Rory is just graduated EM Residency at Beth Israel Newark and is now pursuing advanced training in Resuscitation with Brian Wright and me at Stony Brook Hospital. He is the editor of the amazing EMNerd Blog and tweets at @EMNerd_.
This post will serve as a discussion of serum osmolarity*, its clinical utility, and the relationship between the Osm and anion gaps.
The serum osmolarity has been relegated to the dark arts of medical science. Primarily, it is used to calculate the exact fluid status of patients presenting in various dysnatremic states by the physicians who happen to care for such physiological disruptions.
Simply put the serum osmolarity is the number of particles present in the serum. The osmolarity does not discriminate based on a particle’s size or weight, but rather is concerned only with its concentration in the blood (1). As such, particles with low molecular weight that are capable of accumulating in large quantities in the serum, have the greatest potential to influence the osmolarity. In a healthy subject, the osmolarity is predominantly comprised of sodium ions and their counter anions, serum glucose, as well as blood urea nitrogen (BUN) (1).
The serum osmolarity can be grossly estimated using the following formula:†
(Na x 2) + (Glucose/18) + (BUN/2.8)
Briefly, this formula insures that each molecule is accounted for in its molar quantity (mmol/L) (1).
The serum osmolality can also be directly measured by observing either the serum’s freezing point depression or boiling point elevation.
The Osm Gap
If we compare this measured value to the calculated osmolarity, the difference between the two measurements is the Osm gap. Ideally this would equate to the amount of particles present in the serum that are not accounted for by the calculated formula. As such, the Osm gap should be positive in most physiologic states. Unfortunately due to imprecisions in both the measuring process and the formula used to calculate the serum osmolarity, a normal Osm gap varies widely from person to person, ranging from -14 mmol/L to +10 mmol/L (2).
For a substance to influence the Osm gap, it must possess two important qualities. The first attribute is a simple enough concept to grasp. Any substance, if it is to have a significant effect on the osmolarity, must exist in a substantial molar quantity in the serum (1). Very few possess the molar influence to cause a clinically relevant increase in the measured serum osmolarity. In fact the only substances that consistently increase the serum Osm gap are ethanol, methanol, ethylene glycol, isopropyl alcohol, acetone, mannitol, and glycerol (3). The molar quantity of a substance is directly responsible for its effects on the aggregate serum osmolarity.
However, for a substance to influence the Osm gap, not only must it exist in a large enough quantity to increase the osmolarity, it must also maintain a significant degree of electroneutrality. Strong acids that completely dissociate in the serum do not result in an increase in the Osm gap because they are accounted for by the sodium in the formula (2, 4). Once dissociated in the blood, they directly and immediately lower the serum bicarbonate, causing an anion gap acidosis. Essentially this new unmeasured anion directly replaces an identical quantity of bicarbonate, causing the gap between the cations and anions to widen (5). In certain circumstances these substances can be present in the serum in large enough quantities to increase the serum osmolarity, but they do not cause an increase in the Osm gap. Since they are electrochemically active they are accounted for in the calculated formula as sodium’s contiguous anion (Na x 2) (2). Any substance that causes a decrease in the serum bicarbonate concentration and in the process an anion gap acidosis, will inherently be included in the calculated osmolarity because of its association with sodium.
An important example of this physiologic phenomenon is the temporal and inverse relationship between the Osm and anionic gaps in both methanol and ethylene glycol poisoning. Shortly after ingestion, these toxic alcohols exist in the serum in their original form in a large enough quantity to directly influence the measured osmolality. Neither methanol nor ethylene glycol dissociate appreciably in serum, and thus they have no effect on the serum bicarbonate concentration and, in turn, the anion gap. Therefore they cannot be accounted for by the calculated Osm gap.
Both methanol and ethylene glycol are metabolized by alcohol and aldehyde dehydrogenase forming their respective toxic end products: formic acid in the case of the former and glycolic and oxalic acid for the latter. These byproducts demonstrate a greater tendency to dissociate in the serum, and quickly become electrochemically active. Because of this, as the effects of poisoning intensify and more of these toxic byproducts are produced, the bicarbonate concentration will decrease, causing an observable increase in the anion gap. These substrates will now interact with bicarbonate and thus are accounted for in the calculated osmolarity, causing a simultaneous decrease in the Osm gap.†
A second physiologic illustration of the relationship between the anion and Osm gaps can be exhibited in patients presenting with diabetic ketoacidosis (DKA). The degree of acidosis is directly related to the ratio of the various ketones/ketone metabolites: acetone, acetoacetate and beta-hydroxybutyrate present in the serum. The proportion of each respective substance is determined by the existing redox state in the blood. At any given time acetoacetate and beta-hydroxybutyrate exist in an equilibrium dependent upon the ratio of NAD+ and NADH+. These substances freely convert with the assistance of the enzyme beta-hydroxybutyrate dehydrogenase (7). This conversion requires the donation of a hydrogen atom from NADH+. The balance between beta-hydroxybutyrate and acetoacetate, is determined by the ratio of NADH+ to NAD+. Acetoacetate will freely degrade into acetone through non-enzymatic decarboxylation. Early in DKA, acetoacetate is the most prevalent substance. This abundance will drive a portion of acetoacetate towards spontaneous degradation to acetone. As the disease progresses and the serum ratio of NADH+ to NAD+ increases, the proportion beta-hydroxybutyrate rises, decreasing both the quantity of acetoacetate and in turn acetone.
