Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis. Hyperglycemia causes an osmotic diuresis with significant fluid and electrolyte loss. DKA occurs mostly in type 1 diabetes mellitus. 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.
(See also Diabetes Mellitus and Complications of Diabetes Mellitus.)
Diabetic ketoacidosis (DKA) occurs in patients with type 1 diabetes mellitus and is less common in those with type 2 diabetes. It develops when insulin levels are insufficient to meet the body’s basic metabolic requirements. DKA is the first manifestation of type 1 diabetes 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
Acute infection (eg, pneumonia, urinary tract infection, COVID-19)
Pregnancy
Trauma
Missed insulin doses
Some medications implicated in causing DKA include
Corticosteroids
Thiazide diuretics
Sympathomimetics
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors
DKA is less common in type 2 diabetes mellitus, but it may occur in situations of unusual physiologic stress. Ketosis-prone type 2 diabetes (also referred to as Flatbush diabetes) is a variant of type 2 diabetes, which sometimes occurs in patients with obesity, often those with African (including African American or Afro-Caribbean) ancestry. Patients with ketosis-prone diabetes can have significant impairment of beta-cell function with hyperglycemia, and are therefore more likely to develop DKA when significant hyperglycemia occurs.
SGLT-2 inhibitors have been implicated in causing DKA in both type 1 and type 2 diabetes. In pregnant patients and in patients taking SGLT2 inhibitors, DKA may occur at lower or even normal blood glucose levels.
Euglycemic DKA can also occur with alcohol overuse or cirrhosis.
Pathophysiology of 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 DKA
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.
Diagnosis of DKA
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
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).
Diagnosis references
1.Buse JB, Wexler DJ, Tsapas A, et al: 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 43(2):487–493, 2020. doi: 10.2337/dci19-0066
2. Garber AJ, Handelsman Y, Grunberger G, et al: Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm--2020 executive summary. Endocrine Practice 26:107–139, 2020.
Treatment of DKA
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.
Correction of hyperglycemia and acidosis
≥ 3.3 mEq/L (≥ 3.3 mmol/L). 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 (2.8 to 4.2 mmol/L) in the first hour, insulin doses should be doubled. Children should be given a continuous IV insulin infusion of 0.1 unit/kg/hour 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 beta-hydroxybutyrate to acetoacetate (which is the “ketone” measured in most hospital laboratories) as acidosis resolves.
Serum pH and bicarbonate levels should also quickly improve, but restoration of a normal serum bicarbonate level may take 24 hours. Bicarbonate should not be given routinely because it can lead to development of acute cerebral edema (primarily in children). If bicarbonate is used, it should be started only if the pH is < 7, and only modest pH elevation should be attempted with doses of 50 to 100 mEq (50 to 100 mmol) given over 2 hours, followed by repeat measurement of arterial pH and serum potassium.
When plasma glucose becomes < 200 mg/dL (<insulin dose can be reduced to maintain glucose 150 to 200 mg/dL (8.3 to 11.1 mmol/L), but the continuous IV infusion of regular insulin should be maintained until the anion gap has narrowed on 2 consecutive blood tests and blood and urine are consistently negative for ketones. A longer duration of treatment with insulin
When the patient is stable and able to eat, a typical is begun. IV insulin should be continued for 2 hours after the initial dose of basal subcutaneous insulin is given. Children should continue to receive 0.05 unit/kg/hour insulin infusion until subcutaneous insulin is initiated and pH is > 7.3.
Hypokalemia prevention
Prevention of hypokalemia requires replacement of 20 to 30 mEq (20 to 30 mmol) potassium in each liter of IV fluid to keep serum potassium between 4 and 5 mEq/L (4 and 5 mmol/L). If serum potassium is < 3.3 mEq/L (< 3.3 mmol/L), insulin should be withheld and potassium given at 40 mEq/hour until serum potassium is ≥ 3.3 mEq/L (≥ 3.3 mmol/L); if serum potassium is > 5 mEq/L (> 5 mmol/L), potassium supplementation can be withheld.
Initially normal or elevated serum potassium measurements may reflect shifts from intracellular stores in response to acidemia and belie the true potassium deficits that almost all patients with DKA have. Insulin replacement rapidly shifts potassium into cells, so levels should be checked hourly or every other hour in the initial stages of treatment.
Other measures
Treatment references
1. Gosmanov AR, Gosmanova EO, Dillard-Cannon E: Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes 7:255–264, 2014. doi:10.2147/DMSO.S50516
2. French EK, Donihi AC, Korytkowski MT: Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ 365:l1114, 2019. doi: 10.1136/bmj.l1114
Prognosis for DKA
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).
Prognosis references
1. Edge JA, Hawkins MM, Winter DL, Dunger DB: The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child 85(1):16-22, 2001. doi:10.1136/adc.85.1.16
2. Marcin JP, Glaser N, Barnett P, et al: Factors associated with adverse outcomes in children with diabetic ketoacidosis-related cerebral edema. J Pediatr 141(6):793-797, 2002. doi:10.1067/mpd.2002.128888
3. Glaser N. Cerebral edema in children with diabetic ketoacidosis. Curr Diab Rep 2001;1(1):41-46. doi:10.1007/s11892-001-0009-7
4. Kuppermann N, Ghetti S, Schunk JE, et al. Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis. N Engl J Med 2018;378(24):2275-2287. doi:10.1056/NEJMoa1716816
Key Points
Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis.
DKA can occur when acute physiologic stressors (eg, infections, myocardial infarction) trigger acidosis, moderate glucose elevation, dehydration, and severe potassium loss in patients with type 1 diabetes.
Diagnose by an arterial pH < 7.30, with an anion gap > 12 and serum ketones in the presence of hyperglycemia.
Acidosis typically corrects with IV fluid and insulin; consider bicarbonate only if marked acidosis (pH < 7) persists after 1 hour of therapy.
Withhold insulin until serum potassium is ≥ 3.3 mEq/L (≥ 3.3 mmol/L).
Acute cerebral edema is a rare (about 1%) but lethal complication, primarily in children and less often in adolescents and young adults.
