AUTHOR AND EDITOR INFORMATION

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• Follow-up
• Miscellaneous
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INTRODUCTION

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Background

Diabetic ketoacidosis (DKA) is a complex metabolic state of hyperglycemia, ketosis, and acidosis. DKA results from untreated absolute or relative deficiency of insulin in type 1 or type 2 diabetes mellitus, respectively.

Pathophysiology

Hyperglycemia results from impaired glucose uptake because of insulin deficiency and excess glucagon with resultant gluconeogenesis and glycogenolysis. Glucagon excess also increases lipolysis with the formation of ketoacids. Ketone bodies provide alternative usable energy sources in the absence of intracellular glucose. The ketoacids (acetoacetate, beta-hydroxybutyrate, acetone) are products of proteolysis and lipolysis.

Hyperglycemia causes an osmotic diuresis that leads to excessive loss of free water and electrolytes. Resultant hypovolemia leads to tissue hypoperfusion and lactic acidosis.

Ketosis and lactic acidosis produce a metabolic acidosis; however, supplemental bicarbonate is not recommended. Acidosis usually resolves with isotonic fluid volume replenishment and insulin therapy. A recent pediatric trial of bicarbonate in severe metabolic acidosis during DKA (pH <7.15) showed no benefit when compared with placebo. Indeed, multiple studies suggest that bicarbonate therapy may cause paradoxical intracellular acidosis, worsening tissue perfusion and hypokalemia, and cerebral edema.

As acidosis corrects, acetoacetate and acetone levels increase in proportion to beta-hydroxybutyrate. As it worsens, the reverse occurs. Routine laboratory testing for ketones measures only the presence of acetoacetate and acetone, not beta-hydroxybutyrate. Therefore, ketosis may appear to be absent in early DKA and to worsen as severe DKA resolves.

Electrolyte imbalances are the consequences of hyperglycemia, hyperosmolality, and acidosis.

Despite what may be severe total body potassium depletion, apparent serum hyperkalemia often is observed in patients with DKA prior to volume resuscitation. Serum hyperkalemia occurs as potassium ions shift from the intracellular to extracellular space because of acidosis from insulin deficiency and decreased renal tubular secretion. Similar decreases in serum phosphate and magnesium concentrations are the result of ion shifts.

Hyponatremia results from a dilutional effect as free water shifts extracellularly because of high serum osmolarity. True serum sodium values can be calculated by adjusting measured sodium levels upward 1.6 mEq/L for every 100 mg/dL increase in serum glucose concentration.

As serum osmolarity increases from hyperglycemia, intracellular osmolality in the brain also increases. Overly rapid correction of serum hyperglycemia and osmolarity may create a large gradient between intracerebral and serum osmolarity. Free water then shifts into the brain and may cause cerebral edema with herniation. Therefore, fluid resuscitation and correction of hyperglycemia should be gradual and closely monitored.

Frequency

United States

Incidence of type 1 diabetes mellitus is 2 per 1000. The exact incidence of DKA is unknown but is estimated to be 4-8 per 1000. DKA occurring at the time of diagnosis of diabetes mellitus is more common in younger children. In the United States, the rate of DKA is about 25% at the time of diagnosis.

International

Exact incidence is unknown.

Mortality/Morbidity

With current medical therapy, DKA has a 2-5% mortality rate. Mortality results from the precipitating underlying cause, which is primarily cerebral edema. Cerebral edema occurs in 0.3-1% of all episodes of DKA.

Race

Because of an association with human leukocyte antigen (HLA) groups DR3 and DR4 (which occur more commonly in white populations), type 1 diabetes mellitus and DKA are more common in white children. The exact racial frequency is unknown.

CLINICAL

Section 3 of 11  

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• Follow-up
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• Multimedia
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History

Classic symptoms of diabetic ketoacidosis (DKA) often are absent in toddlers. If a patient has known diabetes, obtain a history for compliance with insulin regimens and the name of the patient's endocrinologist.

• Often insidious
• Fatigue and malaise
• Nausea/vomiting
• Abdominal pain
• Polydipsia
• Polyuria
• Polyphagia
• Weight loss
• Fever

Physical

• Altered mental status without evidence of head trauma
• Tachycardia
• Tachypnea or hyperventilation (Kussmaul respirations)
• Normal or low blood pressure
• Increased capillary refill time
• Poor perfusion
• Lethargy and weakness
• Fever
• Acetone odor of the breath reflecting metabolic acidosis

Causes

• DKA is the presenting complaint in approximately one fourth of newly diagnosed patients with type 1 diabetes mellitus.
• Infection is the most frequent cause of DKA, particularly in known diabetics.
• • Aggressive evaluation for infection always is warranted.
  • Strongly consider empiric antibiotic therapy until cultures return.
• Patient has poor compliance with existing insulin regimens.
• Patient exhibits underlying endocrine changes of adolescence (thelarche, adrenarche, menarche).
• Caregiver's lack of competence may be a cause.
• Pump failure may occur (insulin pumps are increasingly in use).

