Diabetic Ketoacidosis
Erin Gabriel, MD*, Sonia Soni, MD
KEYWORDS
Diabetic ketoacidosis Hyperglycemic crisis Ketonemia Insulin deficiency
HOSPITAL MEDICINE CLINICS CHECKLIST
1. The defining features of diabetic ketoacidosis (DKA) are metabolic acidosis, ke-
tonemia, and hyperglycemia.
2. The most common precipitating factors of DKA are acute medical illness (infec-
tion), nonadherence to insulin therapy, new onset diabetes, and medications
that interfere with carbohydrate metabolism.
3. DKA can also occur in a subset of patients with ketosis-prone type 2 diabetes.
4. DKA occurs when the combination of insulin deficiency and increase of coun-
teregulatory hormones causes release of free fatty acids from adipose tissue
as the body is unable to use glucose. These free fatty acids are subsequently
oxidized in the liver to ketone bodies, which results in metabolic acidosis.
5. The diagnostic criteria for DKA include acidosis, low serum bicarbonate,
increased anion gap, ketonemia, and ketonuria.
6. Treatment of DKA includes intravenous fluid resuscitation, correction of hyper-
glycemia and ketoacidosis with insulin, management of electrolyte abnormal-
ities, and the treatment of any precipitating causes of DKA.
7. Implementation of standardized protocols to treat DKA can improve outcomes
and potentially reduce hospital length of stay.
DEFINITION
What are the defining clinical features of diabetic ketoacidosis?
The most important clinical features of diabetic ketoacidosis (DKA) are:
Metabolic acidosis
Hyperglycemia
Ketonemia
DKA can range from mild to severe depending on the degree of metabolic acidosis
and the presence of altered mental status.1,2
Department of Medicine, Division of Hospital Medicine, Mount Sinai Medical Center, One
Gustave L Levy Place, Box 1087, New York, NY 10029, USA
* Corresponding author.
E-mail address: [email protected]
Hosp Med Clin 3 (2014) 556–566
http://dx.doi.org/10.1016/j.ehmc.2014.06.007
2211-5943/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
Diabetic Ketoacidosis 557
How does DKA differ from hyperglycemic hyperosmolar state?
Both DKA and hyperglycemic hyperosmolar state (HHS) are severe complications of
uncontrolled diabetes and are life-threatening. There can be some overlap between
these two syndromes in about one-third of patients.3 HHS typically involves a greater
severity of hyperglycemia and dehydration than DKA. HHS is defined by the pres-
ence of hyperosmolality, altered mental status, and the absence of significant
ketosis.1
EPIDEMIOLOGY
How common is DKA?
The incidence of DKA varies widely worldwide.4 In the United States, the number of
hospital discharges with DKA listed as the first diagnosis has been trending up. The
incidence was reported by the National Diabetes Surveillance Program of the Centers
for Disease Control and Prevention as 140,000 in 2009.5
PATHOPHYSIOLOGY
What is the mechanism for the development of DKA?
DKA occurs in the setting of reduced or absent insulin concentrations in addition to
increased levels of counter-regulatory hormones such as catecholamines, cortisol,
glucagon, and growth hormone.3
This imbalance leads to lipolysis, or the release of free fatty acids from adipose tis-
sue. In the setting of impaired carbohydrate use caused by insulin deficiency, the fatty
acids are oxidized in the liver into ketone bodies (primarily acetoacetate and beta-
hydroxybutyrate), which results in ketonemia and metabolic acidosis.3
Hyperglycemia is caused by increased gluconeogenesis and glycogenolysis and
decreased use by peripheral tissues.1
How does this differ from the development of HHS?
In HHS there is enough insulin present to prevent unrestrained free fatty acid oxidation
and thus prevent ketonemia and metabolic acidosis.1
As glucose levels continue to increase in HHS, there is a marked osmotic diuresis
resulting in severe dehydration with typical total body water deficits of 7 to 12 L.
Elderly patients with impaired thirst mechanism or reduced access to water are partic-
ularly at risk.3
What are the precipitating factors that can lead to DKA?
Underlying medical illness1
Infection: often pneumonia or urinary tract infection
Ischemic events such as myocardial infarction or cerebrovascular accident
Acute pancreatitis
Discontinuation of usual insulin therapy3
Noncompliance with medication
Poor patient education regarding diabetes management
Intentional discontinuation of insulin in patients with eating disorders because
insulin causes weight gain1
558 Gabriel & Soni
New-onset type 1 diabetes mellitus (about 15% of DKA cases3)
Medications that affect carbohydrate metabolism1,3
Corticosteroids
Thiazides
Pentamadine
Atypical antipsychotics
Substance abuse3
Alcohol
Cocaine
Which patients are at risk for DKA?
