Effects of Prophylactic Low-Dose Acetazolamide on the Chemoreflex Control of Breathing and Acute Mountain Sickness at High Altitude

ABSTRACT Introduction High altitude is a physiologically stressful environment due to low barometric pressure and low oxygen availability. This hypoxic stress commonly leads to Acute Mountain Sickness (AMS) during high altitude travel. Additionally, among the physiological adaptations to sustained hypobaric hypoxia, ventilatory acclimatization is characterized by increases in the ventilatory chemoreflex responses to hypoxia and hypercapnia. This study aimed to determine how low-dose prophylactic use of Acetazolamide (ACZ), as utilized for recreational high-altitude travel, impacts these breathing reflexes. Methods In a double-blind, randomized, placebo-controlled design, participants received 125 mg of ACZ taken twice daily (N=9) or placebo (N=9) starting 2 days prior to ascent to high-altitude (3801 m) and continued until departure. Ventilatory chemoreflex tests were performed at sea level prior to treatment and after 2 days at high altitude. Results ACZ reduced AMS severity on the first two days at high altitude. ACZ also lowered end-tidal P CO2 , indicating elevated baseline alveolar ventilation. Among the ventilatory chemoreflex characteristics, the ventilatory recruitment threshold was significantly lower at high altitude in both groups. We also found a highly significant three-way interaction between location, treatment, and P CO2 on the hypoxic ventilatory response (HVR), indicating that the relationship between P CO2 and the amplitude of the reflex increase in breathing in response to hypoxia is impacted by ACZ. Conclusions ACZ may sensitize the interaction between the peripheral and central chemoreflex responses. This data provides insight into the mechanisms underlying ACZ’s beneficial effects on sleep quality and AMS symptoms at high altitude. Trial registry ClinicalTrials.gov Registration number NCT07517068