Visuomotor performance at high altitude in COPD patients. Randomized placebo-controlled trial of acetazolamide

Abstract

Introduction: We evaluated whether exposure to high altitude impairs visuomotor learning in lowlanders with chronic obstructive pulmonary disease (COPD) and whether this can be prevented by acetazolamide treatment. Methods: 45 patients with COPD, living <800 m, FEV1 ≥40 to <80%predicted, were randomized to acetazolamide (375 mg/d) or placebo, administered 24h before and during a 2-day stay in a clinic at 3100 m. Visuomotor performance was evaluated with a validated, computer-assisted test (Motor-Task-Manager) at 760 m above sea level (baseline, before starting the study drug), within 4h after arrival at 3100 m and in the morning after one night at 3100 m. Main outcome was the directional error (DE) of cursor movements controlled by the participant via mouse on a computer screen during a target tracking task. Effects of high altitude and acetazolamide on DE during an adaptation phase, immediate recall and post-sleep recall were evaluated by regression analyses. www.ClinicalTrials.gov NCT03165890. Results: In 22 patients receiving placebo, DE at 3100 m increased during adaptation by mean 2.5°, 95%CI 2.2° to 2.7° (p < 0.001), during immediate recall by 5.3°, 4.6° to 6.1° (p < 0.001), and post-sleep recall by 5.8°, 5.0 to 6.7° (p < 0.001), vs. corresponding values at 760 m. In 23 participants receiving acetazolamide, corresponding DE were reduced by -0.3° (-0.6° to 0.1°, p = 0.120), -2.7° (-3.7° to -1.6°, p < 0.001) and -3.1° (-4.3° to -2.0°, p < 0.001), compared to placebo at 3100 m. Conclusion: Lowlanders with COPD travelling to 3100 m experienced altitude-induced impairments in immediate and post-sleep recall of a visuomotor task. Preventive acetazolamide treatment mitigated these undesirable effects.

Keywords: COPD; acetazolamide; altitude; placebo; sleep; visuo-motor task.

FIGURE 1

(A) Schematic representation of the computer video screen as presented to a patient during the visuomotor learning task. The patients had to operate a handheld mouse on a drawing board below an opaque shield. The position of the mouse was indicated as a cursor on a computer screen. Four different targets (1–4) were located in a semi-circular array around the center. Participants were instructed to move the cursor from the center circle (= starting point) to the flashing target and immediately back, in the most direct and fastest way possible, and in one go. The flashing of targets appeared in a one second interval at a random sequence. (B) Explanation of test protocol. The evening part was conducted in the evening on the day of arrival at the study location between 7:00 and 9:00 p.m., the morning part in the following morning between 6:30 and 8:00 a.m. The evening part consisted of an adaptation part followed by an immediate recall. The post-sleep recall in the morning was identical to the immediate recall in the evening. The adaptation part, immediate and post-sleep recall ended with a wash out to reset any residual rotation of the newly acquired motor memory. The test was started without rotation to familiarize the patients with the task. During the adaption part, the rotation increased by steps of 15° after every 132^th movement (corresponding 33 movements to each of the four targets) up to a maximum of 60° and ended by a 0° wash-out and followed by the immediate recall, where the rotation switched directly from 0° to 60°. After one night post-sleep recall was assessed in the morning.

FIGURE 2

Patient flow.

FIGURE 3

Illustration of means (and 95% confidence intervals) of directional errors for the acetazolamide (blue) and placebo (orange) group in 3 successive blocks of 44 movements each during immediate (evening) and post-sleep (morning) recall tests. Upper panels: baseline evaluations at 760 m were performed before starting the study drug. Upper left panel: immediate recall at 760 m; upper right panel, post-sleep recall at 760 m; lower left panel, immediate recall at 3100 m; lower right panel, post-sleep recall at 3100 m. According to Table 2, in tests at 3100 m, directional errors were significantly reduced by acetazolamide during immediate recall (by 2.7°, 95% CI 1.6–3.7) and post-sleep recall by 3.1°, 95% CI 2.0–4.3). The progressive decrease in directional error with increasing number of the 132 blocks is consistent with a learning effect, while the last block of aggregated movements (89–132) is a surrogate of final performance level.