FROM JAMA

Acetazolamide failed to reduce the duration of invasive mechanical ventilation in chronic obstructive pulmonary disease (COPD) patients who had pure or mixed metabolic alkalosis, according to results from a clinical trial published online Feb. 2 in JAMA.

Acetazolamide is a carbonic anhydrase inhibitor used as a respiratory stimulant in patients who have COPD and metabolic alkalosis. Recent studies suggested that high doses of the drug (1,000 mg/day or more) might shorten the duration of mechanical ventilation in critically ill COPD patients who require invasive mechanical ventilation, by markedly lowering serum bicarbonate and raising minute ventilation, said Dr. Christophe Faisy of the medical intensive care unit, European Georges Pompidou Hospital, Paris, and his associates.

To test this hypothesis, Dr. Faisy and his associates in the DIABOLO trial assessed 380 adults with COPD who were being treated at 15 French ICUs. One patient was receiving ventilation through a tracheotomy tube and the rest through endotracheal intubation. These study participants were randomly assigned in a double-blind fashion to receive either 500 mg acetazolamide twice daily or 1,000 mg acetazolamide twice daily if they were concomitantly receiving loop diuretics (187 patients), or a matching placebo (193 patients), administered as a slow intravenous injection.

Patients in the active-treatment group achieved larger reductions in serum bicarbonate and had fewer days with metabolic acidosis. Nevertheless, the primary efficacy outcome – the duration of invasive ventilation – did not differ significantly between the two study groups. The median duration of ventilation was 136.5 hours with acetazolamide and 163.0 hours with placebo, which is clinically substantial but did not reach statistical significance, the investigators said ( JAMA. 2016 Feb 2. doi: 10.1001/jama.2016.0019 ).

Acetazolamide didn’t exert a respiratory stimulant effect as measured by changes in respiratory rate, tidal volume, or minute ventilation. And there were no significant differences between the two study groups in secondary outcomes such as time to weaning off ventilation, rate of successful weaning, number of spontaneous breathing trials, use of tracheotomy or noninvasive ventilation after extubation, unplanned extubations, episodes of ventilator-associated pneumonia, laboratory values, length of ICU stay, or in-ICU mortality.

In addition, rates of adjunctive treatment using loop diuretics, glucocorticoids, beta-agonists, or catecholamines were the same between the two study groups, and left ventricular ejection fraction at weaning from ventilation also was the same. The rate of serious adverse events also was comparable.

“Taken together, these findings indicate that the inhibition of the renal carbonic anhydrase enzyme and the resulting serum bicarbonate reduction did not trigger a sufficient respiratory-stimulating effect to affect outcomes of critically ill patients with COPD,” Dr. Faisy and his associates wrote.

However, they noted that in both study groups the median duration of invasive mechanical ventilation was shorter than had been anticipated when the trial was designed, which likely decreased the statistical power of the primary endpoint. “It is possible that the study was underpowered to establish statistical significance,” the researchers said.

It is also possible that higher doses of acetazolamide may have exerted a greater effect on respiratory parameters. However, higher doses also may have increased the workload of the respiratory muscles and induced respiratory muscle fatigue, they added.

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