs recommended as orally.39 If this increase in lung deposition is twofold or less, it will
preferred treatment for mild persistent asthma with the addition of increase systemic activity without producing a clinically important
 487

TABLE 28-13 Effects of Inhaled Corticosteroids potential for increasing systemic concentrations of these ICSs by
increasing oral availability and decreasing systemic clearance. Some

CHAPTER 28
Beneficial Effects Potential Adverse Effects
cases of clinically significant Cushing syndrome and secondary
Decrease eosinophil numbers Growth retardation, skeletal muscle myopathy adrenal insufficiency have been reported.41
Decrease mast cell numbers Osteoporosis, fractures, and aseptic necrosis Most patients with moderate disease can be controlled with twice-
of hip daily dosing of most ICSs.6,8,53 Twice-daily dosing produces less
Decrease T-lymphocyte cytokine Posterior subcapsular cataract formation and thrush than three- to four-times-daily dosing regimens. In milder
production glaucoma
asthma, once-daily dosing is often sufficient to maintain control.53
Inhibit transcription of inflamma- Adrenal axis suppression, immunosuppression
tory genes in airway epithelium
Some of the newer products have gained once-daily dosing indica-
Reduce endothelial cell leak Impaired wound healing, easy bruising, skin tions, particularly in mild asthma once initial control is established.41

Asthma
striae There does not appear to be any specific pharmacologic or pharma-
Upregulate β2-receptor production Hyperglycemia/hypokalemia, hypertension cokinetic aspect of the ICSs that allows for once-daily dosing because
Reduce airway epithelial subbase- Psychiatric disturbances all the agents studied (both the older low-potency and newer high-
ment membrane thickening potency ICSs) have been effective, provided that patients had rela-
tively mild to moderate asthma.39,53 Patients with more severe asthma
require multiple daily dosing. The inflammatory response of asthma
increase in efficacy, thus decreasing the therapeutic index.39 Mouth
inhibits steroid-receptor binding.53 This provides strong theoretical
rinsing and spitting also will reduce the oral availability and are
evidence for initially beginning patients on higher and more frequent
particularly useful for DPI devices.2,25
doses and then tapering down once control has been achieved. Once
The response to ICSs is somewhat delayed. Most patients’ symp-
asthma is controlled, many patients are able to reduce the ICS dose
toms will improve in the first 1 to 2 weeks of therapy and will reach
and maintain control.53
maximum improvement in 4 to 8 weeks.53 Improvement in baseline
FEV1 and PEFs may require 3 to 6 weeks for maximum improvement,
whereas improvement in BHR requires 2 to 3 weeks and approaches Long-Acting Inhaled β2-Agonists
maximum in 1 to 3 months but may continue to improve over 1 The two LABAs, formoterol and salmeterol, provide long-lasting
year.53 Most of the improvement in these parameters occurs at low to bronchodilation (12 or more hours) when administered as aerosols
medium doses, and there is a large variability in response, with 10% (see Table 28–8).30 Unlike the more water-soluble short-acting β2-
of patients not demonstrating an improvement in either parameter.53 agonists, the long-acting agents are lipid soluble, readily partition-
Whether these nonresponders also show no improvement in rates of ing into the outer phospholipid layer of the cell membrane.30
exacerbations is unknown. Maximum decrease in FeNO occurs Salmeterol is more β2-selective than albuterol and more bronchose-
within 2 to 3 weeks.54 Sensitivity to exercise challenge decreases after lective by virtue of its property of remaining in the lung tissue cell
4 weeks of therapy.18,53 Although single doses do not inhibit the membrane, which produces its longer duration.30 However, both
immediate asthmatic response to antigen challenge, continued ther- formoterol and salmeterol will produce dose-dependent systemic
apy for 1 week partially suppresses the response. These two latter β2-agonist effects.30
effects are likely caused by a reduction in mucosal mast cells.53 The principal differences between formoterol and salmeterol are
Local adverse effects from ICSs include oropharyngeal candidia- that formoterol has a more rapid onset of action (similar to that of
sis and dysphonia that are dose-dependent. The dysphonia albuterol) and formoterol is a full agonist, whereas salmeterol is a
(reported in 5% to 50% of patients) appears to be caused by a local partial agonist. These differences are unlikely to produce clinically
corticosteroid-induced myopathy of the vocal cords.2 The use of a significant differences because both are recommended for chronic
spacer device with MDIs can decrease oropharyngeal deposition therapy only in combination with ICSs.6 They are available singly
and thus decrease the incidence and severity of local side effects.25,53 and as fixed-dose combinations with ICSs. Patients should be
There is less data on the use of spacers with ICS HFA MDIs. In warned to not use salmeterol for acute relief of asthma because it
infants who require delivery through a facemask, the parent should can take up to 20 minutes for onset and 1 to 4 hours for maximum
clean the nasal-perioral area with a damp cloth following each bronchodilation following inhalation.2,6 Formoterol also does not
treatment to prevent topical candidal infections. have approved FDA labeling for acute relief. Patients need to be
Systemic adverse effects can occur with any of the ICSs given in a counseled to continue to use their short-acting inhaled β2-agonists
sufficiently high dose.39 Long-term adverse effects of greatest con- for acute exacerbations while receiving the LABAs.
cern include growth suppression in children, osteoporosis, cataracts, The LABAs are the preferred adjunctive therapy to ICSs in
dermal thinning, and adrenal insufficiency and crisis.39,53 Of these, children ≥12 years of age and in adults for step 3, and in children 5
only growth retardation occurs in low to medium doses. However, to 11 years of age for steps 4 and 5.6 Combination treatment with
the growth reduction appears to be transient in that growth velocity ICS/LABA provides greater asthma control than increasing the dose
is reduced in the first 6 months to 1 year of therapy and then returns of ICS alone while at the same time reducing the frequency and
to normal.6,39 The effect is small (1 to 2 cm total) and not cumulative, perhaps the severity of exacerbations.48–50 Because they are devoid
and current studies suggest that attainment of predicted adult height of antiinflammatory activity, LABAs should not be used as mono-
is not affected.6,39 The suppression of the hypothalamic–pituitary– therapy for asthma. Recent evidence suggests that patients treated
adrenal axis and decreased bone mineralization are dose-dependent with LABA monotherapy added to usual therapy are at an increased
and do not appear to be significant clinically except at high doses.39 risk for severe, life-threatening exacerbations and asthma-related
The risks of these adverse effects are all dose-dependent and depend death.55,56 This risk may be greater in African American patients.
on the therapeutic index of each ICS and its delivery device. The Whether this risk is obviated by concomitant ICS use is unknown at
effect of delivery device is illustrated by fluticasone propionate, this time but preliminary evidence does not support an increased
which has both the greatest therapeutic index when administered by risk of severe, life-threatening exacerbations in patients receiving
DPI and the lowest therapeutic index when administered by MDI LABAs in combination with ICSs.57,58
plus VHC.39 Some of the ICSs including fluticasone propionate, As with short-acting β2-agonists, tolerance is produced with
budesonide and mometasone are metabolized in the gastrointestinal chronic administration of LABAs. Long-term trials show no dimi-
tract and liver by cytochrome P450 (CYP) 3A4 isoenzymes. Potent nution in bronchodilator response, but do show a partial loss of the
inhibitors of CYP3A4, such as ritonavir and ketoconazole, have the bronchoprotective effect against methacholine, histamine, and
 488
exercise challenge.58 In particular, the duration of protection against
EIB following a single dose of salmeterol is up to 9 hours but is Adults and children >1 y old :
SECTION 3

10 mg/kg/day up to 300 mg/day

reduced to less than 4 hours following regular treatment.58 Follow- Infants <1 y old: Dose mg/kg = (0.2) (age in weeks) + 5.0
ing regular treatment with salmeterol and formoterol, decreased
protection against nonspecific bronchoprovocation with methacho-
If tolerated after 3 days increase dose to:
line also occurs, although it provides greater protection than pla- Adults: 400 mg/day
cebo.58 Responsiveness to short-acting β2-agonists is reported to be Children <45 kg: 16 mg/kg/day up to 400 mg/day
slightly decreased but easily overcome by increasing the dose (by
approximately 1 puff) following chronic therapy with LABAs.58 Check serum concentration:
There is ample evidence that the use of a LABA in combination 4–6 h after morning dose of q 12 h SRT;
8 h after q 24 h SRT preparation (5–15 mcg/mL)
Respiratory Disorders

with ICS therapy does not mask inflammation.57 A meta-analysis of

studies comparing the addition of salmeterol to ICS therapy versus
Further dosage adjustments based on patient symptoms
at least a doubling of ICS dose demonstrates that rather than and serum concentrations
increasing asthma exacerbations, the number of these events was
reduced.48 As stated previously LABAs added to ICS in children
FIGURE 28-9. Algorithm for slow titration of theophylline dosage and
improve impairment but have yet to be adequately studied for
guide for final dosage adjustment based on serum theophylline concen-
reducing exacerbations over ICS alone.59 tration measurement. For infants younger than 1 year of age, the initial
daily dosage can be calculated by the following regression equation: Dose
Methylxanthines (mg/kg) = (0.2) (age in weeks) + 5.0. Whenever side effects occur,
dosage should be reduced to a previously tolerated lower dose. (SRT,
Methylxanthines have been used for asthma therapy for more than
sustained-release theophylline.)
50 years but their use in recent years has declined markedly owing
to the high risk of severe life-threatening toxicity and numerous
drug interactions, as well as decreased efficacy when compared with kidney.60 Theophylline clearance is age-dependent, with 1- to 9-
ICSs and LABAs. Theophylline, the primary methylxanthine of year-olds having the highest systemic clearances and therefore
interest, is a moderately potent bronchodilator with mild antiin- requiring the largest dosages (on a weight basis). However, even
flammatory properties.2,8 Like the β2-agonists, the methylxanthines within the same age groups, theophylline clearance can vary two- to
are functional antagonists of bronchospasm; however, their clinical threefold.60 Figure 28–9 gives a dosing and monitoring schedule for
usefulness is limited by their low therapeutic index.2 Theophylline theophylline. Table 28–14 lists factors that affect theophylline’s
as a sustained-release product is the preferred oral preparation, hepatic metabolism.2 Only drugs or diseases that produce a 20% or
whereas its complex with ethylenediamine (aminophylline) is the greater inhibition or a 50% or greater induction of theophylline
preferred injectable product because of increased solubility.60 metabolism are likely to result in clinically significant interactions.60
The mechanism by which theophylline produces bronchodilation Sustained-release theophylline is less effective than ICSs and no
appears to be through nonselective phosphodiesterase inhibition.60 more effective than oral sustained-release β2-agonists, cromolyn, or
Inhibition of phosphodiesterase results in increased cAMP and leukotriene antagonists.6 The addition of theophylline to ICSs is
cyclic guanosine monophosphate concentrations. The phosphodi- similar to doubling the dose of the ICS and is less effective overall
esterase isoenzymes currently thought to be important for theoph- than the LABAs as adjunctive therapy.6
ylline’s clinical effects are isoenzymes III, predominant in airway
smooth muscle, and IV, important in inflammatory cell regulation Cromolyn Sodium and Nedocromil Sodium
such as mast cells, neutrophils, eosinophils, and T lymphocytes.60 Cromolyn sodium and nedocromil sodium are pharmacologically
Selective phosphodiesterase isoenzyme IV inhibitors, however, have similar.2 They are classified as mast cell stabilizers, and the principal
no significant effects in clinical asthma. Theophylline is a competi- difference appears to be potency, with 4 mg nedocromil by MDI
tive antagonist of adenosine and stimulates endogenous catechol- equivalent to 10 mg cromolyn.2,61 However, there is no apparent
amine release.60 These latter two effects are important determinants difference in the clinical efficacy between these two drugs.2 They
of toxic symptoms of excess theophylline.60 inhibit the early and late asthmatic response to allergen challenge, as
Theophylline has a log-linear dose–response curve.60 Most chronic well inhibit EIB.2,8 Treatment prevents the usual rise in bronchial
stable asthmatics will obtain significant bronchodilation when the hyperresponsiveness with specific pollen seasons, but long-term
serum theophylline concentration reaches 5 mcg/mL, and most treatment produces minimal to no change in baseline bronchial
patients will have no toxic symptoms with serum concentrations of
less than 15 mcg/mL.6,60 The percentage of patients experiencing
adverse effects increases sharply as concentrations exceed 15 mcg/mL. TABLE 28-14 Factors Affecting Theophylline Clearance
As with the β2-agonists, the dose–response curves for smooth muscle % Increased %
relaxation by theophylline are dynamic and shifted to the right in the Decreased Clearance Decrease Clearance Increase
face of increasing contractile stimuli.60 This probably explains the-
Cimetidine –25 to –60 Rifampin +53
ophylline’s relative lack of bronchodilatory effect in acute severe Macrolides: erythromycin, –25 to –50 Carbamazepine +50
asthma.6,60 The severity of theophylline’s toxicity precludes even clarithromycin Phenobarbital +34
doubling the usual dosage. Toxicities include caffeine-like effects of Phenytoin +70
nausea, vomiting, tachycardia, jitteriness, and difficulty sleeping to Allopurinol –20 Charcoal-broiled +30
more severe toxicities such as cardiac tachyarrhythmias and seizures. Propranolol –30 meat
Death has occurred in children receiving their usual doses of theoph- Quinolones: ciprofloxacin, –20 to –50 High-protein diet +25
ylline during acute systemic viral illnesses.60 enoxacin, pefloxacin Smoking +40
Routine monitoring of serum concentrations is essential for the Interferon –50 Sulfinpyrazone +22
safe and effective use of theophylline.6 Theophylline is eliminated Thiabendazole –65 Moricizine +50
Ticlopidine –25 Aminoglutethimide +50
primarily by metabolism via the hepatic cytochrome P450 mixed-
Zileuton –35
function oxidase microsomal enzymes (primarily the CYP1A2 and
Systemic viral illness –10 to –50
CYP3A3 isozymes), with 10% or less excreted unchanged in the
 489
6,61
hyperresponsiveness. They inhibit neurally mediated broncho- been receiving high-dose inhaled or oral corticosteroids and were able
constriction, through C-fiber sensory nerve stimulation in the to reduce the dose as a consequence of the LTD4 receptor antagonists.

CHAPTER 28
airways, although neither drug has a bronchodilatory effect.61 It is unclear whether the increased reports are a result of increased
Cromolyn and nedocromil are only effective by inhalation and are case findings among patients with asthma prescribed a new drug or
available as MDIs, whereas cromolyn also is available as a nebulizer whether the syndrome is related to corticosteroid dose reduction or
solution. The pharmacokinetics of both drugs are very similar. They an idiosyncratic effect of leukotriene modifiers in general. Whatever
are not bioavailable orally, but the portion of the dose that reaches the cause, it appears to be a rare syndrome, with an estimated
the lung is absorbed completely.61 Absorption from the airway is incidence of fewer than 1 case per 15,000 to 20,000 patient-years of
significantly slower than elimination (hours versus minutes). The treatment.6 Montelukast has been prescribed widely worldwide owing
short duration in the lung likely limits their efficacy. Both the to its approval for use in young children. Churg-Strauss syndrome

