How do you differentiate and manage a patient with severe hyperglycemia, suspected of having either Hyperosmolar Hyperglycemic State (HHS) or Diabetic Ketoacidosis (DKA)?

Differentiating and Managing HHS vs DKA

The key to differentiating HHS from DKA lies in three critical laboratory values: serum osmolality (>320 mOsm/kg in HHS), pH (>7.3 in HHS vs <7.3 in DKA), and bicarbonate (>15 mEq/L in HHS vs <15 mEq/L in DKA), with glucose typically >600 mg/dL in HHS compared to >250 mg/dL in DKA. 1

Initial Diagnostic Workup

Upon presentation of severe hyperglycemia, immediately obtain:

• Venous blood gas to measure pH and bicarbonate—this is the single most important test to differentiate the two conditions 2
• Complete metabolic panel including glucose, electrolytes (sodium, potassium, chloride), BUN, and creatinine 2
• Serum osmolality calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18 1
• β-hydroxybutyrate (preferred over nitroprusside-based ketone tests) for accurate ketone measurement 2
• Anion gap calculation: [Na⁺] - ([Cl⁻] + [HCO₃⁻]) 2
• Electrocardiogram to detect cardiac complications and potassium-related arrhythmias 2
• Complete blood count with differential and urinalysis to identify precipitating infections 2

Corrected Sodium Calculation

Always correct sodium for hyperglycemia: add 1.6 mEq/L for every 100 mg/dL glucose above 100 mg/dL 1, 2

Diagnostic Criteria Comparison

DKA Criteria:

• Blood glucose >250 mg/dL 1, 2
• Venous pH <7.3 1, 2
• Bicarbonate <15 mEq/L 1, 2
• Anion gap >10-12 mEq/L 2
• Moderate to severe ketonemia/ketonuria 1

HHS Criteria:

• Blood glucose >600 mg/dL 1
• Venous pH >7.3 1
• Bicarbonate >15 mEq/L 1
• Effective serum osmolality >320 mOsm/kg 1
• Minimal to mild ketonuria/ketonemia 1
• Altered mental status or severe dehydration 1

Mixed Presentations:

Approximately one-third of patients present with overlapping features of both DKA and HHS, requiring treatment tailored to the dominant clinical features 3, 4

Management Algorithm

Step 1: Fluid Resuscitation (CRITICAL FIRST STEP)

For DKA:

• Start with 0.9% NaCl at 15-20 mL/kg/h (1-1.5 L) during the first hour 1
• After initial bolus, continue 0.9% NaCl at 250-500 mL/h if corrected sodium is low or normal 1
• Switch to 0.45% NaCl at 250-500 mL/h if corrected sodium is high 1

For HHS:

• More aggressive fluid replacement is required due to severe dehydration 3, 5
• Start with 0.9% NaCl at 15-20 mL/kg/h during the first hour 1
• Continue with 0.45% or 0.9% NaCl at 250-500 mL/h based on corrected sodium and hydration status 1
• In HHS, fluid resuscitation alone should decrease glucose before insulin is started 5

In pediatric patients (<20 years):

• Use 1.5 times the 24-hour maintenance requirements (5 mL/kg/h) for smooth rehydration 1
• Do not exceed two times maintenance requirement to avoid cerebral edema risk 1

Step 2: Potassium Replacement (BEFORE INSULIN)

CRITICAL PITFALL: Never start insulin if potassium <3.3 mEq/L—this can cause fatal arrhythmias 1, 2

• If K+ <3.3 mEq/L: Hold insulin and give 20-30 mEq/h potassium until K+ >3.3 mEq/L 1
• If K+ 3.3-5.2 mEq/L: Add 20-40 mEq potassium to each liter of IV fluid 1
• If K+ >5.2 mEq/L: Do not give potassium but check levels every 2 hours 1
• Use 2/3 KCl (or potassium acetate) and 1/3 KPO₄ 1

