What is eDKA (euglycemic diabetic ketoacidosis), what are its common precipitants, and how should it be diagnosed and managed?

Euglycemic Diabetic Ketoacidosis (eDKA)

Definition and Diagnostic Criteria

Euglycemic DKA is diabetic ketoacidosis presenting with plasma glucose <200 mg/dL (11.1 mmol/L), occurring in approximately 10% of all DKA cases, and requires the same diagnostic criteria as typical DKA except for the glucose threshold. 1

The diagnostic criteria for eDKA include:

• Plasma glucose <200 mg/dL (distinguishing feature from classic DKA) 1
• Arterial pH <7.3 1
• Serum bicarbonate <15 mEq/L 1, 2
• Anion gap >10 mEq/L (>12 mEq/L in moderate-severe cases) 2
• Presence of ketones in blood or urine 2, 3

The key diagnostic pitfall is that normal glucose levels mask the underlying ketoacidosis, leading to delayed recognition and treatment. 3, 4 Blood pH and ketones must be checked in all ill diabetic patients regardless of glucose levels. 3

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Common Precipitants

The most critical precipitant to recognize is SGLT2 inhibitor use, which has emerged as a leading cause of eDKA in the modern era, though traditional precipitants remain important. 1, 5, 6

SGLT2 Inhibitor-Associated eDKA

• SGLT2 inhibitors increase urinary glucose excretion, creating a state of relative euglycemia despite insulin deficiency and ongoing ketogenesis. 4, 5
• Risk is 2.46 times higher in type 2 diabetes patients on SGLT2 inhibitors versus placebo (though absolute risk remains low at 0.6-4.9 events per 1,000 patient-years). 1
• Specific risk factors with SGLT2 inhibitors include very-low-carbohydrate/ketogenic diets, prolonged fasting, dehydration, excessive alcohol intake, and presence of autoimmunity. 1, 7

Traditional Precipitants

• Reduced food intake/starvation (creates insulin deficiency with poor glucose availability) 1, 3, 4
• Pregnancy (physiologic changes increase ketone production) 1
• Alcohol use (impairs gluconeogenesis while promoting ketogenesis) 1, 4
• Chronic liver disease (reduces glucose production capacity) 4
• Infection (though less common than in hyperglycemic DKA) 8, 3
• Insulin pump failure or missed insulin doses (absolute insulin deficiency) 3

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Pathophysiology

The underlying mechanism requires insulin deficiency or resistance combined with factors that limit glucose availability or increase urinary glucose loss:

• Insulin deficiency triggers glucagon release and lipolysis 4
• Free fatty acids are converted to ketone bodies (beta-hydroxybutyrate and acetoacetate) 2
• Simultaneously, glucose production is limited (starvation, liver disease) or glucose is lost in urine (SGLT2 inhibitors) 4
• This creates the paradox of severe ketoacidosis without marked hyperglycemia 4, 5

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Clinical Presentation

Patients typically present with vague, nonspecific symptoms that can delay diagnosis:

• Nausea, vomiting, malaise, fatigue 4, 6
• Abdominal pain 4
• Kussmaul respirations (deep, labored breathing from metabolic acidosis) 8
• Altered mental status may be present but is less common than in hyperglycemic DKA 8

The absence of marked hyperglycemia creates a diagnostic dilemma, as clinicians may not consider DKA when glucose is near-normal. 3, 6

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Diagnostic Workup

Obtain the following laboratory tests immediately upon suspicion:

• Venous blood gas (pH, bicarbonate, anion gap) - venous pH is adequate for monitoring and typically 0.03 units lower than arterial 1, 4
• Serum or urine ketones (beta-hydroxybutyrate preferred over nitroprusside method) 1, 2
• Basic metabolic panel (electrolytes, glucose, BUN, creatinine) 1
• Complete blood count with differential 1
• Urinalysis and cultures (blood, urine, throat) if infection suspected 8

Critical diagnostic consideration: Beta-hydroxybutyrate measurement is superior to nitroprusside-based ketone tests, as the latter only detects acetoacetate and acetone, potentially underestimating ketosis severity. 1

