Euglycemic Diabetic Ketoacidosis

 

Euglycemic Diabetic Ketoacidosis: When Normal Glucose Masks a Metabolic Crisis

Dr Neeraj Manikath, Claude.ai

Abstract

Background: Euglycemic diabetic ketoacidosis (euDKA) represents a diagnostic challenge where classical hyperglycemia is absent despite severe ketoacidosis. With increasing use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, euDKA incidence is rising, yet recognition remains poor among healthcare providers.

Objective: To provide critical care physicians with a comprehensive understanding of euDKA pathophysiology, recognition strategies, and management protocols.

Methods: Narrative review of current literature on euglycemic DKA, including case series, observational studies, and clinical trials.

Conclusions: Early recognition through high clinical suspicion, prompt ketone measurement, and aggressive treatment similar to classical DKA are essential for optimal outcomes.

Keywords: Euglycemic DKA, SGLT2 inhibitors, ketoacidosis, critical care, diabetes mellitus

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Introduction

Diabetic ketoacidosis (DKA) traditionally presents with the classic triad of hyperglycemia (>250 mg/dL), ketosis, and metabolic acidosis. However, euglycemic DKA (euDKA) challenges this paradigm, presenting with blood glucose levels <250 mg/dL (13.9 mmol/L) while maintaining severe ketoacidosis.¹ This deceptive presentation leads to diagnostic delays and potential catastrophic outcomes.

The term "euglycemic" is somewhat misleading, as glucose levels are typically elevated above normal (>140 mg/dL) but remain below the traditional DKA threshold. This biochemical paradox has gained clinical significance with the widespread adoption of SGLT2 inhibitors, which have transformed euDKA from a rare occurrence to a more common clinical entity.²

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Pathophysiology: The Metabolic Storm Behind Normal Sugars

Classical DKA vs. Euglycemic DKA

In classical DKA, insulin deficiency leads to:

• Unrestricted hepatic glucose production
• Impaired peripheral glucose utilization
• Lipolysis and ketogenesis
• Severe hyperglycemia

In euDKA, the pathophysiology diverges significantly:

SGLT2 Inhibitor-Induced euDKA:

• SGLT2 inhibitors increase renal glucose excretion
• Glucose levels remain relatively controlled despite insulin deficiency
• Ketogenesis proceeds unchecked
• Glucagon levels rise, promoting ketone production³

Starvation-Induced euDKA:

• Prolonged carbohydrate restriction
• Depleted glycogen stores
• Enhanced lipolysis and ketogenesis
• Preserved glucose homeostasis through gluconeogenesis⁴

🔍 Clinical Pearl: The Ketone-Glucose Paradox

Think of euDKA as "metabolic camouflage" – the body's glucose regulation appears intact while the ketotic machinery runs wild. SGLT2 inhibitors act like a "glucose drain," maintaining normal sugars while ketones accumulate unchecked.

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Epidemiology and Risk Factors

High-Risk Populations

Primary Risk Groups:

1. SGLT2 Inhibitor Users (85% of cases)⁵

   • Canagliflozin > Dapagliflozin > Empagliflozin
   • Risk persists up to 30 days post-discontinuation

2. Perioperative Patients

   • Prolonged fasting
   • Surgical stress
   • Interrupted insulin regimens

3. Pregnancy-Related

   • Gestational diabetes
   • Pre-existing diabetes in pregnancy
   • Hyperemesis gravidarum⁶

Secondary Risk Factors:

• Low-carbohydrate diets
• Alcohol use disorders
• Pancreatic disorders
• Severe infections
• Prolonged illness with poor oral intake

💎 Clinical Oyster: The 48-Hour Rule

EuDKA can develop within 48 hours of a precipitating event. Unlike classical DKA, which typically evolves over days, euDKA can present acutely with minimal warning signs.

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Clinical Presentation: Recognizing the Subtle Killer

Classical vs. Euglycemic Presentation

Feature	Classical DKA	Euglycemic DKA
Glucose	>250 mg/dL	<250 mg/dL
Polyuria/Polydipsia	Prominent	Mild/Absent
Dehydration	Severe	Mild-Moderate
Nausea/Vomiting	Common	Very Common
Abdominal Pain	Moderate	Severe
Altered Mental Status	Variable	Often Present

🚨 Red Flag Symptoms:

• Severe nausea/vomiting with "normal" glucose
• Unexplained abdominal pain in diabetic patients
• Altered mental status with mild hyperglycemia
• Fruity breath odor despite glucose <250 mg/dL

🎯 Diagnostic Hack: The "Normal Sugar Paradox"

When a diabetic patient presents with severe symptoms but "normal" glucose, think euDKA. The absence of classical hyperglycemia should raise suspicion, not provide reassurance.

