Exercise Performance of Lowlanders with Chronic Obstructive Pulmonary Disease Acutely Exposed to 2048 m: A Randomized Cross-Over Trial.

Background: Amongst the millions of travelers to high altitude worldwide are many with chronic obstructive pulmonary disease (COPD), but data regarding the effects of acute exposure to altitude on exercise performance are limited. The current study investigated how acute exposure to moderate altitude influences exercise performance in COPD patients, providing novel insights to the underlying physiological mechanisms. Methods: Twenty-nine COPD patients, GOLD grade 2-3, median (quartile) forced expiratory volume in 1 second (FEV1) of 60% predicted (46; 69) performed cycling incremental ramp exercise test (IET) at 490 m and after acute exposure of 2-6 hours to 2048 m or vice versa, according to a randomized cross-over design. Exercise performance and breath-by-breath analyses of the last 30 seconds of each IET were compared between locations. Results: At 2048 m compared to 490 m, the maximum power output (Wmax) was 77 watts (62;104) vs 88 watts (75;112), median reduction 5 watts (95% CI, 2 to 8, P<0.05), corresponding to a median reduction of 6% (95% CI, 2 to 11, P<0.05) compared to 490 m. The peak oxygen uptake (V'O2peak) was 70% predicted (56;86) at 2048 m vs 79% predicted (63;90) at 490 m, median reduction of 6% (95% CI, 3 to 9, P<0.05). The oxygen saturation by pulse oximetry (SpO2) at 2048 m was reduced by 8% (95% CI, 4 to 9, P<0.05) compared to 490 m. The minute ventilation (V'E) increased by 2.8L/min (95% CI, 0.9 to 4.2, P<0.05) at 2048 m. The maximum heart rate and the subjective sense of dyspnea and leg fatigue did not change. Conclusion: Lowlanders with moderate-to-severe COPD acutely exposed to 2048 m reveal small but significant reduction in cycling IET along with a reduced V'O2peak. As dyspnea perception and maximal heart rate were unchanged, the lower blood oxygenation and exaggerated ventilatory response were culprit factors for the reduced performance.

Prognostic factors, disease course, and treatment efficacy in Duchenne muscular dystrophy: A systematic review and meta-analysis.

INTRODUCTION/AIMS: Prognostic factors in Duchenne muscular dystrophy (DMD) predict the disease course and may help individualize patient care. The aim was to summarize the evidence on prognostic factors that may support treatment decisions. METHODS: We searched six databases for prospective studies that each included ≥50 DMD patients with a minimum follow-up of 1 y. Primary outcomes were age at loss of ambulation (LoA), pulmonary function (forced vital capacity percent of predicted, FVC%p), and heart failure. RESULTS: Out of 5074 references, 59 studies were analyzed. Corticosteroid use was associated with a delayed LoA (pooled effect hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.23-0.75, I2 94%), better pulmonary function tests (higher peak FVC%, prolonged time with FVC%p > 50%, and reduced need for assisted ventilation) and delayed cardiomyopathy. Longer corticosteroid treatment was associated with later LoA (>1 y compared to <1 y; pooled HR: 0.50, 95% CI 0.27-0.90) and early treatment start (aged <5 y) may be associated with early cardiomyopathy and higher fracture risk. Genotype appeared to be an independent driver of LoA in some studies. Higher baseline physical function tests (e.g., 6-minute walk test) were associated with delayed LoA. Left ventricular dysfunction and FVC <1 L increased and the use of angiotensin-converting enzyme (ACE) inhibitors reduced the risk of heart failure and death. Fusion surgery in scoliosis may potentially preserve pulmonary function. DISCUSSION: Prognostic factors that may inform clinical decisions include age at corticosteroid treatment initiation and treatment duration, ACE-inhibitor use, baseline physical function tests, pulmonary function, and cardiac dysfunction.

