Diabetic ketoacidosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Key Recommendations

The symptoms of diabetic ketoacidosis (DKA) usually develop rapidly over 1 day or less. DKA may be the initial presentation in up to 25% of people with newly diagnosed diabetes. Hyperglycemia is a key diagnostic criterion for DKA; however, a wide range of plasma glucose levels can be present on admission, and approximately 10% of patients present with glucose <200 mg/dL (<11.1 mmol/L; “euglycemic DKA”).[1] Hyperosmolar hyperglycemic state (HHS) is often discussed as a separate condition. However, DKA and HHS represent two points on the spectrum of metabolic derangements in diabetes and often present concurrently.[4] In contrast to DKA, HHS may evolve insidiously over days to weeks. Symptoms of hyperglycemia in both DKA and HHS include polyuria, polydipsia, weakness, and weight loss.[1]

Important factors to consider in the patient's past or current medical history include infection, myocardial infarction (MI), pancreatitis, stroke, acromegaly, hyperthyroidism, and Cushing syndrome, as these may be precipitants or risk factors for DKA. In euglycemic DKA, pregnancy, starvation, concomitant alcohol use, liver failure, and sodium-glucose cotransporter-2 (SGLT2) inhibitor and dual SGLT1/2 inhibitor use have all been implicated as etiologic factors.[4][17][19][58]

It is essential to take a full drug history, in particular looking for corticosteroids, thiazide diuretics, pentamidine, sympathomimetics, atypical antipsychotics, and immune checkpoint inhibitors, as these affect carbohydrate metabolism and may participate in the development of hyperglycemic crises.[1][16] SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), used for glycemic control of type 2 diabetes (or more recently, cardiovascular event risk reduction), have been the subject of a Food and Drug Administration (FDA) warning about a risk for DKA.[40] The risk is heightened with their use in certain situations, such as during severe illness or a period of prolonged fasting, or perioperatively, and they should be avoided in such cases.[4] The dual SGLT1/2 inhibitor sotagliflozin has been associated with an increased risk of DKA in patients with type 1, but not type 2, diabetes.[59][60]

It is also important to ask about illicit drug use. Cocaine use may be an independent risk factor associated with recurrent DKA.[39] Cannabis use (and associated hyperemesis syndrome) has been associated with an increased risk of DKA in adults with type 1 diabetes.[4]

Physical exam

Physical signs of volume depletion include dry mucous membranes, poor skin turgor, tachycardia, hypotension, and, in severe cases, shock. Patients may exhibit nausea, vomiting, Kussmaul respiration (characterized by deep, rapid, and labored breathing), acetone breath, and, occasionally, abdominal pain. Abdominal pain may correlate with the degree of acidosis and may be confused with an acute abdominal crisis. Most patients are normothermic or even hypothermic at presentation, even in the presence of infection.[9]

Mental status may be altered, varying from alert in mild DKA to stupor and/or coma in severe DKA. In HHS, mental obtundation and coma are more frequent.[1] Focal neurologic signs (hemianopia and hemiparesis) and seizures may also be present in HHS.[61][62] See Hyperosmolar hyperglycemic state.

Initial laboratory evaluation

Plasma glucose

Plasma glucose is typically ≥200 mg/dL (≥11.1 mmol/L) with presence of acidosis and ketonemia. However, a wide range of plasma glucose levels can be present on admission, and approximately 10% of patients present with glucose <200 mg/dL (<11.1 mmol/L; termed euglycemic DKA).[1]

Arterial and venous blood gases

Arterial blood gas (ABG) shows a metabolic acidosis, which is essential for the diagnosis of DKA. Arterial pH measurement is necessary for diagnosis of DKA, but venous pH is recommended for monitoring treatment, due to the pain and risk of infection in obtaining frequent arterial samples. A venous pH sample is usually 0.03 units lower than arterial pH, and this difference should be considered.
The pH varies from <7.00 to 7.30, and the arterial bicarbonate ranges from <10 mEq/L (<10 mmol/L) in severe DKA to >15 mEq/L (>15 mmol/L) in mild DKA.

