Osmol Gaps: What, How, and When?
By Robert Hoffman, MD
A high anion gap metabolic acidosis is one of the most common and consequential acid-base abnormalities encountered in the practice of emergency medicine. For the purpose of this discussion, the normal anion gap { [Na] - ([Cl] + [HCO3])} will be defined as 3-11 mmoL/L. While this value may be lower than the 12-16 mmoL/L that many of us learned previously, it is reflective of an upward trend in chloride concentrations as determined by most modern autoanalyzers.1
The differential diagnosis of a high anion gap metabolic acidosis is extensive, and the therapeutic approach to the patient is usually defined by the specific etiology. The ability to define a causative factor is in part related to the magnitude of the anion gap. In one study, when the anion gap was greater than 30 mmoL/L, the cause could be diagnosed clinically in nearly 90% of cases. In patients with anion gaps of 25-29 mmoL/L, the diagnosis was only established in 60% of cases. As the elevation in the gap was less severe, the ability to correctly identify the cause diminished.2
Patients with high anion gap metabolic acidoses usually have significant medical illnesses. Brenner studied the outcomes of 671 ED patients, 100 of whom had elevated anion gaps. When compared to those patients with normal anion gaps, the group with elevated gaps had higher admission rates, many of which were to intensive care units, and a higher mortality. Specifically, patients with a high anion gap and no other severe electrolyte abnormalities had a 50-fold increase in mortality when compared with those patients with similar electrolytes and a normal anion gap.3
Thus, it is incumbent upon clinicians to rapidly and accurately determine the etiology of an elevated anion gap so that appropriate treatment can begin. Many physicians use memory aides such as "mudpiles" (methanol, uremia, diabetic ketoacidosis, phenformin, isoniazid, lactate, ethylene glycol, salicylates) to help sort out the differential diagnosis. It is important, however, to also remember that significant causes of elevated anion gaps, such as cyanide poisoning, iron overdose, and theophylline toxicity, are not listed in these common mnemonics.
History and physical examination are often used to exclude some etiologies. The absence of seizures excludes isoniazid toxicity. Similarly, patients with significant poisonings from iron and theophylline usually have severe gastrointestinal complaints. This clinical approach is followed by rapid and inexpensive screening tests such as ferric chloride or Trinders reaction for salicylates, urine for ketones, fluorescence of urinary oxalate crystals, and an arterial lactate level. However, when all these studies are nondiagnostic and the patient continues to mount a metabolic acidosis, the clinician is required to consider the presence of a toxic alcohol (methanol or ethylene glycol). The diagnosis could easily be established with a serum level, but, unfortunately, these are rarely available on an emergent basis. Thus, the concept of using an osmol gap has arisen.
Osmolality is a measure of the total number of particles in solution and is unaffected by the size, charge, or chemical nature of the particles. The osmol gap is defined as the difference between the measured osmolality and the calculated osmolarity. Osmolality, the number of particles per kilogram of solution, is usually measured by freezing point depression; as the number of particles is increased, the freezing point of water decreases in a linear fashion. Osmolarity, the number of particles per liter of solution, is usually calculated from known concentrations of the major constituents of solution.
It should be obvious that while measured osmolality and calculated osmolarity approximate each other, they can only be identical by chance. One is defined per kilogram of solution and the other per liter. While it is true that one liter of water weighs one kilogram, serum, although dilute, is not water. Also, we traditionally use sodium, blood urea nitrogen, and glucose to calculate the osmolarity, knowing that potassium, calcium, magnesium, proteins, fats, and every other molecule all contribute to the actual osmolarity of the solution.
Many problems arise in the use of an osmol gap, the most fundamental of which is the formula used to calculate osmolarity. Previous studies have rigorously evaluated the various formulas commonly used.4,5 Most commonly, the osmolarity is calculated by multiplying the sodium by two, dividing the glucose by 18, and dividing the blood urea nitrogen by 2.8. Problems occur when variants of this formula are used (rounding of 18 and 2.8 to 20 and 3, respectively, or multiplying the sodium by 1.86). For example, a patient is brought to the hospital with altered mental status and is noted to have an anion gap metabolic acidosis. The patient was given 50% dextrose by the paramedics and has a glucose of 400 mg/dL. Dividing this by 18 yields 22 mOsm/L, but dividing by 20 yields 20 mOsm/L. Although 2 mOsm/L does not sound exciting, it correlates with an ethylene glycol level of 13 mg/dL (half the level required for dialysis). Imagine now if the sodium is in error by 1-2 mEq/L.
The second problem surrounds the discussion of what constitutes a normal osmol gap. Clearly this value is dependent on the formula used to calculate osmolarity. One study demonstrated that the osmol gap in a general ED population could vary by as much as 17 mOsm depending on how it was calculated.5 This variation could represent methanol and ethylene glycol levels of as high as 54 and 109 mg/dL, respectively. Many authors agree that the normal osmol gap is -2 ± 6 mOsm. Knowing this, about 95% of patients will have gaps between -14 and +10 (2 standard deviations in either direction). Thus, when a patient presents with a gap of zero, which is normal, and that person lives at -10, for example, they have 10 extra mOsm/L in their serum. This could represent an ethylene glycol level of 64 mg/dL. Furthermore, it is important to remember that as these toxic alcohols are metabolized, the osmol gap will decline because the charged metabolites are accounted for when the sodium is doubled.
Using this logic, it should be clear that no value of osmol gap is sufficient to exclude a diagnosis of toxic alcohol ingestion. With that in mind, we should consider the use of an elevated osmol gap. Unfortunately, conditions such as liver failure, renal failure, sepsis, shock, alcoholic ketoacidosis, and lactic acidosis are all associated with elevated osmol gaps. Thus, in a patient with a high anion gap metabolic acidosis and an elevated osmol gap, the diagnosis of toxic alcohol poisoning should still be questioned. In addition, non-toxic compounds such as mannitol and propylene glycol also raise the osmol gap. The latter is a common diluent of intravenous benzodiazepines and barbiturates, medications commonly given to severely ill patients.
In summary, clinicians must remember that a low osmol gap can never be used as the sole criterion for exclusion of the diagnosis of toxic alcohol ingestion, and a high osmol gap is never definitively confirmatory of a toxic alcohol ingestion. Given this information, one might question when, if ever, the test is indicated. In my opinion, the determination of osmol gaps has the greatest use in patients with normal acid-base physiology and ingestion of a toxic alcohol by history. Under these circumstances, an elevated osmol gap may be sufficient to begin definitive therapy while confirmatory levels are pending. Also, in patients who already have severe acid-base abnormalities, marked elevations of the osmol gap (usually above 20-30 mOsm/L) are usually associated with toxic alcohol ingestion, as the other conditions listed above rarely raise the osmol gap to that magnitude.
References
1. Winter SD, et al. The fall of the serum anion gap. Arch Intern Med 1990;150:311-313.
2. Gabow PA, et al. Diagnostic importance of an increased anion gap. N Engl J Med 1980;303:854-858.
3. Brenner BE. Clinical significance of the anion gap. Am J Med 1985;79:289-296.
4. Dorward WV, Chalmers L. Comparison of methods for calculating serum osmolality from chemical concentrations and the prognostic value of such calculations. Clin Chem 1975;21:190-194.
5. Hoffman RS, et al. Diagnostic importance of an increased anion gap. N Engl J Med 1980:303:854-858.
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