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 ([Formula: see text]) at 490 m were: SpO2 92 ± 1%, CTO 65 ± 1%, [Formula: see text] 37.7 ± 2.0 L/min; at 2048 m with placebo: SpO2 85 ± 1%, CTO 61 ± 1%, [Formula: see text] 40.6 ± 2.0 L/min and with NOT: SpO2 84 ± 1%; CTO 61 ± 1%; [Formula: see text] 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.

Nocturnal cerebral tissue oxygenation in lowlanders with chronic obstructive pulmonary disease travelling to an altitude of 2,590 m: Data from a randomised trial.

Altitude exposure induces hypoxaemia in patients with chronic obstructive pulmonary disease (COPD), particularly during sleep. The present study tested the hypothesis in patients with COPD staying overnight at high altitude that nocturnal arterial hypoxaemia is associated with impaired cerebral tissue oxygenation (CTO). A total of 35 patients with moderate-to-severe COPD, living at <800 m (mean [SD] age 62.4 [12.3] years, forced expiratory volume in 1 s [FEV1 ] 61 [16]% predicted, awake pulse oximetry ≥92%) underwent continuous overnight monitoring of pulse oximetry (oxygen saturation [SpO2 ]) and near-infrared spectroscopy of prefrontal CTO, respectively, at 490 m and 2,590 m. Regression analysis was used to evaluate whether nocturnal arterial desaturation (COPDDesat , SpO2 <90% for >30% of night-time) at 490 m predicted CTO at 2,590 m when controlling for baseline variables. At 2,590 m, mean nocturnal SpO2 and CTO were decreased versus 490 m, mean change -8.8% (95% confidence interval [CI] -10.0 to -7.6) and -3.6% (95% CI -5.7 to -1.6), difference in change ΔCTO-ΔSpO2 5.2% (95% CI 3.0 to 7.3; p < .001). Moreover, frequent cyclic desaturations (≥4% dips/hr) occurred in SpO2 and CTO, mean change from 490 m 35.3/hr (95% CI 24.9 to 45.7) and 3.4/hr (95% CI 1.4 to 5.3), difference in change ΔCTO-ΔSpO2 -32.8/hr (95% CI -43.8 to -21.8; p < .001). Regression analysis confirmed an association of COPDDesat with lower CTO at 2,590 m (coefficient -7.6%, 95% CI -13.2 to -2.0; p = .007) when controlling for several confounders. We conclude that lowlanders with COPD staying overnight at 2,590 m experience altitude-induced hypoxaemia and periodic breathing in association with sustained and intermittent cerebral deoxygenation. Although less pronounced than the arterial deoxygenation, the altitude-induced cerebral tissue deoxygenation may represent a risk of brain dysfunction, especially in patients with COPD with nocturnal hypoxaemia at low altitude.

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.

Health Preference Measures in Patients with Obstructive Sleep Apnea Syndrome Undergoing Continuous Positive Airway Pressure Therapy: Data from a Randomized Trial.

BACKGROUND: In patients with obstructive sleep apnea syndrome (OSAS), the preference-based, health-related quality of life in terms of utility has not been extensively studied. OBJECTIVE: To address this point, we compared the performance of different instruments assessing utility in patients with OSAS undergoing continuous positive airway pressure (CPAP) therapy. MATERIALS AND METHODS: Data of 208 patients with OSAS (28 women, mean ± SE age 54.4 ± 0.7 years, apnea-hypopnea index (AHI) 51.9 ± 1.8/h, Epworth sleepiness score 13.4 ± 0.2) participating in a randomized trial of different CPAP modalities over 2 years were analyzed. Evaluations included sleep studies, Epworth sleepiness scale, and several utility instruments that measure subjective health preference on a scale ranging from 1 (most preferred and perfect health) to 0 (least preferred and very poor health). RESULTS: After 2 years of CPAP therapy, the mean ± SE AHI was 6.7 ± 1.5/h and Epworth score 7.9 ± 0.4, both p < 0.001 versus baseline. Baseline utilities and changes (95% confidence interval) after 2 years of CPAP therapy were EuroQol 5-dimensions 0.79 ± 0.01, 0.02 (0.00-0.05, p = 0.064); short-form 6-dimension medical outcome questionnaire 0.72 ± 0.01, 0.06 (0.04-0.08, p < 0.001); Euro-thermometer visual analog scale 0.70 ± 0.01, 0.09 (0.07-0.12, p < 0.001); time trade-off 0.82 ± 0.01, 0.03 (0.01-0.06, p = 0.002); and standard gamble 0.82 ± 0.01, -0.01 (-0.03 to 0.02, p = 0.712). CONCLUSION: The short-form 6-dimensions questionnaire, the Euro-thermometer, and the time trade-off instruments reflected the major clinical improvements in OSAS, while the EuroQoL 5-dimensions and standard gamble tests were not sensitive to CPAP effects. These results indicate that the evaluation of utility of a treatment for OSAS depends critically on the instrument used, which is important from an individual and societal perspective.

