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

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

Acetazolamide to Prevent Adverse Altitude Effects in COPD and Healthy Adults

Background We evaluated the efficacy of acetazolamide in preventing adverse altitude effects in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and in healthy lowlanders 40 years of age or older. Methods Trial 1 was a randomized, double-blind, parallel-design trial in which 176 patients with COPD were treated with acetazolamide capsules (375 mg/day) or placebo, starting 24 hours before staying for 2 days at 3100 m. The mean (±SD) age of participants was 57±9 years, and 34% were women. At 760 m, COPD patients had oxygen saturation measured by pulse oximetry of 92% or greater, arterial partial pressure of carbon dioxide less than 45 mm Hg, and mean forced expiratory volume in 1 second of 63±11% of predicted. The primary outcome in trial 1 was the incidence of the composite end point of altitude-related adverse health effects (ARAHE) at 3100 m. Criteria for ARAHE included acute mountain sickness (AMS) and symptoms or findings relevant to well-being and safety, such as severe hypoxemia, requiring intervention. Trial 2 comprised 345 healthy lowlanders. Their mean age was 53±7 years, and 69% were women. The participants in trial 2 underwent the same protocol as did the patients with COPD in trial 1. The primary outcome in trial 2 was the incidence of AMS assessed at 3100 m by the Lake Louise questionnaire score (the scale of self-assessed symptoms ranges from 0 to 15 points, indicating absent to severe, with 3 or more points including headache, indicating AMS). Results In trial 1 of patients with COPD, 68 of 90 (76%) receiving placebo and 42 of 86 (49%) receiving acetazolamide experienced ARAHE (hazard ratio, 0.54; 95% confidence interval [CI], 0.37 to 0.79; P<0.001). The number needed to treat (NNT) to prevent one case of ARAHE was 4 (95% CI, 3 to 8). In trial 2 of healthy individuals, 54 of 170 (32%) receiving placebo and 38 of 175 (22%) receiving acetazolamide experienced AMS (hazard ratio, 0.48; 95% CI, 0.29 to 0.80; chi-square statistic P=0.035). The NNT to prevent one case of AMS was 10 (95% CI, 5 to 141). No serious adverse events occurred in these trials. Conclusions Preventive treatment with acetazolamide reduced the incidence of adverse altitude effects requiring an intervention in patients with COPD and the incidence of AMS in healthy lowlanders 40 years of age or older during a high-altitude sojourn. (Funded by the Swiss National Science Foundation [Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung], Lunge Zürich, and the Swiss Lung Foundation; ClinicalTrials.gov numbers, NCT03156231 and NCT03561675.

Validation of Noninvasive Assessment of Pulmonary Gas Exchange in Patients with Chronic Obstructive Pulmonary Disease during Initial Exposure to High Altitude

Investigation of pulmonary gas exchange efficacy usually requires arterial blood gas analysis (aBGA) to determine arterial partial pressure of oxygen (mPaO2) and compute the Riley alveolar-to-arterial oxygen difference (A-aDO2); that is a demanding and invasive procedure. A noninvasive approach (AGM100), allowing the calculation of PaO2 (cPaO2) derived from pulse oximetry (SpO2), has been developed, but this has not been validated in a large cohort of chronic obstructive pulmonary disease (COPD) patients. Our aim was to conduct a validation study of the AG100 in hypoxemic moderate-to-severe COPD. Concurrent measurements of cPaO2 (AGM100) and mPaO2 (EPOC, portable aBGA device) were performed in 131 moderate-to-severe COPD patients (mean ±SD FEV1: 60 ± 10% of predicted value) and low-altitude residents, becoming hypoxemic (i.e., SpO2 < 94%) during a short stay at 3100 m (Too-Ashu, Kyrgyzstan). Agreements between cPaO2 (AGM100) and mPaO2 (EPOC) and between the O2-deficit (calculated as the difference between end-tidal pressure of O2 and cPaO2 by the AGM100) and Riley A-aDO2 were assessed. Mean bias (±SD) between cPaO2 and mPaO2 was 2.0 ± 4.6 mmHg (95% Confidence Interval (CI): 1.2 to 2.8 mmHg) with 95% limits of agreement (LoA): −7.1 to 11.1 mmHg. In multivariable analysis, larger body mass index (p = 0.046), an increase in SpO2 (p < 0.001), and an increase in PaCO2-PETCO2 difference (p < 0.001) were associated with imprecision (i.e., the discrepancy between cPaO2 and mPaO2). The positive predictive value of cPaO2 to detect severe hypoxemia (i.e., PaO2 ≤ 55 mmHg) was 0.94 (95% CI: 0.87 to 0.98) with a positive likelihood ratio of 3.77 (95% CI: 1.71 to 8.33). The mean bias between O2-deficit and A-aDO2 was 6.2 ± 5.5 mmHg (95% CI: 5.3 to 7.2 mmHg; 95%LoA: −4.5 to 17.0 mmHg). AGM100 provided an accurate estimate of PaO2 in hypoxemic patients with COPD, but the precision for individual values was modest. This device is promising for noninvasive assessment of pulmonary gas exchange efficacy in COPD patients