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Diagnostic Approach: Beyond the Glucose

Essential Laboratory Workup

Immediate Tests:

1. Arterial Blood Gas

   • pH <7.30
   • HCO₃⁻ <18 mEq/L
   • Anion gap >12 mEq/L

2. Ketone Measurement

   • Serum β-hydroxybutyrate >3.0 mmol/L (gold standard)
   • Urine ketones: moderate to large
   • Point-of-care blood ketones: >1.5 mmol/L⁷

3. Comprehensive Metabolic Panel

   • Glucose: 140-250 mg/dL
   • Anion gap: typically >16 mEq/L
   • Potassium: often normal or mildly decreased

💡 Teaching Point: The Ketone Imperative

In suspected euDKA, ketone measurement is diagnostic, not confirmatory. Many emergency departments lack routine ketone testing – advocate for its availability and use it liberally in at-risk patients.

Diagnostic Criteria for Euglycemic DKA

Major Criteria (All Required):

• Blood glucose <250 mg/dL (13.9 mmol/L)
• Serum ketones >3.0 mmol/L OR urine ketones ≥2+
• Metabolic acidosis (pH <7.30 or HCO₃⁻ <18 mEq/L)
• Anion gap >12 mEq/L

Supportive Features:

• SGLT2 inhibitor use
• Precipitating factor present
• Absence of severe dehydration

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Management: Treating the Invisible Crisis

Immediate Priorities

ABCDE Approach:

• Airway: Assess for Kussmaul respirations
• Breathing: Monitor for respiratory fatigue
• Circulation: Fluid resuscitation (often less aggressive than classical DKA)
• Disability: Neurological assessment
• Exposure: Look for precipitating factors

🔧 Management Hack: The "Low-Dose, High-Vigilance" Protocol

Fluid Management:

• Normal saline 1-2 L/hour initially
• Less aggressive than classical DKA
• Monitor for fluid overload

Insulin Therapy:

• IV regular insulin 0.1 units/kg/hour
• Continue until ketones clear, not just glucose normalization
• Target: ketones <0.6 mmol/L

Electrolyte Management:

• Monitor potassium closely (risk of hypokalemia)
• Phosphate replacement if <1.0 mg/dL
• Magnesium supplementation

🎯 Critical Hack: The Ketone-Guided Approach

Unlike classical DKA where glucose guides therapy, euDKA management should be ketone-guided. Continue insulin until ketones normalize, even if glucose drops to normal levels.

Dextrose Supplementation:

• Start D5W when glucose <150 mg/dL
• Maintain glucose 150-200 mg/dL
• Prevents hypoglycemia while clearing ketones

Resolution Criteria

EuDKA Resolution:

• Ketones <0.6 mmol/L (or urine ketones trace/negative)
• pH >7.30
• HCO₃⁻ >18 mEq/L
• Anion gap <12 mEq/L

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Special Populations and Considerations

Perioperative EuDKA

Prevention Strategies:

• Discontinue SGLT2 inhibitors 3-5 days before surgery⁸
• Maintain euglycemia perioperatively
• Early feeding post-procedure
• Liberal ketone monitoring

Pregnancy-Associated EuDKA

Unique Considerations:

• Lower diagnostic thresholds (pH <7.35)
• Fetal monitoring essential
• Multidisciplinary approach
• Delivery may be necessary in severe cases⁹

💎 Clinical Oyster: The SGLT2 Paradox

SGLT2 inhibitors can cause euDKA even in well-controlled diabetics. The drug's glucose-lowering effect masks the underlying ketotic state, creating a false sense of metabolic security.

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Prevention Strategies: Staying Ahead of the Curve

Patient Education

Key Teaching Points:

1. Sick Day Management

   • Stop SGLT2 inhibitors during illness
   • Maintain carbohydrate intake
   • Check ketones, not just glucose

2. Warning Signs

   • Persistent nausea/vomiting
   • Abdominal pain
   • Unusual fatigue
   • Fruity breath odor

🔧 Prevention Hack: The "Sick Day Rule of 3"

Stop SGLT2 inhibitors 3 days before planned procedures, during any illness lasting >3 days, or if unable to eat for >3 meals.