Effect of Nocturnal Oxygen on Blood Pressure Response to Altitude Exposure in COPD - Data from a Randomized Placebo-Controlled Cross-Over Trial.

PURPOSE: Patients with chronic obstructive pulmonary disease (COPD) are particularly vulnerable to hypoxia-induced autonomic dysregulation. Hypoxemia is marked during sleep. In COPD, altitude exposure is associated with an increase in blood pressure (BP) and a decrease in baroreflex-sensitivity (BRS). Whether nocturnal oxygen therapy (NOT) may mitigate these cardiovascular autonomic changes in COPD at altitude is unknown. MATERIALS AND METHODS: In a randomized placebo-controlled cross-over trial, 32 patients with moderate-to-severe COPD living <800 m were subsequently allocated to NOT and placebo during acute exposure to altitude. Measurements were done at low altitude at 490 m and during two stays at 2048 m on NOT (3 L/min) and placebo (3 L/min, ambient air) via nasal cannula. Allocation and intervention sequences were randomized. Outcomes of interest were BP, BRS (from beat-to-beat BP measurement), BP variability (BPV), and heart rate. RESULTS: About 23/32 patients finished the trial per protocol (mean (SD) age 66 (5) y, FEV1 62 (14) % predicted) and 9/32 experienced altitude-related illnesses (8 vs 1, p < 0.05 placebo vs NOT). NOT significantly mitigated the altitude-induced increase in systolic BP compared to placebo (Δ median -5.8 [95% CI -22.2 to -1.4] mmHg, p = 0.05) but not diastolic BP (-3.5 [95% CI -12.6 to 3.0] mmHg; p = 0.21) or BPV. BRS at altitude was significantly higher in NOT than in placebo (1.7 [95% CI 0.3 to 3.4] ms/mmHg, p = 0.02). CONCLUSION: NOT may protect from hypoxia-induced autonomic dysregulation upon altitude exposure in COPD and thus protect from a relevant increase in BP and decrease in BRS. NOT may provide cardiovascular benefits in COPD during conditions of increased hypoxemia and may be considered in COPD travelling to altitude.

Altered cardiac repolarisation in highlanders with high-altitude pulmonary hypertension during wakefulness and sleep.

