Laboratory Measurement Technique: freezing point depression technique
Calculation of Serum Osmolality
Calculated Serum Osm = (2 x Na) + (Glucose/18) + (BUN/2.8)
Sodium: expressed in mEq/L
Glucose: expressed in mg/dL
BUN: expressed in mg/dL
Calculated Serum Osmolality Using Serum Ethanol = (2 x Na) + (Glucose/18) + (BUN/2.8) + (Ethanol/3.7)
Sodium: expressed in mEq/L
Glucose: expressed in mg/dL
BUN: expressed in mg/dL
Ethanol: expressed in mg/dL
Osmolal Gap
Osmolal Gap = Measured Serum Osm – Calculated Serum Osm
Measured Serum Osmolality is Normally <10 mOsm/L Higher than the Calculated Serum Osmolality: this accounts for the normal osmolal gap being <10 mOsm/L
Elevated Osmolal Gap Indicates the Presence of an Osmotically-Active Substance
Mechanisms Contributing to Development of the Osmolal Gap: the mechanism by which ketoacidosis contributes to an osmolal gap is not clear, since ketoacids are completely ionized at physiologic pH (β-hydroxybutyrate requires an accompanying sodium cation) and do not contribute directly to the osmolal gap
May be caused by accumulation of glycerol (derived from fat breakdown) or acetone/acetone metabolites
Clinical: typically results in a small osmolal gap (<15-20 mOsm/L)
Intoxications
Diethylene Glycol Intoxication (see Diethylene Glycol, [[Diethylene Glycol]])
Mechanisms Contributing to Development of the Osmolal Gap: presence of low molecular weight solute, diethylene glycol
Clinical: may produce a large osmolal gap (>20 mOsm/L)
However, the absence of an osmolal gap does not exclude the presence of diethylene glycol
In addition, there are often discrepancies between the degree of osmolal gap and the severity of clinical manifestations
Ethylene Glycol (see Ethylene Glycol, [[Ethylene Glycol]]): presence of low molecular weight solute
Mechanisms Contributing to Development of the Osmolal Gap: presence of low molecular weight solute, ethylene glycol
Since the serum osmolal gap estimates the molar quantity of uncharged molecules, the osmolal gap is increased due to the presence of ethylene glycol itself
The toxic ethylene glycol metabolites, glycolate/glyoxylate/oxalate, exist primarily in a dissociated (charged) form at physiologic pH -> as these anions are accompanied by a cation (mostly sodium), they do not contribute to the serum osmolal gap since they are accounted for in the serum sodium term in the serum osmolal gap formula
Clinical: may produce a large osmolal gap (>20 mOsm/L)
An elevated osmolal gap may appear before the development of metabolic acidosis in cases with concomitant ethanol and ethylene glycol ingestion
A normal osmolal gap does not exclude ethylene glycol intoxication and a small osmolal gap can be seen with high ethylene glycol levels (the sensitivity/specificity of osmolal gap depends on timing of ingestion)
There are often discrepancies between the degree of osmolal gap and the severity of clinical manifestations
Formaldehyde Intoxication (see Formaldehyde, [[Formaldehyde]])
Mechanisms Contributing to Development of the Osmolal Gap: presence of low molecular weight solute, formaldehyde
Mechanisms Contributing to Development of the Osmolal Gap: presence of low molecular weight solute, methanol
Since the serum osmolal gap estimates the molar quantity of uncharged molecules, the osmolal gap is increased due to the presence of methanol itself
The toxic methanol metabolite, formic acid, exists primarily in a dissociated (charged) form at physiologic pH -> as this anion is accompanied by a cation (mostly sodium), it does not contribute to the serum osmolal gap since it is accounted for in the serum sodium term in the serum osmolal gap formula
Clinical: may produce a large osmolal gap (>20 mOsm/L)
However, the absence of an osmolal gap does not exclude the presence of methanol
In addition, there are often discrepancies between the degree of osmolal gap and the severity of clinical manifestations
Paraldehyde Intoxication (see Paraldehyde, [[Paraldehyde]])
Mechanisms Contributing to Development of the Osmolal Gap: presence of low molecular weight solute, paraldehyde
Mechanisms Contributing to Development of the Osmolal Gap: presence of solute, toluene
Other
Chronic Kidney Disease (CKD) without Regular Hemodialysis (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): with GFR <10 ml/min
Mechanisms Contributing to Development of the Osmolal Gap: due to presence of urea and unidentified small solutes (the latter of which are generally cleared with hemodialysis and are not present in acute kidney injury)
Clinical: typically results in small osmolal gap (<15-20 mOsm/L)
Mechanisms Contributing to Development of the Osmolal Gap: the mechanism by which lactate contributes to an osmolal gap is not clear, since lactate is completely ionized at physiologic pH (lactic acid requires an accompanying sodium cation) and does not contribute directly to the osmolal gap
May be caused by tissue release of smaller glycogen breakdown products
Clinical: typically results in small osmolal gap (<15-20 mOsm/L)
Epidemiology: most common etiology of an elevated osmolal gap
Mechanisms Contributing to Development of the Osmolal Gap: ethanol is an osmotically active substance
Clinical: may produce a large osmolal gap (>20 mOsm/L)
However, the absence of an osmolal gap does not exclude the presence of ethanol
In addition, there are often discrepancies between the degree of osmolal gap and the severity of clinical manifestations
Isopropanol Intoxication (see Isopropanol, [[Isopropanol]])
Mechanisms Contributing to Development of the Osmolal Gap: isopropanol is osmotically-active and is metabolized to acetone (which is also osmotically-active)
However, acetone is a non-ionized molecule that is not an acid and, therefore, does not result in metabolic acidosis
Clinical: may produce a large osmolal gap (>20 mOsm/L)
However, the absence of an osmolal gap does not exclude the presence of isopropanol
In addition, there are often discrepancies between the degree of osmolal gap and the severity of clinical manifestations
Infusion or Absorption of Non-Conductive Sugar Solution
Glycine
Clinical Scenarios
Inadvertent absorption of irrigant solution (or accidental systemic infusion) during trans-urethral resection of the prostate//bladder or hysteroscopy
Intravenous mannitol infusion administered for increased intracranial pressure
Inadvertent absorption of irrigant solution (or accidental systemic infusion) during trans-urethral resection of the prostate//bladder or hysteroscopy
Maltose
Clinical Scenarios
Patient with chronic kidney disease receiving intravenous immunoglobulin in a 10% maltose solution (maltose is not metabolized in the setting of chronic kidney disease)
Sorbitol
Clinical Scenarios
Inadvertent absorption of irrigant solution (or accidental systemic infusion) during trans-urethral resection of the prostate//bladder or hysteroscopy
Other
Severe Hyperlipidemia (see Hyperlipidemia, [[Hyperlipidemia]])
Mechanisms Contributing to Development of the Osmolal Gap: since the specimen contains less serum water, the serum sodium concentration will be spuriously decreased (pseudohyponatremia)
Clinical: in this case, the “true” serum sodium and the serum osmalility are actually both normal
Severe Hyperproteinemia
Mechanisms Contributing to Development of the Osmolal Gap: since the specimen contains less serum water, the serum sodium concentration will be spuriously decreased (pseudohyponatremia)
Clinical: in this case, the “true” serum sodium and the serum osmalility are actually both normal
Sick Cell Syndrome
Epidemiology: occurs in the setting of multi-organ failure
References
Ann Int Med 1991;114: 337-8
Clin Chem 1992;38: 755-757
Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008 Jan;3(1):208-25. Epub 2007 Nov 28 [MEDLINE]