In general, DKA occurs in patients with type 1 diabetes, whereas HHS occurs in pa-
tients with type 2 diabetes. However, there is overlap between the two syndromes.2
What is ketosis-prone type 2 diabetes?
There is a subset of patients with type 2 diabetes who are prone to developing DKA,
usually without a precipitant. Many names have been used to describe this variant in
the literature, including idiopathic type 1 diabetes, atypical diabetes, type 1.5 diabetes,
and Flatbush diabetes. Ketosis-prone type 2 diabetes is particularly common in patients
of African and Hispanic descent. More than half of newly diagnosed adult African
American and Hispanic patients with unprovoked DKA have type 2 diabetes. However,
this phenomenon has also been reported in white, Asian, and Native American
populations.1,6
These patients tend to be obese, middle aged, with a strong family history of type 2
diabetes, and low prevalence of autoimmune markers including glutamic acid decar-
boxylase and IA-2. At presentation they have impairment of both insulin secretion and
insulin action. Therefore, initial management of DKA is the same regardless of the un-
derlying diagnosis.
Aggressive diabetes management in these patients results in significant improve-
ment in B-cell function and insulin sensitivity.7 Recognizing this subset of patients is
important because they can be titrated off insulin and managed successfully with
oral diabetes medication within 3 to 6 months of initial presentation.6,8 Ketosis-
prone type 2 diabetes can only be diagnosed weeks after the initial presentation
with DKA. At that point, measurement of fasting or stimulated C-peptide levels can
be used to confirm pancreatic beta-cell recovery.
PATIENT EVALUATION AND DIAGNOSIS
How do patients present with DKA?
General symptoms of hyperglycemia, such as polydipsia and polyuria, may precede
the onset of DKA by several days. Symptoms of DKA usually develop over less than
24 hours. Common symptoms include nausea, vomiting, abdominal pain, dehydra-
tion, weakness, and altered mental status. In contrast, HHS typically has a slow onset,
typically occurring over days to weeks.1
Physical examination findings can include signs of dehydration such as tachycardia
and hypotension and Kussmaul respirations secondary to the metabolic acidosis. A
patient’s mental status may vary from fully alert to comatose. Profound mental status
changes are more suggestive of HHS.1 History and physical examination should also
Diabetic Ketoacidosis 559
focus on eliciting possible precipitating factors, including infection, ischemia (such as
myocardial infarction or stroke), and medication changes.
What tests and studies should be performed?
Initial laboratory evaluation suggested by the American Diabetes Association (ADA)
consensus statement includes serum glucose, serum electrolytes and blood urea
nitrogen/creatinine (with calculation of the anion gap), arterial blood gas, serum osmo-
lality, serum and urinary ketones, urinalysis, and complete blood count. Initial studies
include an electrocardiogram, chest radiograph, and cultures.
Additional studies that should be considered in the appropriate clinical setting are
liver enzymes, cardiac enzymes, coagulation profile, amylase, and lipase.3
Further work-up should be driven by the clinical presentation and may include lum-
bar puncture or imaging of the head or abdomen.3
What are the diagnostic criteria for DKA?
Diagnostic criteria for DKA and HHS are shown in Table 1.
What if my patient does not clearly fit into one of these categories?
DKA and HHS exist along a spectrum of hyperglycemic crisis. They can be distin-
guished based on history and laboratory findings, but some patients may have fea-
tures of both syndromes.5
What if serum and/or urine ketones are negative?
Most routine serum and urine tests for ketones use the nitroprusside reaction. This
test can underestimate the severity of ketosis because it does not test for the pres-
ence of beta-hydroxybutyrate. Some institutions offer a separate test for beta-
hydroxybutyrate.1
What other laboratory abnormalities are commonly seen in DKA?
Hyperkalemia is common on initial presentation, although patients with DKA usu-
ally have a total body potassium deficit. Potassium is driven extracellularly as a
Table 1
Diagnostic criteria for DKA and HHS
Mild DKA Moderate DKA Severe DKA HHS
Plasma glucose (mg/dL) >250 >250 >250 >600
Arterial pH 7.25–7.30 7.00–7.24 <7.00 >7.30
Serum bicarbonate (mEq/L) 15–18 10–15 <10 >18
Urine ketone Positive Positive Positive Small
Serum ketone Positive Positive Positive Small
Serum osmolality Variable Variable Variable >320 mOsm/kg
Anion gap >10 >12 >12 Variable
Mental status Alert Alert/drowsy Stupor/coma Stupor/coma
Data from Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with
diabetes. Diabetes Care 2009;32(7):1335–43.