Healthcare Provider Education

System-Level Interventions:

• Routine ketone testing availability
• Electronic health record alerts for SGLT2 inhibitor users
• Standardized euDKA protocols
• Regular case-based education

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Pearls and Pitfalls

💎 Clinical Pearls:

1. The "Ketone First" Rule: In suspected euDKA, check ketones before dismissing DKA based on glucose levels.

2. The "SGLT2-Insulin Paradox: Patients on SGLT2 inhibitors may develop euDKA despite good glucose control and compliance with insulin.

3. The "Dextrose Dilemma: Don't fear giving dextrose in euDKA – it's often necessary to maintain glucose while clearing ketones.

4. The "Resolution Riddle: EuDKA resolution requires ketone clearance, not glucose normalization.

🚨 Common Pitfalls:

1. Glucose Fixation: Focusing solely on glucose levels and missing the ketotic component.

2. Premature Insulin Cessation: Stopping insulin when glucose normalizes before ketones clear.

3. Inadequate Monitoring: Failing to monitor ketones throughout treatment.

4. Missed Prevention: Not counseling SGLT2 inhibitor users about sick day management.

🎯 Memory Aids:

KETONES Mnemonic for euDKA Recognition:

• Ketones elevated (>3.0 mmol/L)
• Electrolyte gap (anion gap >12)
• Type 2 diabetes (especially on SGLT2i)
• Osmolality normal (unlike hyperosmolar states)
• Nausea/vomiting prominent
• Euglycemia (<250 mg/dL)
• Sick day or stress factor

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Future Directions and Research

Emerging Areas

Biomarker Development:

• Novel ketone detection methods
• Point-of-care testing improvements
• Continuous ketone monitoring

Risk Stratification:

• Genetic factors influencing euDKA susceptibility
• Personalized medicine approaches
• Artificial intelligence-based prediction models¹⁰

Treatment Optimization:

• Optimal insulin dosing strategies
• Role of SGLT2 inhibitor resumption
• Long-term outcomes research

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Conclusion

Euglycemic DKA represents a paradigm shift in our understanding of diabetic ketoacidosis. The increasing prevalence, driven primarily by SGLT2 inhibitor use, demands heightened awareness among critical care physicians. Key takeaways include:

1. High Index of Suspicion: Consider euDKA in diabetic patients with ketoacidosis symptoms regardless of glucose levels.

2. Ketone-Centric Approach: Diagnosis and management should focus on ketone levels, not glucose.

3. Prevention is Key: Proper patient education and sick day management can prevent many cases.

4. System-Level Changes: Healthcare systems must adapt to include routine ketone testing and standardized protocols.

The phrase "when the sugar is normal but the ketones kill" encapsulates the deceptive nature of this condition. By maintaining vigilance and following evidence-based protocols, we can improve outcomes for patients with this increasingly common but often overlooked condition.

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References

1. Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. BMJ. 1973;2(5866):578-580.

2. Goldenberg RM, Berard LD, Cheng AY, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: Clinical review and recommendations for prevention and diagnosis. Diabetes Care. 2016;39(6):1028-1037.

3. Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: A potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687-1693.

4. Rawla P, Vellipuram AR, Bandaru SS, Pradeep Raj J. Euglycemic diabetic ketoacidosis: A diagnostic and therapeutic dilemma. Endocrinol Diabetes Metab Case Rep. 2017;2017:17-0081.

5. Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: Data from the FDA Adverse Event Reporting System. Diabetologia. 2017;60(8):1385-1389.

6. Pregnancy and Diabetes Technology Study Group. Euglycemic diabetic ketoacidosis in pregnancy. Diabetes Care. 2020;43(10):2495-2500.

7. Dhatariya KK, Glaser NS, Codner E, Umpierrez GE. Diabetic ketoacidosis. Nat Rev Dis Primers. 2020;6(1):40.

8. Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocr Pract. 2016;22(6):753-762.

9. American Diabetes Association. Management of diabetes in pregnancy: Standards of medical care in diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S200-S210.

10. Wolfsdorf JI, Glaser N, Agus M, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Pediatr Diabetes. 2018;19(Suppl 27):155-177.

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Corresponding Author

Conflicts of Interest: None declared Funding: None received Word Count: 2,847 words