Euglycaemic Diabetic Ketoacidosis

Euglycaemic diabetic ketoacidosis is ketoacidosis with a plasma glucose lower than usually expected, commonly under 11.1 mmol/L (200 mg/dL), although some definitions use under 14 mmol/L (250 mg/dL). Diagnosis needs ketonaemia (beta hydroxybutyrate 3 mmol/L or more) and acidosis (pH under 7.3 or bicarbonate under 18 mmol/L).

Epidemiology. It is a recognised complication of sodium-glucose cotransporter-2 inhibitors, with a much higher risk in type 1 diabetes (where use is off label) than in type 2 diabetes. It also occurs in pregnancy, starvation, low carbohydrate or ketogenic diets, alcohol excess and pancreatitis.

Causes and triggers.

• SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin), whose effect can last several days after the last dose.
• Insulin omission or dose reduction, and insulin deficiency states (type 1, latent autoimmune diabetes, pancreatic disease).
• Acute illness, infection, surgery and fasting before surgery, reduced oral intake, vomiting and dehydration.
• Heavy alcohol use, a low carbohydrate diet, pregnancy and liver disease.

Pathophysiology. SGLT2 inhibition lowers glucose and insulin secretion and raises glucagon, promoting lipolysis and hepatic ketogenesis, while reduced renal clearance of ketones prolongs ketosis. Glucose is lost in the urine, so plasma glucose stays normal or modestly raised despite severe insulin deficiency, which hides the diagnosis.

Presentation is nausea, vomiting, abdominal pain, malaise, deep breathing, polyuria or reduced intake, and confusion. Glucose may be normal or only mildly raised. A precipitant should be sought. Urine dipsticks may be negative early, because beta hydroxybutyrate is poorly detected.

Red flags.

• An unwell patient taking an SGLT2 inhibitor, even with normal glucose.
• Pregnancy with vomiting or reduced intake.
• Abdominal pain with acidosis, reduced consciousness, hypotension or pH under 7.1.
• Recent surgery or prolonged fasting.

Measure capillary or plasma beta hydroxybutyrate (3 mmol/L or more), venous blood gas, bicarbonate, anion gap, lactate, glucose, electrolytes (potassium, sodium, phosphate, magnesium), urea and creatinine, full blood count and ECG. Look for infection, pancreatitis (lipase) and pregnancy.

Differential diagnosis.

• Alcoholic ketoacidosis and starvation ketosis.
• Lactic acidosis and metformin toxicity.
• Salicylate toxicity and toxic alcohols.
• Sepsis with acidosis and renal failure.
• Typical diabetic ketoacidosis with moderate hyperglycaemia.

Stop the SGLT2 inhibitor at presentation and do not restart it without specialist review. Stop metformin during acute illness.

Fluids. 0.9% sodium chloride 1 L IV over the first hour, then 1 L over 2 hours, then 1 L over 4 hours, adjusted to haemodynamics and sodium. Reduce volumes in heart failure, renal failure and older adults.

Insulin and glucose. Start fixed rate IV insulin 0.1 units/kg/h. Because glucose is normal, add 10% dextrose at 125 mL/h (or 5 to 10% dextrose with the saline) from the start, so that insulin can continue and suppress ketogenesis. Check glucose hourly, and adjust dextrose to keep glucose 8 to 12 mmol/L. Continue insulin until beta hydroxybutyrate is under 0.6 mmol/L and pH is over 7.3, then start subcutaneous insulin with a 30 to 60 minute overlap.

Potassium.

• Under 3.3 mmol/L: potassium chloride 10 to 20 mmol/h IV with cardiac monitoring, and delay insulin until potassium is over 3.3 mmol/L.
• 3.3 to 5.2 mmol/L: add 20 to 30 mmol to each litre of fluid, aiming for 4 to 5 mmol/L.
• Over 5.2 mmol/L: withhold potassium and recheck every 2 hours.
• Without cardiac monitoring give no more than 20 mmol/h peripherally, and recheck every 1 to 2 hours.

Bicarbonate. Only if pH is under 6.9: sodium bicarbonate 100 mmol in 400 mL sterile water with 20 mmol potassium chloride, infused over 2 hours, repeated if pH stays under 7.0.

Phosphate, magnesium and thiamine. Replace phosphate and magnesium when severely low or with respiratory or cardiac muscle weakness. Give thiamine 100 mg IV when alcohol excess or malnutrition is likely.

Monitoring. Hourly capillary glucose and beta hydroxybutyrate, venous gas and electrolytes every 2 to 4 hours, urine output, GCS, ECG for potassium, and fluid balance. Reassess if ketones do not fall by 0.5 mmol/L/h within 4 to 6 hours.

Perioperative prevention. Stop canagliflozin, dapagliflozin and empagliflozin at least 3 days before elective surgery, and ertugliflozin at least 4 days before. Restart only when eating and drinking normally.

Referral and escalation. Diabetes team review, and intensive care for pH under 7.1, shock, reduced consciousness, pregnancy or failure to improve.

Special groups. In pregnancy, ketoacidosis can occur at lower glucose and carries high foetal loss, so treat urgently with obstetric and diabetes input and avoid SGLT2 inhibitors. In children and adolescents, use weight based fluids with cautious volume and the same insulin rate. In renal impairment, reduce fluid volume and monitor potassium closely.