Method-specific reference intervals for serum anion gap and osmolality.

To the Editor: We wish to comment on reference intervals for the serum anion gap and osmolality. The serum anion gap, which is most commonly defined as AG 5 Na-Cl-TCO2, traditionally has had a reference interval of 8 –16 mmol/L with a mean value (i.e., mean of values used to determine its reference interval) of 12 mmol/L (1, 2). In a recent report (3), the stated reference interval for the anion gap was 12–16 mmol/L with potassium included in the calculation, approximately equivalent to 8 –12 mmol/L without inclusion of potassium. This range of only 4 mmol/L appears to be too narrow for a healthy human population. Moreover, recent studies have shown that mean values for current analyzers often differ from the traditional value and may vary from 5.9 mmol/L for the Beckman Synchron to 12.4 mmol/L for the Nova analyzer (4 – 6). Consequently, depending on the analyzer used, the serum anion gap reference interval may be as low as 2–10 mmol/L or as high as the traditional range of 8 –16 mmol/L. We have also found marked interlaboratory differences in measurements by the same type of analyzer (6). Thus, interpretation of the anion gap requires that each clinical laboratory determine its own reference interval. The reference interval for serum osmolality also deserves study. One recent report (3) included a reference interval of 270 –290 mOsm/kg. We believe this interval is inappropriately low, based on our duplicate measurements of serum osmolality by freezing point depression (Advanced Instruments Model 3MO osmometer) in 59 healthy volunteers of ages 20 – 60 years. Kolmogorov-Smirnov analysis indicated that we could not reject the hypothesis that the results were normally distributed (P 5 0.64). The mean serum osmolality was 288 mOsm/kg, with a SD of 4.1 mOsm/kg, yielding a parametric reference interval of 280 –298 mOsm/kg. The lowest and highest values measured were 280 and 298 mOsm/kg, respectively. Other published serum osmolality reference intervals based on freezing point depression measurements are 275–290 or 275–295 mOsm/kg in children and adults and 280 –301 mOsm/kg in adults .60 years of age (7, 8). Both analytical methodology and characteristics of the reference population, such as age, can contribute to differences in serum osmolality reference intervals. Again, the clinical laboratory must establish or at least verify the serum osmolality reference interval to aid in accurate interpretation.