What is the differential diagnosis and treatment approach for a patient presenting with severe hyperglycemia, potentially indicating either Hyperosmolar Hyperglycemic State (HHS) or Diabetic Ketoacidosis (DKA)?

Differentiating and Managing HHS vs DKA

The key distinction is that DKA presents with blood glucose >250 mg/dL, pH <7.3, bicarbonate <15 mEq/L, and significant ketonemia, while HHS presents with more severe hyperglycemia (often >600 mg/dL), serum osmolality >320 mOsm/kg, minimal to no ketones, and absence of significant acidosis. 1, 2

Diagnostic Differentiation

DKA Diagnostic Criteria

• Blood glucose >250 mg/dL (though can be lower in euglycemic DKA) 1
• Venous pH <7.3 1
• Serum bicarbonate <15 mEq/L 1
• Moderate ketonuria or ketonemia (β-hydroxybutyrate is the preferred measurement method) 1
• Anion gap >10-12 mEq/L calculated as [Na⁺] - ([Cl⁻] + [HCO₃⁻]) 1, 3

HHS Diagnostic Criteria

• Serum osmolality >320 mOsm/kg (the defining feature) 2
• Blood glucose typically >600 mg/dL (much higher than DKA) 2
• Minimal to no ketones present 2
• Lack of significant metabolic acidosis (pH usually >7.3, bicarbonate >15 mEq/L) 2
• More severe dehydration than DKA 4, 5

Mixed Presentations

One-third of patients may present with overlapping features of both DKA and HHS, requiring a tailored therapeutic approach based on the dominant clinical features 4, 6

Initial Laboratory Workup

Obtain immediately upon presentation 1, 3:

• Complete metabolic panel (glucose, electrolytes, BUN, creatinine) 1, 3
• Venous blood gas (pH, bicarbonate) 1, 3
• Serum β-hydroxybutyrate (not urine ketones or nitroprusside methods) 1, 3
• Calculate corrected sodium: add 1.6 mEq/L for every 100 mg/dL glucose above 100 1, 3
• Calculate anion gap 1, 3
• Calculate serum osmolality 3
• Complete blood count with differential 3
• Urinalysis 3
• Electrocardiogram 3
• Bacterial cultures (blood, urine, throat) if infection suspected 1

Treatment Approach

For DKA

Fluid Resuscitation

• Begin with isotonic saline (0.9% NaCl) at 15-20 mL/kg/hour during the first hour 1, 7
• Subsequent fluid choice depends on corrected sodium and hydration status 1
• Add 5% dextrose to IV fluids when glucose falls to 200-250 mg/dL while continuing insulin to clear ketones 1

Insulin Therapy

• Start continuous IV regular insulin at 0.1 units/kg/hour without bolus 1, 3
• If glucose doesn't fall by 50 mg/dL in first hour, double the insulin rate hourly until steady decline of 50-75 mg/dL per hour 1
• Continue insulin infusion until ketones clear, not just until glucose normalizes 1, 8
• Administer basal subcutaneous insulin 2-4 hours before stopping IV insulin to prevent rebound 1, 8

Potassium Management

• If initial K+ <3.3 mEq/L: delay insulin and aggressively replace potassium first to prevent fatal arrhythmias 1, 3
• Once K+ known and renal function assured, add 20-30 mEq/L potassium to IV fluids 1, 7
• Target serum potassium 4-5 mEq/L 1

Resolution Criteria

DKA is resolved when ALL of the following are met 1, 3:

• Glucose <200 mg/dL
• Serum bicarbonate ≥18 mEq/L
• Venous pH >7.3
• Anion gap ≤12 mEq/L

For HHS

Fluid Resuscitation (Primary Treatment)

• Fluid replacement is the cornerstone of HHS therapy (more critical than in DKA) 4, 2
• HHS requires double the fluid replacement compared to DKA due to more severe dehydration 5
• Begin with isotonic saline at 15-20 mL/kg/hour, then adjust based on corrected sodium 1
• Control serum osmolality reduction carefully to prevent encephalopathy 5

Insulin Therapy (Delayed Approach)

• Delay and decrease initial insulin therapy in HHS until serum glucose decline is managed by fluid resuscitation alone 5
• Once insulin is started, use lower rates than in DKA 5
• In mixed cases with prominent ketoacidosis, use standard DKA insulin protocols 4

Electrolyte Management

• Profound electrolyte losses require more aggressive replacement than DKA 5
• Potassium replacement follows same principles as DKA 1

Severity Classification for DKA

• Mild: pH 7.25-7.30, bicarbonate 15-18 mEq/L, alert mental status 1, 3
• Moderate: pH 7.00-7.24, bicarbonate 10-15 mEq/L, drowsy mental status 1, 3
• Severe: pH <7.00, bicarbonate <10 mEq/L, requires intensive monitoring including possible central venous and intra-arterial pressure monitoring 1, 3

Monitoring During Treatment

Frequency

• Draw blood every 2-4 hours for glucose, electrolytes, BUN, creatinine, osmolality, venous pH 1
• Monitor β-hydroxybutyrate every 2-4 hours during active treatment 1
• After initial diagnosis, venous pH suffices—repeated arterial blood gases are unnecessary 1

Clinical Monitoring

• Vital signs, fluid input/output, mental status 7
• Watch for cerebral edema (rare in adults, more common in children with overly aggressive fluid resuscitation) 1, 5
• Screen for HHS complications: renal failure, respiratory distress, rhabdomyolysis, heart failure, hypercoagulation, hyperthermia, arrhythmias, pancreatitis 5

Critical Pitfalls to Avoid

• Never use urine ketones or nitroprusside methods for monitoring—they only measure acetoacetate/acetone, not β-hydroxybutyrate, and can falsely suggest worsening during treatment 1, 3
• Never stop IV insulin when glucose normalizes—ketoacidosis takes longer to resolve than hyperglycemia 1, 8
• Never discontinue IV insulin without giving subcutaneous basal insulin 2-4 hours prior 1, 8
• Never give insulin if initial K+ <3.3 mEq/L—replace potassium first 1, 3
• Never use bicarbonate therapy unless pH <6.9 1
• In HHS, never rush insulin therapy—let fluids work first 5
• Never assume normal temperature rules out infection—patients can be hypothermic despite serious infection 3

Precipitating Factors to Identify

Both conditions require identification and treatment of underlying cause 1, 8:

• Infection (most common trigger for HHS) 3, 2
• New-onset diabetes or insulin omission 3
• Cardiovascular events (MI, stroke) 3, 2
• Medications (corticosteroids, thiazides, sympathomimetics, SGLT2 inhibitors) 3
• Trauma, surgery, physiological stress 3
• Alcohol abuse (consider alcoholic ketoacidosis in differential) 7

Special Considerations for Mixed Cases

• In adults with mixed features, administer fluids more rapidly than in pure DKA because cerebral edema risk is low and consequences of undertreatment (vascular occlusion, mortality) are severe 4
• Tailor therapy according to prominent clinical features—if ketoacidosis dominates, treat as DKA; if hyperosmolarity dominates, treat as HHS 4
• Patients with prominent ketoacidosis in mixed cases may have type 1 diabetes requiring lifelong insulin 4

ICU Admission Criteria

Admit to ICU for 4:

• Cardiovascular instability
• Inability to protect airway
• Obtundation or severe mental status changes
• Acute abdominal signs suggesting gastric dilatation
• Inadequate floor capacity for continuous IV insulin infusion and frequent monitoring