Pulmonary haemodynamic response to exercise in highlanders versus lowlanders

The aim of the study was to investigate the pulmonary haemodynamic response to exercise in Central Asian high- and lowlanders. This was a cross-sectional study in Central Asian highlanders (living >2500 m) compared with lowlanders (living <800 m), assessing cardiac function, including tricuspid regurgitation pressure gradient (TRPG), cardiac index and tricuspid annular plane systolic excursion (TAPSE) by echocardiography combined with heart rate and oxygen saturation measured by pulse oximetry (SpO2) during submaximal stepwise cycle exercise (10 W increase per 3 min) at their altitude of residence (at 760 m or 3250 m, respectively). 52 highlanders (26 females; aged 47.9±10.7 years; body mass index (BMI) 26.7±4.6 kg·m−2; heart rate 75±11 beats·min−1; SpO2 91±5%;) and 22 lowlanders (eight females; age 42.3±8.0 years; BMI 26.9±4.1 kg·m−2; heart rate 68±7 beats·min−1; SpO2 96±1%) were studied. Highlanders had a lower resting SpO2 compared to lowlanders but change during exercise was similar between groups (highlanders versus lowlanders −1.4±2.9% versus −0.4±1.1%, respectively, p=0.133). Highlanders had a significantly elevated TRPG and exercise-induced increase was significantly higher (13.6±10.5 mmHg versus 6.1±4.8 mmHg, difference 7.5 (2.8 to 12.2) mmHg; p=0.002), whereas cardiac index increase was slightly lower in highlanders (2.02±0.89 L·min−1 versus 1.78±0.61 L·min−1, difference 0.24 (−0.13 to 0.61) L·min−1; p=0.206) resulting in a significantly steeper pressure–flow ratio (ΔTRPG/Δcardiac index) in highlanders 9.4±11.4 WU and lowlanders 3.0±2.4 WU (difference 6.4 (1.4 to 11.3) WU; p=0.012). Right ventricular-arterial coupling (TAPSE/TRPG) was significantly lower in highlanders but no significant difference in change with exercise in between groups was detected (−0.01 (−0.20 to 0.18); p=0.901). In highlanders, chronic exposure to hypoxia leads to higher pulmonary artery pressure and a steeper pressure–flow relation during exercise

Nocturnal Heart Rate and Cardiac Repolarization in Lowlanders With Chronic Obstructive Pulmonary Disease at High Altitude: Data From a Randomized, Placebo-Controlled Trial of Nocturnal Oxygen Therapy

