What are the causes of a high osmolar gap?

Causes of High Osmolar Gap

The main causes of high osmolar gap include toxic alcohol ingestions (methanol, ethylene glycol, diethylene glycol, isopropanol), alcoholic ketoacidosis, diabetic ketoacidosis, lactic acidosis, and chronic kidney disease. 1

Definition and Normal Values

• Osmolal gap is the difference between measured serum osmolality and calculated osmolality
• Normal osmolal gap values are typically <10 mOsm/kg
• Values >20 mOsm/kg strongly suggest the presence of unmeasured osmotically active substances 1
• Calculation formula: Estimated osmolality = 2 × [Na⁺] + [Glucose]/18 + [BUN]/2.8

Major Causes of Elevated Osmolal Gap

1. Toxic Alcohol Ingestions

• Ethylene glycol - found in antifreeze, causes severe metabolic acidosis

  • Osmolal gap >50 with fomepizole or >20 with ethanol therapy warrants extracorporeal treatment 2, 1
  • Presence of calcium oxalate and hippurate crystals in urine suggests ethylene glycol ingestion 2

• Methanol - found in windshield washer fluid, some solvents

  • Can produce very high osmolal gaps (mean 81 mOsm/kg in one study) 3
  • Causes high anion gap metabolic acidosis as it's metabolized

• Isopropanol - found in rubbing alcohol

  • Causes elevated osmolal gap without significant acidosis
  • Produces acetone, causing fruity breath odor

• Diethylene glycol - found in some antifreeze products and industrial solvents

  • Causes high osmolal gap and metabolic acidosis

• Propylene glycol - used as vehicle in IV medications (lorazepam, phenytoin)

  • Can accumulate with continuous infusions, especially in renal failure

2. Other Common Causes

• Ethanol - most common cause of elevated osmolal gap

  • Can cause osmolal gap >90 mOsm/kg in severe intoxication 1
  • Contribution to osmolal gap can be estimated: Osmolal Gap = 0.23 × (Ethanol [mg/dL]) - 1.43

• Diabetic ketoacidosis (DKA)

  • Can present with both elevated osmolal gap and high anion gap metabolic acidosis
  • Diagnostic criteria include plasma glucose >250 mg/dL, arterial pH <7.3, bicarbonate <15 mEq/L 2

• Alcoholic ketoacidosis

  • Combination of ethanol-induced osmolal gap and ketoacidosis
  • Often occurs after cessation of prolonged alcohol intake

• Chronic kidney disease/Acute kidney injury

  • Accumulation of unmeasured osmotically active substances
  • More commonly causes hyperchloremic metabolic acidosis

• Lactic acidosis

  • Can contribute to both osmolal gap and anion gap
  • Often seen in shock states, severe hypoxemia, or metformin toxicity

Clinical Pearls and Pitfalls

• An elevated osmolal gap with high anion gap metabolic acidosis strongly suggests toxic alcohol ingestion if alcoholic ketoacidosis and DKA are excluded 3

• The osmolal gap may normalize as toxic alcohols are metabolized to their toxic metabolites, while the anion gap increases - timing of presentation is crucial 1

• Freezing point depression osmometry is required to accurately detect volatile substances; vapor pressure osmometry may miss ethanol's contribution 1

• Multiple substances can contribute simultaneously to the osmolal gap (e.g., ethanol plus methanol)

• Laboratory confirmation with specific toxic alcohol levels is essential, as treatment decisions including fomepizole administration and hemodialysis depend on accurate diagnosis 1

• In patients with suspected ethylene glycol poisoning without available antidote, an osmolal gap >10 warrants extracorporeal treatment 2, 1