Asthma
intensity and duration of protection against various challenges are has not been reported in children, and the drug has been very well
dose-dependent.61 Higher doses produce greater and more pro- tolerated and palatable.6 Recent reports of fatal hepatic failure associ-
longed protection. ated with zafirlukast have prompted a warning for patients to be
Both drugs are remarkably nontoxic. No evidence of mutagenesis or made aware of signs and symptoms of hepatic dysfunction.
teratogenesis has been found for cromolyn. Cough and wheeze have Zileuton can be administered four times daily or twice daily as
been reported following inhalation of each, and bad taste and head- controlled release tablets.6 Efficacy data is more limited, liver func-
ache following nedocromil are reported.2 The taste from nedocromil is tion monitoring is recommended, and drug interactions are
sufficiently bad in some patients (approximately 20%) to preclude reported with warfarin and theophylline.
them from taking the drug.61 Tolerance to cromolyn or nedocromil
has not been demonstrated. Neither are ICS-sparing agents. Combination Controller Therapy: ICS/LABA
Cromolyn and nedocromil are no more or less effective than
versus ICS/Leukotriene Receptor Agonists
theophylline or the leukotriene antagonists for persistent asthma.6
Neither cromolyn nor nedocromil is as effective as the ICSs for Whereas ICS therapy is considered the most effective antiinflamma-
controlling persistent asthma.6,46 Neither is as effective as the inhaled tory treatment, in cases of moderate to severe persistent asthma, the
β2-agonists for preventing EIB but can be used in conjunction for addition of a second long-term control medication to ICS therapy is
patients not responding completely to the inhaled β2-agonists.43 one recommended treatment option. Single inhaler combination
Most patients will experience an improvement in 1 to 2 weeks, products containing fluticasone propionate and salmeterol or budes-
but it may take longer to achieve maximum benefit. Patients onide and formoterol are commercially available and there likely will
initially should receive cromolyn or nedocromil four times daily, be more in the future. The inhalers, both DPIs and MDIs, contain
and then only after stabilization of symptoms may the frequency be varied doses of the ICSs and a fixed dose of the respective LABAs.
reduced to two times daily for nedocromil and three times daily for The pivotal trials for gaining FDA approval of fixed-dose combina-
cromolyn. Only the nebulizer solution should be used for children tions require that the combination demonstrate greater efficacy than
younger than 5 years of age.6 either component alone. Importantly, the addition of a LABA allows
reduction in ICS dosage by 50% in most patients with persistent
Leukotriene Modifiers asthma.48,50 Furthermore, combination therapy is more effective
than higher-dose ICS alone in reducing asthma exacerbations in
Two clinically distinct cysteinyl leukotriene receptor antagonists patients with persistent asthma.6,50 The ability to detect deteriorating
(zafirlukast and montelukast) and one 5-lipoxygenase inhibitor asthma and the severity of exacerbation were similar between
(zileuton) have been available in the United States since 1996 for groups. Leukotriene receptor agonists also are successful as additive
both children and adults with persistent asthma.62 In challenge therapy in patients inadequately controlled on ICS alone and as ICS-
studies, they reduce allergen-, exercise-, cold air hyperventilation-, sparing therapy.6 However, the magnitude of these benefits is less
irritant-, and aspirin-induced asthma.63 Clinical use of zileuton is than those reported with the addition of LABAs.6,49
limited because of the potential for elevated liver enzymes (espe-
cially in the first 3 months of therapy), and the potential inhibition
of drugs metabolized by the CYP3A4 isoenzymes.62,63 Anti-IgE (Omalizumab)
In clinical trials, the LTD4 receptor antagonists (zafirlukast and Omalizumab is a recombinant anti-IgE antibody approved for the
montelukast) have demonstrated efficacy in adults and children with treatment of allergic asthma not well controlled by oral corticoster-
persistent asthma. These drugs improve pulmonary function tests oids or ICSs.66 Omalizumab is a composite of 95% human and 5%
(FEV1 and PEF), decrease nocturnal awakenings and β2-agonist use, antihuman murine IgE sequences. The mouse protein becomes part
and improve asthma symptoms.62,63 A major advantage is that they are of the receptor complex and thus is shielded from exposure to the
effective orally, administered once or twice a day, and contribute to immune system, lowering the risk for an anaphylactic response.66
patient adherence and satisfaction with therapy.62 However, they are Omalizumab binds to the Fc portion of the IgE antibody, prevent-
less effective in asthma than low doses of ICSs.64,65 It is not yet possible ing the binding of IgE to its high-affinity receptor (FcεRI) on mast
to predict which patients respond best to leukotriene modifiers, cells and basophils. The decreased binding of IgE on the surface of
although there is some evidence that patients with aspirin-sensitive mast cells leads to a decrease in the release of mediators in response
asthma do well, as predicted by studies showing increased cysteinyl to allergen exposure. Omalizumab also decreases FcεRI expression
leukotriene production in these patients.63 It is possible that genetic on basophils and airway submucosal cells.
polymorphisms in the 5-lipooxygenase or LTC4 synthase pathways or Omalizumab is administered subcutaneously and has a slow absorp-
in cys-LT1 receptors might predict better responders in the future.63 tion rate; peak serum concentration is achieved in 3 to 14 days.66 It is
Antileukotrienes also have modest efficacy in allergic rhinitis. eliminated primarily through the reticuloendothelial system and has an
In general, the LTD4 receptor antagonists are well tolerated and do elimination half-life of 17 to 22 days; serum free IgE levels return to
not appear to have serious class-specific effects.6 An idiosyncratic baseline in about 3 weeks.66 It should be administered under medical
syndrome similar to the Churg-Strauss syndrome, with marked observation with drugs for treating anaphylaxis available.
circulating eosinophilia, heart failure, and associated eosinophilic The dosage of omalizumab is determined by the patient’s baseline
vasculitis, has been reported in a small number of patients treated total serum IgE level (international units per milliliter) and body
with zafirlukast or montelukast.6 The majority of these patients had weight (kilograms).66 Doses range from 150 to 375 mg and are given at
 490
either 2- or 4-week intervals. No further adjustments for variations in measurable costs; both indirect costs or costs to society and direct
total serum IgE are required, and patients receive a consistent dose for medical costs are considered. Using this approach, indirect costs,
SECTION 3

the duration of treatment.66 Omalizumab is approved for patients such as lost work and death, accounted for two-thirds of total
older than 12 years of age who have allergic asthma.66 Clinical trials in expenditures per patient. Although prescription drugs were the
5- to 12-year-olds are ongoing. Because of its significant cost, it is only largest single direct medical expenditure at $5 billion, an increase in
indicated as step 5 or 6 care for patients who have allergies and severe these costs secondary to improved patient adherence could signifi-
persistent asthma that is inadequately controlled with the combination cantly reduce other costs because of school days lost and lost
of high-dose ICS/LABA.6 It is the only adjunctive therapy that has productivity secondary to asthma morbidity and mortality.
demonstrated improved outcomes in patients uncontrolled on ICS/ The medication cost increase over the past 10 years resulted from
LABA and has allowed oral corticosteroid reduction in a number of a doubling of prescribed medications, as well as a 169% increase in
Respiratory Disorders

studies.6,66 However, recent postmarketing surveillance suggests that unit cost per medication, presumably as a result of a shift to more
omalizumab therapy is associated with a 0.1% rate of anaphylaxis, expensive antiinflammatory drugs consistent with the recommen-
prompting an FDA warning that patients should remain in the physi- dations of the NAEPP guidelines.2 Asthma severity obviously has an
cian’s office for a reasonable period of time past the injection because impact on cost of care. Studies from health maintenance organiza-
70% of reactions occur within 2 hours. In addition, patients should be tions suggest that up to 45% of the cost of asthma is accrued by 10%
counseled on the signs and symptoms of anaphylaxis because some of the patients, primarily as a result of emergency care.70
reactions have occurred up to 24 hours following an injection.6 Numerous studies demonstrate the cost-effectiveness of patient
education programs for asthma, particularly those providing guided
■ MISCELLANEOUS THERAPIES self-management.70 Several studies report positive results from
(IMMUNOMODULATORS) pharmacist interventions reducing overall cost of care.70 Similar
studies demonstrate the cost-effectiveness of specialist care com-
The following therapies have been loosely categorized by the NAEPP pared with generalist care. However, the results of these trials may
with omalizumab as immunomodulators because they either affect be confounded by changes in prescribing as part of the overall
the immune system or have antiinflammatory properties. Many have program. Indeed, use of ICSs reduces both morbidity, particularly
been used experimentally in severe persistent uncontrolled asthma for hospitalizations, and mortality in asthma patients.6,53,71
years to try to avoid or lower oral corticosteroid dosages. The NAEPP recommendations provide numerous alternatives for
Low-dose methotrexate (15 mg/week) used for inflammatory dis- long-term controllers in mild to moderate persistent asthma, and
eases, psoriatic and rheumatoid arthritis, and polymyositis has been few studies have compared their relative cost-effectiveness. This is
used to reduce the systemic steroid dose in patients with severe important because outside the realm of randomized clinical trials
steroid-dependent asthma.67 Double-blind, placebo-controlled trials that evaluate efficacy, other factors such as concern about adverse
have given decidedly mixed results, with half the studies showing no effects and adherence to therapy may alter the overall clinical
effect.68 A recent meta-analysis determined that there was insufficient effectiveness. Use of ICSs in children has produced a cost of $9.45 per
evidence to support its use, particularly in light of the risk for severe symptom-free day gained, and in adults a cost of $5.00 per symp-
side effects.67 Methotrexate inhibits chemotaxis of neutrophils, inhib- tom-free day.70 Retrospective analyses of large managed-care-linked
its leukotriene B4-induced adherence to endothelium, and inhibits pharmacy claims and healthcare utilization databases has allowed
the proinflammatory activity of IL-1. Low-dose weekly methotrexate direct comparisons of the various long-term controllers in a general
is associated with hepatotoxicity and pulmonary fibrosis.67 The population to assess clinical effectiveness and cost-effectiveness.
NAEPP has concluded that it should not be used chronic asthma.6 These studies have confirmed comparative randomized clinical trials
A number of the drugs with antiinflammatory or immunomodu- showing ICSs to be significantly more cost-effective than leukotriene
latory activity such as hydroxychloroquine, dapsone, gold, intrave- antagonists despite slightly better compliance with the leukotriene
nous γ-globulin, cyclosporine, and colchicine have been studied in antagonists.72,73 In addition, the combination of ICSs/LABA lowers
severe steroid-dependent asthma with mixed and limited results.6,68 healthcare use and total healthcare costs compared with the combi-
Routine use is not recommended.6 nation of a leukotriene antagonist and an ICS.74

■ FUTURE THERAPIES
Agents that are now in development for asthma focus on the treatment CLINICAL CONTROVERSY
of allergic inflammation.68,69 Examples include inhibitors of eosino- The potential for chronic use of inhaled β2-agonists to worsen
philic inflammation, drugs that may inhibit allergen presentation, and asthma has been a concern for more than 30 years. Large multi-
inhibitors of TH2 cells. Multiple cytokines have been implicated in center, double-blind, placebo-controlled trials with both mild and
allergic inflammation, and several possible inhibiting approaches are moderate persistent asthma did not show that regular administra-
being explored. These range from drugs that inhibit cytokine synthesis tion of short-acting inhaled β2-agonists worsened asthma. How-
(cyclosporine A and tacrolimus), humanized blocking antibodies to ever, studies that have genotyped patients at the β-receptor
cytokines or their receptors, soluble receptors to mop up secreted suggest that homozygous Arg-16 patients (who make up approxi-
cytokines, receptor antagonists, and drugs that block the signal- mately 16% of the population) are predisposed to worsening
transduction pathways activated by cytokines.68 Specifically, human- asthma with regular administration as measured by lower morn-
ized monoclonal antibodies to IL-5 and nebulized soluble IL-4 recep- ing PEFs.58 This phenomenon does not appear to occur with as-
tors have been tested but have been disappointing to date.68,69 needed therapy with short-acting β2-agonists. It is yet unknown if
regular treatment with LABAs produces similar effects as retro-
spective analyses have not shown worsening of asthma or whether
PHARMACOECONOMIC CONSIDERATIONS concurrent use of ICS is protective. These patients still respond
acutely to the β2-agonists, so whether they should avoid all β2-
Of the estimated $11.5 billion cost of asthma in the United States in
agonists is speculative. Because the regular use of short-acting
2004, direct medical expenditure accounted for 60% of the total,
inhaled β2-agonists does not improve control of symptoms, they
with emergency care (emergency department and inpatient hospital
should be used only as needed for symptoms.6,58
care) reaching $2.5 billion.3 A cost-of-illness approach takes in all
 491
much as possible, the patient’s life and prevent chronic irreversible
EVALUATION OF ASTHMA CONTROL lung changes. Drugs are the mainstay of asthma therapy. The goal

CHAPTER 28
of drug therapy is to use the minimum amount of medications
Control of asthma is defined as reducing both impairment and risk
possible to completely control the disease. In chronic asthma,
domains. The stepwise approach to therapy should be used to
therapy should be aimed at both bronchospasm and inflammation
achieve and maintain this control. Figure 28–8 outlines the steps of
so as to produce the best results. Patients should be followed and
care appropriate to the three age ranges of asthma. Depending on
monitored diligently for toxicities. Although death from asthma is
the severity of the patient’s asthma, compromises from the ideal
an uncommon event, the most common cause of death is underas-
control are made, and the best possible outcome, balancing disease
sessment of the severity of obstruction either by the patient or by the
control and possible adverse effects from the drugs, is attempted.
clinician; the next common cause is undertreatment. A cornerstone
Regular followup contact is essential (at 1- to 6-month intervals,

Asthma
of any therapy is education and the realization that most asthma
depending on control). A 3-month interval of well-controlled
deaths are avoidable.
asthma should be considered if a step-down is anticipated.
Components of evaluations control include symptoms, nighttime
awakenings, interference with normal activities, pulmonary func- ABBREVIATIONS
tion, quality of life, exacerbations, adherence, treatment-related
adverse effects, and satisfaction with care. The categories of well- Arg: arginine
controlled, not well-controlled, and very poorly controlled are BHR: bronchial hyperresponsiveness
recommended.6 Validated questionnaires such as the Asthma Ther-
apy Assessment Questionnaire (ATAQ), the Asthma Control Ques- cAMP: cyclic adenosine monophosphate
tionnaire (ACQ), and the Asthma Control Test (ACT) can be CYP: cytochrome P450
regularly administered. The NAEPP minimally recommends spiro- DPI: dry-powder inhaler
metric tests at initial assessment, after treatment is initiated, and
EIB: exercise-induced bronchospasm
then every 1 to 2 years. In moderate to severe persistent asthma,
peak-flow monitoring is recommended. Peak flow monitoring FeNO: fraction of exhaled nitric oxide
should also be considered for patients who are poor symptom FEV1: forced expiratory volume in 1 second
perceivers and for those with a history of severe exacerbations.
Gln: glutamine
Patients also should be asked about exercise tolerance. All patients
on inhaled drugs should have their inhalation delivery technique Glu: glutamic acid
evaluated periodically—monthly initially, and then every 3 to 6 Gly: glycine
months. Before step-up in therapy, adherence, environmental con- GM-CSF: granulocyte-macrophage colony-stimulating factor
trol, and comorbid conditions should be reviewed.
HFA: hydrofluoroalkane
Following initiation of antiinflammatory therapy or an increase in
dosage, most patients should begin experiencing a decrease in ICAM-1: intercellular adhesion molecule 1
symptoms in 1 to 2 weeks and achieve maximum symptomatic ICS: inhaled corticosteroids
improvement within 4 to 8 weeks. The use of higher doses or more IgE: immunoglobulin E
potent ICS agents may accelerate the process. Improvement in FEV1
and PEF should follow a similar time frame; however, a decrease in IL: interleukin
BHR, as measured by morning PEF, PEF variability, and exercise LABA: long-acting β-agonists
tolerance, may take longer and improve over 1 to 3 months.2 Patients LT: leukotriene
should be informed that following a viral respiratory infection, they
MDI: metered-dose inhaler
may experience increased exercise intolerance for up to 4 weeks.
Initial visits with the patient should focus on the patient’s MMAD: mass median aerodynamic diameter
concerns, expectations, and goals of treatment. Basic education NAEPP: National Asthma Education and Prevention Program
should focus on asthma as a chronic lung disease, the types of NANC: nonadrenergic, noncholinergic
medications, and how they are to be used. Inhaler technique is
NO: nitric oxide
taught, as is when to seek medical advice. Written action plans
should be provided. Either peak-flow-based or symptom-based self- PEF: peak expiratory flow
monitoring can be effective, if taught and followed correctly.6 The VCAM-1: vascular cell adhesion molecule 1
first followup visit should be in 2 to 6 weeks, to evaluate control. At
that time, the educational messages of the first visit should be
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58. Kelly HW. Risk versus benefit considerations for the β2-agonists. 67. Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent
Pharmacotherapy 2006;26:164S–174S. for asthma in adults. Cochrane Database Syst Rev 2000(2):CD000391.

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59. Bisgaard H. Effect of long-acting β2-agonists on exacerbation rates of 68. Barnes PJ. New directions in allergic diseases: Mechanism based anti-
asthma in children. Pediatr Pulmonol 2003;36:391–398. inflammatory therapies. J Allergy Clin Immunol 2000;106:5–16.
60. Blake K. Theophylline. In: Murphy SA, Kelly HW, eds. Pediatric 69. Hendeles L, Asmus M, Chesrown S. Evaluation of cytokine modulators
Asthma. New York: Marcel Dekker, 1999:363–431. for asthma. Paediatr Respir Rev 2003;4(Suppl 1):S105–S110.
61. Lowery M, Kelly KJ. Cromolyn and nedocromil. In: Li JT, ed. Pharma- 70. National Asthma Education and Prevention Program. Task force
cotherapy of Asthma. New York: Taylor and Francis, 2006:195–231. report on the cost effectiveness, quality of care, and financing of
62. Sorkness CA. Leukotriene receptor antagonists in the treatment of asthma care. Am J Respir Crit Care Med 1996;154(Suppl):S81–
asthma. Pharmacotherapy 2001;21:34S–37S. S130.
63. Drazen JM, Israel E, O’Byrne PM. Treatment of asthma with drugs 71. Donahue JG, Weiss ST, Livingston JM, et al. Inhaled steroids and the

Asthma
modifying the leukotriene pathway. N Engl J Med 1999;340:197–206. risk of hospitalization for asthma. JAMA 1997;277:887–891.
64. Busse W, Raphael GD, Galant S, et al. Low-dose fluticasone propionate 72. Stempel DA, Meyer JW, Stanford RH, Yancey SW. One-year claims
compared with montelukast for first-line treatment of persistent asthma: analysis comparing inhaled fluticasone propionate with zafirlukast for
A randomized clinical trial. J Allergy Clin Immunol 2001;107:461–468. the treatment of asthma. J Allergy Clin Immunol 2001;107:94–98.
65. Sorkness CA, Lemanske RF Jr, Mauger DT, et al. Long-term compari- 73. Stempel DA, Mauskopf J, McLaughlin T, et al. Comparison of asthma
son of 3 controller regimens for mild-moderate persistent childhood costs in patients starting fluticasone propionate compared to patients
asthma. The Pediatric Asthma Controller Trial. J Allergy Clin Immu- starting montelukast. Respir Med 2001;95:227–234.
nol 2007;119(1):64–72. 74. Stempel DA, O’Donnell JC, Meyer JW. Inhaled corticosteroids plus
66. Strunk RC, Bloomberg GR. Omalizumab for asthma. N Engl J Med salmeterol or montelukast: Effects on resource utilization and costs. J
2006;354:2689–2695. Allergy Clin Immunol 2002;109:433–439.
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 495

C HAP T E R

29 Chronic Obstructive
Pulmonary Disease

DENNIS M. WILLIAMS AND SHARYA V. BOURDET

COPD and frequent exacerbations may benefit from inhaled

KEY CONCEPTS corticosteroids.