Capillary or serum ketones (beta-hydroxybutyrate)

There are three main ketones that are produced in DKA that can be measured: acetone, acetoacetate, and beta-hydroxybutyrate (BOHB).
In early DKA, the acetoacetate concentration is low, but it is a major substrate for ketone measurement by many laboratories (nitroprusside reaction method). Therefore, serum ketone measurement by usual laboratory techniques has a high specificity but low sensitivity for DKA diagnosis (i.e., a negative test for serum ketones does not exclude DKA). Acetone is rarely measured due to its volatile nature.[63] Conversely, BOHB is an early and abundant ketoacid that can be the first signal of the development of DKA. Point-of-care BOHB testing is widely available and is highly sensitive and specific for the diagnosis of DKA.[64] Blood concentrations of BOHB ≥3 mmol/L correlate well with acid-base changes, with >90% sensitivity and specificity for DKA.[1]
During the treatment of DKA, BOHB is converted to acetoacetate. Therefore, the increase in acetoacetate during the treatment of DKA may mistakenly indicate a worsening of ketonemia.
Another potential source of error in detecting ketone bodies is the patient's drugs. Some drugs, such as the ACE inhibitor captopril, contain sulfhydryl groups that can react with the reagent in the nitroprusside test and give a false-positive result. Therefore, clinical judgment and other biochemical tests are required in patients who are receiving such drugs.[1]

Urinalysis

Typically positive for glucose and ketones. Other potential findings include leukocytes and nitrites in the presence of infection, and myoglobinuria and/or hemoglobinuria in rhabdomyolysis.
Reliance on urine ketone testing can underestimate the severity of ketonemia early in the course of DKA because of a lag in the formation of acetoacetate, and conversely overestimate its severity later in the course of DKA when BOHB is being cleared and converted into acetoacetate.[1] In addition, several sulfhydryl drugs (e.g., captopril) and drugs such as valproic acid can give false-positive nitroprusside urine tests. Thus, direct measurement of serum or capillary BOHB is preferred for diagnosis and monitoring of the response to therapy.[1]

Serum blood urea nitrogen and creatinine

Typically increased due to volume depletion.

Serum electrolytes

Sodium: patients commonly present with hyponatremia due to osmotic reflux of water from the intracellular to extracellular space in the presence of hyperglycemia.[65] Total sodium deficit is usually 7-10 mEq/kg (7-10 mmol/kg).[66] Hypernatremia in the presence of hyperglycemia indicates profound volume depletion.[65] Several estimating equations correct the measured serum sodium concentration to account for increased extracellular free water volume from hyperglycemia. The most common correction method is to increase the measured serum sodium concentration by 1.6 mEq/L (1.6 mmol/L) of serum sodium level for every 100 mg/dL (5.6 mmol/L) of serum glucose above 100 mg/dL (5.6 mmol/L).[67]
Potassium: total potassium deficit is 3-5 mEq/kg (3-5 mmol/kg).[66] However, serum potassium is usually normal or elevated due to extracellular shift of potassium caused by insulin insufficiency, hypertonicity, and acidemia. Therefore, low potassium level on admission indicates severe total-body potassium deficit.[65]
Chloride: usually low. The total chloride deficit is 3-5 mEq/kg (3-5 mmol/kg).[66]
Magnesium: usually low.[65][67]
Phosphate: there is a shift of phosphate from intracellular to extracellular fluid, with an excess urinary phosphate loss leading to hypophosphatemia. Whole-body losses can be up to 1 mmol/kg.[1] Despite this, serum phosphate is often normal or increased at presentation, but decreases with insulin therapy.[68]