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Management Protocol

The treatment of eDKA differs from classic DKA in that dextrose-containing fluids must be initiated earlier to prevent hypoglycemia while continuing insulin therapy to clear ketones. 7, 5

Fluid Resuscitation

• Begin with 0.9% normal saline at 15-20 mL/kg/hour (1-1.5 L) in the first hour 1
• Switch to dextrose-containing fluids (D5W or D10W with 0.45% saline) once glucose approaches or is below 250 mg/dL 7, 5
• This differs from classic DKA where dextrose is added only after glucose falls to 250 mg/dL 1

Insulin Therapy

• Do NOT delay insulin therapy despite euglycemia - ketone clearance requires insulin 5
• If glucose is already <250 mg/dL at presentation, start dextrose-containing fluids immediately and begin insulin infusion at 0.1 units/kg/hour 7, 5
• If glucose is >250 mg/dL initially, follow standard DKA protocol: 0.15 units/kg IV bolus, then 0.1 units/kg/hour infusion 1
• Continue insulin infusion until anion gap normalizes and ketones clear, NOT just until glucose normalizes 2, 5
• Stopping insulin when glucose normalizes before acidosis resolves causes rebound ketoacidosis 2

Potassium Replacement

• Check potassium before starting insulin; do not give insulin if K+ <3.3 mEq/L 1
• Add potassium to IV fluids (20-30 mEq/L) to maintain serum K+ between 4-5 mEq/L 1

Monitoring

• Check glucose, electrolytes, venous pH, and anion gap every 2-4 hours 1, 2
• Monitor ketones (preferably beta-hydroxybutyrate) to guide treatment duration 1, 5
• Repeat arterial blood gases are generally unnecessary; venous pH is adequate 1

Resolution Criteria

eDKA is resolved when ALL of the following are met:

• Anion gap <12 mEq/L 2
• Serum bicarbonate ≥18 mEq/L 2
• Venous pH >7.3 2
• Ketones cleared or minimal 5

Transition to Subcutaneous Insulin

• Transition more slowly than in classic DKA to prevent relapse 5
• Overlap IV and subcutaneous insulin by 1-2 hours 1
• Ensure patient can tolerate oral intake before discontinuing IV insulin 1

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Special Considerations and Pitfalls

SGLT2 Inhibitor Management

• Discontinue SGLT2 inhibitor immediately upon diagnosis 6
• Consider permanent discontinuation or provide extensive patient education on risk factors before restarting 1, 6
• Counsel patients to stop SGLT2 inhibitors during illness, fasting, or before surgery 1

Pregnancy

• Pregnant patients may present with eDKA and mixed acid-base disturbances (especially with hyperemesis) 1
• Due to significant feto-maternal harm risk, pregnant patients with suspected eDKA require immediate hospitalization 1
• Lower threshold for diagnosis and treatment in pregnancy 1

Differential Diagnosis

Rule out other causes of high anion gap metabolic acidosis:

• Lactic acidosis (check lactate, assess for sepsis/hypoperfusion) 9
• Alcoholic ketoacidosis (history of alcohol use, typically less severe acidosis) 4
• Starvation ketosis (bicarbonate usually >18 mEq/L, less severe acidosis) 2
• Toxic ingestions (salicylates, methanol, ethylene glycol) 2
• Uremia (check renal function) 9

Common Treatment Errors to Avoid

• Do not withhold insulin due to euglycemia - ketone clearance requires insulin 5
• Do not stop insulin when glucose normalizes - continue until anion gap and ketones normalize 2
• Do not use excessive normal saline - can cause hyperchloremic acidosis 2
• Watch for hypoglycemia, hypokalemia, and cerebral edema (especially in pediatric patients) 1, 2

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Prevention Strategies

Patient education is paramount for preventing eDKA:

• Never discontinue basal insulin, even when not eating or during illness 1, 8
• Provide detailed sick-day management instructions including when to check ketones and contact healthcare providers 1, 8
• Counsel patients on SGLT2 inhibitors about specific risk factors: ketogenic diets, prolonged fasting, dehydration, alcohol use 1
• Measure urine or blood ketones when glucose >200 mg/dL or during illness, regardless of glucose level 1, 3
• Ensure access to affordable insulin and healthcare to prevent DKA from economic factors 8