ToxCard: Osmol Gap – Part 2

Authors: Travis Mok, MD (@tkcm01 on Threads, Emergency Medicine Resident, Rutgers New Jersey Medical School); Cynthia Santos, MD (Emergency Medicine Attending, Medical Toxicologist, Rutgers New Jersey Medical School) // Reviewed by: Anthony Spadaro, MD (@TSpadaro91, Medical Toxicology Fellow, Rutgers New Jersey Medical School, Newark, NJ); James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

Continued from Part 1: The resident correctly calculates the osmol gap to be 16, taking in account for the ethanol level. However, during their workup the patient is found to have multiple lab abnormalities concerning for alcoholic ketoacidosis and acute on chronic kidney disease. The resident becomes concerned that these concurrent conditions will falsely affect the osmol gap and is unsure if he should start fomepizole for possible toxic alcohol ingestion.

Questions:

1. What are common confounders that reduce the utility of calculating the osmol gap?

Discussion:

Late Presentation:

Toxic alcohols are metabolized into unmeasured anions, methanol is metabolized to formic acid and ethylene glycol is metabolized to oxalic acid.¹ Initially these toxic alcohols contribute to the osmol gap, but as metabolism occurs the osmol gap decreases and the anion gap increases.¹ Thus patients who present late after ingesting a toxic alcohol may have a normal osmol gap and a large anion gap acidosis. These patients still need to be rapidly identified and be treated for their ingestion

Small Number, Big Effect:

Due to the nature of calculating serum osmolarity, small changes in concentrations of the involved solutes can result in large changes to the final osmol gap value. An excellent example of this is change of 1 mEq/L of serum Na will result in a change in the osmolar gap value of 2 mOsm/L. Thus, any laboratory or individual variances in these values can lead to values that fall just within or outside “normal” ranges.²

Are You Normal?

Empiric studies have shown that within the population there exists a wide variance of “normal” osmol gap values. When placed on a bell curve, 95% of the population should have a normal osmol gap range of -14 to 10 mOsm/L. However, this leaves 5% of the population that normally exists outside this range.² Without knowing the patient’s baseline osmol gap, it is conceivable that those with gaps that fall on the left side of the bell curve can have clinically significant toxic alcohol ingestions at low enough concentrations that they do not result in “abnormal” osmol gaps.²  Because of this, small or negative osmol gaps can never be used solely to exclude toxic alcohol ingestion. However, very large gaps (>50-70 mOsm/L) are usually indicative of a toxic alcohol ingestion.² Simultaneously, as there are other factors that can cause an osmol gap (described below), the presence of an osmol gap alone cannot be used to determine the presence of a toxic alcohol. Any osmol gap calculation must be combined with appropriate clinical context and pre-test probability. For example, patient presenting with a complaint not suspicious for toxic alcohol ingestion may have a gap due to a combination of a high baseline osmol gap and concurrent metabolic abnormalities, while another patient presenting after a suicide attempt with toxic alcohol ingestion can have no gap due to a low baseline gap and small volumes of ingestion.

Metabolic Derangements:

• Renal Failure: The decreased clearance and the increased production of unknown solutes in renal failure can contribute to an osmol gap.^3,4
• Medications and Contrast: High-osmolality medications such as mannitol (used to treat cerebral edema) can cause elevations in the measured serum osmolality.^5,6 This is not accounted for by the calculated serum osmolarity equation, leading to an increased osmol gap. Low-osmolality IV contrast used for CT scanning can also cause small increases in the osmol gap for similar reasons.¹⁷
• Alcohol Ketoacidosis: The fatty acid metabolism and generation of ketones can produce osmotically active byproducts such as glycerol and acetone.¹⁸
• Sick Cell Syndrome: Increased cell membrane permeability leading to redistribution hyponatremia has been noted in critically ill patients. The mechanism of this is unknown.^3,7
• Laboratory Technique: While this does not affect laboratory osmometers using the more common freezing point depression technique, other analytical methods can miss toxic alcohols that have low boiling points when obtaining measured serum osmolality. ² In addition, sodium levels can be falsely reduced (termed pseudohyponatremia) in the setting of reduced serum water content when using older laboratory methods. This can occur in hyperlipidemia, hyperproteinemia, or various other causes in critically ill patients. This will reduce the calculated serum osmolarity and increase the gap. Newer laboratory methods measure sodium concentration in serum water only and is not affected by the amount of water that is present in serum.⁶

Osmol Gap Misconceptions:

