Toxicology Rounds

Time to Abandon the Osmolal Gap Completely

osmolal gap: After toxic alcohol ingestion, the initially elevated osmol gap decreases and the anion gap simultaneously increases as methanol is metabolized to formic acid or ethylene glycol to oxalic acid.

Figure

David Glaser, MD, nailed the lid on the coffin containing the moldering remains of the osmolal gap for clinical decision-making more than 20 years ago.

“The osmolal gap, he wrote, “is of no use in a patient with a significant anion gap metabolic acidosis of unclear cause. [Technical] limitations invalidate the osmolal gap as a screen for ethylene glycol or methanol ingestion. The osmolal gap is a test with great theoretical appeal but little practical utility in the management of toxic ingestion.” (Ann Emerg Med. 1996:27[3]:343.)

Today, though, we still see many cases in which the osmolal gap is dutifully calculated and passed to consultants or included in case reports. At best, this is a waste of time and resources; at worst, it can contribute to flawed clinical reasoning by a physician who might not understand the characteristics of the test. It's time we abandon the use of the osmolal gap completely.

Osmolality is a measure of the concentration of independent particles in a solution. The usual formula is calculated osmolality = 2 x [Na⁺] + glucose/18 + BUN/2.8 + serum ethanol/4.6. If the actual osmolality of serum is measured by freezing point depression—the only reliable method—we can determine that the osmolal gap = measured osmolality - calculated osmolality.

This osmolal gap represents the quantity of osmotically active particles present that are not accounted for in the calculated formula; in other words, particles that are not sodium, glucose, urea, or ethanol. These missing particles could be toxic alcohols such as methanol, ethylene glycol, or isopropanol, but could also be acetone, glycerol, mannitol, or contrast dye.

Table: Causes of Increased Osmolal Gap

Unreliable and Misleading

The osmolal gap has long been used in a misguided attempt to rule in or out toxic alcohol exposure, but there are dozens of reasons this is inaccurate and inappropriate:

• No consensus exists on the proper formula for determining the calculated osmolal gap. Should the serum sodium level be multiplied by 2 or 1.86? Should the serum alcohol level be divided by 4.6 or 4.22? Josh Farkas, MD, in a brilliant post in his PulmCrit blog, lists 37 different formulas that have been proposed for calculating the osmolal gap. (August 14, 2017; http://bit.ly/2VtYjgw.) None of these has been validated.
• There is no consensus on the range of normal values or the upper limit of normal. Some studies have suggested that the normal osmolal gap ranges from -14 mOsm/kg all the way up to +10 mOsm/kg. If we determine that a patient's osmolal gap is +8 mOsm/kg, does that represent a normal state or an increase of 14 mOsm/kg from the patient's baseline of -6 mOsm/kg because of a significantly toxic ethylene glycol level?
• Even if the formula for calculating the osmolal gap were reliable and the normal value were known precisely, the math would not work unless all the relevant lab values—serum sodium, glucose, BUN, ethanol, and measured serum osmolality—were determined from samples drawn at the same time. This standard is rarely met in my experience.
• The osmolal gap is neither sensitive nor specific as a test for toxic alcohol exposure. Many medical conditions can cause an increased gap. (Table.) A significantly elevated osmolal gap can be hidden if the patient's baseline is toward the low end of normal.
• Finally, toxic alcohol exposure is a constantly evolving clinical situation because methanol and ethylene glycol are metabolized to their toxic end products with time: formate and glycolic acid. The parent alcohols are osmotically active, but do not produce a metabolic acidosis by themselves. Their metabolites, on the other hand, do not contribute to the osmotic gap but do cause an anion gap metabolic acidosis. (Figure.) Toxic alcohol exposure can present with an increased osmolal gap, an increased anion gap metabolic acidosis, both, or neither.

The bottom line: A so-called normal osmolal gap should never be used to exclude the possibility of toxic alcohol exposure. An increased osmolal gap by itself is never dispositive in establishing toxic alcohol exposure. The test is flawed, unreliable, and unhelpful, and could be catastrophically misleading if a diagnosis of toxic alcohol exposure is missed.

We should stop measuring the osmolal gap, stop referencing it in case reports, and stop writing about it. It is a stupid test and a stupid concept. I cannot remember a single case in my career where the osmolal gap changed management in a good way.

I would suggest that the proper management of patients with suspected toxic alcohol exposure or an unexplained anion gap metabolic acidosis is to start fomepizole to block metabolism to formate or glycolic acid while awaiting methanol and ethylene glycol levels. If the ethanol level is above 100 mg/dL, metabolism is already blocked and fomepizole can be deferred. In cases where ingestion is suspected but there is no acidosis, it is also possible to follow progression by frequently monitoring the anion gap to see if it increases.

I would go a step further than Dr. Glaser did in 1996, and say that the osmolal gap has no utility in managing toxicology patients. It is high time we moved on.

Dr. Gussowis a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog atwww.thepoisonreview.com, follow him on Twitter@poisonreview, and read his past columns athttp://bit.ly/EMN-ToxRounds.