 Chronic obstructive pulmonary disease (COPD) is a progres-  Acute exacerbations of COPD have a significant impact on dis-
sive disease characterized by airflow limitation that is not fully ease progression and mortality. Treatment of acute exacerba-
reversible and is associated with an abnormal inflammatory re- tions includes intensification of bronchodilator therapy and a
sponse of the lungs to noxious particles or gases. short course of systemic corticosteroids.

 COPD is historically described as either chronic bronchitis or  Antimicrobial therapy should be used during acute exacerba-
emphysema. Chronic bronchitis is defined in clinical terms, tions of COPD if the patient exhibits at least two of the following:
whereas emphysema is defined in terms of anatomic patholo- increased dyspnea, increased sputum volume, and increased
gy. Because most patients exhibit some features of each dis- sputum purulence.
ease, the appropriate emphasis of COPD pathophysiology is
on small airway disease and parenchymal damage that contrib-
utes to chronic airflow limitation. Chronic obstructive pulmonary disease (COPD) is a common chronic
disease of the airways characterized by the gradual and progressive loss
 Mortality from COPD has increased steadily over the past three
of lung function. The prevalence and mortality of COPD have
decades; it currently is the fourth leading cause of death in the
increased substantially over the past two decades. Currently, COPD is
United States.
the fourth leading cause of death in the United States.
 The primary cause of COPD is cigarette smoking. Other risks in- Although national guidelines for COPD management have been
clude a genetic predisposition, environmental exposures (in- available for nearly two decades, questions were raised concerning
cluding occupational dusts and chemicals), and air pollution. their quality and supporting evidence. To standardize the care of
patients with COPD and present evidence-based recommendations,
 Smoking cessation is the only management strategy proven to the National Heart, Lung, and Blood Institute and the World Health
slow progression of COPD. Organization launched the Global Initiative for Chronic Obstruc-
 Oxygen therapy has been shown to reduce mortality in select- tive Lung Disease (GOLD) in 2001.1 This report was updated most
ed patients with COPD. Oxygen therapy is indicated for pa- recently in 2006. The goals of the GOLD organization are to increase
tients with a resting PaO2 (partial pressure alveolar oxygen) of awareness of COPD and reduce morbidity and mortality associated
less than 55 mm Hg or a PaO2 of less than 60 mm Hg and with the disease. International guidelines have also been developed
evidence of right-sided heart failure, polycythemia, or impaired through a collaborative effort of the American Thoracic Society and
neurologic function. the European Respiratory Society and are widely available.2 These
two guidelines are generally concordant in their recommendations.
 Bronchodilators represent the mainstay of drug therapy for  A consensus definition recognizes COPD as a disease character-
COPD. Pharmacotherapy is used to relieve patient symptoms ized by airflow limitation that is not fully reversible. The airflow
and improve quality of life. Guidelines recommend short-acting limitation is usually both progressive and associated with an abnor-
bronchodilators as initial therapy for patients with mild or inter- mal inflammatory response of the lungs to noxious particles or gases.2
mittent symptoms Although COPD primarily affects the lungs, it also is associated with
For the patient who experiences chronic symptoms, long- significant consequences. Finally, COPD is preventable and treatable.
acting bronchodilators are appropriate. Either a β2-agonist or For many years, clinicians and researchers have exhibited a nihilis-
an anticholinergic offers significant benefits. Combining long- tic attitude toward the value of treatments for COPD. This was based
acting bronchodilators is recommended if necessary despite on the paucity of effective therapies, the destructive nature of the
limited data. condition, and the fact that the common etiology is cigarette smok-
ing, a modifiable health risk. Currently, there is renewed interest in

The role of inhaled corticosteroid therapy in COPD is controver- evaluating the value of treatments and prevention based on the
sial. International guidelines suggest that patients with severe availability of new therapeutic options for pharmacotherapy and
guidelines based on evidence.3 Support for renewed optimism is also
reflected in the availability of research funding to improve under-
Learning objectives, review questions, standing about this disease and its management. This includes
and other resources can be found at National Heart, Lung, and Blood Institute funding of Specialized
www.pharmacotherapyonline.com. Centers of Clinically Oriented Research programs in COPD, whose
objective is to promote multidisciplinary research on clinically rele-

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 496
vant questions enabling basic science findings to be more rapidly States.8 It is the only leading cause of death to increase over the last
applied to clinical problems.4 30 years and is projected to be the third leading cause by 2020.9
SECTION 3

 The most common conditions comprising COPD are chronic Overall, the mortality rate is higher in males; however, the female
bronchitis and emphysema. Chronic bronchitis is associated with death rate has doubled over the last 25 years, and the number of
chronic or recurrent excessive mucus secretion into the bronchial female deaths has exceeded male deaths since 2000. The mortality
tree with cough that is present on most days for at least 3 months of rate is higher in whites than in blacks.9
the year for at least 2 consecutive years in a patient in whom other Cigarette smoking is the primary cause of COPD and although
causes of chronic cough have been excluded.2 Although chronic the prevalence of cigarette smoking has declined compared with
bronchitis is defined in clinical terms, emphysema is defined in 1965, approximately 25% of individuals in the United States cur-
terms of anatomic pathology. Emphysema historically was defined rently smoke. The trend of increasing COPD mortality likely reflects
Respiratory Disorders

on histologic examination at autopsy. Because this histologic defini- the long latency period between smoking exposure and complica-
tion is of limited clinical value, emphysema also has been defined as tions associated with COPD.
abnormal permanent enlargement of the airspaces distal to the Although the mortality of COPD is significant, morbidity associated
terminal bronchioles accompanied by destruction of their walls yet with the disease also has a significant impact on patients, their families,
without obvious fibrosis.2 and the healthcare system. COPD represents the second leading cause
Current guidelines have moved away from chronic bronchitis and of disability in the United States. In the last 20 years, COPD has been
emphysema as descriptive subsets of COPD. This is based on the responsible for nearly 50 million hospital visits nationwide.10 In recent
observation that the majority of COPD is caused by a common risk years, a diagnosis of COPD accounts for more than 15 million
factor (cigarette smoking), and most patients exhibit features of both physician office visits, 1.5 million emergency room visits, and 700,000
chronic bronchitis and emphysema. Therefore, emphasis is currently hospitalizations annually. A survey by the American Lung Association
placed on the pathophysiologic features of small airways disease and revealed that among COPD patients, 51% reported that their condi-
parenchymal destruction as contributors to chronic airflow limitation. tion limits their ability to work, 70% were limited in normal physical
Most patients with COPD demonstrate features of both problems. activity, 56% were limited in performing household chores, and 50%
Chronic inflammation affects the integrity of the airways and causes reported that sleep was affected adversely.11
damage and destruction of the parenchymal structures. The underly- The economic impact of COPD continues to increase as well. It
ing problem is persistent exposure to noxious particles or gases that was estimated at $23 billion in 2000 and rose to $37.2 billion in 2004,
sustain the inflammatory response. The airways of the lung and the including $20.9 billion in direct costs and $16.3 billion in indirect
parenchyma are both susceptible to inflammation and the result is morbidity and mortality costs.9,12 By 2020, COPD will be the fifth
chronic airflow limitation that characterizes COPD (Fig. 29–1). most burdensome disease, as measured by disability-adjusted life
years lost as a consequence of illness.

EPIDEMIOLOGY
ETIOLOGY
The true prevalence of COPD is likely underreported. Data from the
National Health Interview Survey in 2001 indicate that 12.1 million  Although cigarette smoking is the primary modifiable risk factor
people older than age 25 years in the United States have COPD.5 for the development of COPD, the disease can be attributed to a
More than 9 million of these individuals have chronic bronchitis; combination of risk factors that results in lung injury and tissue
the remainder have emphysema or a combination of both diseases. destruction. Smokers are 12 to 13 times more likely to die from COPD
According to national surveys, the true prevalence of people with than nonsmokers.13 Risk factors can be divided into host factors and
symptoms of chronic airflow obstruction may exceed 24 million.6 environmental factors (Table 29–1), and commonly, the interaction
The burden may be even greater because more than one-third of between these risks leads to expression of the disease. Host factors,
adults in the United States reported respiratory complaints compat- such as genetic predisposition, may not be modifiable but are impor-
ible with symptomatic COPD in some surveys.7 tant for identifying patients at high risk of developing the disease.
 COPD is the fourth leading cause of death in the United States, Environmental factors, such as tobacco smoke and occupational
exceeded only by cancer, heart disease, and cerebrovascular acci- dust and chemicals, are modifiable factors that, if avoided, may
dents. In 2004, COPD accounted for 123,884 deaths in the United reduce the risk of disease development. Environmental exposures
associated with COPD are particles that are inhaled by the individual
and result in inflammation and cell injury. Exposure to multiple
INFLAMMATION environmental toxins increases the risk of COPD. Thus, the total
burden of inhaled particles (e.g., cigarette smoke as well as occupa-
tional and environmental particles and pollutants) can play a signif-
icant role in the development of COPD. In such cases, it is helpful to
assess an individual’s total burden of inhaled particles. For example,
an individual who smokes and works in a textile factory has a higher
Small airway disease Parenchymal destruction total burden of inhaled particles than an individual who smokes and
Airway inflammation Loss of alveolar attachments has no occupational exposure.
Airway remodeling Decrease of elastic recoil

TABLE 29-1 Risk Factors for Development of Chronic Obstructive

Pulmonary Disease
Exposures Host Factors
AIRFLOW LIMITATION
Environmental tobacco smoke Genetic predisposition (α1-antitrypsin)
Occupational dusts and chemicals Airway hyperresponsiveness
FIGURE 29-1. Mechanisms for developing chronic airflow limitation in
Air pollution Impaired lung growth
chronic obstructive pulmonary disease. (From reference 1.)
 497
Cigarette smoking is the most common risk factor and accounts increases this risk. A small number of patients have a null, null
for 85% to 90% of cases of COPD.1 Components of tobacco smoke phenotype and are at high risk for developing emphysema because

CHAPTER 29
activate inflammatory cells, which produce and release the inflam- they produce virtually no AAT.
matory mediators characteristic of COPD. Although the risk is Patients with AAT deficiency develop COPD at an early age (20 to
lower in pipe and cigar smokers, it is still higher than in nonsmok- 50 years) primarily owing to an accelerated decline in lung function.
ers. Age of starting, total pack-years, and current smoking status are Compared with an average annual decline in forced expiratory
predictive of COPD mortality. volume in 1 second (FEV1) of 25 mL/year in healthy nonsmokers,
However, only 15% to 20% of all smokers go on to develop patients with homozygous Z deficiency have been reported to have
COPD, and not all smokers who have equivalent smoking histories declines of 54 mL/year for nonsmokers and 108 mL/year for current
develop the same degree of pulmonary impairment, suggesting that smokers. Effective diagnosis is dependent on clinical suspicion,

Chronic Obstructive Pulmonary Disease

other host and environmental factors contribute to the degree of diagnostic testing of serum concentrations, and genotype confirma-
lung dysfunction. Nevertheless, the rate of loss of lung function is tion.14 Patients developing COPD at an early age or those with a
determined primarily by smoking status and history.2 Children and strong family history of COPD should be screened for AAT defi-
spouses of smokers are also at increased risk of developing signifi- ciency. If the concentration is low, genotype testing (DNA) should be
cant pulmonary dysfunction by passive smoking, also known as performed.
environmental tobacco smoke or secondhand smoke. Two additional host factors that may influence the risk of COPD
Occupational exposures are also important risk factors for COPD include airway hyperresponsiveness and lung growth. Individuals
and, in nonindustrialized countries, may be more common than with airway hyperresponsiveness to various inhaled particles may
cigarette smoking. These exposures include dust and chemicals such have an accelerated decline in lung function compared with those
as vapors, irritants, and fumes. Reduced lung function and deaths without airway hyperresponsiveness. Additionally, individuals who
from COPD are higher for individuals who work in gold and coal do not attain maximal lung growth owing to low birth weight,
mining, in the glass or ceramic industries with exposure to silica prematurity at birth, or childhood illnesses may be at risk for COPD
dust, and in jobs that expose them to cotton dust or grain dust, in the future.1
toluene diisocyanate, or asbestos. Other occupational risk factors
include chronic exposure to open cooking or heating fires.
It is unclear whether or not air pollution alone is a significant risk PATHOPHYSIOLOGY
factor for the development of COPD in smokers and nonsmokers
with normal lung function. However, in individuals with existing COPD is characterized by chronic inflammatory changes that lead to
pulmonary dysfunction, significant air pollution worsens symp- destructive changes and the development of chronic airflow limita-
toms. As evidence for this, emergency department visits are tion. The inflammatory process is widespread and involves not only
increased during higher-intensity periods of air pollution. the airways but also extends to the pulmonary vasculature and lung
Individuals exposed to the same environmental risk factors do not parenchyma. The inflammation of COPD is often referred to as
have the same chance of developing COPD, suggesting that host neutrophilic in nature, but macrophages and CD8+ lymphocytes
factors play an important role in pathogenesis.1,2 While many not yet also play major roles.16–18 The inflammatory cells release a variety of
identified genes may influence the risk of developing COPD, the best chemical mediators, of which tumor necrosis factor-α, interleukin
documented genetic factor is a hereditary deficiency of α1-antitryp- (IL-8), and leukotriene (LT) B4 play major roles.1,19 The actions of
sin (AAT). AAT-associated emphysema is an example of a pure these cells and mediators are complementary and redundant, leading
genetic disorder inherited in an autosomal recessive pattern. Some to the widespread destructive changes. The stimulus for activation of
researchers sometimes describe inheritance as autosomal codomi- inflammatory cells and mediators is an exposure to noxious particles
nant because heterozygotes can also have decreased concentrations and gas through inhalation. The most common etiologic factor is
of AAT enzyme.14 The consequences of AAT deficiency are discussed exposure to environmental tobacco smoke, although other chronic
in Pathophysiology below as protease-antiprotease imbalance. True inhalational exposures can lead to similar inflammatory changes.
AAT deficiency accounts for less than 1% of COPD cases.2 Other processes that have been proposed to play a major role in
AAT is a 42-kDa plasma protein that is synthesized in hepato- the pathogenesis of COPD include oxidative stress and an imbal-
cytes. A primary role of AAT is to protect cells, especially those in ance between aggressive and protective defense systems in the lungs
the lung, from destruction by elastase released by neutrophils. In (proteases and antiproteases).16 These processes may be the result of
fact, AAT may be responsible for 90% of the inhibition of this ongoing inflammation or occur as a result of environmental pres-
destructive enzyme.15 In individuals with the most common allele sures and exposures (Fig. 29–2).
(M), plasma levels of AAT are approximately 20 to 50 micromolars An altered interaction between oxidants and antioxidants present
(100 to 350 mg/dL). The protective effect of AAT in the lungs is in the airways is responsible for the increased oxidative stress present
significantly diminished when plasma levels are less than 11 micro- in COPD. Increases in markers (e.g., hydrogen peroxide and nitric
molars (80 mg/dL).15 AAT is an acute-phase reactant, and the serum oxide) of oxidants are seen in the epithelial lining fluid.1 The
concentration can be quite variable. increased oxidants generated by cigarette smoke react with and
Several types of AAT deficiency have been identified and are damage various proteins and lipids, leading to cell and tissue dam-
caused by mutations in the AAT gene. Two main gene variants, S age. Oxidants also promote inflammation directly and exacerbate the
and Z, have been identified. In patients who are homozygous with protease-antiprotease imbalance by inhibiting antiprotease activity.
the S variant, AAT levels are at least 60% of those of normal The consequences of an imbalance between proteases and antipro-
individuals. These patients usually do not have an increased risk of teases in the lungs was described over 40 years ago when the heredi-
COPD compared with normal individuals. Patients with homozy- tary deficiency of the protective antiprotease AAT was discovered to
gous Z deficiency (ZZ), represent 95% of clinical cases of AAT- result in an increased risk of developing emphysema prematurely.
associated emphysema14 and have AAT levels that are 10% of those This enzyme (AAT) is responsible for inhibiting several protease
of normal individuals, whereas patients with heterozygous Z variant enzymes, including neutrophil elastase. In the presence of unopposed
(SZ) have levels closer to 40% of those of normal individuals. activity, elastase attacks elastin, a major component of alveolar walls.1
Homozygous Z patients have a higher risk of developing COPD In the inherited form of emphysema, there is an absolute defi-
than do heterozygous Z patients. A history of cigarette smoking ciency of AAT. In cigarette smoking-associated emphysema, the
 498
in the number and size of goblet cells and mucus glands. Mucus
Noxious particles secretion is increased, and ciliary motility is impaired. There is also
SECTION 3

and gases a thickening of smooth muscle and connective tissue in the airways.
Inflammation is present in central and peripheral airways. The
chronic inflammation results in a repeated injury and repair process
that leads to scarring and fibrosis. Diffuse airway narrowing is
present and is more prominent in smaller peripheral airways. The
Lung inflammation
decrease in FEV1 is attributed to the presence of inflammation in the
Antioxidants Antiproteinases airways while the blood gas abnormalities result from impaired gas
transfer due to parenchymal damage.
Respiratory Disorders

