Diabetic Ketoacidosis (DKA)

Insulin deficiency and an increase in counterregulatory hormones (glucagon, catecholamines, cortisol) causes the body to metabolize triglycerides and amino acids instead of glucose for energy. Serum levels of glycerol and free fatty acids rise because of unrestrained lipolysis. Alanine levels rise 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 free fatty acids into ketones. Insulin normally blocks ketogenesis by inhibiting the transport of free fatty acid derivatives into the mitochondrial matrix, but ketogenesis proceeds in the absence of insulin. The major ketoacids produced, acetoacetic acid and beta-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 sodium and potassium. Serum sodium may fall due to natriuresis or rise due to excretion of large volumes of free water.

Potassium is also lost in large quantities. Despite a significant total body deficit of potassium, initial serum potassium is typically normal or elevated because of the extracellular migration of potassium in response to acidosis. Potassium levels generally fall further during treatment as insulin therapy drives potassium into cells. If serum potassium is not monitored and replaced as needed, life-threatening hypokalemia may develop.

Symptoms and signs of diabetic ketoacidosis include symptoms of hyperglycemia 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 due to 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 years when DKA is the initial manifestation of diabetes mellitus. Children with the highest BUN (blood urea nitrogen) levels and lowest PaCO2 at presentation appear to be at greatest risk. Delays in correction of hyponatremia and the use of bicarbonate during DKA treatment are additional risk factors.

• Arterial pH

• Serum ketones

• Calculation of anion gap

In patients suspected of having diabetic ketoacidosis, serum electrolytes, blood urea nitrogen (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 arterial blood gas measurement.

DKA is diagnosed by an arterial pH < 7.30 with an anion gap > 12 and serum ketones. Guidelines differ on specific levels of hyperglycemia to be included in the diagnostic criteria for DKA. A blood glucose level > 200 (11.1 mmol/L) or > 250 mg/dL (13.8 mmol/L) is most often specified; however, because DKA can occur in patients with normal or mildly elevated glucose levels, some guidelines do not include a specific level (1, 2).

A presumptive diagnosis may be made when urine glucose and ketones are positive on urinalysis. Urine test strips and some assays for serum ketones may underestimate the degree of ketosis because they detect acetoacetic acid and not beta-hydroxybutyric acid, which is usually the predominant ketoacid.

Blood beta-hydroxybutyrate can be measured, or treatment can be initiated based on clinical suspicion and the presence of anion gap acidosis if serum or urine ketones are low.

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 myocardial infarction and to help determine the significance of abnormalities in serum potassium.

Other laboratory abnormalities include

• Hyponatremia

• Elevated serum creatinine

• Elevated plasma osmolality

Hyperglycemia may cause dilutional hyponatremia, so measured serum sodium is corrected by adding 1.6 mEq/L (1.6 mmol/L) for each 100 mg/dL (5.6 mmol/L) elevation of serum glucose over 100 mg/dL (5.6 mmol/L).

To illustrate, for a patient with serum sodium of 124 mEq/L (124 mmol/L) and glucose of 600 mg/dL (33.3 mmol/L), add 1.6 ([600 −100]/100) = 8 mEq/L (8 mmol/L) to 124 for a corrected serum sodium of 132 mEq/L (132 mmol/L).

As acidosis is corrected, serum potassium drops. An initial potassium level < 4.5 mEq/L (< 4.5 mmol/L) indicates marked potassium depletion and requires immediate potassium supplementation.

Serum amylase and lipase are often elevated, even in the absence of pancreatitis (which may be present in patients with alcoholic ketoacidosis and in those with coexisting hypertriglyceridemia).

Clinical Calculators

Anion Gap

• IV 0.9% saline

• Correction of hypokalemia

• IV insulin (as long as serum potassium is ≥ 3.3 mEq/L [3.3 mmol/L])

• < 7 after 1 hour of treatment)

The most urgent goals for treating diabetic ketoacidosis are rapid intravascular volume repletion, correction of hyperglycemia and acidosis, and prevention of hypokalemia (1, 2). 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.

Volume repletion

Intravascular volume should be restored rapidly to raise blood pressure and ensure glomerular perfusion; once intravascular volume is restored, remaining total body water deficits are corrected more slowly, typically over about 24 hours. Initial volume repletion in adults is typically achieved with rapid IV infusion of 1 to 1.5 L of 0.9% saline solution in the first hour, followed by saline infusions at 250 to 500 mL/hour. Additional boluses or a faster rate of infusion may be needed to raise the blood pressure. Slower rates of infusion may be needed in patients with heart failure or in those at risk for volume overload. If the serum sodium level is normal or high, the normal saline is replaced by 0.45% saline after initial volume resuscitation. When plasma glucose falls to < 200 mg/dL (<

For children, fluid deficits are estimated at 30 to 100 mL/kg body weight. Pediatric maintenance fluids< 300 mg/dL (16.7 mmol/L) and blood pressure is stable and urine output adequate. The remaining fluid deficit should be replaced over 24 to 48 hours, typically requiring a rate (including maintenance fluids) of about 2 to 5 mL/kg/hour, depending on the degree of dehydration.

Clinical Calculators

Maintenance Fluid Calculation for Children

Overall mortality rates for diabetic ketoacidosis are < 1%; however, mortality is higher in older patients and in patients with other life-threatening illnesses. Shock or coma on admission indicates a worse prognosis. Main causes of death are circulatory collapse, hypokalemia, and infection. In older studies of children with clinically apparent cerebral edema, about one quarter of patients died, and 15 to 35% survived with persistent neurologic sequelae (1, 2, 3). Another study had lower rates of persistent neurologic sequelae and death (4).