Background: Chronic obstructive pulmonary disease (COPD) is associated with cardiovascular disease. We investigated whether sleeping at altitude increases nocturnal heart rate (HR) and other markers of cardiovascular risk or arrhythmias in lowlanders with COPD and whether this can be prevented by nocturnal oxygen therapy (NOT). Methods: Twenty-four COPD patients, with median age of 66 years and forced expiratory volume in 1 s (FEV1) 55% predicted, living <800 m underwent sleep studies at Zurich (490 m) and during 2 sojourns of 2 days each at St. Moritz (2,048 m) separated by 2-week washout at <800 m. During nights at 2,048 m, patients received either NOT (2,048 m NOT) or ambient air (2,048 m placebo) 3 L/min via nasal cannula according to a randomized, placebo-controlled crossover trial. Sleep studies comprised ECG and pulse oximetry to measure HR, rhythm, HR-adjusted QT interval (QTc), and mean oxygen saturation (SpO2). Results: In the first nights at 490 m, 2,048 m placebo, and 2,048 m NOT, medians (quartiles) of SpO2 were 92% (90; 94), 86% (83; 89), and 97% (95; 98) and of HR were 73 (66; 82), 82 (71; 85), and 78 bpm (67; 74) (P < 0.05 all respective comparisons). QTc increased from 417 ms (404; 439) at 490 m to 426 ms (405; 440) at 2,048 m placebo (P < 0.05) and was 420 ms (405; 440) at 2,048 m NOT (P = NS vs. 2,048 m placebo). The number of extrabeats and complex arrhythmias was similar over all conditions. Conclusions: While staying at 2,048 m, lowlanders with COPD experienced nocturnal hypoxemia in association with an increased HR and prolongation of the QTc interval. NOT significantly improved SpO2 and lowered HR, without changing QTc. Whether oxygen therapy would reduce HR and arrhythmia during longer altitude sojourns remains to be elucidated. Keywords: QTc prolongation; cardiac repolarisation; chronic obstructive pulmonary disease; heart rate; hypoxia

Effect of Nocturnal Oxygen Therapy on Nocturnal Hypoxemia and Sleep Apnea Among Patients With Chronic Obstructive Pulmonary Disease Traveling to 2048 Meters

Importance There are no established measures to prevent nocturnal breathing disturbances and other altitude-related adverse health effects (ARAHEs) among lowlanders with chronic obstructive pulmonary disease (COPD) traveling to high altitude. Objective To evaluate whether nocturnal oxygen therapy (NOT) prevents nocturnal hypoxemia and breathing disturbances during the first night of a stay at 2048 m and reduces the incidence of ARAHEs. Design, Setting, and Participants This randomized, placebo-controlled crossover trial was performed from January to October 2014 with 32 patients with COPD living below 800 m with forced expiratory volume in the first second of expiration (FEV1) between 30% and 80% predicted, pulse oximetry of at least 92%, not requiring oxygen therapy, and without history of sleep apnea. Evaluations were performed at the University Hospital Zurich (490 m, baseline) and during 2 stays of 2 days and nights each in a Swiss Alpine hotel at 2048 m while NOT or placebo treatment was administered in a randomized order. Between altitude sojourns, patients spent at least 2 weeks below 800 m. Data analysis was performed from January 1, 2015, to December 31, 2018. Intervention During nights at 2048 m, NOT or placebo (room air) was administered at 3 L/min by nasal cannula. Main Outcomes and Measures Coprimary outcomes were differences between NOT and placebo intervention in altitude-induced change in mean nocturnal oxygen saturation (SpO2) as measured by pulse oximetry and apnea-hypopnea index (AHI) measured by polysomnography during night 1 at 2048 m and analyzed according to the intention-to-treat principle. Further outcomes were the incidence of predefined ARAHE, other variables from polysomnography results and respiratory sleep studies in the 2 nights at 2048 m, clinical findings, and symptoms. Results Of the 32 patients included, 17 (53%) were women, with a mean (SD) age of 65.6 (5.6) years and a mean (SD) FEV1 of 53.1% (13.2%) predicted. At 490 m, mean (SD) SpO2 was 92% (2%) and mean (SD) AHI was 21.6/h (22.2/h). At 2048 m with placebo, mean (SD) SpO2 was 86% (3%) and mean (SD) AHI was 34.9/h (20.7/h) (P < .001 for both comparisons). Compared with placebo, NOT increased SpO2 by a mean of 9 percentage points (95% CI, 8-11 percentage points; P < .001), decreased AHI by 19.7/h (95% CI, 11.4/h-27.9/h; P < .001), and improved subjective sleep quality measured on a visual analog scale by 9 percentage points (95% CI, 0-17 percentage points; P = .04). During visits to 2048 m or within 24 hours after descent, 8 patients (26%) using placebo and 1 (4%) using NOT experienced ARAHEs (P < .001). Conclusions and Relevance Lowlanders with COPD experienced hypoxemia, sleep apnea, and impaired well-being when staying at 2048 m. Because NOT significantly mitigated these undesirable effects, patients with moderate to severe COPD may benefit from preventive NOT during high altitude travel. Trial Registration ClinicalTrials.gov Identifier: NCT0215059