Parenchymal changes affect the gas-exchanging units of the

lungs, including the alveoli and pulmonary capillaries. The distribu-
Oxidative stress Proteinases tion of destructive changes varies depending on the etiology. Most
commonly, smoking-related disease results in centrilobular emphy-
sema that primarily affects respiratory bronchioles. Panlobular
emphysema is seen in AAT deficiency and extends to the alveolar
Repair mechanisms ducts and sacs.
The vascular changes of COPD include a thickening of pulmo-
nary vessels and often are present early in the disease. Increased
COPD pathology
pulmonary pressures early in the disease are caused by hypoxic
vasoconstriction of pulmonary arteries. If persistent, the presence of
FIGURE 29-2. Pathogenesis of chronic obstructive pulmonary disease chronic inflammation may lead to endothelial dysfunction of the
(COPD). (From reference 1.) pulmonary arteries. Later, structural changes lead to an increase in
pulmonary pressures, especially during exercise. In severe COPD,
imbalance is likely associated with increased protease activity or secondary pulmonary hypertension leads to the development of
reduced activity of antiproteases. Activated inflammatory cells right-sided heart failure.
release several proteases other than AAT, including cathepsins and Mucus hypersecretion is present early in the course of the disease
metalloproteinases. In addition, oxidative stress reduces antipro- and is associated with an increased number and size of mucus-
tease (or protective) activity. producing cells. The presence of chronic inflammation perpetuates
It is helpful to differentiate inflammation occurring in COPD the process, although the resulting airflow obstruction and chronic
from that present in asthma because the response to antiinflamma- airflow limitation may be reversible or irreversible. Table 29–3
tory therapy differs. The inflammatory cells that predominate differ summarizes the various causes of airflow obstruction.
between the two conditions, with neutrophils playing a major role Recently, there has been interest in the role of thoracic overinfla-
in COPD and eosinophils and mast cells in asthma. Mediators of tion as it relates to the pathophysiology of COPD. Chronic airflow
inflammation also differ with LTB4, IL-8, and tumor necrosis obstruction leads to air trapping which results in thoracic hyperinfla-
factor-α predominating in COPD, compared with LTD4, IL-4, and tion that can be detected on chest radiograph. This problem results
IL-5 among the numerous mediators modulating inflammation in in several dynamic changes in the chest, including flattening of
asthma.1 Table 29–2 summarizes the characteristics of inflamma- diaphragmatic muscles. Under normal circumstances, the dia-
tion for the two diseases. phragms are dome-shaped muscles tethered at the base of the lungs.
Pathologic changes of COPD are widespread, affecting large and When the diaphragm contracts, the muscle becomes shorter and
small airways, lung parenchyma, and the pulmonary vasculature.1 flatter, which creates the negative inspiratory force through which air
An inflammatory exudate is often present that leads to an increase flows into the lung during inspiration. In the presence of thoracic
hyperinflation, the diaphragmatic muscle is placed at a disadvantage
and is a less-efficient muscle of ventilation. The increased work
TABLE 29-2 Features of Inflammation in Chronic Obstructive required by diaphragmatic contractions predisposes the patient to
Pulmonary Disease (COPD) Compared with Asthma muscle fatigue especially during periods of exacerbations.
COPD Asthma The other consequence of thoracic hyperinflation is a change in
Cells Neutrophils Eosinophils
lung volumes. In patients with COPD who exhibit thoracic hyperin-
Large increase in Small increase in macrophages flation there is an increase in the functional residual capacity which
macrophages is the amount of air left in the lung after exhalation at rest. Therefore,
Increase in CD8+ T Increase in CD4+ TH2 these patients are breathing at higher lung volumes which perturbs
lymphocytes lymphocytes gas exchange. In addition, the increased functional residual capacity
Activation of mast cells limits the inspiratory reserve capacity which is the amount of air that
Mediators LTB4 LTD4
IL-8 IL-4, IL-5
TNF-α (Plus many others) TABLE 29-3 Etiology of Airflow Limitation in Chronic Obstructive
Consequences Squamous metaplasia of Fragile epithelium Pulmonary Disease
epithelium
Parenchymal destruction Thickening of basement mem- Reversible
brane Presence of mucus and inflammatory cells and mediators in bronchial secretions
Mucus metaplasia Mucus metaplasia Bronchial smooth muscle contraction in peripheral and central airways
Glandular enlargement Glandular enlargement Dynamic hyperinflation during exercise
Response to Glucocorticosteroids have Glucocorticosteroids inhibit Irreversible
treatment variable effect inflammation Fibrosis and narrowing of airways
Reduced elastic recoil with loss of alveolar surface area
IL, interleukin; LT, leukotriene; TH, T-helper; TNF, tumor necrosis factor. Destruction of alveolar support with reduced patency of small airways
From reference 1.
 499
the patient can inhale to fill the lungs. The increased functional ated with ischemia, cachexia, and muscle wasting. There is some
residual capacity also limits the duration of inhalation time and this interest in the role of measuring C-reactive protein as a parameter to

CHAPTER 29
has been associated with an increase in dyspnea complaints by assess systemic inflammation and its impact on COPD severity;
patients.20 Drug therapy for COPD, especially bronchodilators, can however, it is premature to recommend this strategy currently.23
reduce thoracic hyperinflation by reducing airflow obstruction. This
may partially explain the improvement in symptoms reported by
patients with COPD despite minimal improvements in lung func- PATHOPHYSIOLOGY OF EXACERBATION
tion with drug therapy.
The natural history of COPD is characterized by recurrent exacerba-
Airflow limitation is assessed through spirometry, which repre-
tions associated with increased symptoms and a decline in overall
sents the “gold standard” for diagnosing and monitoring COPD.
health status. An exacerbation is defined as a change in the patient’s

Chronic Obstructive Pulmonary Disease

The hallmark of COPD is a reduction in the ratio of FEV1 to forced
baseline symptoms (dyspnea, cough, or sputum production) beyond
vital capacity (FVC) to less than 70%.1,2 The FEV1 generally is
day-to-day variability sufficient to warrant a change in manage-
reduced, except in very mild disease, and the rate of FEV1 decline is
ment.1,2 Exacerbations have a significant impact on the natural
greater in COPD patients compared with normal subjects.
course of COPD and occur more frequently in patients with more
The impact of the numerous pathologic changes in the lung
severe chronic disease. Because many patients experience chronic
perturbs the normal gas-exchange and protective functions of the
symptoms, the diagnosis of an exacerbation is based, in part, on
lung. Ultimately, these are exhibited through the common symp-
subjective measures and clinical judgment. Repeated exacerbations,
toms of COPD, including dyspnea and a chronic cough productive
especially those requiring hospitalization, are associated with an
of sputum. As the disease progresses, abnormalities in gas exchange
increased mortality risk.
lead to hypoxemia and/or hypercapnia; although there often is not
There are limited data about pathology during exacerbations
a strong relationship between pulmonary function and arterial
owing to the nature of the disease and the condition of patients;
blood gas results.
however, inflammatory mediators including neutrophils and eosin-
Significant changes in arterial blood gases usually are not present
ophils are increased in the sputum. Chronic airflow limitation is a
until the FEV1 is less than 1 L.1 In these patients, hypoxemia and
feature of COPD and may not change remarkably even during an
hypercapnia can become chronic problems. Initially, when hypox-
exacerbation.1 The lung hyperinflation present chronic COPD is
emia is present, it usually is associated with exercise. However, as the
worsened during an exacerbation which contributes to worsening
disease progresses, hypoxemia at rest develops. Patients with severe
dyspnea and poor gas exchange.
COPD can have a low arterial oxygen tension (PaO2 = 45 to 60 mm
The primary physiologic change is often a worsening of arterial
Hg) and an elevated arterial carbon dioxide tension (PaCO2 = 50 to
• blood gas results owing to poor gas exchange and increased muscle
60 mm Hg). The hypoxemia is attributed to hypoventilation (V) of
• • • fatigue. In a patient experiencing a severe exacerbation, profound
lung tissue relative to perfusion (Q) of the area. This low V/Q ratio
hypoxemia and hypercapnia can be accompanied by respiratory
will progress over a period of several years, resulting in a consistent
acidosis and respiratory failure.
decline in the PaO2. Some COPD patients lose the ability to increase
the rate or depth of respiration in response to persistent hypercapnia.
Although this is not completely understood, the decreased ventila- CLINICAL PRESENTATION
tory drive may be a result of abnormal peripheral or central respira-
tory receptors responses. This relative hypoventilation subsequently The diagnosis of COPD is made based on the patient’s symptoms,
leads to hypercapnia. In this case, the central respiratory response to including cough, sputum production, and dyspnea, and a history of
a chronically increased PaCO2 can be blunted. These changes in PaO2 exposure to risk factors such as tobacco smoke and occupational
and PaCO2 are subtle and progress over a period of many years; as a exposures. Patients may have these symptoms for several years
result, the pH usually is nearly normal because the kidneys compen- before dyspnea develops and often will not seek medical attention
sate by retaining bicarbonate. If acute respiratory distress develops, until dyspnea is significant. A diagnosis of COPD should be consid-
such as might be seen in pneumonia or a COPD exacerbation with ered in any patient who presents with chronic cough, sputum
impending respiratory failure, the PaCO2 may rise sharply, and the production, or dyspnea and who has risk factors for the disease.
patient presents with an uncompensated respiratory acidosis. The presence of airflow limitation should be confirmed with
The consequences of long-standing COPD and chronic hypox- spirometry. Spirometry represents a comprehensive assessment of
emia include the development of secondary pulmonary hyperten- lung volumes and capacities. The hallmark of COPD is an FEV1:FVC
sion that progresses slowly if appropriate treatment of COPD is not ratio of less than 70%, which indicates airway obstruction, and a
initiated. Pulmonary hypertension is the most common cardiovas- postbronchodilator FEV1 of less than 80% of predicted confirms the
cular complication of COPD and can result in cor pulmonale, or presence of airflow limitation that is not fully reversible.1 An improve-
right-sided heart failure.21 ment in FEV1 of less than 12% following inhalation of a rapid-acting
The elevated pulmonary artery pressures are attributed to vaso- bronchodilator is considered to be evidence of irreversible airflow
constriction (in response to chronic hypoxemia), vascular remodel- obstruction. Reversibility of airflow limitation is measured by a
ing, and loss of pulmonary capillary beds. If elevated pulmonary bronchodilator challenge, which is described in Table 29–4. Although
pressures are sustained, cor pulmonale can develop, characterized a low peak expiratory flow is consistent with COPD, the use of peak
by hypertrophy of the right ventricle in response to increases in expiratory flow measurements is inadequate for the diagnosis of
pulmonary vascular resistance. COPD owing to low specificity and the high degree of effort depen-
The risks of cor pulmonale include venous stasis with the poten- dence. Chapter 27 has a comprehensive discussion of spirometry.
tial for thrombosis and pulmonary embolism. Another important Spirometry combined with a physical examination improves the
systemic consequence of COPD is a loss of skeletal muscle mass and diagnostic accuracy of COPD.7 Spirometry is also used to determine
general decline in the overall health status. the severity of the disease, along with an assessment of symptoms
Although airway inflammation is prominent in patients with and the presence of complications. A primary benefit of spirometry
COPD, there is also evidence of systemic inflammation.22 The sys- is to identify individuals who might benefit from pharmacotherapy
temic manifestations can have devastating effects on overall health to reduce exacerbations. Currently, the GOLD consensus guidelines
status and comorbidities. These include cardiovascular events associ- suggest a four-stage classification system (Table 29–5).
 500

TABLE 29-4 Procedures for Reversibility Testing TABLE 29-6 Modified Medical Research Council (MRC)
Dyspnea Scale
SECTION 3

Preparation
Tests should be performed when patients are clinically stable and free from Grade 0 No dyspnea Not troubled by breathlessness except with stren-
respiratory infection. uous exercise
Patients should not have taken inhaled short-acting bronchodilators in the previous Grade 1 Slight Troubled by shortness of breath when hurrying on
6 hours, long-acting β-agonists in the previous 12 hours, or sustained-release dyspnea a level surface or walking up a slight hill
theophylline in the previous 24 hours. Grade 2 Moderate Walks slower than normal based on age on a level
Spirometry dyspnea surface due to breathlessness or has to stop for
FEV1 should be measured before bronchodilator is given. breath when walking on level surface at own pace
Bronchodilators can be given by either metered-dose inhaler or nebulization. Grade 3 Severe Stops for breath after walking 100 yards or after a
Usual doses are 400 mcg of β-agonist, up to 160 mcg of anticholinergic, or the two
Respiratory Disorders

dyspnea few minutes on a level surface

combined. Grade 4 Very severe Too breathless to leave the house or becomes
FEV1 should be measured 10–15 minutes after the β-agonist or 30–45 minutes dyspnea breathless while dressing or undressing
after combination is given.
From reference 2.
Results
An increase in FEV1 that is both greater than 200 mL and 12% above the
prebronchodilator FEV1 is considered significant. Although a physical examination is appropriate in the diagnosis
and assessment of COPD, most patients who present in the milder
FEV1, forced expiratory volume in the first second of expiration. stages of COPD will have a normal physical examination. In later
From reference 1.
stages of the disease, when airflow limitation is severe, patients may
have cyanosis of mucosal membranes, development of “barrel
The 2006 GOLD guidelines were modified to remove the stage 0 chest” because of hyperinflation of the lungs, an increased respira-
category for COPD classification. Patients at risk (stage 0) have tory rate and shallow breathing, and changes in breathing mechan-
normal spirometry but experience chronic symptoms of cough or ics such as pursing of the lips to help with expiration or use of
sputum production and a history of exposure to risk factors. This accessory respiratory muscles.
change was made because of inadequate evidence to identify patients
who might progress to stage 1 disease. Patients in the remaining four CLINICAL PRESENTATION
stages of classification all exhibit the hallmark finding of airflow
Symptoms
obstruction, that is, a reduction in the FEV1:FVC ratio to less than
70%. FVC is the total amount of air exhaled after a maximal ■ Chronic cough
inhalation. The extent of reduction in FEV1 further defines the ■ Sputum production
patient with mild, moderate, severe, or very severe disease.1 ■ Dyspnea
Spirometry is the primary tool in classifying COPD according to
severity. However, two other factors that influence disease severity, Exposure to Risk Factors
survival, and health-related quality are life are body mass index ■ Tobacco smoke
(BMI) and dyspnea.2 A low BMI is a systemic consequence of ■ α1-Antitrypsin deficiency
chronic COPD and a BMI of less than 21 kg/m2 is associated with
■ Occupational hazards
increased mortality.24
Dyspnea is often the most troublesome complaint for the patient Physical Examination
with COPD. Dyspnea can impair exercise performance and func- ■ Cyanosis of mucosal membranes
tional capacity and is frequently associated with depression and ■ Barrel chest
anxiety. Together, these have a significant effect on health related
■ Increased resting respiratory rate
quality of life.20 As a subjective symptom, dyspnea is often difficult
for the clinician to assess. Various tools are available to evaluate the ■ Shallow breathing
severity of dyspnea. A version of the Medical Research Council scale, ■ Pursed lips during expiration
modified by the American Thoracic Society, is commonly employed ■ Use of accessory respiratory muscles
and categorizes dyspnea grades from 0 to 4 (Table 29–6).25
Diagnostic Tests
TABLE 29-5 Classification of Chronic Obstructive Pulmonary ■ Spirometry with reversibility testing
Disease Severity ■ Radiograph of chest
Stage I: mild ■ Arterial blood gas (not routine)
FEV1 /FVC <70%
FEV1 ≥ 80%
With or without symptoms FEATURES OF CHRONIC OBSTRUCTIVE
Stage II: moderate PULMONARY DISEASE EXACERBATION
FEV1 /FVC <70%
50% <FEV1 <80%
Symptoms
With or without symptoms ■ Increased sputum volume
Stage III: severe ■ Acutely worsening dyspnea
FEV1 /FVC <70%
30% <FEV1 <50% ■ Chest tightness
With or without symptoms ■ Presence of purulent sputum
Stage IV: very severe
■ Increased need for bronchodilators
FEV1 /FVC <70%
FEV1 <30% or <50% with presence of chronic respiratory failure or right heart failure ■ Malaise, fatigue
FEV1, forced expiratory volume in the first second of expiration; FVC, forced vital capacity. ■ Decreased exercise tolerance
From reference 1.
 501