Step 3: Insulin Therapy

For DKA (moderate to severe):

• Give IV bolus of regular insulin 0.15 units/kg body weight 1
• Start continuous IV infusion at 0.1 units/kg/h (5-7 units/h in adults) 1
• In pediatric patients: Skip the bolus and start infusion at 0.1 units/kg/h 1
• Target glucose decline of 50-75 mg/dL/h 1
• If glucose doesn't fall by 50 mg/dL in first hour, double insulin infusion hourly until steady decline achieved 1

For HHS:

• Delay insulin until after initial fluid resuscitation 5
• Use same insulin protocol as DKA once started 1
• When glucose reaches 300 mg/dL (vs 250 mg/dL in DKA), decrease insulin to 0.05-0.1 units/kg/h 1

For mild DKA:

• Subcutaneous rapid-acting insulin can be used in emergency department or step-down units 1
• Give 0.4-0.6 units/kg body weight (half IV bolus, half subcutaneous), then 0.1 units/kg/h subcutaneously 1

Step 4: Dextrose Addition

• When glucose reaches 250 mg/dL in DKA or 300 mg/dL in HHS, add 5-10% dextrose to IV fluids 1
• Continue insulin infusion at reduced rate (0.05-0.1 units/kg/h) to clear ketones 1

Step 5: Monitoring

Monitor every 2-4 hours:

• Serum electrolytes, glucose, BUN, creatinine, osmolality 1
• Venous pH (usually 0.03 units lower than arterial pH) and anion gap 1
• β-hydroxybutyrate is preferred over nitroprusside-based ketone tests 2

CRITICAL PITFALL: Nitroprusside methods only measure acetoacetic acid and acetone, not β-hydroxybutyrate (the predominant ketone). During treatment, β-OHB converts to acetoacetic acid, falsely suggesting worsening ketosis. 1, 2

Resolution Criteria

DKA is resolved when ALL of the following are met:

• Glucose <200 mg/dL 1, 2
• Serum bicarbonate ≥18 mEq/L 1, 2
• Venous pH >7.3 1, 2
• Anion gap ≤12 mEq/L 2

HHS is resolved when:

• Mental status normalizes 1
• Osmolality normalizes 1
• Patient can tolerate oral intake 1

Transition to Subcutaneous Insulin

CRITICAL PITFALL: Premature discontinuation of IV insulin causes rebound hyperglycemia and recurrent ketoacidosis 1, 4

• Administer basal subcutaneous insulin (long-acting or NPH) 2-4 hours BEFORE stopping IV insulin 1
• Overlap is essential to prevent recurrence 1
• Start multiple-dose subcutaneous insulin regimen combining short/rapid-acting with intermediate/long-acting insulin 1

Special Considerations

Bicarbonate Therapy

Bicarbonate use is generally NOT recommended—studies show no difference in resolution of acidosis or time to discharge 1

Phosphate Monitoring

Monitor phosphate levels during treatment, especially if approaching lower limits of normal 2

Mixed DKA/HHS Cases

• Treat based on dominant clinical features 3
• In adults: More aggressive fluid administration is safe (low cerebral edema risk) 3
• In children/young adults: Avoid rapid correction to prevent cerebral edema 3
• Patients with mixed features and prominent ketoacidosis likely have type 1 diabetes requiring lifelong insulin 3

Precipitating Factors to Address

• Infection (most common) 2, 4
• Myocardial infarction or stroke 1, 2
• Medication non-adherence or insulin omission 2
• New-onset diabetes 2
• Medications (corticosteroids, thiazides, sympathomimetics) 2

Key Differences in Clinical Approach

HHS requires more aggressive fluid replacement than DKA due to more severe dehydration and higher osmolality 3, 5. In HHS, fluid resuscitation is the cornerstone of therapy, while in DKA, insulin therapy is the cornerstone 3. The osmolality reduction in HHS should not exceed 3 mOsm/kg/h to prevent cerebral edema 1.