Plasma Osmolar Gap in Toxic Ingestions
A high plasma osmolar gap (>10-12 mOsm/kg) serves as a critical surrogate marker for toxic alcohol ingestion when direct alcohol measurements are unavailable, but its significance must be interpreted based on clinical context, available antidotes, and the presence of metabolic acidosis, as it can be falsely elevated by multiple non-toxic conditions and falsely normal if the toxic alcohol has already been metabolized. 1
Diagnostic Significance
When Osmolar Gap is Elevated
The osmolar gap correlates linearly with toxic alcohol concentration at high levels, making it useful for guiding urgent treatment decisions when ethylene glycol or methanol assays are unavailable (which is the typical scenario in most emergency departments). 1
- Normal osmolar gap range: 0-12 mOsm/kg H₂O 2
- At high toxic alcohol concentrations, the osmolar gap provides a reasonable estimate of the poison burden despite considerable inter- and intra-patient variability 1
- Osmolar gap >50 strongly suggests significant toxic alcohol ingestion requiring aggressive intervention 1
Critical Limitations as a Screening Test
The osmolar gap is a poor screening test for toxic alcohol ingestion, especially at low values, because it can be normal or even negative in several scenarios: 1
- After metabolism has occurred: Once ethylene glycol or methanol is metabolized to toxic metabolites (glycolic acid, oxalic acid, formic acid), the osmolar gap normalizes while metabolic acidosis develops 1, 2
- With insufficient ingestion: Too little toxic alcohol ingested to elevate the gap 1
- Timing of presentation: Delayed presentations may show normal osmolar gap with severe acidosis 2
A normal osmolar gap effectively rules out significant recent ethylene glycol or methanol ingestion ONLY when there is no clinical suspicion, but cannot exclude ingestion if the patient presents with unexplained high anion gap metabolic acidosis or clinical signs of toxic alcohol poisoning. 2
Non-Toxic Causes of Elevated Osmolar Gap
Multiple benign and serious conditions can elevate the osmolar gap, creating false positives: 3, 4
- Acute ethanol intoxication alone can cause osmolar gaps >90 mOsm/kg with high anion gap metabolic acidosis 5
- Alcoholic ketoacidosis can produce very high osmolar gaps without toxic alcohol ingestion 6
- Acute kidney injury and chronic kidney disease 3, 4
- Multiple myeloma (paraproteinemia) 4
- Diabetic ketoacidosis 3
- Shock states and lactic acidosis 3, 4
Baseline osmolar gap variability: 18% of healthy individuals may have an osmolar gap >10 at baseline without any ingestion 7
Management Algorithm Based on Osmolar Gap
Treatment Thresholds for Extracorporeal Treatment (ECTR/Hemodialysis)
When fomepizole is available as antidote:
- Osmolar gap >50: Suggest ECTR (weak recommendation) 1
- Osmolar gap <50: Continue fomepizole alone with monitoring 1
When ethanol is used as antidote:
- Osmolar gap >50: Recommend ECTR (strong recommendation) 1
- Osmolar gap 20-50: Suggest ECTR (weak recommendation) 1
- Rationale: Ethanol provides less predictable ADH blockade with higher treatment failure rates, and prolonged ethanol therapy carries risks of CNS depression and dysphoria requiring >48 hours of high-dependency unit care 1
When no antidote is available:
- Osmolar gap >10: Recommend ECTR (strong recommendation) 1
- This conservative threshold reflects the high risk of adverse outcomes in untreated patients 1
Initiation of Fomepizole Treatment
Begin fomepizole immediately upon suspicion based on: 8
- Patient history of toxic alcohol ingestion 8
- Anion gap metabolic acidosis with suspected exposure 8
- Increased osmolar gap 8
- Visual disturbances (methanol) 8
- Oxalate crystals in urine (ethylene glycol) 8
- Documented serum ethylene glycol or methanol concentration >20 mg/dL 8
Dosing: Loading dose 15 mg/kg IV, then 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours until toxic alcohol levels <20 mg/dL and patient is asymptomatic with normal pH 8
Hemodialysis Indications (in addition to fomepizole)
Hemodialysis should be considered when: 8
- Measured ethylene glycol or methanol concentration ≥50 mg/dL 8
- Renal failure 8
- Significant or worsening metabolic acidosis 8
During hemodialysis: Increase fomepizole dosing frequency to every 4 hours (fomepizole is dialyzable) 8
Discontinuation Criteria
Stop fomepizole when ALL of the following are met: 8
- Ethylene glycol or methanol concentrations undetectable or <20 mg/dL 8
- Patient is asymptomatic 8
- Normal pH 8
Monitoring Strategy When Osmolar Gap is Normal but Suspicion Remains
If clinical suspicion persists despite normal osmolar gap (0-12 mOsm/kg): 2
- Monitor acid-base status and anion gap serially - toxic metabolites cause high anion gap acidosis even after osmolar gap normalizes 2
- Obtain direct measurement of toxic alcohols if available within 2-4 hours 2
- Check renal function and urinalysis for calcium oxalate crystals (ethylene glycol) 2
- Look for clinical signs: altered mental status, seizures, visual disturbances, unexplained high anion gap metabolic acidosis 2, 8
The anion gap becomes the best surrogate marker when glycolate assays are unavailable, with anion gap >27 mmol/L indicating strong consideration for extracorporeal treatment. 2
Key Pitfalls to Avoid
Do not rely on osmolar gap alone - it must be interpreted with clinical context, anion gap, and timing of presentation 1, 3
Do not dismiss toxic alcohol ingestion based solely on normal osmolar gap if the patient has unexplained high anion gap metabolic acidosis or suggestive clinical features 2
Correct for ethanol properly - use a correction factor of 4.6 (molecular weight-based) rather than 3.7 to minimize false positives, though some variation will still occur 7
Consider alternative diagnoses - alcoholic ketoacidosis, diabetic ketoacidosis, acute kidney injury, and multiple myeloma can all produce elevated osmolar gaps 3, 5, 4, 6
Do not delay treatment waiting for confirmatory toxic alcohol levels if clinical suspicion is high - begin fomepizole empirically 8