Physical Examination TABLE 29-7 Staging Acute Exacerbations of Chronic Obstructive

Pulmonary Diseasea

CHAPTER 29
■ Fever
■ Wheezing, decreased breath sounds Mild (type 1) One cardinal symptoma plus at least one of the following:
URTI within 5 days, fever without other explanation,
Diagnostic Tests increased wheezing, increased cough, increase in respira-
■ Sputum sample for Gram stain and culture tory or heart rate >20% above baseline
Moderate (type 2) Two cardinal symptomsa
■ Chest radiograph to evaluate for new infiltrates
Severe (type 3) Three cardinal symptomsa

PROGNOSIS URTI, upper respiratory tract infection.

a
Cardinal symptoms include worsening of dyspnea, increase in sputum volume, and increase in

Chronic Obstructive Pulmonary Disease

sputum purulence.
For the patient with COPD, the combination of impaired lung
function and recurrent exacerbations promote a clinical scenario
are commonly staged as mild, moderate, or severe according to the
characterized by dyspnea, reduced exercise tolerance and physical
criteria summarized in Table 29–7.31
activity, and deconditioning. These factors lead to disease progres-
An important complication of a severe exacerbation is acute
sion, poor quality of life, possible disability, and premature mortal-
respiratory failure. In the emergency department or hospital, an ABG
ity.26 COPD is ultimately a fatal disease if it progresses and advanced
usually is obtained to assess the severity of an exacerbation. The
directives and end-of-life care options are appropriate to consider.
diagnosis of acute respiratory failure in COPD is made on the basis
The FEV1 is the most important prognostic indicator in a patient
of an acute change in the ABGs. Defining acute respiratory failure as
with COPD. The average rate of decline of FEV1 is the most useful
a PaO2 of less than 50 mm Hg or a PaCO2 of greater than 50 mm Hg
objective measure to assess the course of COPD. The average rate of
often may be incorrect and inadequate because these values may not
decline in FEV1 for healthy, nonsmoking patients owing to age alone
represent a significant change from a patient’s baseline values. A
is 25 to 30 mL/year. The rate of decline for smokers is steeper,
more precise definition is an acute drop in PaO2 of 10 to 15 mm Hg
especially for heavy smokers compared with light smokers. The
or any acute increase in PaCO2 that decreases the serum pH to 7.3 or
decline in pulmonary function is a steady curvilinear path. The more
less. Additional acute clinical manifestations of respiratory failure
severely diminished the FEV1 at diagnosis; the steeper is the rate of
include restlessness, confusion, tachycardia, diaphoresis, cyanosis,
decline. Greater numbers of years of smoking and number of
hypotension, irregular breathing, miosis, and unconsciousness.
cigarettes smoked also correlate with a steeper decline in pulmonary
function.27 Conversely, the rate of decline of blood gases has not
been shown to be a useful parameter to assess progression of the PROGNOSIS
disease. Patients with COPD should have spirometry performed at COPD exacerbations are associated with significant morbidity and
least annually to assess disease progression. mortality. While mild exacerbations may be managed at home,
The survival rate of patients with COPD is highly correlated to mortality rates are higher for patients admitted to the hospital. In
the initial level of impairment in the FEV1 and to age. Other, less- one study of patients hospitalized with COPD exacerbations, in-
important factors include degree of reversibility with bronchodila- hospital mortality was 6% to 8%.32 Many patients experiencing an
tors, resting pulse, perceived physical disability, diffusing capacity of exacerbation do not have a return to their baseline clinical status for
lung for carbon monoxide (DLCO), cor pulmonale, and blood gas several weeks, significantly affecting their quality of life. Addition-
abnormalities. A rapid decline in pulmonary function tests indicates ally, as many as half the patients originally hospitalized for an
a poor prognosis. Median survival is approximately 10 years when exacerbation are readmitted within 6 months.33
the FEV1 is 1.4 L, 4 years when the FEV1 is 1.0 L, and about 2 years It is now evident that acute exacerbations of COPD have a
when the FEV1 is 0.5 L. tremendous impact on disease progression and ultimate mortality.
Although arterial blood gas (ABG) measurements are important, For exacerbations requiring hospitalizations, mortality rates range
they do not carry the prognostic value of pulmonary function tests. from 22% to 43% after 1 year, and 36 to 49% in 2 years.32,34,35
Measurement of ABGs is more useful in patients with severe disease
and is recommended for all patients with an FEV1 of less than 40%
of predicted or those with signs of respiratory failure or right-sided
heart failure.1 TREATMENT
It is important to recognize that patients with COPD die from a
variety of causes, not only respiratory failure. Cardiovascular com- Chronic Obstructive
plications, as well as lung cancer, are the leading causes of death in
patients with COPD.28,29
Pulmonary Disease
■ DESIRED OUTCOMES
CLINICAL PRESENTATION OF Given the nature of COPD, a major focus in healthcare should be
CHRONIC OBSTRUCTIVE PULMONARY on prevention. However, in patients with a diagnosis of COPD, the
DISEASE EXACERBATION primary goal is to prevent or minimize progression. Table 29–8 lists
specific management goals. The primary goal of pharmacotherapy
Because of the subjective nature of defining an exacerbation of COPD, has been relief of symptoms, including dyspnea. More recently,
the criteria used among clinicians varies widely; however, most rely on however, there has been increased interest in the value of therapeu-
a change in one or more of the following clinical findings: worsening tic interventions that reduce exacerbation frequency and severity, as
symptoms of dyspnea, increase in sputum volume, or increase in well as reduce mortality.
sputum purulence. Acute exacerbations have a significant impact of Optimally, these goals can be accomplished with minimal risks or
the economics of treating COPD as well, estimated at 35% to 45% of side effects. The therapy of the patient with COPD is multifaceted and
the total costs of the disease in some settings.30 includes pharmacologic and nonpharmacologic strategies. Appropri-
With an exacerbation, patients using rapid-acting bronchodila- ate measures of effectiveness of the management plan include contin-
tors may report an increase in the frequency of use. Exacerbations ued smoking cessation, symptom improvement, reduction in FEV1
 502

TABLE 29-8 Goals of Chronic Obstructive Pulmonary intervention. During an 11-year followup, the rate of decline in
Disease Management FEV1 among subjects who continued to smoke was more than twice
SECTION 3

the rate in sustained quitters. Smokers who underwent smoking-

Prevent disease progression
cessation intervention had fewer respiratory symptoms and a
Relieve symptoms
smaller annual decline in FEV1 compared with smokers who had no
Improve exercise tolerance
Improve overall health status intervention. However, this study also demonstrated the difficulty
Prevent and treat exacerbations in achieving and sustaining successful smoking cessation.
Prevent and treat complications Tobacco cessation has mortality benefits beyond those related to
Reduce morbidity and mortality COPD. A followup analysis of the Lung Health Study data con-
ducted more than 14 years later demonstrated an 18% reduction in
Respiratory Disorders

all-cause mortality in patients who received the intervention com-

decline, reduction in the number of exacerbations, improvements in pared to usual care.29 Intervention patients had lower death rates as
physical and psychological well-being, and reduction in mortality, a consequence of coronary artery disease (the leading cause of
hospitalizations, and days lost from work. mortality), cardiovascular diseases, and lung cancer, although no
Unfortunately, most treatments for COPD have not been shown category reached clinical significance.
to improve survival or to slow the progressive decline in lung Every clinician has a responsibility to assist smokers in smoking-
function. However, many therapies do improve pulmonary func- cessation efforts. A clinical practice guideline for treating tobacco
tion and quality of life and reduce exacerbations and duration of dependence from the U.S. Public Health Service was updated in
hospitalization. Several disease-specific quality-of-life measures are 2000.38 Table 29–9 summarizes the major findings and recommen-
available to assess the overall efficacies of therapies for COPD, dations of that report. In 2004, a report from the Surgeon General
including the Chronic Respiratory Questionnaire and the St. on the health consequences of smoking broadened the scope of the
George’s Respiratory Questionnaire. These questionnaires measure detrimental effects of cigarette smoking, indicating that “Smoking
the impact of various therapies on such disease variables as severity harms nearly every organ of the body, causing many diseases and
of dyspnea and level of activity; they do not measure impact of reducing the health of smokers in general.”13
therapies on survival. Whereas early studies of COPD therapies All clinicians should take an active role in assisting patients with
focused primarily on improvements in pulmonary function mea- tobacco dependence in order to reduce the burden on the individual,
surements such as FEV1, there is a trend toward greater use of these the individual’s family, and the healthcare system. It is estimated that
disease-specific quality-of-life measures to evaluate the benefits of more than 75% of smokers want to quit and that one-third have
therapy on larger clinical outcomes. made a serious effort. Yet complete and permanent tobacco cessation
is difficult.28 Counseling that is provided by clinicians is associated
■ GENERAL APPROACH TO TREATMENT with greater success rates than self-initiated efforts.38
The U.S. Public Health Service guidelines recommend that clini-
To be effective, the clinician should address four primary compo- cians take a comprehensive approach to smoking-cessation counsel-
nents of management: assess and monitor the condition; avoidance ing. Advice should be given to smokers even if they have no
of or reduced exposure to risk factors; manage stable disease; and symptoms of smoking-related disease or if they are receiving care
treat exacerbations. These components are addressed through a for reasons unrelated to smoking. Clinicians should be persistent in
variety of nonpharmacologic and pharmacologic approaches. their efforts because relapse is common among smokers owing to
the chronic nature of dependence. Brief interventions (3 minutes)
■ NONPHARMACOLOGIC THERAPY of counseling are proven effective. However, it must be recognized
Patients with COPD should receive education about their disease, that the patient must be ready to stop smoking because there are
treatment plans, and strategies to slow progression and prevent com- several stages of decision making. Based on this, a five-step inter-
plications.1 Advice and counseling about smoking cessation are essen- vention program is proposed (Table 29–10).
tial, if applicable. Because the natural course of the disease leads to
respiratory failure, the clinician should address end-of-life decisions TABLE 29-9 Treating Tobacco Use and Dependence: Public
and advanced directives prospectively with the patient and family.36 Health Service Report (2000) Major Findings
and Recommendations
Smoking Cessation Tobacco dependence should be recognized as a chronic condition requiring
 A primary component of COPD management is avoidance of or repeated treatment until permanent abstinence is achieved.
reduced exposure to risk factors. Exposure to environmental Effective treatments for tobacco dependence are available and should be offered to
tobacco smoke is a major risk factor, and smoking cessation is the all tobacco users.
Clinicians and healthcare systems should ensure mechanisms to identify, document,
most effective strategy to reduce the risk of developing COPD and
and treat all tobacco users in the system.
to slow or stop disease progression. The cost-effectiveness of smoking-
Brief treatment interventions for tobacco dependence should be offered to all
cessation interventions compares favorably with interventions tobacco users at a minimum.
made for other major chronic diseases.37 The importance of smok- There is a strong dose–response relationship between the intensity of tobacco
ing cessation cannot be overemphasized. Smoking cessation leads to dependence counseling and its effectiveness.
decreased symptomatology and slows the rate of decline of pulmo- The most effective types of counseling and behavioral therapies are (a) practical
nary function even after significant abnormalities in pulmonary counseling employing problem-solving and skills training, (b) social support as
function tests have been detected (FEV1:FVC <60%).27 As con- part of treatment, and (c) social support outside of treatment.
firmed by the Lung Health Study, smoking cessation is the only Numerous pharmacotherapies are effective for smoking cessation and should be
intervention proven at this time to affect long-term decline in FEV1 offered in the absence of contraindications. These include sustained-release bupro-
and slow the progression of COPD.28 In this 5-year prospective trial, pion, nicotine gum, nicotine inhaler, nicotine nasal spray, nicotine patch, and
varenicline.
smokers with early COPD were randomly assigned to one of three
Tobacco dependence treatments are effective and cost-effective compared with
groups: smoking-cessation intervention plus inhaled ipratropium other medical and disease-prevention measures.
three times a day, smoking-cessation intervention alone, or no
 503

TABLE 29-10 Five-Step Strategy for Smoking-Cessation COPD patients, and the level of intensity improves peripheral muscle
and ventilatory function. Studies have demonstrated that pulmonary

CHAPTER 29
Program (5 A’s)
rehabilitation with exercise three to seven times per week can produce
Ask Use systematic approach to identify all tobacco users.
long-term improvement in activities of daily living, quality of life,
Advise Urge all tobacco users to quit.
exercise tolerance, and dyspnea in patients with moderate to severe
Assess Determine willingness to make a cessation attempt.
Assist Provide support for the patient to quit smoking. COPD.41 Improvements in dyspnea can be achieved without con-
Arrange Schedule followup and monitor for continued abstinence. comitant improvements in spirometry. Programs using less-intensive
exercise regimens (two times per week) are not beneficial.42
There is strong evidence to support the use of pharmacotherapy to
assist in smoking cessation. In fact, it should be offered to most Immunizations

Chronic Obstructive Pulmonary Disease

patients as part of a cessation attempt. In general, available therapies Vaccines can be considered as pharmacologic agents; however, their
will double the effectiveness of a cessation effort. Table 29–11 lists role is described here in reducing risk factors for COPD exacerba-
first-line agents. The usual duration of therapy is 8 to 12 weeks, tions. Because influenza is a common complication in COPD that
although some individuals may require longer courses of treatment. can lead to exacerbations and respiratory failure, an annual vaccina-
Precautions to consider before using bupropion include a history of tion with the inactivated intramuscular influenza vaccine is recom-
seizures or an eating disorder. Nicotine-replacement therapies are mended. Immunization against influenza can reduce serious illness
contraindicated in patients with unstable coronary artery disease, and death by 50% in COPD patients.43 Influenza vaccine should be
active peptic ulcers, or recent myocardial infarction or stroke. Nico- administered in the fall of each year (October and November)
tine patch, bupropion, and the combination of bupropion and the during regular medical visits or at vaccination clinics. There are few
nicotine patch were compared with placebo in a controlled trial.39 contraindications to influenza vaccine except for a patient with a
The treatment groups that received bupropion had higher rates of serious allergy to eggs. An oral antiinfluenza agents (oseltamivir)
smoking cessation than the groups that received placebo or the can be considered for patients with COPD during an outbreak for
nicotine patch. The addition of the nicotine patch to bupropion patients who have not been immunized; however, this therapy is less
slightly improved the smoking-cessation rate compared with bupro- effective and causes more side effects.44
pion monotherapy. Recently, a new agent became available to assist The polyvalent pneumococcal vaccine, administered one time, is
in tobacco cessation attempts. Varenicline is a nicotine acetylcholine widely recommended for people from 2 to 64 years of age who have
receptor partial agonist that has shown benefit in tobacco cessation.40 chronic lung disease and for all people older than age 65 years. Thus
Varenicline relieves physical withdrawal symptoms and reduces the COPD patients at any age are candidates for vaccination. Although
rewarding properties of nicotine. Nausea and headache are the most evidence for the benefit of the pneumococcal vaccine in COPD is not
frequent complaints associated with varenicline. Currently, vareni- strong, the argument for continued use is that the current vaccine
cline has not been studied in combination with other tobacco provides coverage for 85% of pneumococcal strains causing invasive
cessation therapies. Second-line agents, such as clonidine and disease and the increasing rate of resistance of pneumococcus to
nortriptyline, a tricyclic antidepressant, are less effective or associ- selected antibiotics. Currently, administering the vaccine remains
ated with greater side effects; however, they may be useful in selected the standard of practice and is recommended by the Centers for
clinical situations. Disease Control and Prevention and the American Lung Association.
Behavioral modification techniques or other forms of psycho- Repeated vaccination with the 23-valent product is not recom-
therapy also may be helpful in assisting in smoking cessation. mended for patients ages 2 to 64 years with chronic lung disease;
Programs that address the many issues associated with smoking however, revaccination is recommended for patients older than 65
(i.e., learned behaviors, environmental influences, and chemical years of age if the first vaccination was more than 5 years earlier and
dependence) using a team approach are more likely to be successful. the patient was younger than age 65 years. The GOLD guidelines
The role of alternative medicine therapies in smoking cessation is recommend pneumococcal vaccine for all COPD patients age 65
controversial. Hypnosis may aid in improving abstinence rates years and older and for patients younger than age 65 years only if the
when added to a smoking-cessation program but appears to give FEV1 is less than 40% of predicted.45,46
little benefit when used alone. Acupuncture has not been shown to
contribute to smoking cessation and is not recommended.2 Long-Term Oxygen Therapy
 The use of supplemental oxygen therapy increases survival in
Pulmonary Rehabilitation COPD patients with chronic hypoxemia. Although long-term oxy-
Exercise training is beneficial in the treatment of COPD to improve gen has been used for many years in patients with advanced COPD,
exercise tolerance and to reduce symptoms of dyspnea and fatigue.1 it was not until 1980 that data became available documenting its
Pulmonary rehabilitation programs are an integral component in the benefits. At that time, the Nocturnal Oxygen Therapy Trial Group
management of COPD and should include exercise training along published its data comparing nocturnal oxygen therapy (12 h/day)
with smoking cessation, breathing exercises, optimal medical treat- with continuous oxygen therapy (average of 20 h/day).47 Among
ment, psychosocial support, and health education. High-intensity patients who were followed for at least 12 months, the results
training (70% maximal workload) is possible even in advanced revealed a mortality rate in the nocturnal oxygen therapy group that