560 Gabriel & Soni
result of insulin deficiency and acidosis causing hyperkalemia. However, signifi-
cant amounts of potassium can be lost through osmotic diuresis and gastrointes-
tinal losses resulting in an overall deficiency.3 The initiation of insulin therapy and
correction of the acidosis drives extracellular potassium back into cells and can
cause hypokalemia. Patient who present with normal or low potassium levels
have severe total body potassium deficits and require careful monitoring and
repletion.
Hyperphosphatemia also reflects an extracellular phosphate shift rather than true
increased levels. This is caused by insulin deficiency, dehydration, and acidosis.3
Treatment of DKA can also lead to hypophosphatemia, which needs to be moni-
tored and repleted.1
Leukocytosis is commonly seen in DKA, even in the absence of infection, caused
by increased levels of stress hormones such as catecholamines and cortisol.3 On
admission, leukocytosis in the range of 10,000 to 15,000 mm 3 may not be indi-
cate an infectious process. However, leukocytosis with cell counts greater than
25,000 mm are more concerning for infection and require further evaluation and
treatment if found.1
Increased amylase and lipase can both be present in DKA in the absence of true
pancreatitis. One study found that nonspecific increases of amylase and lipase
occur in 16% to 25% of cases of DKA.9 Increase in amylase correlated with
pH and serum osmolality. Lipase increase correlated with serum osmolality.
The diagnosis of acute pancreatitis cannot be made on serum amylase and
lipase levels alone in patients with DKA.9 However, pancreatitis can be a precip-
itant for DKA. Clinical judgment should be used to determine the need for further
investigation for true pancreatitis and to manage the patient accordingly.
Can a patient have DKA without hyperglycemia?
There have been cases of DKA occurring with normal glucose levels (<250 mg/dL). In
these cases, patients often have a clinical history of starvation, vomiting, pregnancy,
or depression.10,11
DIFFERENTIAL DIAGNOSIS
Are there other causes of ketoacidosis?
Both starvation and alcoholic ketoacidosis can occur. These patients usually have
normal to low glucose levels and their condition can be differentiated from DKA by his-
tory and by other associated laboratory findings.1
What other causes of increased anion gap metabolic acidosis are there?
Other causes include lactic acidosis, uremia secondary to acute or chronic renal fail-
ure, and ingestions such as methanol, salicylates, ethylene glycol, and paraldehyde.1
PATIENT MANAGEMENT
What are the primary management goals in treatment of DKA?1,3
1. Treatment of dehydration with intravenous fluids
2. Correction of hyperglycemia and ketoacidosis with insulin therapy
Diabetic Ketoacidosis 561
3. Correction of electrolyte abnormalities
4. Treatment of precipitating events:
Management of infection, ischemia, and so forth
Patient education regarding proper insulin and diet management
What tests are monitored during treatment?
Serum glucose should be monitored every hour until it stabilizes. Serum electrolytes,
renal function, osmolality, and venous pH should be monitored every 2 to 4 hours. Fre-
quency of laboratory draws can be adjusted based on the severity of DKA and how
quickly the patient is responding to treatment.1
What is the optimal fluid management strategy for DKA?
The goal of initial fluid therapy in DKA is intravascular volume expansion and main-
taining adequate renal perfusion. The initial fluid recommendation from the ADA is
isotonic saline (0.9% NaCl) at a rate of 15 to 20 mL/kg/h or 1 to 1.5 L during the first
hour.1
Fluids should subsequently be chosen based on hemodynamic stability, hydration
status, serum electrolytes, and urinary output of the patient. Patients are typically con-
verted to half normal saline (0.45% NaCl) at a rate of 250 to 500 mL/h if serum sodium
level is normal or increased. If serum sodium level is low when corrected for serum
glucose, 0.9% NaCl can be continued at a rate of 250 to 500 mL/h. The provider
should frequently reassess the choice of fluids based on the patient’s hydration status,
fluid input and output, and laboratory results (Fig. 1).1
The goal is to correct fluid deficits within the first 24 hours. Patients with significant
cardiac or renal dysfunction need to be monitored closely to avoid volume overload.1
What is the optimal insulin management for patients with DKA?
