C21-08 Acetazolamide to Prevent Ventilatory Drive Withdrawal in REM Sleep Apnea: A Randomized Controlled Trial

Background Obstructive sleep apnea (OSA) pathogenesis during rapid-eye movement (REM) sleep has been linked to dips in ventilatory drive and downstream genioglossus hypotonia. The carbonic anhydrase inhibitor acetazolamide is known to increase ventilatory drive and improve OSA severity. Therefore, we tested the effect of acetazolamide on REM-predominant OSA severity (apnea hypopnea index and hypoxic burden, co-primary outcomes) and underlying physiological mechanisms (ventilatory drive, ventilation and pharyngeal muscle activity). Methods Eleven participants with REM-predominant OSA per baseline polysomnography (REM AHI/nonREM AHI≥2) were allocated to receiving acetazolamide 500 mg for three nights (first night at half dose) or placebo according to a randomized, crossover, double-blind design. Detailed physiological polysomnography with recording of diaphragm and genioglossus electromyography were conducted after each intervention, with a one-week washout in between. Results As hypothesized, acetazolamide reduced AHI by 35.5 [95%CI: 23.1, 46.3] % and hypoxic burden by 35.9 [21.1, 48.4] % vs. placebo (P < 0.001), meeting the primary endpoint. Mechanistic analysis in REM (Figure 1) revealed that, unexpectedly, acetazolamide did not mitigate dips in ventilatory drive versus placebo (1st decile, (+0.1 [-1.0, 1.3] L/min, P = 0.8). Rather, acetazolamide reduced collapsibility (increased ventilation at eupneic drive: +1.4 [1.2, 1.8] L/min) and raised muscle responsiveness (ventilation vs. drive slope: +32 [25, 41] %ventilation/drive, P < 0.001; genioglossus vs. drive slope: +0.33 [0.13, 0.54] %max/(L/min), P = 0.001). Conclusions Acetazolamide modestly improved REM OSA, with meaningful improvements in upper airway physiology, but failed to mitigate the dips in ventilatory drive responsible for REM OSA.