TABLE 29-11 First-Line Pharmacotherapies for Smoking Cessation

Agent Usual Dose Duration Common Complaints
Bupropion SR 150 mg orally daily for 3 days, then twice daily 12 weeks, up to 6 months Insomnia, dry mouth
Nicotine gum 2–4 mg gum prn, up to 24 pieces daily 12 weeks Sore mouth, dyspepsias
Nicotine inhaler 6–16 cartridges daily Up to 6 months Sore mouth and throat
Nicotine nasal spray 8–40 doses daily 3 to 6 months Nasal irritation
Nicotine patches Various, 7–21 mg every 24 hours Up to 8 weeks Skin reaction, insomnia
Varenicline 0.5 mg daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily 12 weeks Nausea, sleep disturbances
 504
was nearly double that of the continuous oxygen therapy group International guidelines recommend a stepwise approach to the
(51% versus 26%). Statistical estimates of the continuous oxygen use of pharmacotherapy based on disease severity,1,2 which is deter-
SECTION 3

therapy group suggest that continuous oxygen therapy may have mined by the extent of airflow limitation and degree of symptoms.
added 3.25 years to a COPD patient’s life. Additional data from the The impact of recurrent exacerbations on disease progression is
Nocturnal Oxygen Therapy Trial Group revealed that continuous increasingly recognized as an important factor and should be consid-
oxygen therapy patients had fewer (but statistically insignificant) ered. The primary goals of pharmacotherapy are to control symp-
hospitalizations, improved quality of life and neuropsychological toms (including dyspnea), reduce exacerbations, and improve
function, reduced hematocrit, and decreased pulmonary vascular exercise tolerance and health status. Currently, there is inadequate
resistance.47 evidence to support the use of more aggressive pharmacotherapy
The decline in mortality with oxygen therapy was further sub- early in the course of disease, although data from ongoing trials may
Respiratory Disorders

stantiated in 1981 in a study by the British Medical Research provide answers.

Council that compared 15 h/day of oxygen versus no supplemental  Pharmacotherapy focuses on the use of bronchodilators to
oxygen in COPD patients.48 Patients receiving oxygen therapy for at control symptoms. There are several classes of bronchodilators to
least part of the day had lower rates of mortality than those not choose from, and no single class has been proven to provide superior
receiving oxygen. Long-term oxygen therapy provides even more benefit over other available agents. The initial and subsequent choice
benefit in terms of survival after at least 5 years of use, and it of medications should be based on the specific clinical situation and
improves the quality of life of these patients by increasing walking patient characteristics. Medications can be used as needed or on a
distance and neuropsychological condition and reducing time spent scheduled basis depending on the clinical situation, and additional
in the hospital.49 Before patients are considered for long-term therapies should be added in a stepwise manner depending on the
oxygen therapy, they should be stabilized in the outpatient setting, response and severity of disease. Considerations should be given to
and pharmacotherapy should be optimized. Once this is accom- individual patient response, tolerability, adherence, and economic
plished, long-term oxygen therapy should be instituted if either of factors. A stepwise approach to the management of COPD has been
two conditions exists: (a) a resting PaO2 of less than 55 mm Hg or proposed based on the stage of disease severity (Fig. 29–3).
(b) evidence of right-sided heart failure, polycythemia, or impaired According to the guidelines, patients with intermittent symp-
neuropsychiatric function with a PaO2 of less than 60 mm Hg. toms should be treated with short-acting bronchodilators. When
The most practical means of administering long-term oxygen is symptoms become more persistent, long-acting bronchodilators
with the nasal cannula, at 1 to 2 L/min which provides 24% to 28% should be initiated. For patients with an FEV1 less than 50% and who
oxygen. The goal is to raise the PaO2 above 60 mm Hg. Patient experience frequent exacerbations, inhaled corticosteroids should be
education about flow rates and avoidance of flames (i.e., smoking) considered. Short-acting bronchodilators relieve symptoms and
is of the utmost importance. increase exercise tolerance. Long-acting bronchodilators relieve symp-
There are three different ways to deliver oxygen, including (a) in toms, reduce exacerbation frequency, and improve quality of life and
liquid reservoirs, (b) compressed into a cylinder, and (c) via an health status. Patients have a variety of choices in using inhalational
oxygen concentrator. Although conventional liquid oxygen and therapies, including metered dose inhalers (MDIs), dry powder inhal-
compressed oxygen are quite bulky, smaller, portable tanks are ers (DPIs), or nebulizers. There is not a clear advantage of one delivery
available to permit greater patient mobility. Oxygen concentrator method over another and it is recommended that patient-specific
devices separate nitrogen from room air and concentrate oxygen. factors and preferences should be considered in selecting the device.51
These are the most convenient and the least-expensive method of
oxygen delivery. Oxygen-conservation devices are available that Bronchodilators
allow oxygen to flow only during inspiration, making the supply last
Bronchodilator classes available for the treatment of COPD include
longer. These may be particularly useful to prolong the oxygen
β2-agonists, anticholinergics, and methylxanthines. There is no
supply for mobile patients using portable cylinders. However, the
clear benefit to one agent or class over others, although inhaled
devices are bulky and subject to failure.
therapy generally is preferred. In general, it can be more difficult for
patients with COPD to use inhalation devices effectively compared
Adjunctive Therapies with other populations owing to advanced age and the presence of
In addition to supplemental oxygen, adjunctive therapies to consider other comorbidities. Clinicians should advise, counsel, and observe
as part of a pulmonary rehabilitation program are psychoeducational patient technique with the devices frequently and consistently.
care and nutritional support. Psychoeducational care (such as relax- Bronchodilators generally work by reducing the tone of airway
ation) has been associated with improvement in the functioning and smooth muscle (relaxation), thus minimizing airflow limitation. In
well-being of adults with COPD.1,2 The role of nutritional support in patients with COPD, the clinical benefits of bronchodilators include
patients with COPD is controversial. Several studies have shown an increased exercise capacity, decreased air trapping in the lungs, and
association between malnutrition, low BMI, and impaired pulmo- relief of symptoms such as dyspnea. However, use of bronchodilators
nary status among patients with COPD. However, a meta-analysis may not be associated with significant improvements in pulmonary
suggests that the effect of nutritional support on outcomes in COPD function measurements such as FEV1. In general, side effects of
is small and not associated with improved anthropometric measures, bronchodilator medications are related to their pharmacologic
lung function, or functional exercise capacity.50 effects and are dose-dependent. Because COPD patients are older
and more likely to have comorbid conditions, the risk for side effects
■ PHARMACOLOGIC THERAPY and drug interactions is higher compared with patients with asthma.
In contrast to the survival benefit conferred by supplemental oxygen Short-Acting Bronchodilators The initial therapy for COPD
therapy, there is no medication available for the treatment of COPD patients who experience symptoms intermittently are short-acting
that has been shown to modify the progressive decline in lung bronchodilators. Among these agents, the choices are a short-
function or prolong survival.1 Thus a primary goal of pharmaco- acting β2-agonist or an anticholinergic. Either class of agents has a
therapy is to control patient symptoms and reduce complications, relatively rapid onset on action, relieves symptoms, and improves
including the frequency and severity of exacerbations and improv- exercise tolerance and lung function. In general, both classes are
ing the overall the health status and exercise tolerance of the patient. equally effective.
 505

CHAPTER 29
0: At risk I: Mild II: Moderate III: Severe IV: Very severe

Characteristics • Chronic symptoms • FEV1:FVC <70% • FEV1:FVC <70% • FEV1:FVC <70% • FEV1:FVC <70%
• Exposure to risk • FEV1 ≥80% • 50% > FEV1 <80% • 30% > FEV1 <50% • FEV1 <30% or presence
factors • With or without • With or without • With or without of chronic respiratory fail-
• Normal spirometry symptoms symptoms symptoms ure or right heart failure

Avoidance of risk factor(s); influenza vaccination pneumococcal vaccine

Add short-acting bronchodilator when needed

Add regular treatment with one or more

Chronic Obstructive Pulmonary Disease

long-acting bronchodilators
Add rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations

Add long-term
oxygen if chronic
respiratory
failure
Consider surgical
treatments

FIGURE 29-3. Recommended therapy of stable chronic obstructive pulmonary disease. (FEV1, forced expiratory volume in the first second
of expiration; FVC, forced vital capacity.) (From reference 1.)

Short-Acting Sympathomimetics (β2-Agonists) A number of single dose of levalbuterol have been compared with those of
sympathomimetic agents are available in the United States. They albuterol and ipratropium plus albuterol in patients with COPD. No
vary in selectivity, route of administration, and duration of action. In significant differences in pulmonary function improvements or
COPD management, sympathomimetic agents with β2-selectivity, or adverse effects were noted.54
β2-agonists, should be used as bronchodilators. β2-Agonists cause In COPD patients, β2-agonists exert a rapid onset of effect,
bronchodilation by stimulating the enzyme adenyl cyclase to although the response generally is less than that seen in asthma.
increase the formation of cyclic adenosine monophosphate. Cyclic Short-acting inhaled β2-agonists cause only a small improvement in
adenosine monophosphate is responsible for mediating relaxation of FEV1 acutely but may improve respiratory symptoms and exercise
bronchial smooth muscle, leading to bronchodilation. In addition, it tolerance despite the small improvement in spirometric measure-
may improve mucociliary clearance. Although shorter-acting and ments.55 Patients with COPD can use quick-onset β2-agonists as
less-selective β-agonists are still used widely (e.g., metaproterenol, needed for relief of symptoms or on a scheduled basis to prevent or
isoetharine, isoproterenol, and epinephrine), they should not be reduce symptoms. The duration of action of short-acting β2-agonists
used owing to their shorter duration of action and increased cardio- is 4 to 6 hours.
stimulatory effects. Short-acting, selective β2-agonists such as
albuterol, levalbuterol, and pirbuterol, are preferred for therapy. Short-Acting Anticholinergics When given by inhalation, anti-
Sympathomimetics are available in inhaled, oral, and parenteral cholinergics such as ipratropium or atropine produce bronchodila-
dosage forms. The preferred route of administration is by inhala- tion by competitively inhibiting cholinergic receptors in bronchial
tion. The use of oral and parenteral β-agonists in COPD is discour- smooth muscle. This activity blocks acetylcholine, with the net
aged because they are no more effective than a properly used MDI effect being a reduction in cyclic guanosine monophosphate, which
or DPI, and the incidence of systemic adverse effects such as normally acts to constrict bronchial smooth muscle. Muscarinic
tachycardia and hand tremor is greater. Administration of β2- receptors on airway smooth muscle include M1, M2, and M3
agonists in the outpatient and emergency room settings via inhalers subtypes. Activation of M1 and M3 receptors by acetylcholine results
(MDIs or DPIs) is at least as effective as nebulization therapy and in bronchoconstriction; however, activation of M2 receptors inhib-
usually favored for reasons of cost and convenience.51 Chapter 28 its further acetylcholine release.
includes a complete description of the devices used for delivering Ipratropium is the primary short-acting anticholinergic agent used
aerosolized medication and a comparison β2-agonist therapies. for COPD in the United States. Atropine has a tertiary structure and
Albuterol is the most frequently used β2-agonist. It is available as is absorbed readily across the oral and respiratory mucosa, whereas
an oral and inhaled preparation. Albuterol is a racemic mixture of ipratropium has a quaternary structure that is absorbed poorly. The
(R)-albuterol that is responsible for the bronchodilator effect and lack of systemic absorption of ipratropium greatly diminishes the
(S)-albuterol that has no therapeutic effect. (S)-Albuterol is consid- anticholinergic side effects such as blurred vision, urinary retention,
ered by some clinicians to be inert, whereas others believe that it may nausea, and tachycardia associated with atropine. Ipratropium bro-
be implicated in worsening airway inflammation and antagonizing mide is available as a MDI and a solution for inhalation. The MDI was
the response to (R)-albuterol. Levalbuterol is a single-isomer formu- recently reformulated with an hydrofluoroalkane propellant and
lation of (R)-albuterol. A retrospective evaluation of levalbuterol delivers 17 mcg per puff. Ipratropium is also available as a MDI in
versus albuterol use in patients with asthma and COPD concluded combination with albuterol and as a solution for nebulization at 200
that levalbuterol offered significant advantages over albuterol for mcg/mL. It provides a peak effect in 1.5 to 2 hours and has a duration
hospitalized patients.52 Other clinicians feel that there are no signifi- of effect of 4 to 6 hours. Ipratropium has a slower onset of action and
cant differences between the products and that the use of levalbuterol a more prolonged bronchodilator effect compared with standard β2-
is not justified owing to its higher acquisition cost.53 The effects of a agonists. Because of the slower onset of effect (15 to 20 minutes
 506
compared with 5 minutes for albuterol), it may be less suitable for as- and reduced short-acting bronchodilator use. These two new prod-
needed use; however, it is often prescribed in that manner. Although ucts are the first long-acting bronchodilator therapies available for
SECTION 3

the role of inhaled anticholinergics in COPD is well established,56–58 use by nebulization. They offer an important option for patients
results from the Lung Health Study showed that treatment with with COPD in whom nebulization therapy is warranted.
ipratropium did not affect the progressive decline in lung function.28
Studies comparing ipratropium with inhaled β2-agonists have gener- Long-Acting Anticholinergics Tiotropium bromide, a long-
ally reported similar improvements in pulmonary function. Others acting quaternary anticholinergic agent, has been available in the
report a modest benefit with ipratropium, including a lower inci- United States since 2004. This agent blocks the effects of acetylcho-
dence of side effects such as tachycardia.56,57 line by binding to muscarinic receptors in airway smooth muscle
Although the recommended dose of ipratropium is 2 puffs four and mucus glands, blocking the cholinergic effects of bronchocon-
Respiratory Disorders

