What are the diagnostic criteria and treatment for mixed Hyperosmolar Hyperglycemic State (HHS) and Diabetic Ketoacidosis (DKA)?

Diagnosing Mixed HHS and DKA

Mixed HHS and DKA is diagnosed when a patient simultaneously meets criteria for both conditions: blood glucose >250 mg/dL with ketosis (elevated β-hydroxybutyrate >3.0 mmol/L) AND hyperosmolality (effective osmolality ≥320 mOsm/kg), with variable degrees of acidosis (pH typically 7.0-7.3, bicarbonate 10-18 mEq/L). 1, 2

Core Diagnostic Criteria

The diagnosis requires identifying overlapping features from both conditions simultaneously:

DKA Components Present:

• Blood glucose >250 mg/dL (though may be lower in euglycemic DKA) 3, 4
• Venous pH <7.3 (typically 7.0-7.3 in mixed cases) 1
• Serum bicarbonate <15-18 mEq/L (moderate range in mixed presentations) 1, 3
• Elevated blood β-hydroxybutyrate (the definitive ketone marker) 3, 4
• Anion gap >10-12 mEq/L 4

HHS Components Present:

• Marked hyperglycemia (often >30 mmol/L or ~540 mg/dL) 2
• Effective plasma osmolality ≥320 mOsm/kg calculated as: 2×[Na+] + [glucose in mg/dL]/18 + [BUN in mg/dL]/2.8 1, 2
• Severe dehydration with fluid deficits of 100-220 ml/kg 2
• Altered mental status or obtundation (more prominent than in isolated DKA) 5, 6

Key Distinguishing Feature:

Mixed cases occur in approximately one-third of hyperglycemic emergencies and represent an intermediate state where both ketoacidosis and hyperosmolality are significant. 5, 6

Essential Laboratory Workup

Obtain immediately upon presentation:

• Blood glucose 1
• Venous blood gas (arterial not necessary after initial assessment) 1, 3
• Complete metabolic panel including sodium, potassium, chloride, bicarbonate, BUN, creatinine 1
• Blood β-hydroxybutyrate (NOT urine ketones or nitroprusside tests) 3, 4
• Calculated anion gap: [Na+] - ([Cl-] + [HCO3-]) 1, 4
• Calculated effective osmolality: 2×[Na+] + [glucose]/18 1, 2
• Corrected sodium: Add 1.6 mEq/L for every 100 mg/dL glucose above 100 mg/dL 1
• Complete blood count with differential 1
• Urinalysis 1
• Serum osmolality (measured) 1
• Electrocardiogram 1
• Cultures (blood, urine, throat) if infection suspected 1, 4
• HbA1c to assess chronicity 1

Critical Ketone Measurement Considerations

Never rely on urine ketones or nitroprusside-based tests for diagnosis or monitoring. 3, 4 These methods only detect acetoacetate and acetone, completely missing β-hydroxybutyrate—the predominant and strongest ketoacid in DKA. 3, 4 During treatment, β-hydroxybutyrate converts to acetoacetate, paradoxically making nitroprusside tests appear worse even as the patient improves. 3, 4

Severity Assessment in Mixed Cases

Classify based on the most severe parameter present:

• Mild-Moderate: pH 7.00-7.30, bicarbonate 10-18 mEq/L, alert to drowsy 3, 4
• Severe: pH <7.00, bicarbonate <10 mEq/L, stuporous/comatose, or osmolality >340 mOsm/kg 4, 2

Severe mixed cases require ICU admission with consideration for central venous and intra-arterial pressure monitoring. 4, 5

Common Diagnostic Pitfalls to Avoid

• Do not dismiss DKA because glucose is <250 mg/dL—euglycemic DKA occurs, especially with SGLT2 inhibitors 3
• Do not use urine ketones for diagnosis—they miss β-hydroxybutyrate and can be falsely negative early 3, 4
• Do not assume type 2 diabetes excludes DKA—mixed presentations increasingly occur in type 2 diabetes 3, 5
• Do not overlook precipitating factors—infection is the most common trigger (70% of cases), followed by newly diagnosed diabetes (17.7%) and medication non-compliance (5.7%) 7

Monitoring During Treatment

Draw blood every 2-4 hours to measure: 1, 3, 4

• Glucose
• Electrolytes (sodium, potassium, chloride, bicarbonate)
• Venous pH (arterial not needed after initial diagnosis)
• β-hydroxybutyrate
• Anion gap
• BUN/creatinine
• Calculated osmolality

Venous pH adequately tracks acidosis resolution (typically 0.03 units lower than arterial pH) and eliminates need for repeated arterial sticks. 1, 3

Resolution Criteria

Mixed HHS-DKA is resolved when ALL of the following are met: 8, 4, 2

• Glucose <200 mg/dL
• Venous pH >7.3
• Serum bicarbonate ≥18 mEq/L
• Anion gap ≤12 mEq/L
• Osmolality <300 mOsm/kg
• Mental status returned to baseline

Ketonemia takes longer to clear than hyperglycemia—continue monitoring β-hydroxybutyrate even after glucose normalizes. 1, 8

Special Considerations for Mixed Cases

In adults with mixed features, fluid resuscitation may be more aggressive (15-20 ml/kg/h initially) because the risk of cerebral edema is low and consequences of undertreatment include vascular thrombosis and increased mortality. 1, 5 However, in younger patients, avoid rapid correction to minimize cerebral edema risk. 5

Elevated BUN on admission is an independent predictor of mortality in HHS-predominant mixed cases. 7 Mortality in mixed DKA-HHS is approximately 5.9%, intermediate between isolated DKA (<1%) and isolated HHS (21.6%). 7, 6