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![Microbial killing
The major inherited mechanisms for
killing microbes in the blood are soluble
molecules:
◦ the mannose-binding lectin & C-reactive
protein (CRP) pathways for activating
complement
◦ the alternative complement pathway
◦ antibacterial proteins (such as bactericidal
permeability-increasing protein [BPI])
◦ natural IgM antibodies.
Increased capillary permeability allows these
molecules to diffuse into tissues where there is
local inflammation.
Mandell Principles of Infectious](https://image.slidesharecdn.com/sepsis-130810055712-phpapp01/75/Sepsis-14-2048.jpg)
Uploaded byTimothy Zagada
Sepsis
1. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It can progress to severe sepsis and septic shock with increased organ dysfunction and risk of death. 2. Common signs and symptoms include fever, increased heart and respiratory rate, and altered mental status. Laboratory findings may include leukocytosis, thrombocytopenia, and elevated lactate. Blood cultures are positive in 20-40% of cases. 3. Treatment involves promptly administering broad-spectrum intravenous antibiotics after obtaining cultures, as well as identifying and treating the infection source. Outcomes depend on early recognition and treatment.
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Sepsis
- 1. DEFINITION OF TERMS •BACTEREMIA: bacteria in blood, evidence with (+) blood culture • SEPTICEMIA: presence of microbes or their toxins in blood • SIRS - ANY Two or more of the following: 1. Temperature ◦ 1.1.Fever → oral T >38ʼC ◦ 1.2.Hypothermia <36ʼ 2. Respiratory Rate ◦ 2.1.Tachypnea >24cpm 3. Tachycardia >90bpm 4. WBC ◦ 4.1.Leukocytosis >12,000/uL ◦ 4.2.Leukopenia <4,000/uL ◦ 4.3. >10%band cells ◦ 4.4. May have non-infectious etiology Harrison’ s Internal Medicine 18th edition SEPS IS GROUP 1 Camacho, Hans Robert C. Francisco, Rimmon Pineda, Francis Ivan G. Yang, Sheryl Ray B. Zagada, Timothy M. SEPSIS
- 2. Sepsis • SEPSIS +severe distant organ dysfunction = SEVERE SEPSIS •SEVERE SEPSIS + Hypoperfusion/Hypotension = SEPTIC SHOCK • Sepsis often reversible • Septic shock usually succumb SEPTIC SHOCK >1hr not respond to fluid resuscitation or pressor administration = REFRACTORY SEPTIC SHOCK Dysfunction of more than one organ, requiring Intervention to maintain Homeostasis = MODS - according to National Institute of Health define as an illness in which the body has a severe response to microbial infections. Harrison’ s Internal Medicine 18th edition
- 3. Severe sepsiscan be a response to any class of microorganism Microbial invasion in the blood stream – not ESSENTIAL , since local inflammation can also illicit organ dysfunction and hypotension. ETIOLOGY Harrison’ s Internal Medicine 18th editio
- 4. Blood culturesare positive: ◦ 20–40% of Severe sepsis cases ◦ 40–70% of septic shock cases Of cases with positive blood cultures, ◦ 40% -gram-positive bacteria, ◦ 35% t - gram-negative bacteria, ◦ 11 % - Polymicrobial ◦ 7% - fungi ◦ <5% - classic pathogens • (-) blood culture patients: the etiologic agent is often established by culture or microscopic examination of infected material from a local site ETIOLOGY Harrison’ s Internal Medicine 18th edition
- 5. The septicresponse is a contributing factor in >200,000 deaths per year in the United States. The incidence of severe sepsis and septic shock has increased over the past 20 years The annual number of cases is now >700,000 (~3 per 1000 population). Epidemiology of sepsis: an update. (2001) National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov/pubmed/11445744 EPIDEMIOLOGY
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- 8. Patients hospitalizedfor septicemia or sepsis were more severely ill than patients hospitalized for another diagnosis. Patients hospitalized for septicemia or sepsis stayed longer than other inpatients. Patients hospitalized for septicemia or sepsis were more than eight times as likely to die during their hospitalization.
