Effect of Nocturnal Oxygen and Acetazolamide on Exercise Performance in Patients With Pre-Capillary Pulmonary Hypertension and Sleep-Disturbed Breathing: Randomized, Double-Blind, Cross-Over Trial

Study Questions:

Does nocturnal oxygen therapy (NOT) or acetazolamide improve exercise performance and quality of life in patients with precapillary pulmonary hypertension (PH) and sleep disturbed breathing (SDB)?

Methods:

This was a randomized, placebo-controlled, double-blind, three-period crossover trial. Men and women ages 20-80 years were recruited from a university pulmonary clinic, diagnosed with either pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension (World Health Organization [WHO] groups I and IV) and stable on therapy for at least 4 weeks. Subjects were excluded for daytime hypoxia, predominantly obstructive sleep apnea, more than mild lung disease, or left heart failure. Data were collected from December 2010 to August 2012. Patients were then randomized in a placebo-controlled, double-blind fashion during three 1-week crossover periods. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo tablets each during 1 week, with 1-week wash-out between treatment periods. SDB was defined as mean nocturnal oxygen saturation <90% or oxygen saturation dips >10h-1. Primary outcomes were the 6-minute walk distance (6MWD) and the Short Form-36 (SF-36) quality-of-life index.

Results:

During the study period, 72 patients were screened with overnight fingertip oximetry. Initially, 51 patients were suitable for inclusion, but 28 (53%) were excluded. Twenty-three patients, 16 with pulmonary arterial hypertension and 7 with chronic thromboembolic PH, finished all crossover randomization. Average age was 66 years, and 15 (65%) were women, with average body mass index of 26.6 kg/m2 (25.2-29.3). Subjects used two (6) or three (4) drug regimens for controlling PH. Medians (quartiles) of the 6MWD after NOT, acetazolamide, and placebo were 480 m (390; 528), 440 m (368; 468), and 454 m (367; 510), respectively, mean differences: NOT versus placebo +25 m (95% confidence interval [CI], 3-46; p = 0.027), acetazolamide versus placebo 29 m (95% CI, -34 to 17; p = 0.223), and NOT versus acetazolamide +33 (95% CI, 12-45; p < 0.001). SF-36 quality of life was similar with all treatments. Nocturnal oxygen saturation significantly improved with both NOT and acetazolamide.

Conclusions:

This randomized, placebo-controlled, double-blind trial demonstrates that treatment with NOT not only ameliorates nocturnal oxygenation and periodic breathing in patients with Groups I and IV PH and SDB, but also improves exercise capacity within 1 week.

Perspective:

This improvement in 6MWD is impressive for several reasons. NOT is an inexpensive therapy compared to the pharmacologic treatments of PH and with fewer side effects. Gains observed here were comparable to pharmacologic trials in PH patients (Galie et al., 2009). Using NOT for 1 week improved exercise capacity analogous to NOT in patients with left heart failure (Andreas et al., 1996). Last, both NOT and acetazolamide were effective in improving SDB; however, acetazolamide did not improve exercise capacity. Future studies mentioned included using acetazolamide in the evening only and studying long-term effects of NOT in this PH population with SDB and preserved left heart function with normal daytime oxygenation.

Clinical Topics: Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Pulmonary Hypertension

Keywords: Oxygen Inhalation Therapy, Oximetry, Quality of Life, Sleep Disorders, Hypertension, Pulmonary


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