Osmolality Gap - Calculation and Interpretation

Plasma osmolality is determined mainly by Sodium (NA), its counter ions, and uncharged species such as Glucose (GLU) and Urea (UN). Knowledge of the plasma concentration of these species allows calculation of the plasma osmolality to a degree that compares quite well to measured osmolality from freezing point depression. The difference between measured osmolality (MO) and calculated osmolality (CO) is known as the osmolality gap (OG). A large positive (>15) osmolality gap can help identify the presence in plasma of substances such as ethanol, methanol, isopropanol, ethylene glycol, propylene glycol (found as a diluent for some intravenous medications such as lorazepam), and acetone. The formula given below was instituted at the University of Iowa Hospitals and Clinics for use on plasma samples starting November 2009 and is based on a published study comparing different calculated osmolality formulas (see ref. 3):

(1). CO = 2 x NA + 1.15 * GLU/18 + UN/2.8 : calculated osmolality

(2). OG = MO - CO : osmolality gap

To calculate the osmolality gap, plasma determination of MO, NA, GLU, and UN are necessary. Proper interpretation of the OG also requires knowledge of the anion gap (AG = NA - HCO3 - CL), the blood pH, and qualitative testing of the plasma ketone bodies (KETO). Determinations of MO and for CO should be performed on the same plasma sample.

An OG value greater than 15 has traditionally been considered a critical value or cutoff. Approximately 97% of osmolality gaps in patients are between -10 and +10.

When the OG is combined with blood pH and AG, poisonings with toxic alcohols can be quickly recognized. The presence of low blood pH, elevated AG, and greatly elevated OG (>15) is a medical emergency that requires prompt treatment. The specific agent(s) responsible can be identified by the gas chromatographic assays for ethanol, methanol, isopropanol, acetone, propylene glycol, and ethylene glycol. The following table summarizes results found in intoxications and other clinical situations.

(Contribution to Osmolar Gap)*
Ethanol only
[Ethanol] / 3.8
Methanol (late)
N or HI
N or HI**
[Methanol] / 3.2
[Isopropanol] / 6.0
Ethylene Glycol
[Ethylene glycol] / 6.2
Alcoholic Ketoacidosis
Weak POS
Mainly via ethanol concentration
Diabetic Ketoacidosis
N or UP
(usually < 20-25)
[Acetone] / 5.8

N = normal

*The contributions to osmolar gap are estimated by taking the plasma concentration and then dividing by the number indicated. For example, an ethylene glycol plasma concentration of 124 mg/dL will contribute approximately 20 (=124/6.2) to the osmolar gap. Note that the some of the substances generate metabolites that themselves may contribute to osmolar gap. For instance, heavy consumption of ethanol 24 hours prior to hospital admission can show an elevated osmolar gap mainly due to metabolites of ethanol (acetaldehyde, etc.) even when the parent drug (ethanol) is mostly gone.

**Osmolality gap may be increased in early methanol poisoning.

Non-toxic examples of an elevated osmolality gap include hyperlipidemia (less plasma water), chronic renal failure, and myeloma (increased plasma proteins).

Because ethanol ingestion is a common cause of elevated osmolality gap, ethanol can be included in calculated osmolality formulas. At the University of Iowa Hospitals and Clinics, the formula used for this is the calculated osmolality equation given above with an additional term for ethanol (EtOH):

(3) CO/EtoH = 2 x NA + 1.15 * GLU/18 + UN/2.8 + 1.2*[EtOH]/4.6: calculated osmolality including ethanol contribution

(4) "Unexplained" osmolality gap = MO - CO/EtoH: osmolality gap remaining after correction for ethanol

For the ethanol/volatile panel orderable in Epic, NA, GLU, UN, MO, and EtOH concentrations in plasma are all determined. The osmolality gap (OSMOL GAP in Epic) uses formula (2) above. The unexplained osmolality gap (UOSMOL GAP in Epic) uses formula (4) above. High unexplained osmolality gaps indicate the possible presence of a toxic compound other than ethanol (ethylene glycol, methanol, acetone, isopropanol, or propylene glycol).


A sixty-seven year old white male was found pulseless and resuscitated; then brought to the emergency room. He had been reported to be drinking in a bar all afternoon, and had then fallen from a ten foot balcony to snow covered ground. He arrived in the emergency room with a fractured occiput and was unresponsive.

Admission Data:

NA=143 mEq/l
UN=4 mg/dL
CL=105 mEq/l
GLU=104 mg/dL
MO=356 mOsm/kg
HCO3=19 mEq/l

AG = NA - CL- HCO3= 143 - 105- 19 = 19

CO = 2 x NA + 1.15 *GLU/18 + UN/2.8 = 286+ 1.15 *104/18 + 4/32.8 = 294

0G = MO - CO= 356 - 294 =62

If we assume OG is due to ethanol, then ethanol concentration (see table) would be approximately 62/21.7 x 100 mg/dL = 286 mg/dL

The measured ethanol concentration on this sample was 257 mg/dL. The OG calculated in this case was consistent with the history and indicated ethanol intoxication. The osmolality gap including the contribution from ethanol in this patient can also be determined using equations (3) and (4) from above:

CO/EtoH = 2 x NA + 1.15 * GLU/18 + UN/2.8 + 1.2*[EtOH]/4.6 = 286+ 1.15*104/18 + 4/2.8 + 1.2*257/4.6 = 362

The "unexplained" osmolality gap is MO-CO/EtOH = 356-362 = -6

1. Glasser, L., et al. : Serum Osmolality and Its Applicability to Drug overdose. Am. J. Clin. Path. 60:695, 1973.
2. Jacobsen, D., et al.: (Series of three articles dealing with methanol and ethylene glycol overdose and use of AG and OG in diagnosis). Acta. Med. Scand. 212:1-20, 1982.
3. Khajuria, A., and Krahn, J: Osmolality revisited – deriving and validating the best formula for osmolality. Clin. Biochem. 38: 514-519, 2005.

Contact the Laboratory Director of Clinical Chemistry (384-9380) with questions.