Contribution of various metabolites to the “unmeasured” anions in critically ill patients with metabolic acidosis*

Abstract

The physicochemical approach, described by Stewart to investigate the acid-base balance, includes the strong ion gap (SIG), a quantitative measure of "unmeasured" anions, which strongly correlates to the corrected anion gap. The chemical nature of these anions is for the most part unknown. We hypothesized that amino acids, uric acid, and organic acids could contribute to the SIG. Prospective observational study. Intensive care department of an academic hospital. Consecutive intensive care unit patients (n = 31) with metabolic acidosis, defined as a pH of < 7.35 and a base excess of < or = -5 mmol/L. A single arterial blood sample was collected. The SIG was calculated and two groups were compared: patients with SIG of < or = 2 mEq/L and patients with SIG of > or = 5 mEq/L. "Unmeasured" anions were examined by ion-exchange column chromatography, reverse-phase high-performance liquid chromatography, and gas chromatography/mass spectrometry measuring amino acids, uric acid, and organic acids, respectively. Comparison of patient characteristics of both SIG groups showed that age, sex, Acute Physiology and Chronic Health Evaluation II, pH, base excess, and lactate were not significantly different. Renal insufficiency and sepsis were more prevalent in the SIG > or = 5 mEq/L group (n = 12; median SIG, 8.3 mEq/L), associated with higher mortality. Concentrations of the anionic compounds aspartic acid, uric acid, succinic acid, pyroglutamic acid, p-hydroxyphenyllactic acid, and the semiquantified organic acid homovanillic acid were all statistically significantly elevated in the SIG > or = 5 mEq/L group compared with the SIG < or = 2 mEq/L group (n = 8; median SIG, 0.6 mEq/L). Overall, the averaged difference between both SIG groups in total anionic amino acids, uric acid, and organic acids concentrations contributed to the SIG for, respectively, 0.07% (5 microEq/L, p = not significant), 2.2% (169 microEq/L, p = .021), and 5.6% (430 microEq/L, p = .025). Amino acids, uric acid, and organic acids together accounted for only 7.9% of the SIG in intensive care unit patients with metabolic acidosis.