times a day, there is evidence for a dose–response, so the dose can striction and mucus secretion. Tiotropium is more selective than
be titrated upward, often to 24 puffs a day. Ipratropium has been ipratropium at blocking important muscarinic receptors. Tiotro-
shown to increase maximum exercise performance in stable COPD pium dissociates slowly from M1 and M3 receptors, allowing pro-
patients with doses of 8 to 12 puffs prior to exercise but not with longed bronchodilation. The dissociation from M2 receptors is
doses of 4 puffs or fewer.58,59 During sleep, ipratropium also has much faster, allowing inhibition of acetylcholine release. Binding
been shown to improve arterial oxygen saturation and sleep qual- studies of tiotropium in the human lung show that it is approxi-
ity.60 Ipratropium is well tolerated. The most frequent patient mately 10-fold more potent than ipratropium and protects against
complaints are dry mouth, nausea, and an occasional metallic taste. cholinergic bronchoconstriction for greater than 24 hours.69
Clinicians differ about preference in choosing the initial short- When inhaled, tiotropium is minimally absorbed into the sys-
acting bronchodilator therapy for the patient with COPD. Both a temic circulation and results in bronchodilation within 30 minutes,
short-acting β2-agonist and ipratropium represent reasonable with a peak effect in 3 hours. Bronchodilation persists for at least 24
choices for initial therapy. hours, allowing for a once-daily dosing. In the United States, it is
delivered via the HandiHaler, a single-load, dry-powder, breath-
Long-Acting Bronchodilators For patients with moderate to actuated device. Because it acts locally, tiotropium is well tolerated,
severe COPD who experience symptoms on a regular and consistent with the most common complaint being a dry mouth. Other anti-
basis, or in whom short-acting therapies do not provide adequate cholinergic side effects that are reported include constipation, uri-
relief, long-acting bronchodilator therapies are the recommended nary retention, tachycardia, blurred vision, and precipitation of
treatment. Long-acting, inhaled bronchodilator therapy can be narrow-angle glaucoma symptoms.
administered as a β2-agonist or an anticholinergic. Long-acting bron- The benefits of tiotropium have been evaluated in numerous
chodilators provide similar benefits to short-acting agents. In addi- trials of patients with COPD. Similar to long-acting β-agonists,
tion, they reduce exacerbation frequency and improve quality of life. tiotropium improves lung function and, dyspnea, exacerbation
frequency, and health-related quality of life.70 The tolerance that is
Long-Acting, Inhaled β2-Agonists Long-acting, inhaled β2- demonstrated with chronic use of β-agonists does not occur with
agonists offer the convenience and benefit of a long duration of tiotropium therapy, as improvements in lung function are sustained
action for patients with persistent symptoms. Both salmeterol and with long-term therapy.71
formoterol are dosed every 12 hours and provide sustained bron- There is a large body of evidence supporting the use of tiotropium
chodilation. Formoterol has an onset of action similar to albuterol as a long-acting bronchodilator for COPD patients. Benefits have
(less than 5 minutes), whereas salmeterol has a slower onset (15 to 20 been demonstrated compared to placebo72 and to ipratropium.73
minutes); however, neither agent is recommended for acute relief of Equivalent or superior effects have been proven compared to long-
symptoms. The clinical benefits of long-acting inhaled β2-agonists acting β-agonist therapy.72 Tiotropium therapy is associated with a
compared to short-acting therapies include similar or superior decreased risk of exacerbations compared to placebo or ipratropium,
improvements in lung function and symptoms, as well as reduced and equal or superior efficacy compared to long-acting β-agonists.74
exacerbation rates.61–63 The use of the long-acting agents should be Tiotropium was evaluated as an addition to standard COPD
considered for patients with frequent and persistent symptoms. medications in a 1-year, placebo-controlled, double-blind study
When patients require short-acting β2-agonists on a scheduled basis, involving more than 900 subjects. Tiotropium 18 mcg/day improved
long-acting agents, such as formoterol and salmeterol, are more the FEV1 response an average of 12% (trough) to 22% (peak) when
convenient based on dosing frequency, but are also more expensive. added to standard therapy.70
Long-acting β-agonists are also useful to reduce nocturnal symp- The efficacy and safety of tiotropium administered via a DPI was
toms and improve quality of life. When compared to short-acting compared with ipratropium administered four times daily by MDI
bronchodilators or theophylline, both salmeterol and formoterol in a multicenter, double-blind study that followed patients for 1
improve lung function, symptoms, exacerbation frequency and year.73 Patients who received once-daily tiotropium demonstrated
quality of life.64 These benefits are apparent even in patients with significantly greater improvements in lung function and selected
poorly reversible lung function and are related to improvements in quality-of-life scores, decreased dyspnea, and fewer exacerbations
inspiratory capacity.65 Both salmeterol and formoterol have been compared with patients who received ipratropium. There were no
compared to ipratropium. In separate studies, each agent improved differences in side effects between the two agents.
FEV1 compared to ipratropium and, in addition, the long-acting As a long-acting bronchodilator, tiotropium is an option to
bronchodilator was more effective for other selected outcomes (e.g., consider in addition to long-acting inhaled β2-agonists for COPD
prolonged time to exacerbation for salmeterol while formoterol management. Once-daily tiotropium has been compared with
reduced symptoms and rescue inhaler use).66,67 twice-daily salmeterol in two placebo-controlled trials of 6 months’
In 2007, two new long-acting, inhaled β-agonists became avail- duration. Tiotropium reduced asthma exacerbations and hospital
able in the United States. Formoterol and arformoterol are unique admissions and improved quality of life, whereas both active treat-
in that they are the first long-acting β-agonists available as nebu- ments improved lung function and reduced dyspnea.72 In another
lized solutions. When arformoterol was compared to salmeterol 6-month randomized, controlled trial of patients with COPD,
(administered by MDI) in a 12-week study, both treatments patients were randomized to receive either tiotropium once daily by
increased the trough FEV1.68 Arfomoterol also improved peak flows DPI, salmeterol twice daily by MDI, or placebo.75 Patients receiving
 507
tiotropium had greater improvements in trough FEV1 and dyspnea The methylxanthines may produce bronchodilation through
scores than those receiving salmeterol. Patients also were more numerous mechanisms, including (a) inhibition of phosphodi-

CHAPTER 29
likely to have improvements in quality-of-life indicators with tiotro- esterase, thereby increasing cyclic adenosine monophosphate levels,
pium than with salmeterol. However, no differences in frequency of (b) inhibition of calcium ion influx into smooth muscle, (c) prosta-
exacerbations were noted among the three groups. glandin antagonism, (d) stimulation of endogenous catecholamines,
These data offer some promise about the long term benefit of (e) adenosine receptor antagonism, and (f ) inhibition of release of
tiotropium on slowing the progressive decline in lung function, mediators from mast cells and leukocytes.84
although this claim is premature. A major clinical trial evaluating the Chronic theophylline use in patients with COPD has been shown
benefit of long-term treatment is currently ongoing. This trial is to exert improvements in lung function, including vital capacity,
evaluating the long-term benefits of tiotropium in the treatment of FEV1, minute ventilation, and gas exchange.83 Subjectively, theophyl-

Chronic Obstructive Pulmonary Disease

COPD, including the effects on FEV1 decline, exacerbation frequency, line has been shown to reduce dyspnea, increase exercise tolerance,
and overall mortality. The results of the UPLIFT (Understanding the and improve respiratory drive in COPD patients.83,84 Other nonpul-
Potential Long-Term Impacts on Function with Tiotropium) trial are monary effects of theophylline that may contribute to improved
anticipated in 2008.76 overall functional capacity in patients with COPD include improved
The potential benefit of tiotropium therapy in augmenting pulmo- cardiac function and decreased pulmonary artery pressure.
nary rehabilitation has been evaluated. The basis for this combination Although theophylline is available in a variety of oral dosage forms,
is that tiotropium can improve ventilatory mechanics and allow sustained-release preparations are most appropriate for the long-term
greater participation in exercise and muscle training. Tiotropium management of COPD. These products have the advantages of
therapy combined with pulmonary rehabilitation improved exercise improving patient compliance and achieving more consistent serum
endurance and health status, and reduced dyspnea compared to concentrations over rapid-release theophylline and aminophylline
pulmonary rehabilitation alone.77 The effects were sustained for three preparations. However, caution must be used in switching from one
months after the pulmonary rehabilitation program was complete. sustained-release preparation to another because there are consider-
able variations in sustained-release characteristics.84 Aside from intra-
Combination Anticholinergics and β-Agonists Combination venous aminophylline, there is no need to use any of the various salts
regimens of bronchodilators are used often in the treatment of forms of theophylline.
COPD, especially as the disease progresses and symptoms worsen Regular use of methylxanthines has not been shown to have either
over time. Combining bronchodilators with different mechanisms a beneficial or a detrimental effect on the progression of COPD.
of action allows the lowest possible effective doses to be used and However, methylxanthines may be added to the treatment plan of
reduces potential adverse effects from individual agents.1 Combina- patients who have not achieved an optimal clinical response to
tions of both short- and long-acting β2-agonists with ipratropium ipratropium and an inhaled β2-agonist. Studies suggest that adding
have been shown to provide added symptomatic relief and improve- theophylline to a combination of albuterol and ipratropium provides
ments in pulmonary function.78–80 added benefit for stable COPD patients, supporting the hypothesis
A combination of albuterol and ipratropium (Combivent) is that there is a synergistic bronchodilator effect.85–87 The efficacy of
available as a MDI in the United States for chronic maintenance combination therapy with salmeterol and theophylline for patients
therapy of COPD. This product offers the obvious convenience of with COPD was reported to improve pulmonary function and reduce
two classes of bronchodilators in a single inhaler. dyspnea better than either treatment alone.88 Combination treatment
Although clinical practice guidelines recommend that combinations also was associated with a reduced number of exacerbations only
of long-acting bronchodilators are appropriate in patients who do not when compared with the theophylline group, suggesting that the
receive adequate benefit from a single agent, data to support the use of salmeterol component was responsible for this beneficial effect.
these combinations have been lacking. These approaches have been the As is the case with other bronchodilator therapy, parameters other
focus of more recent research. Future combination inhalation products than objective measurements, such as FEV1, should be monitored to
may contain long-acting β2-agonists with tiotropium to reduce the assess efficacy of theophylline in COPD. Subjective parameters, such as
need for frequent dosing. In a preliminary single-dose study, the perceived improvements in symptoms of dyspnea, and exercise toler-
combination of tiotropium and formoterol resulted in a faster and ance, become increasingly important in assessing the acceptability of
greater improvement in FEV1 compared with either treatment alone.81 methylxanthines for COPD patients. Although objective improvement
In another trial, 95 subjects received either tiotropium 18 mcg or may be minimal, patients may experience an improvement in clinical
tiotropium plus formoterol 12 mcg, either once or twice daily. All symptoms, and thus benefit to the individual may be meaningful.
patients received each therapy for 2 weeks each in an open-label Theophylline’s role in COPD is as maintenance therapy in the
crossover design. Both combination regimens improved lung function nonacutely ill patient. Therapy can be initiated at 200 mg twice daily
and reduced rescue therapy use compared to tiotropium alone.82 and titrated upward every 3 to 5 days to the target dose. Most
patients required daily doses of 400 to 900 mg. Dosage adjustments
Methylxanthines Methylxanthines, including theophylline and generally should be made based on serum concentration results.
aminophylline, have been available for the treatment of COPD for Traditionally, the therapeutic range of theophylline was identified as
at least five decades and at one time were considered first-line 10 to 20 mcg/mL; however, because of the frequency of dose-related
therapy. However, with the availability of long-acting inhaled β2- side effects and the relatively minor benefit of higher concentrations,
agonists and inhaled anticholinergics, the role of methylxanthine a more conservative therapeutic range of 8 to 15 mcg/mL often is
therapy is significantly limited. Inhaled bronchodilator therapy is targeted. This is especially preferable in the elderly. When concentra-
preferred for COPD. Because of the risk for drug interactions and tions are measured, trough measurements are most appropriate.
the significant intrapatient and interpatient variability in dosage Once a dose is established, serum concentrations should be
requirements, theophylline therapy generally is considered in monitored once or twice a year unless the patient’s disease worsens,
patients who are intolerant or unable to use an inhaled bronchodi- medications that interfere with theophylline metabolism are added
lator. Theophylline is still an alternative to commonly used inhaled to therapy, or toxicity is suspected. The most common side effects
therapies partially because of the potential for multiple mechanisms of theophylline therapy are related to the gastrointestinal system,
(bronchodilation and antiinflammatory) and the possible benefit the cardiovascular system, and the central nervous system. Side
that systemic administration may exert on peripheral airways.83 effects are dose-related; however, there is overlap in side effects
 508
between the therapeutic and toxic ranges. Minor side effects include Previously, a common clinical practice was to administer a short
dyspepsia, nausea, vomiting, diarrhea, headache, dizziness, and course (2 weeks) of oral corticosteroids as a trial to predict which
SECTION 3

tachycardia. More serious toxicities, especially at toxic concentra- patients would benefit from chronic oral or inhaled corticosteroids.
tions, include arrhythmias and seizures. There is now sufficient evidence suggesting that this practice is not
Factors that decrease theophylline clearance and lead to reduced effective in predicting a long-term response to inhaled corticoster-
maintenance-dose requirements include advanced age, bacterial or oid and should not be recommended.91
viral pneumonia, left or right ventricular failure, liver dysfunction, The use of chronic inhaled corticosteroid therapy has been of
hypoxemia from acute decompensation, and use of drugs such as interest for the past decade. Their use has been common despite the
cimetidine, macrolides, and fluoroquinolone antibiotics. Factors lack of firm evidence about significant clinical benefit until recently.
that may enhance theophylline clearance and result in the need for Inhaled corticosteroids have an improved risk-to-benefit ratio com-
Respiratory Disorders

higher maintenance doses include tobacco and marijuana smoking, pared with systemic corticosteroid therapy. Using the model for
hyperthyroidism, and the use of such drugs as phenytoin, phenobar- asthma, it was hoped that the inhalation of potent corticosteroid
bital, and rifampin. would result in high local efficacy and limited systemic exposure and
In summary, there are decades of experience with theophylline toxicity. In the latter part of the 1990s, several large international trials
and other methylxanthine products in the management of patients were initiated to evaluate the effect on inhaled corticosteroids in
with COPD. However, inhalation therapy is currently preferred COPD. Unfortunately, the results of these major clinical trials failed
based on superior efficacy and safety, as well as ease of use by the to demonstrate any benefit from chronic treatment with inhaled
clinician. Theophylline is a challenging medication to dose, moni- corticosteroids in modifying long-term decline in lung function that
tor, and manage because of the significant intrapatient and interpa- is characteristic of COPD. Therefore, the role of inhaled corticoster-
tient variability in pharmacokinetics and the potential for drug oids in COPD continues to be debated in the literature, unlike
interactions and toxicities. asthma, where their use is clearly advocated. Much of the debate
centers on the appropriate outcome measures in this population of
patients.
Corticosteroids During the last decade, several studies of inhaled corticosteroids in

Corticosteroid therapy has been studied and debated in COPD COPD were designed to detect a benefit on slowing the progressive
therapy for half a century; however, owing to the poor risk-to-benefit loss of lung function, but the results were disappointing.92–98 None of
ratio, chronic systemic corticosteroid therapy should be avoided if the large national or international trials were able to demonstrate a
possible.1 Because of the potential role of inflammation in the benefit of high-dose inhaled corticosteroid therapy on this primary
pathogenesis of the disease, clinicians hoped that corticosteroids outcome. However, inhaled corticosteroids are associated with other
would be promising agents in COPD management. However, their important benefits in some patients, including a decrease in exacerba-
use continues to be debated, especially in the management of stable tion frequency and improvements in overall health status.94,98,99
COPD. Clinicians continue to debate the most appropriate and relevant
The antiinflammatory mechanisms whereby corticosteroids exert outcome measure to evaluate in COPD studies. Based on the results
their beneficial effect in COPD include (a) reduction in capillary of clinical trials, consensus guidelines suggest that inhaled corticoster-
permeability to decrease mucus, (b) inhibition of release of pro- oid therapy should be considered for symptomatic patients with stage
teolytic enzymes from leukocytes, and (c) inhibition of prostaglan- III or IV disease (FEV1 <50%) who experience repeated exacerba-
dins. Unfortunately, the clinical benefits of systemic corticosteroid tions.1,2 These are the patients who demonstrated benefit in clinical
therapy in the chronic management of COPD are often not evident, trials and in whom a trial of inhaled corticosteroid therapy is war-
and the risk of toxicity is extensive and far-reaching. Currently, the ranted. There are also data from epidemiologic studies that suggest
appropriate situations to consider corticosteroids in COPD include that chronic treatment with inhaled corticosteroids is associated with
(a) short-term systemic use for acute exacerbations and (b) inhala- a lower risk of rehospitalization for a broader group of patients with
tion therapy for chronic stable COPD. COPD. Thus the debate about the appropriate role for this antiin-
The role of oral steroid use in chronic stable COPD patients was flammatory therapy continues.
evaluated in a meta-analysis over a decade ago.89 Investigators con- A meta-analysis evaluating randomized clinical trials involving
cluded that only a small fraction (10%) of COPD patients treated inhaled corticosteroids in patients COPD indicated that treatment
with steroids showed clinically significant improvement in baseline was associated with a relative risk reduction in exacerbation fre-
FEV1 (increase of 20%) compared with those treated with placebo. quency of 33%. The report indicated that 12 patients would require
While a small number of COPD patients are considered responders treatment for 20.8 months to prevent one exacerbation episode. The
to oral steroids, many of these patients actually may have an asth- benefit was evident for patients with moderate to severe COPD.100
matic, or reversible, component to their disease. The best predictors This meta-analysis did not detect a mortality benefit.
for response to oral steroids is the presence of eosinophils on sputum Other investigators have reported a reduction in mortality in
examination (≥3%) and a significant response on pulmonary func- patients with COPD who were treated with inhaled corticosteroids.
tion tests to sympathomimetics.90 Both the presence of eosinophils in In an epidemiologic study of a Canadian database, patient mortality
sputum and the responsiveness to sympathomimetics suggest an 3 months to 1 year following a hospitalization for a COPD exacer-
asthmatic component to the disease process and thus may explain the bation was evaluated in patients who received inhaled corticoster-
clinical benefit seen with steroids. oids in the first 3 months compared to those who did not. For
Long-term adverse effects associated with systemic corticosteroid patients older than 65 years of age, inhaled corticosteroid therapy
therapy include osteoporosis, muscular atrophy, thinning of the reduced mortality by 25%. Much of the mortality reduction was
skin, development of cataracts, and adrenal suppression and insuf- reflected in deaths from cardiovascular causes. Conversely, patients
ficiency. The risks associated with long-term steroid therapy are who received only bronchodilator therapy trended toward higher
much greater than the clinical benefits. If a decision to treat with mortality rates, although not significant.101 A pooled analysis of
long-term systemic corticosteroids is made, the lowest possible seven large trials also concluded that inhaled corticosteroids
effective dose should be given once per day in the morning to reduced all-cause mortality in COPD patients.102
minimize the risk of adrenal suppression. If therapy with oral agents Currently, the recommended role of inhaled corticosteroid therapy
is required, an alternate-day schedule should be used. is for COPD patients with moderate to severe airflow obstruction
 509
(FEV1 <50% predicted), and who experience frequent exacerbations salmeterol alone. There were 23 cases reported, compared with 7 in
despite bronchodilator therapy. The initial hope that treatment with the salmeterol group.115 An increase in the risk for pneumonia was

