Abstract
IntroductionAcetazolamide is commonly given to chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. Little is known of the pharmacodynamics of acetazolamide in the critically ill. We undertook the pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation.MethodsThis observational, retrospective study included 68 invasively ventilated COPD patients who received one or multiple doses of 250 or 500 mg of acetazolamide during the weaning period. Among the 68 investigated patients, 207 time-serum bicarbonate observations were available for analysis. Population pharmacodynamics was modeled using a nonlinear mixedeffect model. The main covariates of interest were baseline demographic data, Simplified Acute Physiology Score II (SAPS II) at ICU admission, cause of respiratory failure, co-prescription of drugs interfering with the acid-base equilibrium, and serum concentrations of protein, creatinin, potassium and chloride. The effect of acetazolamide on serum bicarbonate levels at different doses and in different clinical conditions was subsequently simulated in silico.ResultsThe main covariates interacting with acetazolamide pharmacodynamics were SAPS II at ICU admission (P = 0.01), serum chloride (P < 0.001) and concomitant administration of corticosteroids (P = 0.02). Co-administration of furosemide significantly decreased bicarbonate elimination. Acetazolamide induced a decrease in serum bicarbonate with a dose-response relationship. The amount of acetazolamide inducing 50% of the putative maximum effect was 117 ± 21 mg. According to our model, an acetazolamide dosage > 500 mg twice daily is required to reduce serum bicarbonate concentrations > 5 mmol/L in the presence of high serum chloride levels or coadministration of systemic corticosteroids or furosemide.ConclusionsThis study identified several covariates that influenced acetazolamide pharmacodynamics and could allow a better individualization of acetazolamide dosing when treating COPD patients with metabolic alkalosis.
Highlights
Acetazolamide is commonly given to chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis
We showed that few covariates affected ACET pharmacodynamics in mechanically ventilated COPD patients
In a recent case-control study, we showed that ACET given at the dosage of 500 mg/day significantly but moderately diminished serum HCO3- without otherwise effecting arterial blood gases or respiratory parameters in weaning COPD patients [10]
Summary
Acetazolamide is commonly given to chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. We undertook the pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation. Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality [1]. Metabolic alkalosis is an acid-base disorder that occurs frequently in the critically ill [5]. Metabolic alkalosis is characterized by an elevated serum pH level secondary to increased plasma bicarbonate (HCO3-) retention. Correction of this acid-base disorder increases both minute ventilation and partial pressure of oxygen (PaO2), potentially allowing COPD patients to be weaned more rapidly from mechanical ventilation [6,7]. ACET (1) induces CO2 retention by inhibiting CA isoenzymes in red cells and tissue and (2) improves cardiac function and gas exchange in cor pulmonale by stimulating diuresis [8]
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