DIFFERENTIALS

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Other Problems to be Considered

Methanol toxicity

WORKUP

Section 5 of 11  

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Lab Studies

• Serum glucose (eg, Accu-Chek, Dextrostix) determination of hyperglycemia provides the opportunity for rapid diagnosis and treatment of DKA. However, a urine analysis (dip for sugar and ketones) also is acceptable.
• Serum potassium level
• • This is the most important electrolyte disturbance in patients with severe DKA.
  • A patient with a low serum potassium level should be assumed to have a potentially life-threatening total body potassium level.
  • Patients with evidence of hypovolemia or history of polydipsia who have normal or high serum potassium level should be assumed to have moderate total potassium depletion.
  • Therapy should begin with volume resuscitation.
  • As a result of the potential for hypokalemia-induced malignant dysrhythmias, do not give insulin to patients known to have profound potassium depletion until potassium replenishment is underway.
• Arterial blood gas level
• • Venous blood gases are an alternative and may be kinder for patients.
  • Historically, venous pH has been believed to overestimate the degree of acidosis because of decreased intravascular volume and increased peripheral lactic acidosis. However, an adult study of patients with DKA concluded that venous blood gases accurately demonstrated the degree of acidosis.
• Obtain serum sodium, chloride, bicarbonate, BUN, creatinine, magnesium, calcium, and phosphate levels.
• Glycosylated hemoglobin: In a patient with known diabetes, high percentages of glycosylated hemoglobin (Hgb A1C) indicate poor compliance with insulin therapy.
• Complete blood count (CBC): Note that an increased white blood cell count may be a response to stress in DKA and not necessarily a sign of infection.
• Urine glucose, ketones, and osmolality
• Serum osmolality
• Blood, urine, and throat cultures

Imaging Studies

• Obtain studies appropriate for suspected infection, obstructive abdominal processes, or cerebral edema.

Other Tests

• Electrocardiogram
• • An ECG is especially helpful when results of serum potassium concentration are not rapidly available.
  • Hyperkalemia causes peaked T waves and cardiac dysrhythmias.
• Any studies appropriate for suspected infections, toxidromes, or other metabolic abnormalities

Procedures

• Establish 2 large intravenous catheter lines for fluids, insulin infusion, drips, and further venous sampling (use distal isolated dedicated saline lock for the latter purpose, which is kinder to patients).
• Arterial catheterization if the following conditions are present:
• • Profoundly altered mental status
  • Signs of severe shock
  • Signs of severe acidosis

TREATMENT

Section 6 of 11  

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Prehospital Care

• Provide oxygen and advanced airway management, if needed.
• Monitor the patient.
• Provide isotonic intravenous fluids (eg, isotonic sodium chloride solution or lactated Ringer solution).
• Perform fingerstick glucose testing.
• Consider empiric naloxone if altered mental status is present.

Emergency Department Care

Multiple goals exist for the acute treatment of diabetic ketoacidosis (DKA), including volume resuscitation, identification and treatment of the precipitant event, insulin therapy, hourly monitoring of serum markers of DKA, and prevention of complications from rapid decreases in serum osmolarity. Each aspect of DKA management must be closely monitored.

Alter fluid, glucose, and insulin administration in response to the dynamic and often volatile metabolic changes that occur during treatment. A flow sheet is invaluable to monitor and document the progression of DKA management (see Image 1).

