Osmolar gap

The osmolar gap is a diagnostic tool which can help identify the presence of some foreign solute in the body fluids. In the CICM fellowship SAQs, it mostly identifies young women who have ingested a toxic alcohol.

Specific questions of this sort include the following examples:

• Question 5.3 from the first paper of 2022  - HAGMA, high osmolar gap
• Question 7.2 from the first paper of 2014 - HAGMA, high osmolar gap
• Question 7.3 from the first paper of 2014 - HAGMA, normal osmolar gap
• Question 25.2 from the second paper of 2010 - HAGMA, high osmolar gap
• Question 25.3 from the second paper of 2010 - no acidosis, but a high osmolar gap
• Question 20.2 from the first paper of 2013 - HAGMA, high osmolar gap
• Question 11 from the second paper of 2005 - HAGMA, high osmolar gap
• Question 19.2 from the first paper of 2009 - HAGMA, high osmolar gap (name 3 causes)

The nature of the model answers suggests that the examiners expect their candidates to be able to generate a robust list of differentials. Descent into biochemical pfuffery will go unrewarded.

In brief:

• Osmolar gap: measured osmolality - (2× Na⁺ + glucose + urea)
• The Americans use unwieldy and ridiculous units to measure glucose and urea; thus, their most accurate equation must look like this:
  1.86 × Na⁺ + (glucose /18) + (BUN/2.8) + 9
  
  or, as a reader has pointed out, a more wieldy alternative:
  2 × Na⁺ + (glucose /18) + (BUN/2.8)
   
• Normal gap: less than 10.
• Measured is osmolality (mOsm/kg) - calculated is osmolarity (mOsm/L) - though this author confesses that he is lazy and error-prone, and habitually uses the wrong units. The difference between osmolality and osmolarity is too nerd for the Fellowship exam, but you can still read about it here. 

Causes of a normal anion gap and a high osmolar gap 

Essentially, this will be any substance administered into the bloodstream which does not dissociate at physiologic pH. Question 7.3  from the first paper of 2014 presented the candidate with such a scenario. Several possible explanations can be offered:

• Mannitol therapy
• Glycine absorption (TURP syndrome)
• Non-metabolised glycols: propylene glycol or polyethylene glycol (found in IV drug ampoules)
• Maltose (IV immunoglobulin is suspended in maltose)
• Ethanol
• Soon (immediately) after toxic alcohol ingestion.
• A normal-looking anion gap in the presence of low albumin - if the albumin is not used to calculate what the "expected normal" anion gap should be (i.e. the "real" anion gap is raised, but it appears normal because you neglected the contribution of albumin)

Causes of high anion gap and a high osmolar gap

Question 7.2 from the first paper of 2014 asks for this specifically. And even more specifically, Question 19.2 from the first paper of 2009 aska about which toxins are responsible for this sort of picture.

• Toxicological causes
  • Methanol intoxication (the anion is formic acid)
  • Ethylene glycol intoxication (the anions are glycolic acid and oxalic acid)
  • Diethylene glycol intoxication (the anion is 2-hydroxyethoxyacetic acid, HEAA)
  • Propylene glycol intoxication (the anions are pyruvate, lactate and acetate)
  • Salicylate intoxication (the anions are salicylate and lactate)
  • Any toxin causing massive lactic acidosis, eg. isoniazid
• Endocrine and metabolic disturbances
  • Lactic acidosis
  • Alcoholic or diabetic ketoacidosis
  • Acute kidney injury

Causes of high anion gap and a normal osmolar gap

• Abnormally large value of albumin or other negatively charged serum protein (i.e. the "expected normal" anion gap is higher, and without correction the calculated anion gap appears raised - but there are no extra osmoles, as all the extra proteins do not contribute much to osmolality) 
• Unusual equations used to calculate osmolality (there are ~15)
• Late stage of toxic alcohol intoxication (all the extra osmoles have been metabolised)
   

The importance of timing in toxicological comedy

As Jeffrey Kraut reminds us, timing is very important in the appearance and disappearance of the raised osmolar gap, particularly where it concerns the ingestion of toxic alcohols. All of these toxic alcohols are non-polar at physiological pH, and so cannot raise the anion gap - only the osmolar gap. Ergo, early in the intoxication only the osmolar gap will be raised. Later, as the intoxicated patient staggers vomiting around the emergency department, some of the toxic alcohol will have been matabolised into organic acids, raising the anion gap (and decreasing the osmolar gap). Ultimately, as they lay in their ICU bed, the extra osmoles will have been metabolised into organic acid anions, and the bicarbonate will have decreased stoichiometrically. Thus only the anion gap will be raised in late intoxication.

Do you use the corrected sodium, or the uncorrected sodium?

The uncorrected, of course.
The corrected sodium merely gives you the impression of what the sodium level would "naturally" be like if the extra osmoles were removed. However, the measured sodium is the actual serum sodium, and this is the concentration which is contributing to the osmolality of the solution.