• Elevated lactic acid level will increase your osmol gap: Incorrect. An elevated lactic acid level in the serum by itself will not increase the osmol gap.⁹ However, it may be secondary to other processes which can create unknown solutes that can increase the osmol gap.¹⁰ The reason for this is that lactic acid is buffered by HCO₃^–, creating CO₂ which is exhaled. When multiplying sodium by 2 in the calculated osmolarity equation, it is approximating for all the chloride and bicarbonate that is theoretically present, including any bicarbonate that may no longer be present after buffering.⁹
• Toxic alcohols can be detected with simple laboratory testing: Mostly incorrect. While laboratory testing exists to identify and quantify the presence of toxic alcohols, it is expensive, labor intensive, and requires specialized equipment that is mostly only available in separate laboratory centers.^2,8,11 This adds complexity and delay to diagnosis, making it inadequate for emergent clinical decision making in the acutely ill patient. The presence of a large osmol gap is a much quicker and adequately specific finding for patient care.

Case Follow-up:

After ruling out other emergent pathologies, the disposition is made to admit the patient for alcoholic ketoacidosis and acute on chronic kidney disease. The patient does not appear to have any other concerning symptoms or any other metabolic pathologies. The decision is made to not start fomepizole but to continue monitoring with serial anion gaps and osmol gaps as the small osmol gap of 16 may be secondary to his metabolic derangements and less likely from an acute toxic alcohol ingestion.

Clinical Pearls:

• A small or negative osmol gap cannot be used to exclude toxic alcohol ingestion.
• There is a wide range of “normal” osmol gaps amongst patients.
• Small amounts of toxic alcohol can lead to small changes to the osmol gap – however they can still be clinically significant even at small concentrations.
• On the other hand, a positive osmol gap cannot be used alone to indicate the presence of a toxic alcohol and must be used with clinical context and patient presentation.
• A large osmol gap (>50-70 mOsm/L) indicates a high likelihood of a toxic alcohol ingestion.
• Any large enough contribution of osmotically active substances into the serum or changes to the sodium level can lead to changes in the osmol gap, including from severe illness, mannitol, and IV contrast.

References:

1. Nelson LS, Goldfrank LR. Goldfrank’s Toxicologic Emergencies. New York Mcgraw-Hill Education; 2019.
2. Hoffman RS, Smilkstein MJ, Rowland MA, Goldfrank LR. Osmol gaps revisited: Normal values and limitations. J Toxicol Clin Toxicol. 1993;31(1):81-93. doi:10.3109/15563659309000375
3. Inaba H, Hirasawa H, Mizuguchi T. SERUM OSMOLALITY GAP IN POSTOPERATIVE PATIENTS IN INTENSIVE CARE. The Lancet. 1987;329(8546):1331-1335. doi:10.1016/s0140-6736(87)90646-5
4. SKLAR AH. The Osmolal Gap in Renal Failure. Ann Intern Med. 1983;98(4):481. doi:10.7326/0003-4819-98-4-481
5. Marts LT, Hsu DJ, Clardy PF. Mind the Gap. Ann Am Thorac Soc. 2014;11(4):671-674. doi:10.1513/annalsats.201401-033cc
6. Weisberg LS. Pseudohyponatremia: A reappraisal. Am J Med. 1989;86(3):315-318. doi:10.1016/0002-9343(89)90302-1
7. Guglielminotti J, Pascal Pernet, Maury É, et al. Osmolar gap hyponatremia in critically ill patients: Evidence for the sick cell syndrome? Crit Care Med. 2002;30(5):1051-1055. doi:10.1097/00003246-200205000-00016
8. Kraut JA, Kurtz I. Toxic Alcohol Ingestions: Clinical Features, Diagnosis, and Management. Clin J Am Soc Nephrol. 2008;3(1):208-225. doi:10.2215/CJN.03220807
9. Dorwart WV, Chalmers L. Comparison of Methods for Calculating Serum Osmolality from Chemical Concentrations, and the Prognostic Value of Such Calculations. Clin Chem. 1975;21(2):190-194. doi:10.1093/clinchem/21.2.190
10. Sood MM, Richardson R. Negative anion gap and elevated osmolar gap due to lithium overdose. Can Med Assoc J. 2007;176(7):921-923. doi:10.1503/cmaj.061057
11. Wu AHB, McKay C, Broussard LA, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Recommendations for the Use of Laboratory Tests to Support Poisoned Patients Who Present to the Emergency Department. Clin Chem. 2003;49(3):357-379. doi:10.1373/49.3.357