From the Guidelines
The osmolar gap in ethanol (ETOH) intoxication should be corrected by subtracting the contribution of ethanol to the measured osmolality, with a recommended correction threshold of > 50 for ECTR initiation when ethanol is used as an antidote, as suggested by the EXTRIP workgroup 1. To calculate this correction, divide the serum ethanol level (in mg/dL) by 4.6 to determine ethanol's contribution to osmolality in mOsm/kg. This value should then be subtracted from the measured osmolar gap to obtain the corrected osmolar gap.
Key Considerations
- The corrected osmolar gap helps clinicians more accurately assess for the presence of other osmotically active substances that might require specific treatments, such as ethylene glycol poisoning.
- A normal corrected osmolar gap should be less than 10 mOsm/kg; values higher than this suggest the presence of unmeasured osmotically active substances beyond ethanol.
- The EXTRIP workgroup recommends ECTR initiation at an osmol gap > 50 when ethanol is used as an antidote, with a strong recommendation and very low-quality evidence 1.
Calculation and Interpretation
- The osmol gap is calculated as measured osmolality − calculated osmolarity, in SI units and adjusted for ethanol.
- The osmol gap may overestimate the EG concentration, and using these cutoffs may lead to unnecessary ECTRs.
- However, at high EG concentration, the osmol gap correlates linearly with the EG concentration, despite considerable inter- and intra-patient variability 1.
Clinical Decision-Making
- Clinicians should individualize decisions to initiate ECTR based on the presence of other clinical indications, such as coma, seizures, or kidney impairment.
- The decision to transfer a patient to another institution to receive ECTR should be individualized, taking into account the cost of fomepizole, ethanol, hospitalization, and ECTR, as well as the EG T1/2 during specific circumstances 1.
From the Research
Osmol Gap and Ethanol Correction
The osmol gap is a useful tool in detecting and managing toxic alcohol exposure, including ethanol. However, the optimal correction for ethanol to allow accurate detection of alternative alcohols is unclear.
- A study published in 2025 2 found that using an ethanol correction coefficient of 4.6 produced a better clinical osmol gap input, albeit still with some variation.
- The same study noted that the osmol gap is occasionally elevated in the absence of any alcohol ingestion, and that the use of an ethanol correction coefficient can help reduce false positives.
Calculation of Osmol Gap
The osmol gap is calculated as the difference between the measured serum osmolality and the calculated serum molarity, which is estimated from the known and readily measurable osmotically active substances in the serum.
- A review published in 2004 3 discussed the principles of evaluating screening tests, including the theory behind the osmol gap as a screening test, and noted that there have been numerous equations derived and proposed for the estimation of the calculated serum molarity.
- However, the review also noted that the methods and statistical analysis employed have generally been inconsistent with recommended guidelines for screening test evaluation, and that the clinical utility of the osmol gap remains hypothetical.
Clinical Utility of Osmol Gap
The osmol gap can be useful in detecting toxic alcohol exposure, including ethylene glycol and methanol poisoning.
- A study published in 2010 4 noted that poisoning with ethylene glycol, methanol, and isopropyl alcohol can present with high anion gap metabolic acidosis and increased osmolality, and that laboratory abnormalities can be helpful for diagnosis.
- Another study published in 2022 5 found that the anion gap was associated with acute kidney injury and mortality in patients with ethylene glycol poisoning, and that the use of fomepizole monotherapy without extracorporeal treatments was safe and effective in patients with minimal metabolic acidemia.
Limitations of Osmol Gap
The osmol gap has several limitations, including the potential for false positives and the need for careful interpretation of results.
- A case report published in 2014 6 noted that rapid changes in serum osmolality from ethylene glycol toxicity or its subsequent treatment can cause osmotic demyelination syndrome, independent of serum sodium levels.
- The study published in 2025 2 also noted that the osmol gap can be elevated in the absence of any alcohol ingestion, highlighting the need for careful interpretation of results.