• Concurrent with management of DKA are basics of emergency resuscitation (eg, management of urgent airway, breathing, and circulation).
• In addition to these basics, patients with DKA should remain NPO, receive supplemental oxygen and, if bacterial infection is suspected, empiric antibiotic therapy.
• The goal of the first hour of treatment is volume resuscitation and confirmation of DKA by laboratory studies.
• • Fluids - Isotonic sodium chloride solution bolus, 20 mL/kg IV over an hour or less
  • Glucose - None, unless serum glucose level falls to 250-300 mg/dL during rehydration
• The goals of the second and succeeding hours are slow correction of hyperglycemia (with glucose level falling at a rate <100 mg/dL/h), metabolic acidosis and ketosis, in addition to continued volume replenishment.
• • These goals must be met in a manner that prevents too rapid a decrease in serum osmolarity.
  • • This usually requires several hours and meticulous attention to the patient's response to therapy.
    • Careful observation is warranted to ensure that the patient does not become hypoglycemic.
    • Hypoglycemia may occur abruptly as insulin resistance resolves.
    • To this end, maintain glucose levels above 150-250 mg/dL.
    • During this period, admit the patient to an inpatient setting.
  • Fluids
  • • Give isotonic sodium chloride solution or 0.45 isotonic sodium chloride solution (0.45% NaCl) with supplemental potassium at twice maintenance rate.
    • Add potassium as KCl, potassium phosphate, or potassium acetate.
    • If serum potassium level is in the low life-threatening range, consider replenishing potassium orally (or by nasogastric tube) in a liquid (not tablet) formulation. This corrects hypokalemia much more rapidly than intravenous replenishment, the rate of which must be reduced because of cardiac considerations.
  • • If serum potassium level is less than 3.5, add 40 mEq/L to intravenous fluids.
    • If serum potassium level is 3.5-5, add 30 mEq/L to intravenous fluids.
    • If serum potassium level is 5-5.5, add 20 mEq/L to intravenous fluids.
    • If serum potassium level is greater than 5.5, do not add additional potassium to intravenous fluids.
    • If serum potassium level is not immediately available, perform an ECG to search for electrocardiographic signs of hyperkalemia.
  • Insulin
  • • Do not give insulin until severe hypokalemia is corrected.
    • Then give 0.1 U/kg IV bolus; follow with insulin 0.1 U/kg/h IV by constant infusion. Prime all intravenous tubing before the bolus because insulin binds to intravenous tubing.
    • As a result of the potential for hypoglycemia, forego the insulin bolus if the serum glucose level is less than 500 mg/dL or if the child is known to be hypersensitive to exogenous insulin.
    • To prepare the insulin drip, add units of regular insulin equal to the patient's kilogram weight to 100 mL saline. Saturate the intravenous tubing with 20 mL of the insulin solution, and set the infusion rate equal to 10 mL/h. This provides 0.1 U/kg/h.
    • Use regular human insulin, unless the patient uses bovine insulin.
  • Glucose
  • • Add 5% dextrose (D5 or D10) to intravenous fluids, if the child remains in ketoacidosis and serum glucose level approaches 250-300 mg/dL.
    • Do not discontinue the insulin drip, as the child remains in ketoacidosis for some time and insulin is critical in eliminating ketoacidosis.
    • Maintain the serum glucose concentration at 150-250 mg/dL during insulin infusion.
    • Titrate the insulin and glucose infusions, noting that 1 unit of regular insulin metabolizes 3 g of glucose.
• The final goal is to obtain a serum glucose concentration within the reference range (serum glucose level, 100-150 mg/dL), to obtain neutral blood pH (pH =7.4; serum bicarbonate = 15-18 mEq/dL), and to eliminate serum ketones.
• • This phase includes the transition from parenteral to subcutaneous insulin and from a fasting state to oral fluids.
  • It usually occurs in the inpatient setting (see Further Inpatient Care) under the direction of a pediatric endocrinologist.
  • Fluids
  • • Give 0.45% sodium chloride solution with dextrose and potassium up to twice maintenance rate.
    • Consider oral fluids if nausea is absent.
  • Insulin: Set the intravenous infusion at 0.05-0.10 U/kg/h.
  • Glucose: Consider 5-10% dextrose in intravenous fluids to maintain serum glucose level at least 150 mg/dL.

Consultations

• A pediatric endocrinologist may be useful in complicated cases.

MEDICATION

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Medical therapy centers on fluid and electrolyte replacement. Initiate insulin therapy after beginning fluid replacement and serum potassium correction.

Drug Category: Antidiabetic agent

Insulin suppresses the formation of ketone bodies.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Admit children with DKA for further evaluation, observation, management, diabetes education, and assessment of compliance by responsible caretakers.
• Assess the need for social service intervention.

Transfer

• Transfer to a pediatric intensive care unit is prudent for the patient with persistent altered mental status, resistant acidosis, and hemodynamic instability, and for the first-time newly diagnosed patient.

Deterrence/Prevention

• If the patient is known to have diabetes, maintain compliance with an insulin therapy regimen and close contact with the treating physician. This is especially important in the presence of nausea, vomiting, and abdominal pain.

Complications

• Cerebral edema
• • Cerebral edema occurs in 0.7-1% of children with DKA.
  • Causes are multifactorial but may include too-rapid infusion of fluids and electrolytes, overhydration, and overly aggressive correction of acidosis or hyperglycemia.
  • Treatment includes intubation, hyperventilation, and mannitol 0.25-1 g/kg IV.
• Hypoglycemia
• • Causes include increased sensitivity to exogenous insulin and insufficient serum glucose for insulin to metabolize.
  • Treatment includes adding 5-10% dextrose to intravenous fluids when serum glucose level is 250-300 mg/dL.
• Hypokalemia
• • Serum potassium begins to reflect actual total body potassium depletion as volume depletion and acidosis resolve.
  • Add potassium to intravenous fluids (see Emergency Department Care) when urine output is present and results of serum potassium level are available.
• Cardiac dysrhythmia
• • Causes include hyperkalemia, hypokalemia, and hypocalcemia.
  • Treatment involves correcting the specific cause.
• Pulmonary edema
• • Causes include low plasma oncotic pressure and increased pulmonary capillary permeability.
  • Treatment includes oxygen and diuresis.