High-altitude pulmonary hypertension (HAPH) is an altitude-related illness associated with hypoxaemia that may promote sympathetic excitation and prolongation of the QT interval. The present case-control study tests whether QT intervals, markers of malignant cardiac arrhythmias, are prolonged in highlanders with HAPH (HAPH+) compared to healthy highlanders (HH) and healthy lowlanders (LL). The mean pulmonary artery pressure (mPAP) was measured by echocardiography in 18 HAPH+ (mPAP, 34 mmHg) and 18 HH (mPAP, 23 mmHg) at 3,250 m, and 18 LL (mPAP, 18 mmHg) at 760 m, Kyrgyzstan (p < .05 all mPAP comparisons). Groups were matched for age, sex and body mass index. Electrocardiography and pulse oximetry were continuously recorded during nocturnal polysomnography. The heart rate-adjusted QT interval, QTc, was averaged over consecutive 1-min periods. Overall, a total of 26,855 averaged 1-min beat-by-beat periods were semi-automatically analysed. In HAPH+, maximum nocturnal QTc was longer during sleep (median 456 ms) than wakefulness (432 ms, p < .05) and exceeded corresponding values in HH (437 and 419 ms) and LL (430 and 406 ms), p < .05, respectively. The duration of night-time QTc >440 ms was longer in HAPH+ (median 144 min) than HH and LL (46 and 14 min, p < .05, respectively). HAPH+ had higher night-time heart rate (median 78 beats/min) than HH and LL (66 and 65 beats/min, p < .05, respectively), lower mean nocturnal oxygen saturation than LL (88% versus 95%, p < .05) and more cyclic oxygen desaturations (median 24/hr) than HH and LL (13 and 3/hr, p < .05, respectively). In conclusion, HAPH was associated with higher night-time heart rate, hypoxaemia and longer QTc versus HH and LL, and may represent a substrate for increased risk of malignant cardiac arrhythmias.

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 <800 m. Assessments included safety, nocturnal pulse oximetry (SpO2), 6-min walk distance (6 MWD), and echocardiography. Results: At 2,048 m, two of nine patients required medical intervention, one for exercise-induced syncope, one for excessive nocturnal hypoxemia (SpO2 < 75% for >30 min). Both recovered immediately with oxygen therapy. Two patients suffered from acute mountain sickness. In 6 patients with complete data, nocturnal mean SpO2 and cyclic SpO2 dips reflecting sleep apnea significantly differed from 490 to 2,048 m with placebo, and 2,048 m with NOT (medians, quartiles): SpO2 93 (91; 95)%, 89 (85; 90)%, 97 (95; 97)%; SpO2 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 Nocturnal Oxygen Therapy on Nocturnal Hypoxemia and Sleep Apnea Among Patients With Chronic Obstructive Pulmonary Disease Traveling to 2048 Meters: A Randomized Clinical Trial.

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: NCT02150590.

Blood pressure response to exposure to moderate altitude in patients with COPD.

Purpose: Patients with COPD might be particularly susceptible to hypoxia-induced autonomic dysregulation. Decreased baroreflex sensitivity (BRS) and increased blood pressure (BP) variability (BPV) are markers of impaired cardiovascular autonomic regulation and there is evidence for an association between decreased BRS/increased BPV and high cardiovascular risk. The aim of this study was to evaluate the effect of short-term exposure to moderate altitude on BP and measures of cardiovascular autonomic regulation in COPD patients. Materials and methods: Continuous morning beat-to-beat BP was noninvasively measured with a Finometer® device for 10 minutes at low altitude (490 m, Zurich, Switzerland) and for 2 days at moderate altitude (2,590 m, Davos Jakobshorn, Switzerland) - the order of altitude exposure was randomized. Outcomes of interest were mean SBP and DBP, BPV expressed as the coefficient of variation (CV), and spontaneous BRS. Changes between low altitude and day 1 and day 2 at moderate altitude were assessed by ANOVA for repeated measurements with Fisher's exact test analysis. Results: Thirty-seven patients with moderate to severe COPD (mean±SD age 64±6 years, FEV1 60%±17%) were included. Morning SBP increased by +10.8 mmHg (95% CI: 4.7-17.0, P=0.001) and morning DBP by +5.0 mmHg (95% CI: 0.8-9.3, P=0.02) in response to altitude exposure. BRS significantly decreased (P=0.03), whereas BPV significantly and progressively increased (P<0.001) upon exposure to altitude. Conclusion: Exposure of COPD patients to moderate altitude is associated with a clinically relevant increase in BP, which seems to be related to autonomic dysregulation. Clinical trial registration: ClinicalTrials.gov (NCT01875133).

Effect of Dexamethasone on Nocturnal Oxygenation in Lowlanders With Chronic Obstructive Pulmonary Disease Traveling to 3100 Meters: A Randomized Clinical Trial.

