The anion gap as a predictive tool for morbidity and mortality

Since the early 1970s, the anion gap has been a fundamental component of acid-base disorder diagnosis and workup. In the past decade, a vastly expanded and ever-increasing literature base has explored its utilization as a morbidity and mortality predictive parameter in various clinical conditions. This discussion will review its history/derivation and reference interval associated issues followed by a literature review of current studies focusing on its relatively recent use as a clinical predictive marker. An English language PUBMED search was performed to include all listings up through 12/31/2022 using the free text search term "ANION GAP." In addition, clinical texts were identified and used as a metric of current standard of care utilization. All references were then sorted into predictive-related and non-predictive-related categories. The predictive references were thus classified by clinical cohort: critical patient, general population, glycemia, intoxication, lactic acidosis, myeloma, renal function, and seizure. A total of 2,068 references were identified and reviewed, of which 95 used the anion gap as a predictive marker and 15 significant for the reference interval discussion. Across all clinical cohorts, except lactic acidosis, an elevated anion gap was found to be significant in predicting morbidity and/or mortality. The published reference intervals of the anion gap were highly variable: the upper reference limit ranged from 10 mmol/L to 19 mmol/L, and the width of the reference intervals (upper minus lower reference limit) ranged from 2 mmol/L to 11 mmol/L. The flaws of the anion gap based on our review are outweighed by its benefits in terms of it being a significant predictive marker of morbidity and mortality. Significant variations in equations and reference limits in the literature raised the question of whether a "normal range" is necessary for utilizing this calculated construct for clinical management.