Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis. DKA occurs mostly in type 1 diabetes mellitus (DM). It causes nausea, vomiting, and abdominal pain and can progress to cerebral edema, coma, and death. DKA is diagnosed by detection of hyperketonemia and anion gap metabolic acidosis in the presence of hyperglycemia. Treatment involves volume expansion, insulin replacement, and prevention of hypokalemia.
DKA is most common among patients with type 1 DM and develops when insulin levels are insufficient to meet the body's basic metabolic requirements. DKA is the first manifestation of type 1 DM in a minority of patients. Insulin deficiency can be absolute (eg, during lapses in the administration of exogenous insulin) or relative (eg, when usual insulin doses do not meet metabolic needs during physiologic stress).
Common physiologic stresses that can trigger DKA include
Drugs implicated in causing DKA include
DKA is less common in type 2 DM, but it may occur in situations of unusual physiologic stress.
Insulin deficiency causes the body to metabolize triglycerides and muscle instead of glucose for energy. Serum levels of glycerol and free fatty acids (FFAs) rise because of unrestrained lipolysis, as does alanine because of muscle catabolism. Glycerol and alanine provide substrate for hepatic gluconeogenesis, which is stimulated by the excess of glucagon that accompanies insulin deficiency. Glucagon also stimulates mitochondrial conversion of FFAs into ketones. Insulin normally blocks ketogenesis by inhibiting the transport of FFA derivatives into the mitochondrial matrix, but ketogenesis proceeds in the absence of insulin. The major ketoacids produced, acetoacetic acid and β-hydroxybutyric acid, are strong organic acids that create metabolic acidosis. Acetone derived from the metabolism of acetoacetic acid accumulates in serum and is slowly disposed of by respiration.
Hyperglycemia due to insulin deficiency causes an osmotic diuresis that leads to marked urinary losses of water and electrolytes. Urinary excretion of ketones obligates additional losses of Na and K. Serum Na may fall from natriuresis or rise due to excretion of large volumes of free water. K is also lost in large quantities, sometimes > 300 mEq/24 h. Despite a significant total body deficit of K, initial serum K is typically normal or elevated because of the extracellular migration of K in response to acidosis. K levels generally fall further during treatment as insulin therapy drives K into cells. If serum K is not monitored and replaced as needed, life-threatening hypokalemia may develop.
Symptoms and Signs
Symptoms and signs of DKA include those of hyperglycemia ( see Symptoms and Signs) with the addition of nausea, vomiting, and—particularly in children—abdominal pain. Lethargy and somnolence are symptoms of more severe decompensation. Patients may be hypotensive and tachycardic from dehydration and acidosis; they may breathe rapidly and deeply to compensate for acidemia (Kussmaul respirations). They may also have fruity breath due to exhaled acetone. Fever is not a sign of DKA itself and, if present, signifies underlying infection. In the absence of timely treatment, DKA progresses to coma and death.
Acute cerebral edema, a complication in about 1% of DKA patients, occurs primarily in children and less often in adolescents and young adults. Headache and fluctuating level of consciousness herald this complication in some patients, but respiratory arrest is the initial manifestation in others. The cause is not well understood but may be related to too-rapid reductions in serum osmolality or to brain ischemia. It is most likely to occur in children < 5 yr when DKA is the initial manifestation of DM. Children with the highest BUN and lowest Paco2 at presentation appear to be at greatest risk. Delays in correction of hyponatremia and the use of HCO3 during DKA treatment are additional risk factors.
In patients suspected of having DKA, serum electrolytes, BUN and creatinine, glucose, ketones, and osmolarity should be measured. Urine should be tested for ketones. Patients who appear significantly ill and those with positive ketones should have ABG measurement. DKA is diagnosed by an arterial pH < 7.30 with an anion gap > 12 (see The Anion Gap) and serum ketones in the presence of hyperglycemia. A presumptive diagnosis can be made when urine glucose and ketones are strongly positive. Urine test strips and some assays for serum ketones may underestimate the degree of ketosis because they detect acetoacetic and not β-hydroxybutyric acid, which is usually the predominant ketoacid.
Symptoms and signs of a triggering illness should be pursued with appropriate studies (eg, cultures, imaging studies). Adults should have an ECG to screen for acute MI and to help determine the significance of abnormalities in serum K.
Other laboratory abnormalities include hyponatremia, elevated serum creatinine, and elevated plasma osmolality. Hyperglycemia may cause dilutional hyponatremia, so measured serum Na is corrected by adding 1.6 mEq/L for each 100 mg/dL elevation of serum glucose over 100 mg/dL. To illustrate, for a patient with serum Na of 124 mEq/L and glucose of 600 mg/dL, add 1.6 ([600 − 100]/100) = 8 mEq/L to 124 for a corrected serum Na of 132 mEq/L. As acidosis is corrected, serum K drops. An initial K level < 4.5 mEq/L indicates marked K depletion and requires immediate K supplementation. Serum amylase and lipase are often elevated, even in the absence of pancreatitis (which may be present in alcoholic DKA patients and in those with coexisting hypertriglyceridemia).