Importance: During mountain travel, patients with chronic obstructive pulmonary disease (COPD) are at risk of experiencing severe hypoxemia, in particular, during sleep. Objective: To evaluate whether preventive dexamethasone treatment improves nocturnal oxygenation in lowlanders with COPD at 3100 m. Design, Setting, and Participants: A randomized, placebo-controlled, double-blind, parallel trial was performed from May 1 to August 31, 2015, in 118 patients with COPD (forced expiratory volume in the first second of expiration [FEV1] >50% predicted, pulse oximetry at 760 m ≥92%) who were living at altitudes below 800 m. The study was conducted at a university hospital (760 m) and high-altitude clinic (3100 m) in Tuja-Ashu, Kyrgyz Republic. Patients underwent baseline evaluation at 760 m, were taken by bus to the clinic at 3100 m, and remained at the clinic for 2 days and nights. Participants were randomized 1:1 to receive either dexamethasone, 4 mg, orally twice daily or placebo starting 24 hours before ascent and while staying at 3100 m. Data analysis was performed from September 1, 2015, to December 31, 2016. Interventions: Dexamethasone, 4 mg, orally twice daily (dexamethasone total daily dose, 8 mg) or placebo starting 24 hours before ascent and while staying at 3100 m. Main Outcomes and Measures: Difference in altitude-induced change in nocturnal mean oxygen saturation measured by pulse oximetry (Spo2) during night 1 at 3100 m between patients receiving dexamethasone and those receiving placebo was the primary outcome and was analyzed according to the intention-to-treat principle. Other outcomes were apnea/hypopnea index (AHI) (mean number of apneas/hypopneas per hour of time in bed), subjective sleep quality measured by a visual analog scale (range, 0 [extremely bad] to 100 [excellent]), and clinical evaluations. Results: Among the 118 patients included, 18 (15.3%) were women; the median (interquartile range [IQR]) age was 58 (52-63) years; and FEV1 was 91% predicted (IQR, 73%-103%). In 58 patients receiving placebo, median nocturnal Spo2 at 760 m was 92% (IQR, 91%-93%) and AHI was 20.5 events/h (IQR, 12.3-48.1); during night 1 at 3100 m, Spo2 was 84% (IQR, 83%-85%) and AHI was 39.4 events/h (IQR, 19.3-66.2) (P < .001 both comparisons vs 760 m). In 60 patients receiving dexamethasone, Spo2 at 760 m was 92% (IQR, 91%-93%) and AHI was 25.9 events/h (IQR, 16.3-37.1); during night 1 at 3100 m, Spo2 was 86% (IQR, 84%-88%) (P < .001 vs 760 m) and AHI was 24.7 events/h (IQR, 13.2-33.7) (P = .99 vs 760 m). Altitude-induced decreases in Spo2 during night 1 were mitigated by dexamethasone vs placebo by a mean of 3% (95% CI, 2%-3%), and increases in AHI were reduced by 18.7 events/h (95% CI, 12.0-25.3). Similar effects were observed during night 2. Subjective sleep quality was improved with dexamethasone during night 2 by 12% (95% CI, 0%-23%). Sixteen (27.6%) patients using dexamethasone had asymptomatic hyperglycemia. Conclusions and Relevance: In lowlanders in Central Asia with COPD traveling to a high altitude, preventive dexamethasone treatment improved nocturnal oxygen saturation, sleep apnea, and subjective sleep quality. Trial Registration: ClinicalTrials.gov Identifier: NCT02450994.

Right and Left Heart Function in Lowlanders with COPD at Altitude: Data from a Randomized Study.