CHAPTER 29
inhaled corticosteroids would prevent or slow the progressive decline also reported in the Towards a Revolution in COPD Health
in FEV1 remains unproven; however, it is often argued that additional (TORCH) study.116 This finding requires further investigation.
important outcomes in patients with COPD include relief of symp- The largest prospective study to date is referred to as the TORCH
toms, fewer and less-severe exacerbations, and improved quality of study.116 This trial consisted of 6,112 patients who received one of
life.103 The role of inhaled corticosteroids in prolonging survival of four treatments for 3 years. Treatment groups were placebo, salmet-
patients with COPD has been widely debated in recent years. Investi- erol 50 mcg twice daily, fluticasone 500 mcg twice daily, or the
gators have reported mixed success and studies are confounded by combination of salmeterol and fluticasone in a single inhaler. The
small sample size and differences in study design.104 primary outcome was death from any cause and secondary outcomes

Chronic Obstructive Pulmonary Disease

Although a dose–response relationship for inhaled corticoster- were exacerbation rates, lung function, and health status. None of
oids has not been demonstrated in COPD, the major clinical trials the active treatments differed significantly from placebo, although
employed moderate to high doses for treatment. Side effects of the combination of salmeterol and fluticasone trended toward fewer
inhaled corticosteroids are relatively mild compared with the toxic- deaths (p = 0.052). The combination also reduced exacerbation
ity from systemic therapy. Hoarseness, sore throat, oral candidiasis, rates, and improved lung function and health status compared to the
and skin bruising have been reported in the clinical trials. Severe other treatments. Exacerbation rates were also significantly reduced
side effects, such as adrenal suppression, osteoporosis, and cataract with combination therapy compared to either single agent alone.
formation, have been reported less frequently than with systemic Both treatment groups that included fluticasone had higher rates of
corticosteroids, but clinicians should monitor patients who are pneumonia. Although this study did not reflect a mortality benefit,
receiving high-dose chronic therapy.105,106 the authors indicated the risk of death was reduced by 17.5% with
There is evidence supporting a dose relationship between inhaled the combination and that the number needed to treat for 1 year to
corticosteroid use and the risk of fractures. In a cohort of more than provide a benefit was 4.
1,600 subjects with a diagnosis of asthma or COPD (mean age: 80
Combinations of Long-Acting Bronchodilators Compared
years), the risk of a fracture was 2.53 times higher (confidence
to Long-Acting Bronchodilators Plus Inhaled Corticoster-
interval: 1.65 to 3.89) in those receiving a mean daily dose of inhaled
oids The combination of salmeterol and tiotropium has also been
corticosteroid of 601 mcg or greater.107 However, the data are
evaluated in a short-term crossover study involving only 22 subjects
conflicting about this issue. A meta-analysis found no evidence
who received either salmeterol (50 mcg twice daily) plus fluticasone
supporting an increased risk of fractures or decreased bone mineral
(500 mcg twice daily), fluticasone plus tiotropium (18 mcg once
density with chronic inhaled corticosteroid use.108 It appears prudent
daily), or fluticasone, salmeterol, and tiotropium for 1 week. The
to suggest that, to minimize the risk of fracture, patients should be
triple combination provided a significant benefit of improved lung
treated with the lowest effective dose of inhaled corticosteroids.109 It
function compared to either of the dual treatments in subjects with
may also be helpful to recommend adequate intake of calcium and
moderate to severe COPD.117 The benefit of triple therapy was
vitamin D, and possibly periodic bone mineral density testing.
evaluated in a 1-year randomized, double-blind, placebo control
study involving 449 subjects with moderate to severe COPD. Treat-
Combination Therapy: Bronchodilators and ment consisted of either tiotropium, tiotropium plus salmeterol, or
Inhaled Corticosteroids tiotropium, salmeterol and fluticasone.118 There was no difference
between treatments for the primary outcome of percentage of
Following the disappointing results of chronic inhaled corticosteroid
patients experiencing an exacerbation requiring systemic corticoster-
studies and the progressive decline in lung function, investigators
oids or antibiotics. The triple-drug regimen improved lung function,
became interested in the combination of potent antiinflammatory
quality of life, and reduced hospitalization compared to tiotropium
therapies and long-acting bronchodilators. Subsequently, several
alone, whereas two-drug therapy did not offer any benefit in lung
studies have shown an additive benefit with long-acting broncho-
function improvement or hospitalization rates compared to the
dilators.110–113 In various studies, combination therapy with salmet-
single agent. Another small study evaluated the addition of tiotro-
erol plus fluticasone or formoterol plus budesonide was associated
pium for 1 month to a regimen of an inhaled corticosteroid and a
with greater improvements in clinical outcomes such as FEV1,
long-acting β-agonist.119 The addition of tiotropium improved lung
health status, and frequency of exacerbations compared with
function and quality-of-life scores, apparently by improving dynam-
inhaled corticosteroids or long-acting bronchodilators alone. The
ics of lung capacity (inspiratory capacity). These effects were
availability of combination inhalers (e.g., salmeterol plus flutica-
reversed when tiotropium therapy was discontinued. These data
sone) makes administration of both inhaled corticosteroids and
involving combinations of long acting bronchodilators are limited
long-acting bronchodilators more convenient for patients and
and preliminary. More research is required and should include other
decreases the total number of inhalations needed daily. Therefore,
outcome parameters including relief of symptoms, exacerbation
there is growing evidence that inhaled corticosteroid and long-
rates and quality of life. Larger sample sizes and longer durations will
acting β-agonist combinations improve lung function, as well as
provide insight into the value of combinations.
reduce symptoms of dyspnea and exacerbation frequency.112–114
The combination of a long-acting β-agonist and inhaled cortico-
steroid has been compared to the long-acting β-agonist therapy α1-Antitrypsin Replacement Therapy
alone. In a study involving nearly 1,000 patients with severe but In patients with inherited AAT deficiency-associated emphysema,
stable COPD, subjects received either salmeterol 50 mcg/fluticasone treatment focuses on reduction of risk factors such as smoking,
500 mcg twice daily or salmeterol 50 mcg twice daily for 44 weeks. symptomatic treatment with bronchodilators, and augmentation
Exacerbation frequency was significantly lower in the combination therapy with replacement AAT. Based on knowledge about the
group (334 versus 464 episodes) which corresponded to a 35% relationship between serum concentrations of AAT and the risk of
reduction in the annualized rate. The time to the first exacerbation developing emphysema, the rationale for augmentation therapy is
was also delayed with the combination therapy.115 One finding of to maintain serum concentrations above the protective threshold
concern reported in this trial was the increased number of pneumo- throughout the dosing interval.120 Indirect evidence of AAT activity
nia cases in patients receiving combination therapy compared to in the interstitium of the lung has been demonstrated by measuring
 510
concentrations of the enzyme in epithelial lining fluid obtained TABLE 29-12 Factors Favoring Hospitalization for Treatment of
during bronchoalveolar lavage. Augmentation therapy consists of Chronic Obstructive Pulmonary Disease Exacerbation
SECTION 3

weekly infusions of pooled human AAT to maintain AAT plasma

Presence of high risk comorbidity (e.g., pneumonia, arrhythmia, congestive heart
levels greater than 10 micromolars. Much of the data supporting the
failure, diabetes, renal or hepatic failure)
use of AAT replacement is based on evidence of biochemical efficacy
Suboptimal response to outpatient management
(e.g., administering the product and demonstrating protective serum Marked worsening of dyspnea
concentrations of AAT). Inability to eat or sleep because of symptoms
Clinical evidence for slowing lung function decline or improving Worsening hypoxemia or hypercapnia
outcomes with augmentation therapy is sparse. Stated challenges to Mental status changes
performing randomized clinical trials include the large sample size Lack of home support for care
Respiratory Disorders

and long duration of followup required, and the expense of conduct- Uncertain diagnosis
ing such a trial. One observational study followed patients in the Modified from the American Thoracic Society.
National Registry of Severe AAT Deficiency over a period of several Adapted from reference 2.
years and documented clinical outcomes. In this study, patients who
received weekly augmentation therapy with purified AAT had slower
tions are closely related to each patient’s overall health status, all
declines in FEV1 and decreased mortality compared with patients
patients should receive optimal chronic treatment, including smok-
who never received augmentation therapy.121 However, this was an
ing cessation, appropriate pharmacologic therapy, and preventative
observational study of patients, not a randomized, placebo-controlled
therapy such as vaccinations.
trial, and so direct cause-and-effect relationships cannot be con-
cluded. One randomized, placebo-controlled study of patients with
severe AAT deficiency (ZZ phenotype) did show a significant reduc- ■ NONPHARMACOLOGIC THERAPY
tion in lung tissue loss and destruction as measured by computed Controlled Oxygen Therapy
tomographic scan in patients receiving augmentation therapy.122
Other measures of lung function and mortality were not recorded. Oxygen therapy should be considered for any patient with hypoxemia
The recommended dosing regimen for replacement AAT is 60 mg/ during an exacerbation. Caution must be used, however, because
kg administered intravenously once a week at a rate of 0.08 mL/kg per many patients with COPD rely on mild hypoxemia to trigger their
minute, adjusted to patient tolerance. It has been estimated that this drive to breathe. In normal, healthy individuals, the drive to breathe is
form of augmentation therapy will cost more than $54,000 annu- triggered by carbon dioxide accumulation. In patients with COPD
ally.123 In the absence of alternative treatments, it is difficult to assess who retain carbon dioxide as a result of their disease progression,
cost-effectiveness using conventional criteria. There have been hypoxemia rather than hypercapnia becomes the main trigger for
repeated problems with supply of this biologic replacement therapy their respiratory drive. Overly aggressive administration of oxygen to
(derived from pooled blood donors) related to production difficulty patients with chronic hypercapnia may result in respiratory depres-
and contamination issues. Currently, there are three products avail- sion and respiratory failure. Oxygen therapy should be used to achieve
able (Prolastin [Bayer], Aralast [Baxter], and Zemaira [ZLB Behring]), a PaO2 of greater than 60 mm Hg or oxygen saturation of greater than
which should minimize this problem in the future. Drug development 90%. However, an ABG should be obtained after oxygen initiation to
research continues in the area of recombinant products and inhala- monitor carbon dioxide retention owing to hypoventilation.
tional therapy.
The safety of AAT replacement therapy has been recently evaluated Noninvasive Mechanical Ventilation
in two large observational studies. In the most recent study, 174 Noninvasive positive-pressure ventilation (NPPV) provides ventila-
patients (n = 747) reported 720 adverse events, classified as severe in tory support with oxygen and pressurized airflow using a face or nasal
8.8% of cases and moderate in 72.4% of cases.124 Common com- mask with a tight seal but without endotracheal intubation. Numerous
plaints included headache, dizziness, nausea, dyspnea, and fever. The
overall rate of adverse events was low (i.e., two events over 5 years).
TABLE 29-13 Therapeutic Options for Acute Exacerbations of
Chronic Obstructive Pulmonary Disease
TREATMENT
Therapy Comments

Chronic Obstructive Pulmonary Antibiotics Recommended if two or more of the following are present:
Increased dyspnea
Disease Exacerbation Increased sputum production
Increased sputum purulence
■ DESIRED OUTCOMES Corticosteroids Oral or intravenous therapy may be used.
If intravenous is used, it should be changed to oral after
 The goals of therapy for patients experiencing exacerbations of
improvement in pulmonary status.
COPD are (a) prevention of hospitalization or reduction in hospi-
If continued longer than 14 days, then the dose should be
tal stay, (b) prevention of acute respiratory failure and death, and tapered to avoid hypothalamic–pituitary–adrenal axis
(c) resolution of exacerbation symptoms and a return to baseline suppression.
clinical status and quality of life. Acute exacerbations can range from Bronchodilators Metered-dose inhalers and dry-powder inhalers equal in
mild to severe. Factors that influence the severity, and subsequently efficacy to nebulization.
the level of care required, include the severity of airflow limitation, β-Agonists also may increase mucociliary clearance.
presence of comorbidities and the history of previous exacerbations. Long-acting β-agonists should not be used for quick relief of
Table 29–12 includes factors that warrant treatment in the hospital. symptoms or on an as-needed basis.
Table 29–13 summarizes the various therapeutic options for Controlled oxygen Titrate oxygen to desired oxygen saturation (>90%).
exacerbation management. Pharmacotherapy consists of intensifi- therapy Monitor arterial blood gas for development of hypercapnia.
Noninvasive Consider for patients with acute respiratory failure.
cation of bronchodilator therapy and a short course of systemic
mechanical Not appropriate for patients with altered mental status, severe
corticosteroids. Antimicrobial therapy is indicated in the presence
ventilation acidosis, respiratory arrest, or cardiovascular instability.
of selected symptoms. As the frequency and severity of exacerba-
 511
trials have reported the benefits of NPPV in patients with acute who received placebo. There was no significant difference between
respiratory failure caused by COPD exacerbations. In one meta- groups at 6-week followup.

CHAPTER 29
analysis of eight studies, NPPV was associated with lower mortality, In total, results from these trials suggest that patients with acute
lower intubation rates, shorter hospital stays, and greater improve- exacerbations of COPD should receive a short course of intravenous
ments in serum pH in 1 hour when compared with treatment with or oral corticosteroids. However, because of the large variability in
usual care alone.125 The benefits seen with NPPV generally can be dosage ranges, the optimal dose and duration of corticosteroid
attributed to a reduction in the complications that often arise with treatment are not known. It appears that short courses (9 to 14 days)
invasive mechanical ventilation. Not all patients with COPD exacerba- are as effective as longer courses and have a lower risk of associated
tions are appropriate candidates for NPPV. Patients with altered adverse effects owing to less time of exposure. Several trials used high
mental status may not be able to protect their airway and thus may be initial doses of steroids before tapering to a lower maintenance dose.

Chronic Obstructive Pulmonary Disease

at increased risk for aspiration. Patients with severe acidosis (pH Adverse effects such as hyperglycemia, insomnia, and hallucinations
<7.25), respiratory arrest, or cardiovascular instability should not be may occur at higher doses. Depending on the clinical status of the
considered for NPPV. Patients failing a trial of NPPV or those patient, treatment may be initiated at a lower dose or tapered more
considered poor candidates may be considered for intubation and quickly if these effects occur. It appears that a regimen of prednisone
mechanical ventilation. 40 mg orally daily (or equivalent) for 10 to 14 days can be effective
for most patients.131 If steroid treatment is continued for longer than
■ PHARMACOLOGIC THERAPY 2 weeks, a tapering oral schedule should be employed to avoid signs
of hypothalamic–pituitary–adrenal axis suppression.
Bronchodilators
During exacerbations, intensification of bronchodilator regimens is Antimicrobial Therapy
used commonly. The doses and frequency of bronchodilators are
 Most acute exacerbations of COPD are thought to be caused by
increased to provide symptomatic relief. Short-acting β2-agonists
viral or bacterial infections. However, as many as 30% of exacerba-
are preferred owing to rapid onset of action. Anticholinergic agents tions are caused by unknown factors.1 A meta-analysis of nine studies
may be added if symptoms persist despite increased doses of β2-
evaluating the effectiveness of antibiotics in treating exacerbations of
agonists. In fact, combinations of these agents are employed often, COPD determined that patients receiving antibiotics had a greater
although data are lacking about the benefit versus higher doses of improvement in peak expiratory flow rate than those who did not.132
one agent. Bronchodilators may be administered via MDIs or
This meta-analysis concluded that antibiotics are of most benefit
nebulization with equal efficacy. Nebulization may be considered
and should be initiated if at least two of the following three symp-
for patients with severe dyspnea who are unable to hold their breath
toms are present: increased dyspnea, increased sputum volume, and
after actuation of an MDI. Clinical evidence supporting the use of
increased sputum pu