What is the recommended treatment approach for hyperosmolar hyperglycemic state (HHS)?

Treatment of Hyperosmolar Hyperglycemic State (HHS)

The cornerstone of HHS management is aggressive fluid resuscitation with isotonic saline followed by insulin therapy only after initial volume expansion, with careful monitoring to avoid rapid osmolality correction that can cause fatal neurological complications. 1, 2

Immediate Initial Assessment and Diagnosis

Upon suspicion of HHS, obtain the following laboratory tests immediately: 1, 2

• Plasma glucose, serum electrolytes with calculated anion gap, and serum osmolality
• Blood urea nitrogen, creatinine, serum ketones (preferably β-hydroxybutyrate)
• Arterial blood gases, complete blood count with differential
• Urinalysis with urine ketones, electrocardiogram, and HbA1c
• Bacterial cultures (blood, urine, throat) if infection is suspected
• Chest X-ray if pneumonia is suspected

Calculate effective serum osmolality using: 2[measured Na (mEq/L)] + glucose (mg/dL)/18 1, 2

Correct serum sodium for hyperglycemia by adding 1.6 mEq/L for each 100 mg/dL glucose elevation above 100 mg/dL 1, 2

HHS is diagnosed when: 1, 2

• Blood glucose ≥600 mg/dL
• Effective serum osmolality ≥320 mOsm/kg H₂O
• Arterial pH ≥7.30
• Serum bicarbonate ≥15 mEq/L
• Small or absent ketones in urine and serum

Fluid Resuscitation Protocol

Begin with isotonic saline (0.9% NaCl) at 15-20 mL/kg/hour (1-1.5 L in average adult) during the first hour to restore intravascular volume and renal perfusion. 1, 2 This is the single most critical intervention, as fluid replacement alone will cause blood glucose to fall. 3

The total body water deficit in HHS is approximately 9 liters (100-220 mL/kg), and you must aim to correct this deficit within 24 hours. 1, 2 After initial resuscitation, adjust fluid choice based on corrected serum sodium and hemodynamic status. 1

Critical monitoring target: Reduce osmolality by only 3-8 mOsm/kg/hour to prevent cerebral edema and central pontine myelinolysis, which carries 70% mortality. 2, 3 This is slower than you might instinctively push fluids, but rapid correction is one of the most dangerous pitfalls in HHS management.

Insulin Therapy

Withhold insulin until blood glucose is no longer falling with IV fluids alone, unless ketonemia is present. 2, 3 This is a key distinction from DKA management and reflects the fact that HHS patients are profoundly volume-depleted but not significantly ketotic.

Once insulin is indicated: 1, 2

• Start with IV bolus of regular insulin at 0.1 units/kg body weight (some protocols use 0.15 units/kg)
• Follow with continuous infusion at 0.1 units/kg/hour (typically 5-10 units/hour)
• Target glucose decline of 50-75 mg/dL per hour

If glucose does not fall by 50 mg/dL in the first hour, reassess hydration status; if acceptable, double insulin infusion every hour until steady glucose decline is achieved. 2

When plasma glucose reaches 250-300 mg/dL, reduce insulin infusion to 0.05-0.1 units/kg/hour and add 5-10% dextrose to IV fluids. 1, 2 Maintain glucose at 250-300 mg/dL until hyperosmolarity and mental status improve—do not aggressively lower to normal ranges, as this increases risk of cerebral edema. 2

Potassium Management

Check serum potassium before starting insulin. Total body potassium deficit in HHS is 5-15 mEq/kg despite potentially normal or elevated initial levels, because insulin drives potassium intracellularly. 2

Follow this algorithm: 1, 2

• If K+ <3.3 mEq/L: Hold insulin and give aggressive potassium replacement until K+ ≥3.3 mEq/L to prevent fatal cardiac arrhythmias
• If K+ 3.3-5.5 mEq/L: Add 20-30 mEq/L potassium to IV fluids (use 2/3 KCl and 1/3 KPO₄)
• If K+ >5.5 mEq/L: Hold potassium supplementation and recheck frequently

Once renal function is assured (adequate urine output), include potassium in all IV fluids until the patient can tolerate oral supplementation. 1

Monitoring During Treatment

Monitor the following parameters every 2-4 hours: 1, 2

• Blood glucose (every 1-2 hours until stable)
• Serum electrolytes (sodium, potassium, chloride, bicarbonate, phosphate, magnesium)
• Calculated effective serum osmolality
• BUN, creatinine
• Venous pH if ketonemia present

Monitor vital signs, mental status, fluid input/output, and hemodynamic parameters hourly. 1

Transition to Subcutaneous Insulin

Administer basal subcutaneous insulin 2-4 hours before stopping the IV insulin infusion to prevent rebound hyperglycemia and recurrent hyperglycemic crisis. 4, 1 This overlap period is essential—discontinuing IV insulin without adequate subcutaneous coverage is a common and dangerous error.

Special Considerations and Pitfalls

Elderly patients and those with cardiac or renal compromise require more cautious fluid rates with closer monitoring for fluid overload. 1, 2 Watch for signs of pulmonary edema, particularly in patients with widened alveolo-arteriolar oxygen gradient or pulmonary rales on initial examination. 2

Do not use bicarbonate therapy routinely in HHS, as pH is typically ≥7.30 and no prospective studies support its use. 2 Reserve bicarbonate only for pH <6.9 if this rare scenario occurs. 5

An initial rise in sodium level is expected as glucose falls and is not itself an indication for hypotonic fluids. 3 This often confuses clinicians, but remember you are correcting hyperosmolarity, not just sodium.

Identify and treat precipitating factors simultaneously: 1, 2

• Infection (most common—pneumonia, urinary tract infection, sepsis)
• Acute cerebrovascular accident or myocardial infarction
• Medications (diuretics, corticosteroids, beta-blockers, SGLT2 inhibitors)
• Non-compliance with diabetes medications or undiagnosed diabetes

Resolution Criteria

HHS is considered resolved when: 2

• Effective serum osmolality <300 mOsm/kg
• Blood glucose <270 mg/dL (15 mmol/L)
• Hypovolemia corrected
• Cognitive status returns to pre-morbid baseline

Care Setting

Patients with HHS should be immediately evaluated and treated in an intensive care unit due to greater volume depletion, typical triggering by acute illness, and mortality rates up to 15%. 2, 6, 7 Involve the diabetes specialist team as soon as possible. 2, 3