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Acetazolamide in Critically Ill Neonates and Children with Metabolic Alkalosis
Study Question: What acetazolamide dose and frequency is supported for metabolic alkalosis in a critically ill neonatal and pediatric population including those with and without cardiac disease?
Study Description: This was a retrospective analysis of patients less than 18 years of age admitted to a neonatal or pediatric intensive care unit during a one-year period. Patients were included if they received at least 3 doses of acetazolamide for the treatment of metabolic alkalosis, defined as a pH ≥ 7.45 and bicarbonate (HCO3) > 26 mEq/L. The primary objective was to describe the mean dose, frequency, and duration of acetazolamide for this indication in a pediatric population. Secondary outcomes included number of patients that achieved “success” and abnormal laboratory values attributed to acetazolamide therapy. Success was defined as return of HCO3 to 22 – 26 mEq/L. Therapy was considered failure for the following reasons: inability to reach HCO3 goal, use of alternative agents (i.e., arginine hydrochloride, ammonium chloride, or hydrochloric acid), or another course of acetazolamide within 24 hours following completion of the evaluated course.
Results: A total of 131 children received acetazolamide during the study period and 34 met study inclusion criteria. The average age was 1.9 years (range 0.05 – 12). Eleven patients (32.4%) were admitted for cardiothoracic surgery and the majority had respiratory failure on mechanical ventilation (82.3%). The majority of patients received concomitant diuretic therapy (79.4%) with 100% of those patients on loop diuretics and 18.5% on a combination of loop and thiazide diuretics.
Patients received a mean acetazolamide dose of 4.98 ± 1.14 mg/kg/dose with the majority administered intravenously (94.1%). It was administered every 8 hours in 70.6% of patients with the frequency of every 6 hours being the second most common (29.4%). A wide variety of doses were given (6.1 ± 5.3) with the median number of doses being 3 (range: 3-24). Within 24 hours of the analyzed course, 5 patients (14.7%) were restarted on acetazolamide and no patients were given alternative agents. When the mean (± SD) pre-treatment and post-treatment laboratory values were compared, pH decreased (7.51 ± 0.05 to 7.37 ± 0.05, p < 0.001), HCO3 decreased (39.4 ± 6.1 to 31.4 ± 7.5, p < 0.001), base excess (BE) decreased (16.2 ± 5.5 to 6.6 ± 8.3, p < 0.001), chloride increased (95 ± 13.8 to 97 ± 16.3, p = 0.041), and BUN increased (13 ± 11 to 18 ± 17, p = 0.021). Sodium, potassium, serum creatinine, and urine output were not statistically different. Treatment success was only achieved in 10 patients (29.4%). There were no significant differences in acetazolamide dose, duration, and doses per day between those who achieved success versus those who failed. However, the success group was found to have a lower pre-acetazolamide pCO2 (41.8 ± 7.7 vs. 53.6 ± 9.6, p = 0.002) and BE (12.1 ± 4.2 vs. 17.9 ± 5.1, p = 0.003) compared to the failure group, respectively. The baseline pH was not different between groups. No adverse events or laboratory abnormalities due to acetazolamide therapy were observed.
Conclusion(s): Acetazolamide 5 mg/kg for the use of metabolic alkalosis in a pediatric population (up to 12 years of age) appears to improve acid-base parameters, such as pH and HCO3, without any adverse effects.
Perspective: The acetazolamide regimen evaluated in this analysis offers insight into the dosing regimen utilized in clinical practice at a single center for metabolic alkalosis in a pediatric population. The most popular regimen utilized was 5 mg/kg/dose IV every 8 hours for 3 or more doses, although it was only found to be successful in 29.4% of patients according to the author’s pre-defined definition. It appears the dose of 5 mg/kg improves acid-base parameters, including pH and HCO3, without adverse effects. It is also worth bearing in mind that it is not entirely clear whether the surrogate marker used to define treatment success (HCO3) strongly correlates with or directly affects clinical outcomes. Confounding factors that may have accounted for changes in acid-base parameters include mechanical ventilation, which may have been adjusted to compensate for this metabolic disturbance, fluid administration, or decreasing or discontinuing diuretic therapy. Although diuretic therapy was utilized in the majority of patients, the presence of alternative etiologies that may have caused metabolic alkalosis, such as gastric suctioning, vomiting, or excess base administration, was not clear. Metabolic alkalosis may have resolved or improved with the resolution of these etiologies. Urine chloride analysis prior to acetazolamide therapy might have been clinically useful information to determine whether this disorder was “saline responsive” or “saline unresponsive”, with the latter being less likely respond to acetazolamide therapy. Baseline serum chloride values prior to acetazolamide were low-normal and did not significantly change after administration.