Abstract
Background and Aims
The urea & electrolyte panel (U&E) is a basic test commonly performed in clinical medicine. A quick evaluation can often reveal the presence of acid-base disturbances which in turn flags up potentially serious physiologic disturbances and critical conditions.
While there are a few ways to screen for acid-base disorders, evaluation of the anion gap remains popular today. The AG is the difference between measured cations and anions and calculated from the main components of the U&E. For mixed acid-base disorders, the delta gap (ΔGap) provides further information (Table 1).
However, every test has a range within tolerance limits. The tolerance limit in turn depends on the precision of the laboratory methodology. Figure 1 illustrates how tolerance intervals are determined in a normal distribution.
To date, most clinical texts quote a tolerance interval of ±6 mEq/L for ΔGap, referencing the 1990 article by Dr Kieth Wrenn (Ann Emerg Med. 1990 Nov;19(11):1310). The range of ±6 mEq/L was calculated using the standard deviation (SD) of the tests for Na, Cl and bicarbonate in the 1980s, and an ΔGap > +6 or < –6 mEq/L suggests a mixed disorder.
Derivation of tolerance interval of ΔGap:
ΔGap = ΔAG – ΔHCO3-
ΔGap = (AG –12) – (24 – HCO3-)
ΔGap = (Na+ – Cl- – HCO3- –12) – (24 – HCO3-)
Variance (SD2) of ΔGap = Sum of variances of component electrolytes
Variance (SD2) of ΔGap = SD2Na + SD2Cl + SD2HCO+ SD2HCO
Standard deviation (SD) of ΔGap = √( SD2ΔGap)
Tolerance interval of ΔGap = ±1.96 x SDΔGap
However, laboratory techniques have improved in precision since the 1980s. A ΔGap of ±6 mEq/L may be too wide, inadvertently missing mixed metabolic disorders.
The aim of this study was to update the reference range of the ΔGap based on current laboratory precision. Interpretation of the acid-base disorder will be applied using the updated ΔGap range in a validation cohort.
Method
The current SD for Na, Cl and bicarbonate was obtained from the laboratory system data sheet and the tolerance interval of ΔGap was calculated .
A validation cohort was generated retrospectively from electronic medical records according to a pre-determined criteria from 1 Jan – 31 Dec 2018. We identified a group of patients with a strong possibility of mixed HAGMA and MALK in the presence of:
1. High AG
2. Significant organic acidosis (lactic acidosis, ketosis or elevated salicylates) AND
3. A serum bicarbonate ≥19.0 mmol/L despite the presence of organic acids.
The ΔGap was computed and interpreted based on the original vs new tolerance range. The Chi Square test was used to compare the interpretations based on the 2 tolerance ranges.
Results
The current SD of Na, Cl, bicarbonate was 0.9, 0.7, 0.3 respectively and the new tolerance interval of AG was ±2.3 mEq/L (rounded to ±2 mEq/L)
The validation cohort comprised of 1,565 patients with HAGMA and MALK, aged 58.0±30.9 years with 873 (55.8%) males.
Using the original range of ±6 mEq/L, 165 (10.5%) cases were classified correctly. With the new range of ±2 mEq/L, the 813 (51.9%) cases were classified correctly (P<0.001).
Conclusion
In summary, based on the precision of current laboratory techiques, the tolerance interval of AG is proposed as ±2 mEq/L. This was validated to significantly increase correct classification of mixed acid-base disorders.
A Diagram to Facilitate the Understanding and Therapy of Mixed Acid Base Disorders