Although the goal is to correct both hyperglycemia and ketoacidosis, hyperglycemia
resolves faster than the ketoacidosis. On average, glucose decreases less than
250 mg/dL 6 hours after initiation of treatment, whereas resolution of ketoacidosis
takes an average of 12 hours. Ongoing insulin therapy is required until the ketoacidosis
is resolved. For this reason, when glucose levels decrease less than or equal to
200 mg/dL, 5% dextrose should be added to the fluid regimen in order to prevent hy-
poglycemia. The amount of dextrose in the fluids may need to be adjusted to keep
glucose between 150 and 200 mg/dL.1
Many studies have been performed to determine the optimal dose and route of
administration of insulin. One study showed that insulin given intravenously, intramus-
cularly, or subcutaneously is effective for treatment of DKA.10 In general, treatment al-
gorithms recommend a continuous intravenous infusion of regular insulin because it
has a short half-life and can easily be titrated.1 Previous treatment protocols have rec-
ommended giving an initial intravenous bolus dose of regular insulin at 0.1 units/kg
and then starting the continuous infusion at 0.1 units/kg/h.12 A recent study found
that the bolus dose (or priming dose) is not necessary if the continuous infusion is
started at a rate of 0.14 units/kg/h.12 The current ADA treatment protocol recommends
either of these treatment plans.
If glucose levels do not decrease by 10% in the first hour, a bolus of 0.14 units/kg
should be given. The infusion is then resumed at the same rate.1
562 Gabriel & Soni
When glucose levels reach 200 mg/dL, the infusion rate should be reduced to 0.02
to 0.05 units/kg/h. As earlier, dextrose should be added to the intravenous fluids at this
time. Insulin and fluid infusion rates should be adjusted to maintain serum glucose be-
tween 150 and 200 mg/dL (See Fig. 1).1
Can patients with DKA be managed with subcutaneous insulin?
Studies have shown success in management with subcutaneous rapid-acting insulin
for uncomplicated mild to moderate DKA. One study used an initial dose of lispro 0.3
units/kg subcutaneously, followed by 0.1 units/kg subcutaneously each hour. When
glucose levels decreased to less than 250 mg/dL, the dose was reduced to 0.05
units/kg/h until DKA was resolved. This study showed no difference in hospital length
of stay or time to resolution of DKA. The investigators were able to show a 39% reduc-
tion in hospital costs with this protocol because patients could be managed on general
medical wards or step-down units rather than in the intensive care unit.13,14 Another
study compared subcutaneous aspart insulin with intravenous aspart insulin or intra-
venous regular insulin guided by simultaneous bedside measurement of blood
glucose and beta-hydroxybutyrate for the management of DKA. There was no signif-
icant difference in median time to reach resolution of DKA as defined by a beta-
hydroxybutyrate less than 0.6 mmol/L, serum bicarbonate greater than 18 mEq/L,
venous pH greater than 7.3, and anion gap less than 16.15
A review of the literature concluded that the use of subcutaneous rapid-acting insu-
lin every 1 or 2 hours to treat DKA would be safe and effective.16 However, these
studies excluded patients with severe DKA, hypotension, anasarca, and other critical
illnesses. Patients with any of these conditions should continue to be managed with
intravenous insulin infusion.1
What is the appropriate management of electrolyte abnormalities in DKA?
Potassium is often high at the time of presentation with DKA, but begins to decrease
with the initiation of treatment. In patients with adequate renal function, potassium
repletion should be started when levels decrease to less than the upper limit of
normal (5.0–5.2 mEq/L). A goal potassium level of 4 to 5 mEq/L can generally be
maintained by adding 20 to 30 mEq of potassium in each liter of intravenous fluids
given.1
When patients present with hypokalemia less than 3.3 mEq/L repletion must begin
with initiation of fluid infusion. In this case, the initiation of insulin therapy should be
delayed until potassium is repleted to greater than 3.3 mEq/L.1
Phosphate is often normal or high at presentation but also decreases with the initi-
ation of treatment with insulin. There is no evidence that phosphate repletion changes
clinical outcomes in the management of DKA. However, severe hypophosphatemia
should be avoided because this can cause cardiac and skeletal muscle weakness
with subsequent respiratory depression.10
Bicarbonate use in the treatment of DKA is controversial. Studies have failed to
show any improvement in patient outcomes with the administration of bicarbonate
to patients with pH between 6.9 and 7.1.17,18
The current ADA consensus recommendation is to treat with bicarbonate in patients
with severe acidosis (pH<6.9). The recommended dose is 100 mmol of sodium bicar-
bonate in 400 mL sterile water with 20 mEq of potassium chloride administered at
200 mL/h over 2 hours until the venous pH increases to more than 7.0. Bicarbonate
Diabetic Ketoacidosis 563
administration can cause hypokalemia, therefore the addition of potassium to the infu-
sion is recommended (See Fig. 1).1
What criteria can be used to determine when DKA has resolved?