Effect of nocturnal oxygen therapy on exercise performance of COPD patients at 2048 m: data from a randomized clinical trial

This trial evaluates whether nocturnal oxygen therapy (NOT) during a stay at 2048 m improves altitude-induced exercise intolerance in lowlanders with chronic obstructive pulmonary disease (COPD). 32 lowlanders with moderate to severe COPD, mean ± SD forced expiratory volume in the first second of expiration (FEV1) 54 ± 13% predicted, stayed for 2 days at 2048 m twice, once with NOT, once with placebo according to a randomized, crossover trial with a 2-week washout period at < 800 m in-between. Semi-supine, constant-load cycle exercise to exhaustion at 60% of maximal work-rate was performed at 490 m and after the first night at 2048 m. Endurance time was the primary outcome. Additional outcomes were cerebral tissue oxygenation (CTO), arterial blood gases and breath-by-breath measurements (http://www.ClinicalTrials.gov NCT02150590). Mean ± SE endurance time at 490 m was 602 ± 65 s, at 2048 m after placebo 345 ± 62 s and at 2048 m after NOT 293 ± 60 s, respectively (P < 0.001 vs. 490 m). Mean difference (95%CI) NOT versus placebo was − 52 s (− 174 to 70), P = 0.401. End-exercise pulse oximetry (SpO2), CTO and minute ventilation (V˙E) at 490 m were: SpO2 92 ± 1%, CTO 65 ± 1%, V˙E 37.7 ± 2.0 L/min; at 2048 m with placebo: SpO2 85 ± 1%, CTO 61 ± 1%, V˙E 40.6 ± 2.0 L/min and with NOT: SpO2 84 ± 1%; CTO 61 ± 1%; V˙E 40.6 ± 2.0 L/min (P < 0.05, SpO2, CTO at 2048 m with placebo vs. 490 m; P = NS, NOT vs. placebo). Altitude-related hypoxemia and cerebral hypoxia impaired exercise endurance in patients with moderate to severe COPD and were not prevented by NOT

Effect of Nocturnal Oxygen Therapy on Daytime Pulmonary Hemodynamics in Patients With Chronic Obstructive Pulmonary Disease Traveling to Altitude: A Randomized Controlled Trial

Introduction: We investigated whether nocturnal oxygen therapy (NOT) mitigates the increase of pulmonary artery pressure in patients during daytime with chronic obstructive pulmonary disease (COPD) traveling to altitude. Methods: Patients with COPD living below 800 m underwent examinations at 490 m and during two sojourns at 2,048 m (with a washout period of 2 weeks < 800 m between altitude sojourns). During nights at altitude, patients received either NOT (3 L/min) or placebo (ambient air 3 L/min) via nasal cannula according to a randomized crossover design. The main outcomes were the tricuspid regurgitation pressure gradient (TRPG) measured by echocardiography on the second day at altitude (under ambient air) and various other echocardiographic measures of the right and left heart function. Patients fulfilling predefined safety criteria were withdrawn from the study. Results: Twenty-three COPD patients [70% Global Initiative for Chronic Obstructive Lung Disease (GOLD) II/30% GOLD III, mean ± SD age 66 ± 5 years, FEV1 54% ± 13% predicted] were included in the per-protocol analysis. TRPG significantly increased when patients traveled to altitude (from low altitude 21.7 ± 5.2 mmHg to 2,048 m placebo 27.4 ± 7.3 mmHg and 2,048 m NOT 27.8 ± 8.3 mmHg) difference between interventions (mean difference 0.4 mmHg, 95% CI −2.1 to 3.0, p = 0.736). The tricuspid annular plane systolic excursion was significantly higher after NOT vs. placebo [2.6 ± 0.6 vs. 2.3 ± 0.4 cm, mean difference (95% confidence interval) 0.3 (0.1 − 0.5) cm, p = 0.005]. During visits to 2,048 m until 24 h after descent, eight patients (26%) using placebo and one (4%) using NOT had to be withdrawn because of altitude-related adverse health effects (p < 0.001). Conclusion: In lowlanders with COPD remaining free of clinically relevant altitude-related adverse health effects, changes in daytime pulmonary hemodynamics during a stay at high altitude were trivial and not modified by NOT. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02150590