Anion gap

The calculated serum anion gap in (serum sodium - [serum chloride + bicarbonate]) gives an estimate of the unmeasured anions in plasma, which in DKA are ketoacids. [ Anion Gap Opens in new window ] An anion gap >12 mEq/L (>12 mmol/L) indicates the presence of a high anion gap metabolic acidosis consistent with DKA.[1]
Mixed acid-base disorders are present in about one third of patients because of hyperglycemia-induced osmotic diuresis and natriuresis, nausea and vomiting leading to volume contraction and metabolic alkalosis, and a compensatory respiratory alkalosis caused by hyperventilation due to rapid and/or deep breathing (Kussmaul respiration).[1] In addition, hyperchloremic normal anion gap acidosis is commonly seen following successful treatment of DKA and may delay transition back to subcutaneous insulin if mistaken for persistent DKA.[1] Therefore, while normalization of the anion gap reflects correction of the ketoacidosis in the majority of patients, the anion gap is not recommended as a first-line diagnostic or resolution criterion.[1] It may still have some utility in resource-limited settings where ketone measurement is unavailable.[1]

Serum lactate

Measured to exclude lactic acidosis.[65][66] Lactate levels are normal in DKA but elevated in lactic acidosis.

Liver function tests (LFTs)

Usually normal and are used to screen for an underlying hepatic precipitant. Abnormal LFTs indicate underlying liver disease such as fatty liver, or other conditions such as congestive heart failure. Chronic liver disease is a risk factor for euglycemic DKA.[69]

Serum amylase and lipase

Nonspecific elevations of amylase can be seen.[70] In one study, amylase was elevated in 21% of patients with DKA.[35] Amylase is also elevated in acute pancreatitis, which can be a trigger for DKA development.
Measurement of serum lipase may be beneficial in differentiating pancreatitis from DKA in patients with elevated amylase levels. However, elevated lipase, traditionally thought to be more specific for pancreatitis, may also accompany DKA and does not necessarily denote concomitant pancreatic inflammation.[35][70][71]

Plasma osmolality

This is variable in DKA but is >320 mOsm/kg (>320 mmol/kg) in HHS.[1]

CBC with differential

Leukocytosis is present in hyperglycemic crises and correlates with blood ketone levels. However, leukocytosis >25,000/microliter (25 × 10⁹/L) may indicate infection and requires further evaluation.[65]

ECG

Used to exclude MI as a precipitant or to look for cardiac effects of electrolyte disturbances (usually of potassium).[1] Evidence of MI includes Q waves or ST segment changes. A high index of suspicion for MI should be maintained as patients with diabetes often present with atypical symptoms.
Evidence of hypokalemia (U waves) or hyperkalemia (tall T waves) may also be present in patients with DKA.[1]

Additional tests

Serum creatine kinase (CK)

Rhabdomyolysis is common in cocaine users with concurrent DKA.[39] CK levels should be assessed in patients with DKA if clinically indicated: for example, if acute kidney injury is present and/or a known or suspected history of cocaine use.
Establishing a diagnosis of rhabdomyolysis is based primarily on a marked elevation in serum CK level or the appearance of myoglobin in the urine (myoglobinuria).[72] After muscle injury, plasma myoglobin increases rapidly and is cleared quickly through renal excretion, and a normal level is reestablished within 24 hours. In contrast, serum CK levels elevate 2-12 hours after onset of muscle injury, peak at 3-5 days after injury, and decline over the subsequent 6-10 days.[72] Given that not all patients present within 24 hours of muscle damage, measurement of CK levels may provide the most reliable biochemical marker of rhabdomyolysis and its severity.[72]
CK elevation five times the upper limit of normal is considered as the defining biochemical abnormality for rhabdomyolysis.[72]

Chest x-ray

Indicated to exclude pneumonia. Typical changes of pneumonia include infiltration, consolidation, effusions, and cavitation.

Blood, urine, or sputum cultures

Should be obtained if there are signs of infection such as chills, constitutional upset (e.g., fatigue, confusion, anxiety), or symptoms and signs of specific infections.[13] The most common precipitating infections are pneumonia and urinary tract infections.[13] Patients are usually normothermic or hypothermic due to peripheral vasodilation, so fever may not be seen.

High-sensitivity cardiac troponin

Usually normal, but elevated if MI is the precipitant. A high index of suspicion should be maintained as patients with diabetes often present with atypical symptoms. See Non-ST-elevation myocardial infarction.