- 9. 11th National Conventionon Statistics (NCS), 2010 NEWBORN DEATHS IN THE PHILIPPINES Aurora T. Reolalas* and Ma. Goretti M. Novilla Chief, Vital Statistics Division National Statistics Office
- 10. Neonatal Sepsis inthe Philippines Gram-negative organisms comprised the majority of the neonatal infections, with Pseudomonas and Burkholderia being the most prevalent. PIDSP Journal 2011 Vol 12 No.2 ETIOLOGY OF NEONATAL SEPSIS IN FIVE URBAN HOSPITALS IN THE PHILIPPINES Copyright ® 2011
- 11. Bacteria LP S Phagocyte Toxin Recognitionby the Host
- 12. LBPBacteria LP S Phagocyte MD- 2 TLR- 4 TLR4 –transmembrane protein, transmits the LPS recognition signal to the interior of the cell, where signal transduction and gene transcription pathways promote the production and/or secretion of numerous molecules that mediate the inflammatory response LP S MD-2 Extracellular protein which binds the lipid A moiety of LPS Toxin Recognition by the Host Signaling complex Mandell Principles of Infectious
- 13. Inflammatory Mediators TNFalpha ◦ Potent mediator of the subsequent inflammatory response ◦ Stimulates muscle breakdown and cachexia, mediates coagulation activation, enhances expression of adhesion molecules, prostaglandin E2 & PAF • IL-1 – Released in response to inflammation – Endogenous pyrogen • IL-6 – Increasingly expressed during stress as in septic shock. – Promote intravascular coagulation • Other Interleukins, Cytokines and Chemokines increased capillary permeability and blood flow, infiltration of neutrophils, and pain. Schwartz Principles of Surgery Mandell Principles of Infectious
- 14. Microbial killing Themajor inherited mechanisms for killing microbes in the blood are soluble molecules: ◦ the mannose-binding lectin & C-reactive protein (CRP) pathways for activating complement ◦ the alternative complement pathway ◦ antibacterial proteins (such as bactericidal permeability-increasing protein [BPI]) ◦ natural IgM antibodies. Increased capillary permeability allows these molecules to diffuse into tissues where there is local inflammation. Mandell Principles of Infectious
- 15. Control Mechanisms Local ControlMechanisms Intracellular factors (e.g., suppressor of cytokine signaling 3 and IL-1 receptor associated kinase 3) Molecules derived from essential polyunsaturated fatty acids (lipoxins, resolvins, and protectins) Enzymatic inactivation of microbial signal molecules (e.g., LPS) Systemic Control Mechanisms • LPS-binding protein • Glucocorticoids • Epinephrine • Prostaglandin E2 • IL-10, and C-reactive protein • IL-1 receptor antagonist. • soluble TNF receptors • protease inhibitors or antioxidants; • Hepcidin Harrison’s Principle of IM
- 17. CLINICAL MANIFESTATION Patientsusually manifests symptoms and signs related to primary infection. Manifestations of Systemic Inflammatory Response Evidence of shock (-) fever: most common in neonates, elderly patients and in persons with uremia or alcoholism Harrison’ s Internal Medicine 18th edition
- 18. Hyperventilation Encephalopathy Hypotension DIC, acrocyanosis, ischemic necrosis of peripheral tissues (e.g., digits) • Skin: hemorrhagic lesions, bullae, cellulitis. Skin lesions may suggest specific pathogens—e.g., petechiae and purpura with Neisseria meningitidis, ecthyma gangrenosum with Pseudomonas aeruginosa. • Gastrointestinal • Hypoxemia CLINICAL MANIFESTATION Harrison’ s Internal Medicine 18th edition
- 19. 1. Cardiopulmonary Complications ◦Acute respiratory distress syndrome ◦ Hypotension ◦ Decrease Myocardial function II. Renal Complications o Oliguira o Azotemia o Proteinuria o Nonspecific casts MAJOR COMPLICATIONS
- 20. III. Coagulopathy • Thrombocytopeniain 10-30% • Platelet usually very low <50,000/uL in px with DIC IV. Neurological Complications • DDX: Guillain-Barre syndrome, metabolic disturbance, toxin activity MAJOR COMPLICATIONS Harrison’ s Internal Medicine 18th edition
