DESCRIPTION

• The osmolar gap is the difference in the measured and calculated serum osmolarity (measured osmolarity minus calculated osmolarity).
  • The measured osmolarity is measured by the clinical laboratory.
  • The calculated osmolarity is determined as follows: 2 × [Na (mEq/L)] + [BUN (mg/dl)/2.8] + [glucose (mg/dl)/18].
  • The normal osmolar gap is less than 10 mEq/L.
• An elevated osmolar gap suggests the presence of an unmeasured solute; the primary toxic compounds of medical interest are ethylene glycol, methanol, and isopropyl alcohol (isopropanol).
• For clinical purposes, the terms osmolal gap, osmolar gap, and osmol gap are equivalent.

PATHOPHYSIOLOGY

• The main osmotically active compounds normally found in the body are sodium, glucose, bicarbonate, urea, chloride, and potassium; these are measurable and are accounted for in the calculation of serum osmolarity.
• The cause of the normal gap is serum proteins and lipids that contribute slightly to serum osmolarity, but they are typically not measured by clinical laboratories.
• Other compounds that are not usually measured include mannitol, ethanol, isopropyl alcohol, methanol, ethylene glycol, propylene glycol, and acetone.
• The osmolarity of serum should be measured by freezing point depression (vapor pressure methods [i.e., boiling point evaluation] do not accurately detect volatile compounds such as the alcohols and thus should not be used).

Section Outline:

• DESCRIPTION
• PATHOPHYSIOLOGY

DIFFERENTIAL DIAGNOSIS

Further information on each poison is available in SECTION IV, CHEMICAL AND BIOLOGICAL AGENTS.

• Common toxicologic causes of an elevated osmolar gap include ethanol, methanol, isopropyl alcohol, and ethylene glycol.
• Uncommon toxicologic causes include acetone and propylene glycol (usually detected after administration of a medication that uses this agent as a diluent).
• Nontoxicologic causes of increased osmolar gap include renal failure, hyperlipidemia, hyperparaproteinemia, and the therapeutic administration of mannitol or glycerol.

SIGNS AND SYMPTOMS

Associated physical signs may help reveal the poison involved when they occur in the setting of increased osmolar gap. The presence of an osmolar gap produces no symptoms itself, but specific agents that cause an osmolar gap may result in symptoms.

Vital Signs

• Tachypnea suggests a metabolic acidosis as seen with ethylene glycol or methanol.
• Hypotension may occur with very large methanol, ethanol, ethylene glycol, or isopropyl alcohol toxicity.

HEENT

• Blurred vision, perception of peering through a "snowstorm," and other visual complaints, including blindness and optic disk pallor, can occur with methanol ingestion.
• Sweet odor of the patient's breath suggests acetone, ethanol, or isopropyl alcohol ingestion.

Cardiovascular

Hypotension may occur with very large methanol, ethanol, ethylene glycol, or isopropyl alcohol ingestion.

Pulmonary

Tachypnea suggests a metabolic acidosis as seen with ethylene glycol or methanol.

Gastrointestinal

• Abdominal pain, nausea, and vomiting may occur with methanol, ethanol, ethylene glycol, or isopropyl alcohol ingestion.
• Hemorrhagic gastritis is common with isopropyl alcohol ingestion.

Hepatic

Chronic ethanol ingestion can cause hepatitis and cirrhosis.

Renal

Hematuria, proteinuria, and renal insufficiency are associated with ethylene glycol.

Fluids and Electrolytes

Profound increased anion gap metabolic acidosis can result from methanol or ethylene glycol poisoning.

Musculoskeletal

Rhabdomyolysis can occur with ethylene glycol ingestion or prolonged coma.

Neurologic

Initial intoxication followed by CNS depression and coma is associated with ethanol, methanol, isopropyl alcohol, or ethylene glycol intoxication.

PROCEDURES AND LABORATORY TESTS

• The presence of an osmolar gap produces no symptoms; precise identification of the cause requires specific laboratory testing.
• Serum osmolarity should be measured using the freezing point depression method.
• Serum electrolytes, BUN, and glucose should be measured to allow determination of the calculated serum osmolarity.
• If osmolar gap is elevated, serum ethanol, methanol, ethylene glycol, and isopropyl alcohol should be determined on the same blood sample; it is possible to estimate the contribution of each compound to the osmolar gap.
  • Ethanol contribution = serum ethanol concentration (mg/dl) ÷ 4.6.
  • Methanol contribution = serum methanol concentration (mg/dl) ÷ 3.2.
  • Ethylene glycol contribution = serum ethylene glycol (mg/dl) ÷ 6.2.
  • Acetone contribution = serum acetone concentration (mg/dl) ÷ 5.8.
  • Isopropyl alcohol contribution = isopropyl alcohol concentration ÷ 6.
• Anion gap calculation should also be performed
  • [Serum sodium] - [serum chloride + serum bicarbonate]. Normal is less than 16 mEq/L.
  • If elevated, it is likely that significant metabolism of ethylene glycol or methanol has occurred.
  • If not elevated, these toxic alcohols cannot be excluded because they may not yet have been metabolized.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Hepatic
  • Renal
  • Fluids and Electrolytes
  • Musculoskeletal
  • Neurologic
• PROCEDURES AND LABORATORY TESTS

• Supportive care with appropriate airway management is vital.
• Dose and time of exposure should be determined for all substances involved.
• Treatment with fomepizole should be considered while supportive care continues.

