By Kathryn Radigan, MD

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: Compared to placebo, the use of acetazolamide in mechanically ventilated patients with COPD does not significantly reduce the duration of mechanical ventilation.

SOURCE: Faisy C, Meziani F, Planquette B, et al. Effect of acetazolamide vs placebo on duration of invasive mechanical ventilation among patients with chronic obstructive pulmonary disease: A randomized clinical trial. JAMA 2016;315:480-488.

Although there are no randomized, controlled trials to support its use, acetazolamide is used frequently as a respiratory stimulant in mechanically ventilated patients suffering from COPD and metabolic alkalosis. To determine whether acetazolamide shortens duration of mechanical ventilation in patients with COPD, Faisy et al conducted the DIABOLO study, a randomized, double-blind, multicenter trial from October 2011 to July 2014. Throughout 15 ICUs in France, 382 patients with COPD who were expected to be mechanically ventilated for > 24 hours were randomized to acetazolamide or placebo. Within 48 hours of ICU admission, patients with pure or mixed metabolic alkalosis received IV acetazolamide 500-1000 mg twice daily or placebo for the duration of their ICU stay. The primary outcome was duration of mechanical ventilation. Secondary outcomes were changes in arterial blood gas and respiratory parameters, weaning duration, adverse events, use of noninvasive ventilation after extubation, successful weaning, duration of ICU stay, and ICU mortality. Of the 382 randomized patients, 380 completed the study. There were no significant differences between the acetazolamide group (n = 187) and the placebo group (n = 193) in median duration of mechanical ventilation (-16.0 hours; 95% confidence interval [CI], -36.5 to 4 hours; P = 0.17), duration of weaning off mechanical ventilation (-0.9 hours; 95% CI, -4.3 to 1.3 hours; P = 0.36), daily changes of minute ventilation (-0.0 L/min; 95% CI, -0.2 to 0.2 L/min; P = 0.72), or partial carbon dioxide pressure in arterial blood (-0.3 mmHg; 95% CI, -0.8 to 0.2 mmHg; P = 0.25). Compared to placebo, daily changes of serum bicarbonate (between-group difference, -0.8 mEq/L; 95% CI, -1.2 to -0.5 mEq/L; P < 0.001) and number of days with metabolic alkalosis (between-group difference, -1; 95% CI, -2 to -1 days; P < 0.001) were decreased significantly in the acetazolamide group. Although there is concern that the study may have been underpowered, the use of acetazolamide in mechanically ventilated COPD patients does not reduce the duration of mechanical ventilation.

COMMENTARY

The principal acid-base disturbances in mechanically ventilated COPD patients are often respiratory acidosis and metabolic alkalosis. Although the causes of metabolic alkalosis in these patients often are multifactorial, there is concern that alkalosis may depress cardiac output and/or respiratory drive, alter oxyhemoglobin dissociation, and favor the development of hypokalemia and hypophosphatemia. These factors may lead to prolonged weaning and duration of mechanical ventilation.1,2

Acetazolamide, a carbonic anhydrase inhibitor, frequently has been used as a respiratory stimulant in patients with COPD and metabolic alkalosis. The inhibition of renal carbonic anhydrase enzyme leads to decreased serum bicarbonate and arterial pH and increased minute ventilation as a result of stimulation of peripheral and central chemoreceptors.3 As the drug is relatively safe, with rare occurrences of undesirable effects, it is used often as a respiratory stimulant in mechanically ventilated patients presenting with COPD and metabolic alkalosis but has not been well-studied. Faisy et al showed that despite achieving significant decreases in serum bicarbonate and fewer days of metabolic alkalosis in patients who were randomized to acetazolamide compared to placebo, there was no significant difference in duration of mechanical ventilation. Although there was no statistically significant decrease in length of mechanical ventilation in patients who received acetazolamide, the between-group difference in median duration of mechanical ventilation may be clinically relevant at 16 hours. Unfortunately, the study was powered to detect a 15% difference in invasive mechanical ventilation duration, and the observed median duration of mechanical ventilation was lower in both groups than anticipated for statistical power. If the study was designed to detect a 10% reduction in mechanical ventilation, it is plausible that the study would have reached statistical significance.

Although a difference in ventilator time may have been missed due to unfortunate statistics, it also must be noted that acetazolamide is a drug that features a complex mechanism of action and that its use is often even more complicated in the ICU setting. Although the acetazolamide dose was maximized at 500-1000 mg IV twice daily, it is possible that the dose remained inadequate. To appreciate a clinically relevant respiratory effect, a decrease in serum bicarbonate of at least 5 mEq/L is often necessary. Although serum bicarbonate decreased significantly, it did not affect respiratory parameters. It is unclear whether this decrease in bicarbonate was insufficient to affect respiratory parameters or whether the lack of response was due to tissue compartmentalization of carbonic anhydrase isozymes and low acetazolamide selectivity. Despite the obvious benefit higher doses may have on respiratory drive, it is also important to be wary of increased respiratory drive, especially in patients with COPD, as increased respiratory drive may also lead to increased work of breathing, respiratory muscle fatigue, decreased exhalation time, and possibly placing the patient at increased risk of auto-positive end-expiratory pressure. Furthermore, the authors noted that the PaO2/FiO2 ratio of the acetazolamide group was significantly higher than control. It is plausible that if there was a benefit, it may be due to its diuretic effect or the increased oxygen saturation of hemoglobin.

In review of this study, it remains unclear whether acetazolamide is of benefit in mechanically ventilated patients with COPD. Although there was no statistically significant decrease in duration of mechanical ventilation, there was no harm, and patients treated with acetazolamide were found to have increased daily PaO2/FiO2 ratio, with a trend toward shorter duration of mechanical ventilation. Therefore, it is the responsibility of clinicians to remain thoughtful regarding the use of acetazolamide in mechanically ventilated patients with COPD and consider its use on a case-by-case basis.

REFERENCES

  1. Berthelsen P. Cardiovascular performance and oxyhemoglobin dissociation after acetazolamide in metabolic alkalosis. Intensive Care Med 1982;8:269-274.
  2. Krintel JJ, Haxholdt OS, Berthelsen P, et al. Carbon dioxide elimination after acetazolamide in patients with chronic obstructive pulmonary disease and metabolic alkalosis. Acta Anaesthesiol Scand 1983;27:252-254.
  3. Swenson ER. Carbonic anhydrase inhibitors and ventilation: A complex interplay of stimulation and suppression. Eur Respir J 1998;12:1242-1247.