Mortality rates for DKA are between 1 and 10%. Shock or coma on admission indicates a worse prognosis. Main causes of death are circulatory collapse, hypokalemia, and infection. Among children with cerebral edema, 57% recover completely, 21% survive with neurologic sequelae, and 21% die.
The most urgent goals are rapid intravascular volume repletion, correction of hyperglycemia and acidosis, and prevention of hypokalemia. Identification of precipitating factors is also important. Treatment should occur in intensive care settings because clinical and laboratory assessments are initially needed every hour or every other hour with appropriate adjustments in treatment.
Intravascular volume should be restored rapidly to raise BP and ensure glomerular perfusion; once intravascular volume is restored, remaining total body water deficits are corrected more slowly, typically over about 24 h. Initial volume repletion in adults is typically achieved with rapid IV infusion of 1 to 3 L of 0.9% saline solution, followed by saline infusions at 1 L/h or faster as needed to raise BP, correct hyperglycemia, and keep urine flow adequate. Adults with DKA typically need a minimum of 3 L of saline over the first 5 h. When BP is stable and urine flow adequate, normal saline is replaced by 0.45% saline. When plasma glucose falls to < 200 mg/dL, IV fluid should be changed to 5% dextrose in 0.45% saline.
For children, fluid deficits are estimated at 60 to 100 mL/kg body weight. Maintenance fluids (for ongoing losses) must also be provided (see Maintenance requirements). Initial fluid therapy should be 0.9% saline (20 mL/kg) over 1 to 2 h, followed by 0.45% saline once BP is stable and urine output adequate. The remaining fluid deficit should be replaced over 36 h, typically requiring a rate (including maintenance fluids) of about 2 to 4 mL/kg/h, depending on the degree of dehydration.
Hyperglycemia is corrected by giving regular insulin 0.1 unit/kg IV bolus initially, followed by continuous IV infusion of 0.1 unit/kg/h in 0.9% saline solution. Insulin should be withheld until serum K is ≥ 3.3 mEq/L (see Treatment). Insulin adsorption onto IV tubing can lead to inconsistent effects, which can be minimized by preflushing the IV tubing with insulin solution. If plasma glucose does not fall by 50 to 75 mg/dL in the first hour, insulin doses should be doubled. Children should be given a continuous IV insulin infusion of 0.1 unit/kg/h or higher with or without a bolus.
Ketones should begin to clear within hours if insulin is given in sufficient doses. However, clearance of ketones may appear to lag because of conversion of β-hydroxybutyrate to acetoacetate (which is the “ketone” measured in most hospital laboratories) as acidosis resolves. Serum pH and HCO3 levels should also quickly improve, but restoration of a normal serum HCO3 level may take 24 h. Rapid correction of pH by HCO3 administration may be considered if pH remains < 7 after about an hour of initial fluid resuscitation, but HCO3 is associated with development of acute cerebral edema (primarily in children) and should not be used routinely. If used, only modest pH elevation should be attempted (target pH of about 7.1), with doses of 50 to 100 mEq over 30 to 60 min, followed by repeat measurement of arterial pH and serum K.
When plasma glucose becomes < 200 mg/dL (< 11.1 mmol/L) in adults, 5% dextrose should be added to IV fluids to reduce the risk of hypoglycemia. Insulin dosage can then be reduced to 0.02 to 0.05 unit/kg/h, but the continuous IV infusion of regular insulin should be maintained until the anion gap has narrowed and blood and urine are consistently negative for ketones. Insulin replacement may then be switched to regular insulin 5 to 10 units sc q 4 to 6 h. When the patient is stable and able to eat, a typical split-mixed or basal-bolus insulin regimen is begun. IV insulin should be continued for 1 to 4 h after the initial dose of sc insulin is given. Children should continue to receive 0.05 unit/kg/h insulin infusion until sc insulin is initiated and pH is > 7.3.
Hypokalemia prevention requires replacement of 20 to 30 mEq K in each liter of IV fluid to keep serum K between 4 and 5 mEq/L. If serum K is < 3.3 mEq/L, insulin should be withheld and K given at 40 mEq/h until serum K is ≥ 3.3 mEq/L; if serum K is > 5 mEq/L, K supplementation can be withheld. Initially normal or elevated serum K measurements may reflect shifts from intracellular stores in response to acidemia and belie the true K deficits that almost all DKA patients have. Insulin replacement rapidly shifts K into cells, so levels should be checked hourly or every other hour in the initial stages of treatment. Hypophosphatemia often develops during treatment of DKA, but phosphate repletion is of unclear benefit in most cases. If indicated (eg, if rhabdomyolysis, hemolysis, or neurologic deterioration occurs), K phosphate 1 to 2 mmol/kg of phosphate, can be infused over 6 to 12 h. If K phosphate is given, the serum Ca level usually decreases and should be monitored.
Treatment of suspected cerebral edema is hyperventilation, corticosteroids, and mannitol, but these measures are often ineffective after the onset of respiratory arrest.
Last full review/revision December 2012 by Preeti Kishore, MD
Content last modified October 2013