DECONTAMINATION

• Causes of an increased osmol gap involve liquids composed of small-molecular-weight molecules; thus, decontamination is rarely an option.
• Nasogastric aspiration using a nasogastric tube within the first 30 to 60 minutes following a large ingestion may be beneficial.
• If there is concern for a coingestant, gastric lavage with a large-bore orogastric tube may be indicated.
• If there is concern for a coingestant, one dose of activated charcoal (1-2 g/kg) can be administered.

ANTIDOTES

• 4-methylpyrazole (fomepizole) is the preferred antidote for methanol and ethylene glycol poisoning, the most dangerous causes of an increased osmolar gap.
• Ethanol is much more difficult and dangerous to use and should only be used if fomepizole is unavailable.

Fomepizole

• Indications: Ethylene glycol or methanol level greater than 20 mg/dl, reliable history of significant ingestion, unexplained anion gap metabolic acidosis, or unexplained osmol gap.
• Dose: 15 mg/kg loading dose followed by 10 mg/kg every 12 hours as a maintenance dose until ethylene glycol or methanol level is less than 20 mg/dl.

Ethanol 10%

• Indications: Ethylene glycol or methanol level above 20 mg/dl (if levels are not immediately available, therapy should be instituted for a reliable history of significant ingestion, unexplained anion gap acidosis, or unexplained osmolar gap).
• Contraindications: Preexisting ethanol level greater than 100 mg/dl obviates need for the ethanol loading dose.
• Administration: loading dose
  • 10 ml/kg of a 10% ethanol solution infused intravenously over 1 hour; if intravenous route is not possible, four 1-oz "shots" of a 40% (80 proof) ethanol beverage should be administered. This dose is based on a 70-kg adult. Dosing should be adjusted for patient's weight.
  • Determine ethanol level upon completion of loading dose; target serum ethanol level is 100 to 150 mg/dl.
• Maintenance dose
  • 1 to 2 ml/kg/h of a 10% ethanol solution should be administered intravenously; use 2.0 ml/kg/h for alcoholic patients.
  • Rate should be adjusted to maintain an ethanol level above 100 mg/dl; if an intravenous route is not possible, one 1-oz "shot" of a 40% (80 proof) ethanol should be given orally every hour. This dose is based on a 70-kg patient and should be adjusted accordingly.
  • Ethanol level should be checked each hour initially, decreasing the frequency as the ethanol level stabilizes between 100 and 150 mg/dl.
  • During hemodialysis, the maintenance 10% ethanol infusion should be increased to 3.0 ml/kg/h.
• Potential adverse effects. Hypotension or hypoglycemia may develop, especially in children.

ADJUNCTIVE TREATMENT

Hemodialysis is used to treat methanol poisoning, ethylene glycol poisoning, or very severe isopropyl alcohol poisoning.

Section Outline:

• DECONTAMINATION
• ANTIDOTES
  • Fomepizole
  • Ethanol 10%
• ADJUNCTIVE TREATMENT

• Intoxication develops soon after ingestion; however, toxic effects are delayed until metabolism of the toxic alcohol occurs, which usually requires several hours.
• Patients with ethanol, isopropyl alcohol, and acetone ingestion do well with supportive care. Patients with isopropyl ingestion may develop hemorrhagic gastritis.
• Patients with methanol or ethylene glycol poisoning may have significant effects if untreated, but do well if the ingestion is detected early and proper treatment is instituted.

DIAGNOSIS

• Due to inherent inaccuracies in its measurement, the absence of an osmolar gap does not exclude a significant ethylene glycol or methanol ingestion.
• Osmometers that measure vapor pressure (i.e., boiling point elevation) commonly underestimate the osmotic contribution of methanol and sometimes ethylene glycol.

TREATMENT

The osmolar gap will decrease as the ingested product is metabolized; however, toxic metabolites may still be present even though the osmolar gap has resolved.

Section Outline:

• DIAGNOSIS
• TREATMENT

Toxic effect of alcohol.

See Also: SECTION III, Ethanol and Fomepizole chapters, and SECTION IV, Ethylene Glycol, Isopropyl Alcohol, and Methanol chapters.

RECOMMENDED READING

Hoffman RS, Smilkstein MJ, Howland MA, et al. Osmol gaps revisited: normal values and limitations. J Toxicol Clin Toxicol 1993;31:81-93.

Glaser DS. Utility of the serum osmol gap in the diagnosis of methanol or ethylene glycol ingestion. Ann Emerg Med 1996;27:343-346.

Author: Kennon Heard

Reviewer: Katherine M. Hurlbut