DKA is resolved when serum glucose is less than 200 mg/dL and the patient meets 2 of
the following 3 criteria: serum bicarbonate level greater than or equal to 15 mEq/L, a
venous pH greater than 7.30, or an anion gap less than or equal to 12 mEq/L.1
How is the patient transitioned to long-acting subcutaneous insulin once DKA is
resolved?
Once DKA has resolved and the patient can tolerate food, the patient can be tran-
sitioned to long-acting subcutaneous insulin therapy. In patients with known dia-
betes, the patients’ usual outpatient insulin regimens can be restarted. In patients
who were not previously on insulin, a weight-based regimen can be initiated at
0.5 to 0.8 units/kg/d divided between basal and bolus insulin.1
The insulin infusion should be continued for 1 to 2 hours after the subcutaneous
basal insulin is initiated. If for any reason the patient cannot take oral nutrition, the in-
sulin infusion can be continued until the patient is able to do so.1,10
What complications of treatment may occur?
Hypoglycemia and hypokalemia are the most common complications of treatment of
DKA. These complications can be avoided with proper monitoring of serum glucose
and potassium levels and repletion with dextrose and potassium chloride when levels
decrease.1
Cerebral edema occurs in 0.3% to 1.0% of cases of DKA in children, but is rare in
adult patients.1 Signs of cerebral edema vary and include headache, reduced level of
consciousness, seizure, incontinence, papilledema, bradycardia, increased blood
pressure, and respiratory arrest.19
How can DKA be prevented?
For many patients, medication noncompliance or lack of education regarding
proper diabetes management is the precipitating cause. For these patients, appro-
priate treatment includes evaluation of the underlying reason for noncompliance and
diabetes education.10 Evaluation of any socioeconomic barriers to care is also
prudent.
The ADA consensus statement recommends:
1. Early contact with the health care provider
2. Emphasizing the importance of insulin during an illness and the reasons never to
discontinue insulin without contacting the health care team
3. Review of blood glucose goals and the use of supplemental short-acting or rapid-
acting insulin
4. Having medications available to suppress a fever and treat an infection
5. Initiation of an easily digestible liquid diet containing carbohydrates and salt when
nauseated
6. Education of family members on sick day management and record keeping
including assessing and documenting temperature, blood glucose, and urine or
blood ketone testing; insulin administration; oral intake; and weight1
564
Gabriel & Soni
Fig. 1. Protocol for management of adult patients with DKA or HHS. BUN, blood urea nitrogen; IV, intravenous; SC, subcutaneous. y 15–20 ml/kg/h;
z
serum Na should be corrected for hyperglycemia (for each 100 mg/dl glucose 100 mg/dl, add 1.6 mEq to sodium value for corrected serum value).
(From Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;32(7):1335–43. Copyright
and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.)
Diabetic Ketoacidosis 565
PERFORMANCE IMPROVEMENT
Can the implementation of hyperglycemia protocols improve outcomes in DKA?
Several studies have shown improved outcomes with the implementation of a DKA
treatment protocol.
One retrospective study showed that patients treated after the implementation of
the protocol for DKA and HHS decreased time to resolution of DKA by 9.2 hours. There
was no difference in adverse outcomes including hypoglycemia and hypokalemia.20
Another retrospective study showed similar results with reduced time to resolution
of DKA of 9.5 hours, and reduced hospital length of stay of 11.3 hours. In this study, a
lower incidence of hypokalemia and hypoglycemia was noted.21
REFERENCES
1. Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult pa-
tients with diabetes. Diabetes Care 2009;32(7):1335–43. http://dx.doi.org/10.
2337/dc09-9032.
2. Powers AC. Diabetes mellitus. Harrison’s Principles of Internal Medicine. 18th
edition. Chapter 344. 2012.
3. Magee M, Bhatt B. Management of decompensated diabetes. Diabetes ketoaci-
dosis and hyperglycemic hyperosmolar syndrome. Crit Care Clin 2001;17(1):
75–106.
