Serum Osmolality

Physiology

Normal Biologic Determinants of Serum Osmolality

  • Sodium
  • Glucose
  • Blood Urea Nitrogen (BUN)

Normal Value of Serum Osmolality

  • Normal Serum Osmolality: 285-290 mOsm/L

Measurement of Serum Osmolality

  • 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
    • Example: methanol
    • Example: ethylene glycol

Etiology of Elevated Osmolal Gap

Osmolal Gap with Anion Gap Metabolic Acidosis (AGMA) (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]])

Ketoacidoses

  • Alcoholic Ketoacidosis (AKA) (see Alcoholic Ketoacidosis, [[Alcoholic Ketoacidosis]])
    • Mechanisms Contributing to Development of the Osmolal Gap
      • Presence of the low molecular weight osmotically-active solute, ethanol
      • Persistence of osmotically-active acetone after ethanol is metabolized
    • Clinical: may produce a large osmolal gap (>20 mOsm/L)
  • Diabetic Ketoacidosis (DKA) (see Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State, [[Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State]]): presence of low molecular weight solute
    • 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
  • Methanol (see Methanol, [[Methanol]])
    • 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
  • Propylene Glycol (see Propylene Glycol, [[Propylene Glycol]])
    • Mechanisms Contributing to Development of the Osmolal Gap: propylene glycol is metabolized to L-lactate, D-lactate, and glyoxal
    • Clinical: may produce a large osmolal gap (>20 mOsm/L)
      • However, the absence of an osmolal gap does not exclude the presence of propylene glycol
      • In addition, there are often discrepancies between the degree of osmolal gap and the severity of clinical manifestations
  • Toluene Intoxication (see Toluene, [[Toluene]])
    • 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)
  • Lactic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])
    • 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)

Osmolal Gap without Anion Gap Metabolic Acidosis

Intoxications

  • Acetone (see Acetone, [[Acetone]])
    • Mechanisms Contributing to Development of the Osmolal Gap: acetone is osmotically-active
      • However, acetone is a non-ionized molecule that is not an acid and therefore, does not result in metabolic acidosis
    • Clinical: xxx
  • Diethyl Ether Intoxication (see Diethyl Ether, [[Diethyl Ether]])
    • Mechanisms Contributing to Development of the Osmolal Gap: xxx
    • Clinical: xxx
  • Ethanol Intoxication (see Ethanol, [[Ethanol]])
    • 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
  • Mannitol (see Mannitol, [[Mannitol]])
    • Clinical Scenarios
      • 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]