- 21. LEUKOCYTOSIS with aleft shift Thrombocytopenia Hyperbilirubinemia Proteinuria Neutrophils - may contain toxic granulations, Dohle bodies or cytoplasmic vacuoles Early sepsis: hyperventilation respiratory alkalosis Respiratory muscle fatigue & accum. of lactate metabolic acidosis ABG: hypoxemia (initially correctable with supplemental oxygen) LABORATORY FINDINGS Harrison’ s Internal Medicine 18th edition
- 22. CXR: normalor may show evidence of underlying pneumonia, volume overload, or the diffuse infiltrates of ARDS ECG: sinus tachycardia & nonspecific ST-T wave abnormalities Diabetic patients: ◦ develops hyperglycemia ◦ Severe infection diabetic ketoacidosis (may exacerbate hypotension) ◦ Serum albumin - initially within normal range, declines as sepsis continues LABORATORY FINDINGS Harrison’ s Internal Medicine 18th edition
- 23. NO specificdiagnostic test Diagnostically sensitive findings: Fever or hypothermia Tachypnea Tachycardia Leukocytosis or leukopenia Acutely altered mental status Thrombocytopenia Elevated blood lactate level hypotension DIAGNOSIS
- 24. 36% normaltemperature 40% normal respiratory rate 10% normal pulse rate 33% normal WBC count Systemic responses of uninfected patien with other conditions are similar to those characteristic of sepsis DIAGNOSIS Harrison’ s Internal Medicine 18th edition
- 25. Definitive etiologicdiagnosis ◦ requires isolation of the microorganism from blood or a local site of infection Culture: At least 2 blood samples (10mL each) ◦ should be obtained (from different venipuncture sites) Gram (-) bacteremia ◦ typically low grade (10 organism/mL of blood), prolonged incubation may be necessary S. aureus grows more rapidly – detectable in blood within 48 hours Harrison’ s Internal Medicine 18th edition
- 26. Antimicrobial Agents Givenafter blood and other relevant sites have been cultured. major determinant of outcome: ◦ interval between hypotension and the administration antimicrobial chemotherapy ◦ a delay of 1 h is associated with lower survival rates. Harrison’ s Internal Medicine 18th edition Treatment:
- 27. A Singleantimicrobial agent for treatment of known pathogens is adequate. Combination antimicrobial therapy is NOT superior to monotherapy in treating Gram(-) bacteremia. EXCEPT in P.aeruginosa bacteremia where aminoglycoside monotherapy is less effective than combination of an aminoglycoside with an antipseudomonal - lactam agent. antimicrobial therapy-at least 1 week; Factors in duration of treatment: ◦ site of infection ◦ adequacy of surgical drainage, ◦ underlying diseases ◦ susceptibility of the bacterial isolate(s) to antimicrobials. Harrison’ s Internal Medicine 18th edition Antimicrobial Agents
- 28. Factors induration of treatment: site of infection adequacy of surgical drainage, underlying diseases susceptibility of the bacterial isolate(s) to antimicrobials. Harrison’ s Internal Medicine 18th edition Antimicrobial Agents
- 29. Clinical Condition AntimicrobialRegimens (Intravenous Therapy) Immunocompetent adult The many acceptable regimens include (1) ceftriaxone (2 g q24h) or ticarcillin-clavulanate (3.1 g q4–6h) or piperacillin-tazobactam (3.375 g q4–6h); (2) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h) or cefepime (2 g q12h). Gentamicin or tobramycin (5–7 mg/kg q24h) may be addedto either regimen. If the patient is allergic to -lactam agents, use ciprofloxacin (400 mg q12h) or levofloxacin (500–750 mg q12h) plus clindamycin (600 mg q8h). If the institution or the community has a high prevalence of MRSA isolates, add vancomycin (15 mg/kg q12h) to each of the above regimens. Neutropeniaa (<500 neutrophils/L) Regimens include (1) imipenem-cilastatin (0.5 g q6h) ormeropenem (1 g q8h) or cefepime (2 g q8h); (2) ticarcillin-clavulanate (3.1 g q4h) or piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h). Vancomycin (15 mg/kg q12h) should be added if the patient has an infected vascular catheter, if staphylococci are suspected, if the patient has received