4. Maletkovic J, Drexler A. Diabetic ketoacidosis and hyperglycemic hyperosmolar
state. Endocrinol Metab Clin North Am 2013;42(4):677–95. http://dx.doi.org/10.
1016/j.ecl.2013.07.001.
5. Centers for Disease Control and Prevention. National hospital discharge survey.
2012. Available at: http://www.cdc.gov/diabetes/statistics/hospitalization_national.
htm. Accessed February 28, 2014.
6. Misra S, Oliver NS, Dornhorst A. Diabetic ketoacidosis: not always due to type 1
diabetes. BMJ 2013;346:f3501. http://dx.doi.org/10.1136/bmj.f3501.
7. Umpierrez G. Ketosis-prone type 2 diabetes. Diabetes Care 2006;29(12):2755–7.
8. Ramos-Román MA, Piñero-Piloña A, Adams-Huet B, et al. Comparison of type 1,
type 2, and atypical ketosis-prone diabetes at 4 years of diabetes duration.
J Diabetes Complications 2006;20(3):137–44. http://dx.doi.org/10.1016/j.
jdiacomp.2006.01.005.
9. Yadav D, Nair S, Norkus E, et al. Nonspecific hyperamylasemia and hyperlipase-
mia in diabetic ketoacidosis: incidence and correlation with biochemical abnormal-
ities. Am J Gastroenterol 2000;95:3123–8. http://dx.doi.org/10.1111/j.1572-0241.
2000.03279.x.
10. Nyenwe EA, Kitabchi AE. Evidence-based management of hyperglycemic emer-
gencies in diabetes mellitus. Diabetes Res Clin Pract 2011;94(3):340–51. http://
dx.doi.org/10.1016/j.diabres.2011.09.012.
11. de Veciana M. Diabetes ketoacidosis in pregnancy. Semin Perinatol 2013;37(4):
267–73. http://dx.doi.org/10.1053/j.semperi.2013.04.005.
12. Kitabchi AE, Murphy MB, Spencer J, et al. Is a priming dose of insulin necessary
in a low-dose insulin protocol for the treatment of diabetic ketoacidosis? Diabetes
Care 2008;31(11):2081–5. http://dx.doi.org/10.2337/dc08-0509.
13. Umpierrez GE, Cuervo R, Karabell A, et al. Treatment of diabetic ketoacidosis
with subcutaneous insulin aspart. Diabetes Care 2004;27(8):1873–8. http://dx.
doi.org/10.2337/diacare.27.8.1873.
566 Gabriel & Soni
14. Umpierrez GE, Latif K, Stoever J, et al. Efficacy of subcutaneous insulin lispro
versus continuous intravenous regular insulin for the treatment of patients with
diabetic ketoacidosis. Am J Med 2004;117(5):291–6. http://dx.doi.org/10.1016/
j.amjmed.2004.05.010.
15. Bernard J, Gupta R, Baldwin D. Treatment of diabetic ketoacidosis: a randomized
trial comparing subcutaneous insulin aspart with IV insulin aspart or IV regular
guided by simultaneous bedside measurement of blood glucose and B-hydrox-
ybutyrate, American Diabetes Abstract 2006.
16. Mazer M, Chen E. Is subcutaneous administration of rapid-acting insulin as effec-
tive as intravenous insulin for treating diabetic ketoacidosis? Ann Emerg Med
2009;53(2):259–63. http://dx.doi.org/10.1016/j.annemergmed.2008.07.023.
17. Duhon B, Attridge RL, Franco-Martinez AC, et al. Intravenous sodium bicarbon-
ate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother 2013;
47(7–8):970–5. http://dx.doi.org/10.1345/aph.1S014.
18. Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the manage-
ment of severe diabetic ketoacidosis? Crit Care Med 1999;27(12):2690–3.
19. Marcin JP, Glaser N, Barnett P, et al. Factors associated with adverse outcomes in
children with diabetic ketoacidosis-related cerebral edema. J Pediatr 2002;
141(6):793–7. http://dx.doi.org/10.1067/mpd.2002.128888.
20. Hara J, Rahbar A, Jeffres M, et al. Impact of a hyperglycemic crises protocol. En-
docr Pract 2013;19(6):953–9. http://dx.doi.org/10.4158/EP13077.OR.
21. Thuzar M, Malabu UH, Tisdell B, et al. Use of a standardised diabetic ketoacido-
sis management protocol improved clinical outcomes. Diabetes Res Clin Pract
2014;104:e8–11. http://dx.doi.org/10.1016/j.diabres.2014.01.016.