Altitude Travel in Patients With Pulmonary Hypertension: Randomized Pilot-Trial Evaluating Nocturnal Oxygen Therapy

Introduction: Stable patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension (PH) wish to undergo altitude sojourns or air travel but fear disease worsening. This pilot study investigates health effects of altitude sojourns and potential benefits of nocturnal oxygen therapy (NOT) in PH patients. Methods: Nine stable PH patients, age 65 (47; 71) years, 5 women, in NYHA class II, on optimized medication, were investigated at 490 m and during two sojourns of 2 days/nights at 2,048 m, once using NOT, once placebo (ambient air), 3 L/min per nasal cannula, according to a randomized crossover design with 2 weeks washout at 30 min). Both recovered immediately with oxygen therapy. Two patients suffered from acute mountain sickness. In 6 patients with complete data, nocturnal mean SpO$_{2}$ and cyclic SpO$_{2}$ dips reflecting sleep apnea significantly differed from 490 to 2,048 m with placebo, and 2,048 m with NOT (medians, quartiles): SpO$_{2}$ 93 (91; 95)%, 89 (85; 90)%, 97 (95; 97)%; SpO$_{2}$ dips 10.4/h (3.1; 26.9), 34.0/h (5.3; 81.3), 0.3/h (0.1; 2.3). 6 MWD at 490, 2,048 m without and with NOT was 620 m (563; 720), 583 m (467; 696), and 561 m (501; 688). Echocardiographic indices of heart function and PH were unchanged at 2,048 m with/without NOT vs. 490 m. Conclusions: 7/9 PH patients stayed safely at 2,048 m but revealed hypoxemia, sleep apnea, and reduced 6 MWD. Hemodynamic changes were trivial. NOT improved oxygenation and sleep apnea. The current pilot trial is important for designing further studies on altitude tolerance of PH patients

Effect of Acetazolamide on Postural Control in Patients with COPD Travelling to 3100 m Randomized Trial

Patients with chronic obstructive pulmonary disease (COPD) may be susceptible to impairments in postural control (PC) when exposed to hypoxia at high altitude. This randomized, placebo-controlled, double-blind, parallel-design trial evaluated the effect of preventive acetazolamide treatment on PC in lowlanders with COPD traveling to 3100 m. 127 lowlanders (85 men, 42 women) with moderate to severe COPD, aged 57 ± 8 y, living below 800 m, were randomized to treatment with acetazolamide 375 mg/d starting 24 h before ascent from 760 m to 3100 m and during a 2-day sojourn in a clinic at 3100 m. PC was evaluated at both altitudes with a balance platform on which patients were standing during five tests of 30 s each. The primary outcome was the center of pressure path length (COPL). In the placebo group, COPL significantly increased from (mean ± SD) 28.8 ± 9.7 cm at 760 m to 30.0 ± 10.0 cm at 3100 m (p = 0.002). In the acetazolamide group, COPL at 760 m and 3100 m were similar with 27.6 ± 9.6 cm and 28.4 ± 9.7 cm (p = 0.069). The mean between-groups difference (acetazolamide-placebo) in altitude-induced change of COPL was −0.54 cm (95%CI −1.66 to 0.58, p = 0.289). Multivariable regression analysis confirmed an increase in COPL of 0.98 cm (0.39 to 1.58, p = 0.001) with ascent from 760 to 3100 m, but no significant effect of acetazolamide (0.66 cm, 95%CI −0.25 to 1.57, p = 0.156) when adjusting for several confounders. In lowlanders with moderate to severe COPD, an ascent to high altitude was associated with impaired postural control and this was not prevented by acetazolamide