Osmolality revisited—Deriving and validating the best formula for calculated osmolality
Introduction
Osmolality (OSM) represents a measure of number of particles in a kilogram of water (osmoles per kilogram). In human serum or plasma, osmolality can be measured experimentally by freezing point depression or it can be calculated by using different formulas that account for the contribution of the common osmotically active constituents (sodium, potassium, glucose, and urea) of serum. The difference between measured osmolality (OSMm) and calculated osmolality (OSMc) is referred to as osmol gap (OG). When ethanol is present, it can be included in the OSMc so the OG now becomes indicative of other osmotically active compounds, i.e., methanol, ethylene glycol, isopropyl alcohol, propylene glycol, etc.
The calculation of OG is commonly used as a screen for toxic alcohol ingestion (ethanol, methanol, ethylene glycol, and propylene glycol). Elevated OG implies the presence of unmeasured osmotically active substances. Currently, the determination of OG for ethanol poisoning has lost its usefulness because ethanol can be measured quickly on most chemistry analyzers. Since other toxic alcohols can only be measured by gas–liquid chromatography, OSMm should still be ordered for other toxic alcohol poisoning and in such cases ethanol should also be ordered, since it is often consumed in these poisoning. In these cases, the laboratory should calculate the OG incorporating ethanol in that calculation. This should theoretically predict the presence of other osmotically active compounds like methanol, ethylene glycol, and propylene glycol, etc.
It has been observed that ethanol does not follow a 1:1 relationship with OG. In ethanol intoxication, where OG is calculated by including ethanol on a molar basis, OG increases with increasing ethanol, making it appear that there is something else present beside ethanol [1], [2], [3], [4]. This results in frequent requests for the clinical laboratory to rule out methanol and ethylene glycol in simple ethanol intoxication, i.e., the clinician calculates the OG and compares it to the ethanol concentration, finds there is still a large gap, and initiates a search for the missing osmoles. Significant elevation in OG has also been found in diabetic ketoacidosis due to the presence of acetone [5], [6]. It has also been observed in several instances that high glucose concentration increases osmolality significantly without the presence of acetone.
The formulas commonly in use do not adequately reflect the contribution of ethanol and glucose to serum osmolality. For this reason, OG increases with increasing ethanol and glucose levels. The common formulas that are in use were created to allow for the simple calculation of osmolality at the bedside. This allowed the clinician to rapidly rule a toxic ingestion in or out. Since computerization of our laboratory, we offered an automated calculated OG (Dorwart et al.) along with other laboratory data. It has long been apparent that in cases of simple intoxication, our automated OG calculation does not accurately predict the ethanol concentration and furthermore that the error is proportional, i.e., it increases with increasing ethanol concentration. This in fact created unnecessary work for us, since physicians were reluctant to discharge patients that were very inebriated but appeared to have some other toxic compound present on the basis of a raised OG. It is now possible to do sophisticated calculation automatically so that the result is available at the same time that the other results are available. For this reason, we set out to develop a calculation that would accurately predict the osmolality both in the presence and absence of ethanol. This would then also accurately predict the presence of toxic compounds other than ethanol using the OG.
The objectives of the study were to:
- 1.
Evaluate the contribution of glucose, ethanol, methanol, and ethylene glycol on the osmolality.
- 2.
Determine if we could experimentally determine factors that can be applied to these compounds to create a more accurate determination of calculated osmolality (OSMc) and also of the osmolal gap (OG).
- 3.
Select an OG calculation that would be predictive of the presence of other compounds like methanol and ethylene glycol even when ethanol was present in the sample.
- 4.
To validate the formula against data extracted from our patient data base.
Section snippets
Materials and methods
The study was divided into two parts. In the first part, we experimentally determined the relationship between increasing analyte concentration to osmolality. This allowed us to calculate factors, which we could then verify in our clinical data. In the experimental part, in vitro experiments were done to determine the contribution of glucose, ethanol, methanol, and ethylene glycol on osmolality in pooled plasma samples which were spiked with varied concentrations of glucose, 5–50 mmol/L (n =
Results and discussion
In the first part of our study, the objective was to determine the relationship between OG and plasma glucose, ethanol, methanol, and ethylene glycol levels. OG was shown to increase with increasing glucose concentration. The slope of the line that describes the relationship between glucose and OG would provide us with a factor. The slope obtained was 1.15 (Fig. 1), indicating that for calculated osmolality a factor of 1.15 must be applied to glucose to account completely for its contribution
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