Effect of acetazolamide on obstructive sleep apnoea in highlanders: protocol for a randomised, placebo-controlled, double-blinded crossover trial

Abstract

IntroductionObstructive sleep apnoea (OSA) is a highly prevalent disease that causing systemic hypertension. Furthermore, altitude-dependent hypobaric hypoxic condition and Tibetan ethnicity have been associated with systemic hypertension independent of OSA, therefore patients with OSA living at high altitude might be at profound risk to develop systemic hypertension. Acetazolamide has been shown to decrease blood pressure, improve arterial oxygenation and prevent high altitude periodic breathing in healthy volunteers ascending to high altitude and decrease blood pressure in patients with systemic hypertension at low altitude. However, the effect of acetazolamide on 24-hour blood pressure, sleep-disordered disturbance and daytime cognitive performance in patients with OSA permanently living at high altitude has not been studied.Methods and analysisThis study protocol describes a randomised, placebo-controlled, double-blinded crossover trial. Highland residents of both sexes, aged 30–60 years, Tibetan ethnicity, living at an elevation of 3650 m and apnoea–hypopnoea index over 15/hour will be included. Participants will be randomly assigned to a 2×2 week treatment period starting with 750 mg/day acetazolamide followed by placebo treatment or vice versa, separated by a 1-week wash-out phase. Clinical assessments, 24-hour ambulatory blood pressure monitoring (ABPM), polysomnography (PSG), near-infrared spectroscopy, nocturnal fluid shift and cognitive performance will be assessed before and at the end of each treatment period. The primary outcome will be the difference in 24-hour mean blood pressure between acetazolamide therapy and placebo; secondary outcomes will be the difference in other 24-hour ABPM-derived parameters, PSG-derived parameters, cognitive performance and overnight change in different segments of fluid volume between acetazolamide therapy and placebo. Accounting for potential dropouts, 40 participants will be recruited.Ethics and disseminationThe protocol was approved by the West China Hospital of Sichuan University Biomedical Research Ethics Committee. Recruitment will start in spring 2022. Dissemination of the results include presentations at conferences and publications in peer-reviewed journals.Trial registration numberChiCTR2100049304.

Medical management of obstructive sleep apnea: a review article

“…Tan et al in their randomised cross over trial, concluded that in highlander with OSA, acetazolamide could reduce blood pressure, improve sleep-disordered breathing and oxygen saturation, and result in improved cognitive performance. 57 Possible mechanisms behind improved blood pressure due to acetazolamide therapy might be acetazolamide-related reduction in the CO2 to HCO3 − conversions by inhibiting the synthesis of carbonic anhydrase, resulting in metabolic acidosis and increased minute ventilation. 57 The increased ventilation might increase the oxygen saturation and stabilise the breathing pattern by left shifting the CO2-ventilation response curve, which, therefore, may prevent periodic breathing.…”

“…57 Possible mechanisms behind improved blood pressure due to acetazolamide therapy might be acetazolamide-related reduction in the CO2 to HCO3 − conversions by inhibiting the synthesis of carbonic anhydrase, resulting in metabolic acidosis and increased minute ventilation. 57 The increased ventilation might increase the oxygen saturation and stabilise the breathing pattern by left shifting the CO2-ventilation response curve, which, therefore, may prevent periodic breathing. Another pathway might be that acetazolamide inhibits the activity of carbonic anhydrase in renal proximal convoluted tubules.…”

“…Another pathway might be that acetazolamide inhibits the activity of carbonic anhydrase in renal proximal convoluted tubules. 57 This might result in a diuretic role by reducing H + production and Na + reabsorption, and increase of excretion of Na + , water and carbonate. This diuretic effect of acetazolamide could reduce the fluid transfer from the legs to neck by reducing the fluid accumulation from daytime orthostatic gravity and associated sleep-disordered breathing at night.…”

“…This diuretic effect of acetazolamide could reduce the fluid transfer from the legs to neck by reducing the fluid accumulation from daytime orthostatic gravity and associated sleep-disordered breathing at night. 57 Carbonic anhydrase inhibition may constitute a potential target for drug therapy in patients with sleep apnea and comorbid hypertension. 58…”