Patients with Obstructive Sleep Apnea Have Cardiac Repolarization Disturbances when Travelling to Altitude: Randomized, Placebo-Controlled Trial of Acetazolamide

Abstract

Study objectives: Obstructive sleep apnea (OSA) promotes myocardial electrical instability and may predispose to nocturnal sudden cardiac death. We evaluated whether hypobaric hypoxia during altitude travel further impairs cardiac repolarization in patients with OSA, and whether this is prevented by acetazolamide, a drug known to improve oxygenation and central sleep apnea at altitude.

Methods: Thirty-nine OSA patients living < 600 m, discontinued continuous positive airway pressure therapy during studies at 490 m and during two sojourns of 3 days at altitude (2 days at 1860 m, 1 day at 2590 m). During one altitude sojourn, patients took acetazolamide, during the other placebo, or vice versa, according to a randomized, double-blind crossover design. Twelve-lead electrocardiography and pulse oximetry (SpO2) were recorded during nocturnal polysomnography. Heart rate corrected mean QT intervals during the entire night (meanQTc) and during 1 min of the night with the longest meanQTc (maxQTc) were determined.

Results: At 490 m the median nocturnal SpO2 was 93%, medians of meanQTc and maxQTc were 420 ms and 478 ms. At 2590 m, on placebo, SpO2 was lower (85%), and meanQTc and maxQTc were prolonged to 430 ms and 510 ms (P < 0.02 vs. 490 m, all corresponding comparisons). At 2590 m on acetazolamide, median SpO2 was increased to 88% (P < 0.05 vs. placebo), meanQTc was reduced to 427 ms (P < 0.05 vs. placebo), whereas maxQTc remained increased at 502 ms (P = ns vs. placebo).

Conclusions: At 2590 m OSA patients experienced cardiac repolarization disturbances in association with hypoxemia. Prolongation of meanQTc at altitude was prevented and hypoxemia was improved by acetazolamide, whereas maxQTc remained increased suggesting imperfect protection from repolarization disturbances.

Clinical trial registration: ClinicalTrials.gov ID: NTC-00714740. URL: www.clinicaltrials.gov.

Keywords: altitude; cardiac arrhythmias; cardiac repolarization; sleep apnea; sudden cardiac death.

Figure 1

Patient flow. AHI, apnea-hypopnea index; b/o, because of; CPAP, continuous positive airway pressure; CSA, predominant central sleep apnea; ODI, oxygen desaturation index.

Figure 2

QTc intervals in patients with obstructive sleep apnea at three different altitudes during discontinuation of continuous positive airway pressure therapy. White boxes with whiskers and dots represent medians, quartiles, 5^th, 10^th, 90^th and 95^th percentiles during placebo treatment, gray boxes represent corresponding values during acetazolamide treatment. Mean QTc intervals during entire nights (meanQTc, lower panel) and mean QTc intervals during minutes with the highest values of the nights (maxQTc, upper panel) are shown. Significant differences (P < 0.05) between values at the higher altitudes versus values at 490 m, and between acetazolamide and placebo are indicated.

Figure 3

The effects of exposure to higher altitudes in patients using placebo (1860 and 2590 m, respectively) versus 490 m are illustrated by plotting median differences with 95% confidence interval (CI) of the corresponding mean QTc intervals during entire nights (meanQTc, panel A1), mean QTc intervals during minutes with the highest values of the nights (maxQTc, panel A2), and the QT dispersion (panel A3). The effects of acetazolamide vs. placebo at 1860 and 2590 m on meanQTc, maxQTc, and QT dispersion are illustrated in a similar way in panels B1-B3. MeanQTc, maxQTc and QT dispersion were prolonged at the higher altitudes and acetazolamide prevented the altitude induced increase in meanQTc and in QT dispersion.