Serum Osmolality and Osmolar Gap

Serum osmolality measures the concentration of osmotically active particles in serum, expressed in milliosmoles for each kilogram of water (mOsm/kg). It is measured by freezing point depression or by vapour pressure. Sodium and its anions contribute about 90% of it, glucose and urea most of the rest. Osmolality, not total body water, drives movement of water across cell membranes and the release of antidiuretic hormone.

The osmolar gap is the difference between the measured osmolality and a calculated value. A raised gap shows the presence of osmotically active substances that are not sodium, glucose or urea, such as toxic alcohols. Used with the anion gap, it is the main laboratory clue to methanol, ethylene glycol and isopropanol poisoning.

Hyponatraemia is the most frequent electrolyte disorder in hospital patients (about 15 to 30% on admission). Toxic alcohol poisoning is uncommon but time critical, and its outcome depends on early treatment, so the osmolar gap is often the first signal.

Indications. Hyponatraemia or hypernatraemia of uncertain cause, polyuria and polydipsia, suspected syndrome of inappropriate antidiuresis, unexplained high anion gap acidosis, suspected ingestion of methanol, ethylene glycol, isopropanol or other alcohols, altered consciousness with suspected poisoning, hyperglycaemic emergencies, mannitol and glycerol therapy, and assessment of fluid shifts.

Specimen. Serum or heparin plasma, with a paired urine sample for urine osmolality. Use a plain tube or lithium heparin, since sodium heparin, fluoride oxalate and EDTA salts add osmoles. Separate promptly, and avoid evaporation. Freezing point methods detect volatile alcohols, and vapour pressure methods do not and must not be used for an osmolar gap.

Reference range. Serum osmolality 275 to 295 mOsm/kg. Urine osmolality 50 to 1200 mOsm/kg depending on hydration, and at least 600 mOsm/kg after water restriction in a healthy adult.

Calculated osmolality. Two times sodium plus glucose plus urea (all in mmol/L), plus ethanol in mmol/L if present. The calculated value in healthy people is about 270 to 290.

Osmolar gap. Measured minus calculated. Normal is under 10 mOsm/kg (within about 10 either side of zero by method). Each 1 mmol/L of an osmotically active alcohol or glycol adds about 1 mOsm/kg, so a gap of 30 corresponds to about 30 mmol/L of such a substance (for example methanol 100 mg/dL, ethylene glycol 190 mg/dL).

Causes of a raised osmolar gap.

• Toxic alcohols and glycols: methanol, ethylene glycol, isopropanol, propylene glycol (including lorazepam infusion carriers), diethylene glycol.
• Ethanol (if not already included in the calculation).
• Other solutes: mannitol, glycerol, sorbitol, contrast media, acetone.
• Metabolic states: ketoacidosis, lactic acidosis, shock, alcoholic ketoacidosis, kidney failure, and cardiac arrest, usually with a gap under 25.
• Artefact: severe hyperlipidaemia or hyperproteinaemia with indirect measurement of sodium.

Toxic alcohol interpretation.

• A gap over 25 to 30 mOsm/kg with a high anion gap acidosis is toxic alcohol poisoning until proven otherwise.
• Early after ingestion the gap is high and the anion gap is normal. Later, the parent alcohol is metabolised to acids, so the gap falls and the anion gap and acidosis rise.
• A normal gap in a late presenter does not exclude poisoning, and a normal anion gap does not exclude early poisoning.
• Isopropanol raises the gap and produces ketosis without acidosis.

Osmolality in hyponatraemia.

• Hypotonic (under 275 mOsm/kg): true hyponatraemia, classified by volume status.
• Normal osmolality: pseudohyponatraemia from severe hyperlipidaemia or paraproteinaemia with indirect electrode measurement.
• High osmolality: hyperglycaemia (sodium falls by about 2.4 mmol/L for each 10 mmol/L glucose over 5.5), mannitol, glycerol, and contrast.

Syndrome of inappropriate antidiuresis. Serum osmolality under 275 mOsm/kg, urine osmolality over 100 mOsm/kg, urine sodium over 30 mmol/L, in a euvolaemic patient with normal thyroid, adrenal and kidney function and no diuretic use.

Polyuria. Urine osmolality under 300 mOsm/kg with serum osmolality over 295 suggests diabetes insipidus. Urine osmolality over 600 mOsm/kg rules it out, and a low urine osmolality with low serum osmolality suggests primary polydipsia.

Hypernatraemia. Serum osmolality is raised, and urine osmolality over 800 mOsm/kg suggests extrarenal water loss, while a low value suggests diabetes insipidus.

Critical values and findings needing immediate action.

• Serum osmolality over 320 mOsm/kg or under 250 mOsm/kg, or any change with seizures or coma.
• Osmolar gap over 10 mOsm/kg with a high anion gap acidosis, visual disturbance or altered consciousness.
• Osmolar gap over 25 mOsm/kg without a known cause.
• Serum osmolality over 340 mOsm/kg in hyperglycaemic hyperosmolar state, or correction of hyponatraemia faster than 8 mmol/L in 24 hours.

Interferences and pitfalls.

• Sampling in the wrong tube adds osmoles and creates a false gap.
• Vapour pressure osmometry misses volatile alcohols and gives a falsely low gap.
• The calculated value depends on the formula used, and different formulas give different gaps.
• A late presentation, or an ingestion of a small amount, can give a gap in the normal range.
• Raised lactate and ketones contribute a modest gap and can mislead if alcohol is not considered.
• Ethanol co-ingestion delays toxic alcohol metabolism, so acidosis appears later.
• Osmolal gap should be taken at the same time as sodium, glucose and urea, since delay allows discordant values.
• A normal gap does not exclude diethylene glycol or other poor osmotic agents.

Special groups.

• Neonates: values are lower in preterm infants, and osmolality is used when feeding or glucose loads are unusual.
• Children: accidental ingestion of ethylene glycol and methanol in antifreeze and windscreen fluid is the main cause.
• Pregnancy: serum osmolality is about 10 mOsm/kg lower (about 270).
• Older adults: reduced renal concentrating ability and thirst give hypernatraemia.
• Regions: methanol outbreaks from adulterated spirits occur in clusters.

Follow up tests. Sodium, glucose, urea, creatinine, anion gap, blood gas, lactate, ketones, measured ethanol, methanol and ethylene glycol levels (gas chromatography), urine osmolality, urine sodium, plasma antidiuretic hormone or copeptin, thyroid and adrenal function, and urine crystal examination for calcium oxalate in ethylene glycol poisoning.