quinolone prophylaxis, if the patient has received intensive chemotherapy that produces mucosal damage, if the institution has a high incidence of MRSA infections, or if there is a high prevalence of MRSA isolates in the community. Splenectomy Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used. If the local prevalence of cephalosporin-resistant pneumococci is high, add vancomycin. If the patient is allergic to - lactam drugs, vancomycin (15 mg/kg q12h) plus ciprofloxacin (400 mg q12h) or levofloxacin (750 mg q12h) or aztreonam (2 g q8h) should be used. IV drug user Nafcillin or oxacillin (2 g q8h) plus gentamicin (5–7 mg/kg q24h). If the local prevalence of MRSA is high or if the patient is allergic to -lactam drugs, vancomycin (15 mg/kg q12h) with gentamicin should be used. AIDS Cefepime (2 g q8h), ticarcillin-clavulanate (3.1 g q4h), or piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h) should be used. If the patient is allergic to -lactam drugs, ciprofloxacin (400 mg q12h) or levofloxacin (750 mg q12h) plus vancomycin (15 mg/kg q12h) plus tobramycin should be used. Initial Antimicrobial Therapy for Severe Sepsis with No Obvious Source in Adults with Normal Renal Function Harrison’ s Internal Medicine 18th edition
- 30. Removal of theSource of Infection Indwelling IV cathethers should be removed and the tip should be rolled over an agar plate for culture. After antibiotic therapy, a new catheter should be replaced at a different site and Foley and drainage catherters should be replaced Consider paranasal sinusitis in patients who have undergone nasal intubation. In patients with abnormal CXR, a CT of the chest may identify parenchymal,mediastinal or pleural diseases. In neutropenic patients, sites of tenderness and erythema must be carefully sought. In sacral or ischial decubitus ulcers, exclude pelvic of soft tissue pus collections wit CT/MRI In severe sepsis from the urinary tract, rule out urethereal obstruction, pernephric abcess and renall abcess by sonography or CT. Harrison’ s Internal Medicine 18th edition Treatment:
- 31. Hemodynamic, Respiratory, andMetabolic Support Primary goals ◦ restore adequate oxygen and substrate delivery to the tissues. ◦ improve tissue oxygen utilization and cellular metabolism. Initial management of hypotension • Administration of IV fluids (1-2L of NSS over 1-2 h) Circulatory adequacy can be assessed by: ◦ clinical parameters (mentation, urine output, skin perfusion) ◦ measurements of oxygen delivery and consumption. Harrison’ s Internal Medicine 18th edition Treatment:
- 32. "early goal-directedtherapy" (EGDT) • resuscitation based on maintenance of the SvO2 at >70% was associated with significantly improved survival of patients • The treatment algorithm ◦ rapid administration of fluids, ◦ antibiotics, and ◦ vasopressor support; erythrocyte transfusion (to maintain the hematocrit above 30%); and ◦ Dobutamine is administered if fluids, erythrocytes, and pressors did not result in an SvO2 of >70%. Harrison’ s Internal Medicine 18th edition Hemodynamic, Respiratory, and Metabolic Support
- 33. Vasopressin ◦ potentvasoconstrictor ◦ Useful in vasodilatory shock and relative resistance to other pressor hormones. Ventilator therapy ◦ For progressive hypoxemia, hypercapnia, neurologic deterioration, or respiratory muscle failure. Bicarbonates administered if severe metabolic acidosis <7.2ph FFP and platelet transfusion in DIC if complicated by major bleeding. In hypercatabolic patients and Acute renal failure, hemodialysis or hemofiltration isHarrison’ s Internal Medicine 18th edition
- 34. General Support Nutritionalsupplementation may reduce the impact of protein hypercatabolism in patients with prolonged sepsis. Prophylactic heparinization to prevent deep venous thrombosis for patients without active bleeding or coagulopathy. Maintenance of blood glucose improved survival rates among patients who have undergone major surgery and received IV glucose. Hypoglycemia was much more common in theHarrison’ s Internal Medicine 18th edition Treatment:
- 35. Other Measures Endotoxin-neutralizingproteins, inhibitors of COX or nitric oxide synthase, anticoagulants, polyclonal immunoglobulins, glucocorticoids, and antagonists to TNF-, IL-1, PAF, and bradykinin. Harrison’ s Internal Medicine 18th edition Treatment:
- 36. Recombinant activatedprotein C (aPC) ◦ Treatment of patients with severe sepsis or septic shock. ◦ The FDA approved aPC for use in adults (>18 years of age) who meet the APACHE II criterion and have a low risk of hemorrhage- related side effects. ◦ aPC is administered as a constant IV infusion of 24 g/kg per hour for 96 h. Harrison’ s Internal Medicine 18th edition
- 37. should notbe given to patients • platelet counts of <30,000/L • dysfunction of one organ system and surgery within 30 days. Treatment with aPC should not be started >24 h after the onset of severe sepsis, nor should it be used in the patient subsets— e.g., patients with pancreatitis or AIDS—that were excluded from the clinical trial. Harrison’ s Internal Medicine 18th edition
- 38. "bundling" ofmultiple therapeutic maneuvers as the standard of care for severe sepsis. The proposed resuscitation (6-h) bundle incorporates most of the elements discussed above for acute (EGDT) resuscitation. The management (24-h) bundle includes three measures of uncertain or marginal benefit: ◦ tight control of blood glucose, administration of low-dose hydrocortisone, and treatment with aPC. Harrison’ s Internal Medicine 18th edition
- 39. Harrison’ s InternalMedicine 18th edition Prevention Limit the use of indwelling vascular and bladder catheters Reduce the incidence and duration of profound neutropenia (<500 neutrophils/L) Aggressively treating localized nosocomial infections Indiscriminate use of antimicrobial agents and glucocorticoids should be avoided, and optimal infection-control measures should be used
Editor's Notes
- #3 • Severe sepsis may have hypotension/hypoperfusion (ABP = <90mmHg or <40mmHg of the patients normal BP for at least 1 hour despite of resucitation.If hypotension canʼt be corrected with fluid infusion = SEPTIC SHOCK = = poor prognosis
- #10 The respiratory distress ofnewborn was the leading cause of early neonatal deaths in Regions I, IVA, V, X and ARMMfor both periods 2006 and 2007, while bacterial sepsis of newborn was the leading cause ofdeaths in NCR and Region VI for both periods also.
- #12 These mediators include cytokines (in particular, tumor necrosis factor [TNF]; interleukin [IL]-1â, IL-12); chemokines (IL-8, macrophage inflammatory protein [MIP]-1á); lipid mediators (prostaglandins, leukotrienes); and others, and they result in the familiar elements of local inflammation: increased capil- lary permeability and blood flow, infiltration of neutrophils, and pain.In addition, local deposition of fibrin that is initiated by the expression of tissue factor on activated macrophages and endothelial cells helps wall off the infected tissue and provides an important impediment to bloodstream invasion.Although neutrophils circulate in the bloodstream, they carry out phagocytosis largely in tissue spaces, where they can attach to extracel- lular matrix, spread out, get traction, and ingest. Because phagocytes may regurgitate the contents of their lysosomes as they eat, limiting this activity to local tissues minimizes the release of digestive enzymes and oxidants into the circulating blood. The major inherited mecha- nisms for killing microbes in the blood are soluble molecules: the mannose-binding lectin and C-reactive protein (CRP) pathways for activating complement, the alternative complement pathway, antibac- terial proteins (such as bactericidal permeability-increasing protein [BPI]), and natural IgM antibodies. Increased capillary permeability allows these molecules to diffuse into tissues where there is local inflammation.