Typically when patients in DKA present to the Emergency Department, the disease will have progressed such that the majority of ketone/ketone metabolites will be in the form of beta-hydroxybutyrate. Both beta-hydroxybutyrate and acetoacetate are electrochemically active (strong anions), and freely dissociate in the serum. Their presence in any measurable quantity will lower bicarbonate to preserve neutrality, causing an anion gap acidosis. Conversely acetone is not electrochemically active and will not cause an anion gap acidosis. Shortly after presentation, the preponderance of beta-hydroxybutyrate will cause a significant anion gap acidosis, but will have little effect on the Osm gap. With resuscitation and insulin therapy, the ratio of NADH/NAD+ will start to normalize causing an increase in the quantity of acetoacetate. A proportion of the acetoacetate will undergo spontaneous degradation to acetone. As the number of the ketones present in this electrochemically inactive form increases, there will be a measurable decrease in the anion gap along with a concomitant increase in the Osm gap. (7,8,15,16).
Given the inconsistency of the tools used to measure the serum osmolarity and its variability throughout the general population, it is not surprising that using the Osm gap in a clinical context proves difficult. Though the majority of patients with concerns for toxic alcohol ingestion will present with elevations in their Osm gap, a normal Osm gap is incapable of excluding the ingestion of toxic alcohols. The wide range of what is considered a normal Osm gap (-14 to 10 mmol/L), allows for a lethal dose of either methanol or ethylene glycol to remain hidden in this standard deviation from the mean(2,9,10). Furthermore depending on the delay from ingestion to presentation, a large majority of the toxic alcohol may already have been metabolized into its noxious, anionic endpoints. The inconsistencies between the measured and calculated osmolarity will have resolved over time, leaving only the elevated anion gap as a clue of their presence.
Conversely an elevated Osm gap in no way definitively substantiates the presence of a toxic alcohol. The mere existence of a severe illness can create Osm gaps far beyond what is considered normal. In fact the degree of discrepancy between the measured and calculated osmolarity is directly related to the severity of illness. This discrepancy is thought to be a result of spillage of small organics from the sick cells of a critically ill patient. (11, 12)
It is said that physiology explains much but predicts little. And while this is in some ways true, the reality is that physiologic states exist in varying degrees of uncertainty. Understanding both the underlying biologic concepts as well as how these theories function clinically is important to the practice of medicine. This has never been more true than when discussing the Osm gap. Except in instances of extreme elevation, the Osm gap has little clinical utility (10). And yet the understanding of its intricacies is of the utmost importance to the management of both toxicologic and acid-base disorders. I can only hope this post serves to clarify some of the underlying physiologic principles of the Osm gap as well as highlight its clinically imperfections.
Test your understanding by reading this post: Precious Bodily Fluids
* Though the serum osmolarity and osmolality measure different ratios (mOsmol/L vs mOsmol/kg), for the purpose of this post, they will be used interchangeably.
† Given that we practice in the ED or ICU, it is usually worth sending an ethanol level and adding it to the equation. All of the alcohols are measurable, but the assays have variable availability with ethanol being ubiquitous. If you have a quantitative measurement, then you can account for that substances contribution to the Osm gap: Will list here:
Ethanol: 1 mmol/L= 4.6 mg/dL
Methanol 1 mmol/L= 3.2 mg/dL
Ethylene glycol= 1 mmol/L = 6.2 mg/dL
Isopropanol= 1 mmol/L=6.0 mg/dL
- DiNubile MJ. Serum osmolality. N Engl J Med 1984;310:1609.
- Hoffman RS, Smilkstein MJ, Howland MA, Goldfrank LR. Osmol gaps revisited: normal values and limitations. J Toxicol Clin Toxicol. 1993;31(1):81-93.
- Glasser L, Sternglanz PD, Combie J, Robinson A. Serum osmolality and its applicability to drug overdose. Am J Clin Pathol. 1973;60(5):695-9
- Rosenberg FM. Lactate and the Osm gap. CMAJ?: Canadian Medical Association Journal. 2007;177(5):489. doi:10.1503/cmaj.1070061.
- Kaplan LJ, Frangos S. Clinical review: Acid-base abnormalities in the intensive care unit — part II. Crit Care. 2005;9(2):198-203.
- Hoffman R, Howland MA, et al. Goldfrank's Toxicologic Emergencies, 10th Edition. McGraw-Hill Medical; December 23, 2014.
- Konijn, Abraham M., Naama Carmel, and Nathan A. Kaufmann. “The redox state and the concentration of ketone bodies in tissues of rats fed carbohydrate free diets.”The Journal of nutrition 10 (1976): 1507.
- Laffel, Lori. “Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes.”Diabetes/metabolism research and reviews6 (1999): 412-426.
- Steinhart B. Case report: severe ethylene glycol intoxication with normal osmolal gap–“a chilling thought”. J Emerg Med. 1990;8(5):583-5.
- Lynd LD, Richardson KJ, Purssell RA, et al. An evaluation of the osmole gap as a screening test for toxic alcohol poisoning. BMC Emerg Med. 2008;8:5
- Schelling JR, Howard RL, Winter SD, et al. Increased Osm gap in alcoholic ketoacidosis and lactic acidosis. Ann Intern Med 1990;113:580.
- Braden GL, Strayhorn C, Germain M, et al. Increased osmolal gap in alcoholic acidosis. Arch Intern Med 1993;153:2377-80.
- Inaba H, Hirasawa H, Mizuguchi T. Serum osmolality gap in postoperative patients in intensive care. Lancet. 1987;1(8546):1331-5.
- Sklar AH, Linas SL. The Osmolal Gap in Renal Failure. Ann Intern Med. 1983;98:481-482. doi:10.7326/0003-4819-98-4-481
- Laffel L. Diabetes Metab Res Rev. 1999 Nov-Dec.
- Umpierrez GE, Digirolamo M, Tuvlin JA, Isaacs SD, Bhoola SM, Kokko JP. Differences in metabolic and hormonal milieu in diabetic- and alcohol-induced ketoacidosis. J Crit Care. 2000;15(2):52-9.