Hyperosmolar Hyperglycemic State (HHS)

Risk factors

• Older age, nursing home residence, dementia (impaired thirst response)
• Infection (most common precipitant, ~50-60% of cases): pneumonia, UTI, sepsis
• Acute illness: MI, stroke, pancreatitis, mesenteric ischemia
• Medications: thiazides, glucocorticoids, atypical antipsychotics, total parenteral nutrition
• Newly diagnosed T2DM, medication non-adherence
• Restricted access to water (institutionalized, post-stroke, debilitated)

Pathophysiology

Relative insulin deficiency permits hyperglycemia and hepatic glucose output but is sufficient to suppress hepatic ketogenesis. Sustained osmotic diuresis produces profound water and electrolyte losses (free water deficit 8-12 L). Hyperosmolarity draws water from intracellular compartments, including neurons, producing altered mentation, seizures, and coma.

Clinical presentation

Differential diagnosis

• DKA — Younger T1DM, anion-gap acidosis, ketonemia, glucose often <600; clinical course over hours
• Mixed DKA/HHS — ~20-30% of cases — meets criteria for both; treat as DKA with attention to osmolarity
• Sepsis with hyperglycemia — SIRS criteria, hypotension, lactic acidosis; treat underlying infection aggressively
• Stroke or intracranial event — Focal neurologic deficits persisting after metabolic correction; obtain CT/MRI
• Diabetes insipidus with hyperglycemia — Hypernatremia with dilute urine; rare overlap
• Toxic ingestion — Salicylates, lithium toxicity can cause altered mentation and metabolic derangement

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Suspected HHS<br/>glucose >600, AMS] --> B[0.9% NaCl 1-1.5 L<br/>first hour]
  B --> C[Check K, ECG]
  C --> D{K <3.3?}
  D -->|Yes| E[Replace K<br/>before insulin]
  D -->|No| F[Start insulin 0.1 u/kg/hr<br/>after initial fluids]
  E --> F
  F --> G[Recalculate corrected Na]
  G --> H{Na normal/high?}
  H -->|Yes| I[Switch to 0.45% NaCl]
  H -->|No| J[Continue 0.9% NaCl]
  I --> K{Glucose <300?}
  J --> K
  K -->|Yes| L[Add D5 to fluids]
  L --> M[Continue insulin until<br/>osm normal, AMS resolved]
  M --> N[Overlap SC insulin<br/>1-2 h before stopping drip]

Treatment

Complications

• Thromboembolism — DVT, PE, stroke from hyperviscosity and dehydration; consider therapeutic prophylaxis in high-risk patients
• Cerebral edema — rare in adults; risk increased with rapid osmolarity correction
• Rhabdomyolysis from prolonged immobility and hyperosmolarity
• Acute kidney injury (volume depletion, contrast exposure)
• Hypokalemia, hypophosphatemia during insulin therapy
• Aspiration pneumonia in obtunded patients
• Persistent neurologic deficits or death (mortality 5-20%, higher with advanced age and comorbidities)

PANCE pearls

• Fluid resuscitation is the priority — insulin too early can collapse intravascular volume by driving glucose (and water) intracellularly.
• Mortality in HHS is largely driven by the precipitating illness (sepsis, MI), not the hyperglycemia itself — identify and treat the trigger early.
• Glucose can drop dramatically with fluids alone before insulin is started.
• Lower osmolarity gradually — rapid correction risks cerebral edema.
• Free water deficit (L) ≈ 0.6 × weight(kg) × [1 − (140/measured Na)]; use to plan ongoing replacement after initial resuscitation.

References

• ADA 2025 — American Diabetes Association Standards of Care in Diabetes—2025 (Diabetes Care 2025; 48 Suppl 1)
• ADA Consensus 2024 — Hyperglycemic Crises in Adults With Diabetes: A Consensus Report (Umpierrez et al., Diabetes Care 2024)
• Endocrine Society — Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings (J Clin Endocrinol Metab 2022)