- #13 These mediators include cytokines (in particular, tumor necrosis factor [TNF]; interleukin [IL]-1â, IL-12); chemokines (IL-8, macrophage inflammatory protein [MIP]-1á); lipid mediators (prostaglandins, leukotrienes); and others, and they result in the familiar elements of local inflammation: increased capil- lary permeability and blood flow, infiltration of neutrophils, and pain.In addition, local deposition of fibrin that is initiated by the expression of tissue factor on activated macrophages and endothelial cells helps wall off the infected tissue and provides an important impediment to bloodstream invasion.Although neutrophils circulate in the bloodstream, they carry out phagocytosis largely in tissue spaces, where they can attach to extracel- lular matrix, spread out, get traction, and ingest. Because phagocytes may regurgitate the contents of their lysosomes as they eat, limiting this activity to local tissues minimizes the release of digestive enzymes and oxidants into the circulating blood. The major inherited mecha- nisms for killing microbes in the blood are soluble molecules: the mannose-binding lectin and C-reactive protein (CRP) pathways for activating complement, the alternative complement pathway, antibac- terial proteins (such as bactericidal permeability-increasing protein [BPI]), and natural IgM antibodies. Increased capillary permeability allows these molecules to diffuse into tissues where there is local inflammation.
- #18 Ex: Pneumonia ( cough, dypnea, productive sputum)Fever, chills, hypothermia, Hypotension, lactic acidemia, progressive organ system dysfunction. S/S rate differ from px to px• Different variations, too• Some sepsis are normo or hypothermic• Absence of fever MOST COMMON
- #19 Hyperventilation – earliest signEncephalopathy (disorientation, confusion)HypotensionDIC, acrocyanosis, ischemic necrosisof peripheral tissues (e.g., digits)• Skin: hemorrhagic lesions, bullae, cellulitis. Skin lesions may suggest specific pathogens—e.g., petechiae and purpura with Neisseria meningitidis, ecthymagangrenosum withPseudomonas aeruginosa.• Gastrointestinal: nausea, vomiting, diarrhea, ileus, cholestatic jaundice• Hypoxemia: ventilation-perfusion mismatchand increased alveolar capillary permeability with increased pulmonary water content
- #20 Acute respiratory distress syndrome VQ mismatch -> fall in arterial PO2 early in courseInc alveolar capillary permeability↓pulmonary water content↓decrease compliance and interferes with gas exchange(progressive diffuse pulmonary infiltratesand arterial hypoxemia (PaO2/FIO2 <200)) is ARD which develops in 50% of pts with severesepsis or septic shock.Hypotension: Normal or increased cardiac output and decreased systemicvascular resistance distinguish septic shock from cardiogenic or hypovolemicshock. a. generalized maldistribution of blood flow and blood volumeb. hypovolemia (dt diffuse capillary leakage of intravascular fluid)c. Dehydration from atecedentdse or insensible fluid losses, v/d, and polyuriaMyocardial function is depressed manifested with Decreased Ejection fraction• Increased end-diastolic and systolic ventricular volumes*CO normal even if decrease Ejection Fraction because of ventricular dilatation which permits normal strokevolumeRenal complications2) Renal Complications• Oliguira• Azotemia• Proteinuria• Nonspecific casts• Polyuric (Hypergly can exacerbate)• Most renal failure dt ATN induced by hypotension or capillary injury• Some may have glomerulonephritis, renal cortical necrosis or interstitial nephritis• Drug induced renal damage can complicate therapy
- #30 It is important, pending culture results, to initiate empirical antimicrobial therapy that is effective against both gram-positive and gram-negative bacteria (Table 265-3).
- #31 Removal or drainage of a focal source of infection is essential.
- #36 Despite aggressive management, many patients with severe sepsis or septic shock die. Numerous interventions have been tested for their ability to improve survival in patients with severe sepsis.
- #39 Some experts have advocated