Prognosis

• The prognosis is excellent if aggressive fluid and insulin therapy commence in the first few hours of diagnosis.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Overreliance on a serum glucose level greater than 350 to diagnose DKA
• Failure to diagnose DKA or its complications
• Lack of vigilance with regard to electrolyte shifts
• Failure to diagnose underlying infection or other precipitating event
• Aggressive insulin therapy before correction of potassium
• Failure to provide adequate potassium replacement in the potassium-depleted patient

Special Concerns

• The pregnant patient with gestational diabetes should be treated in consultation with a pediatric endocrinologist and obstetrician.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Sample diabetic ketoacidosis flow sheet.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
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• Follow-up
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• Agus MS, Wolfsdorf JI. Diabetic ketoacidosis in children. Pediatr Clin North Am. Aug 2005;52(4):1147-63, ix. [Medline].
• Brandenburg MA, Dire DJ. Comparison of arterial and venous blood gas values in the initial emergency department evaluation of patients with diabetic ketoacidosis. Ann Emerg Med. Apr 1998;31(4):459-65. [Medline].
• Brink SJ. Diabetic ketoacidosis. Acta Paediatr Suppl. Jan 1999;88(427):14-24. [Medline].
• Cardella F. Insulin therapy during diabetic ketoacidosis in children. Acta Biomed Ateneo Parmense. 2005;76 Suppl 3:49-54. [Medline].
• Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child. Feb 2004;89(2):188-94. [Medline].
• Dunger DB, Sperling MA, Acerini CL, et al. European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society consensus statement on diabetic ketoacidosis in children and adolescents. Pediatrics. Feb 2004;113(2):e133-40. [Medline].
• Edge JA, Hawkins MM, Winter DL, Dunger DB. The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child. Jul 2001;85(1):16-22. [Medline].
• Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Engl J Med. Jan 25 2001;344(4):264-9. [Medline].
• Glaser N. New perspectives on the pathogenesis of cerebral edema complicating diabetic ketoacidosis in children. Pediatr Endocrinol Rev. Jun 2006;3(4):379-86. [Medline].
• Glaser N, Kuppermann N. The evaluation and management of children with diabetic ketoacidosis in the emergency department. Pediatr Emerg Care. Jul 2004;20(7):477-81; quiz 482-4. [Medline].
• Glaser NS, Wootton-Gorges SL, Buonocore MH, et al. Frequency of sub-clinical cerebral edema in children with diabetic ketoacidosis. Pediatr Diabetes. Apr 2006;7(2):75-80. [Medline].
• Green SM, Rothrock SG, Ho JD, et al. Failure of adjunctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emerg Med. Jan 1998;31(1):41-8. [Medline].
• Hale PM, Rezvani I, Braunstein AW, et al. Factors predicting cerebral edema in young children with diabetic ketoacidosis and new onset type I diabetes. Acta Paediatr. Jun 1997;86(6):626-31. [Medline].
• Kaufman FR, Halvorson M. The treatment and prevention of diabetic ketoacidosis in children and adolescents with type I diabetes mellitus. Pediatr Ann. Sep 1999;28(9):576-82. [Medline].
• Kelly AM. The case for venous rather than arterial blood gases in diabetic ketoacidosis. Emerg Med Australas. Feb 2006;18(1):64-7. [Medline].
• Lawson M. Predictors of acute complications in children with type I diabetes. J Pediatr. Nov 2002;141(5):739-40. [Medline].
• Mahoney CP, Vlcek BW, DelAguila M. Risk factors for developing brain herniation during diabetic ketoacidosis. Pediatr Neurol. Oct 1999;21(4):721-7. [Medline].
• Marcin JP, Glaser N, Barnett P, et al. Factors associated with adverse outcomes in children with diabetic ketoacidosis-related cerebral edema. J Pediatr. Dec 2002;141(6):793-7. [Medline].
• Rewers A, Chase HP, Mackenzie T, et al. Predictors of acute complications in children with type 1 diabetes. JAMA. May 15 2002;287(19):2511-8. [Medline].
• Smith CP, Firth D, Bennett S, et al. Ketoacidosis occurring in newly diagnosed and established diabetic children. Acta Paediatr. May 1998;87(5):537-41. [Medline].
• Wolfsdorf J, Glaser N, Sperling MA; American Diabetes Association. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care. May 2006;29(5):1150-9. [Medline].

Article Last Updated: Jan 4, 2007