Acetazolamide-mediated decrease in strong ion difference accounts for the correction of metabolic alkalosis in critically ill patients

INTRODUCTION: Metabolic alkalosis is a commonly encountered acid–base derangement in the intensive care unit. Treatment with the carbonic anhydrase inhibitor acetazolamide is indicated in selected cases. According to the quantitative approach described by Stewart, correction of serum pH due to carbonic anhydrase inhibition in the proximal tubule cannot be explained by excretion of bicarbonate. Using the Stewart approach, we studied the mechanism of action of acetazolamide in critically ill patients with a metabolic alkalosis. METHODS: Fifteen consecutive intensive care unit patients with metabolic alkalosis (pH ≥ 7.48 and HCO(3)(- )≥ 28 mmol/l) were treated with a single administration of 500 mg acetazolamide intravenously. Serum levels of strong ions, creatinine, lactate, weak acids, pH and partial carbon dioxide tension were measured at 0, 12, 24, 48 and 72 hours. The main strong ions in urine and pH were measured at 0, 3, 6, 12, 24, 48 and 72 hours. Strong ion difference (SID), strong ion gap, sodium–chloride effect, and the urinary SID were calculated. Data (mean ± standard error were analyzed by comparing baseline variables and time dependent changes by one way analysis of variance for repeated measures. RESULTS: After a single administration of acetazolamide, correction of serum pH (from 7.49 ± 0.01 to 7.46 ± 0.01; P = 0.001) was maximal at 24 hours and sustained during the period of observation. The parallel decrease in partial carbon dioxide tension was not significant (from 5.7 ± 0.2 to 5.3 ± 0.2 kPa; P = 0.08) and there was no significant change in total concentration of weak acids. Serum SID decreased significantly (from 41.5 ± 1.3 to 38.0 ± 1.0 mEq/l; P = 0.03) due to an increase in serum chloride (from 105 ± 1.2 to 110 ± 1.2 mmol/l; P < 0.0001). The decrease in serum SID was explained by a significant increase in the urinary excretion of sodium without chloride during the first 24 hours (increase in urinary SID: from 48.4 ± 15.1 to 85.3 ± 7.7; P = 0.02). CONCLUSION: A single dose of acetazolamide effectively corrects metabolic alkalosis in critically ill patients by decreasing the serum SID. This effect is completely explained by the increased renal excretion ratio of sodium to chloride, resulting in an increase in serum chloride.