What medical conditions, medications, or substances can cause a high osmolar gap?

Medical Conditions and Substances That Cause High Osmolar Gap

A high osmolar gap can be caused by toxic alcohol ingestion (methanol, ethylene glycol), diabetic ketoacidosis, alcoholic ketoacidosis, and lactic acidosis, with toxic alcohols requiring the most urgent intervention due to their high mortality risk. 1

Toxic Alcohols

• Methanol: Found in windshield washer fluid, antifreeze, and industrial solvents
• Ethylene glycol: Found in antifreeze, coolants, and some detergents
• Diethylene glycol: Industrial solvent and component in some medications
• Propylene glycol: Used in medications, cosmetics, and food products
• Isopropanol (isopropyl alcohol): Found in rubbing alcohol and cleaning products

Medical Conditions

• Diabetic ketoacidosis (DKA):

  • Causes elevated osmolar gap due to ketone bodies (acetone, beta-hydroxybutyrate)
  • Usually presents with hyperglycemia (>250 mg/dL), acidosis, and positive ketones 1

• Alcoholic ketoacidosis (AKA):

  • Can produce osmolar gap of 11-27 mmol/kg even after accounting for ethanol 2
  • Distinguished by clinical history and glucose levels rarely >250 mg/dL 1

• Lactic acidosis:

  • Can elevate osmolar gap to approximately 17 mmol/kg 2
  • Often accompanied by high anion gap metabolic acidosis

Medications/Substances

• Ethanol: Most common cause of elevated osmolar gap
• Mannitol: Osmotic diuretic used in various medical conditions
• Glycerol: Can be elevated endogenously in alcoholic patients 3
• Acetone and acetone metabolites: Can contribute to osmolar gap in alcoholic patients 3
• Paraldehyde: Sedative medication (rarely used today)

Diagnostic Thresholds and Clinical Significance

Osmolar Gap Thresholds for Toxic Alcohol Ingestion 1:

1. When fomepizole is used:

   • Osmolar gap >50: Consider extracorporeal treatment

2. When ethanol is used as antidote:

   • Osmolar gap >50: Strongly recommend extracorporeal treatment
   • Osmolar gap 20-50: Consider extracorporeal treatment

3. When no antidote is available:

   • Osmolar gap >10: Strongly recommend extracorporeal treatment

Clinical Approach

1. Calculate the osmolar gap:

   • Measured osmolality - Calculated osmolality
   • Calculated osmolality = 2[Na⁺] + glucose/18 + BUN/2.8 + ethanol/4.6

2. Interpret based on magnitude:

   • Normal: <10 mOsm/kg
   • 10-20 mOsm/kg: Suspicious for toxic ingestion or metabolic disorder

   • 20 mOsm/kg: Highly suggestive of toxic alcohol ingestion

3. Consider timing:

   • Early in toxic alcohol ingestion: High osmolar gap, normal anion gap
   • Later stages: Decreasing osmolar gap, increasing anion gap as parent alcohols are metabolized to toxic acids 4

Important Clinical Pearls

• A normal osmolality (275-295 mOsm/kg) with normal/low anion gap effectively rules out toxic alcohol ingestion requiring intervention 5
• Osmolar gap may be normal or even negative if the toxic alcohol has been extensively metabolized 1
• Treatment with fomepizole should be initiated immediately upon suspicion of toxic alcohol ingestion based on history and elevated osmolar gap, even before confirmatory testing 6
• Hemodialysis should be considered when ethylene glycol or methanol concentration is ≥50 mg/dL, or with significant metabolic acidosis or renal failure 6
• False elevations in osmolar gap can occur with severe hyperproteinemia or hyperlipidemia

Remember that the osmolar gap is a screening tool with limitations, and clinical correlation is essential for accurate diagnosis and appropriate management of the underlying condition.