BACKGROUND: Changes in pulmonary hemodynamics and cardiac function in patients with chronic obstructive pulmonary disease (COPD) traveling to altitude have not been assessed despite an increasing prevalence of the disease. OBJECTIVES: We hypothesized that pulmonary artery pressure (PAP) significantly increases and cardiac function deteriorates during exposure to hypobaric hypoxia as encountered by traveling to moderate altitude or air flight. METHODS: A total of 37 patients (17 female; median age [quartiles] 66 years [60; 69] with COPD GOLD grade 2-3 [FEV1 57% predicted (49; 71)]) living < 800 m underwent echocardiography in Zurich (490 m) and after 1 night at Davos Jakobshorn (2,590 m) in a randomized order of allocation. RESULTS: The transtricuspid pressure gradient increased from 23 mm Hg (18; 29) to 32 mm Hg (25; 41) (p < 0.0001; Δmedian [95% CI] 7.5 [2.0; 13.0]), the right ventricular fractional area change decreased from 45% (39; 49) to 38% (33; 43) (p = 0.002), while the heart rate and systolic blood pressure increased from 70 bpm (64; 78) to 82 bpm (70; 86) (p < 0.0001) and from 133 mm Hg (123; 141) to 136 mm Hg (126; 148) (p = 0.002), respectively, and left ventricular diastolic dysfunction was more prevalent (24-54%, p = 0.02). CONCLUSIONS: This is a first study assessing changes in pulmonary hemodynamics and cardiac function in patients with COPD during a short altitude sojourn. Despite the increase in PAP and indications of change in cardiac function, the exposure was well tolerated. None of the patients had to descend to lower altitude for symptomatic altitude-related disease.

Sleep and breathing disturbances in patients with chronic obstructive pulmonary disease traveling to altitude: a randomized trial.

Study Objectives: Patients with chronic obstructive pulmonary disease (COPD) have impaired pulmonary gas exchange near sea level. The purpose of the current study was to investigate whether exposure to hypobaric hypoxia during a stay at altitude affects nocturnal oxygen saturation, breathing pattern, and sleep in patients with moderate to severe COPD. Methods: Thirty-two patients with COPD, median age 67 years, FEV1 59% predicted, PaO2 68 mmHg, living below 800 m, underwent polysomnography and questionnaire evaluations in Zurich (490 m), and in Swiss Alpine villages at 1650 and 2590 m, for two nights each, in random order. Mean nocturnal oxygen saturation (SpO2), the apnea-hypopnea index (AHI), and sleep structure were compared between altitudes. Results: Polysomnography during the first night at each altitude revealed a reduced SpO2 at 1650 and 2590 m (medians 89% and 85%) compared with 490 m (92%, p <0.05 vs. higher altitudes) and a higher AHI (medians 26.8/hr and 55.7/hr) vs. 490 m (15.4/hr, p <0.05 vs. higher altitudes) due to emergence of frequent central apneas/hypopneas. At 2590 m, sleep efficiency (median 59%) and slow-wave sleep (median 17% of total sleep time) were reduced compared with 490 m (72% and 20%, respectively, p <0.05). In the morning after one night at 2590 m, patients estimated to have spent more time awake (median 110 min) than at 490 m (43 min, p <0.05) and felt slightly less alert. Conclusions: During a stay at moderate altitude, lowlanders with moderate to severe COPD experience nocturnal hypoxemia that induces central sleep apneas, altered sleep structure, and insomnia. These novel findings help us to counsel patients with COPD planning altitude travel. Trial Registration: ClinicalTrials.gov: NCT01870830.

Exercise performance and symptoms in lowlanders with COPD ascending to moderate altitude: randomized trial.

OBJECTIVE: To evaluate the effects of altitude travel on exercise performance and symptoms in lowlanders with COPD. DESIGN: Randomized crossover trial. SETTING: University Hospital Zurich (490 m), research facility in mountain villages, Davos Clavadel (1,650 m) and Davos Jakobshorn (2,590 m). PARTICIPANTS: Forty COPD patients, Global Initiative for Obstructive Lung Disease (GOLD) grade 2-3, living below 800 m, median (quartiles) age 67 y (60; 69), forced expiratory volume in 1 second 57% predicted (49; 70). INTERVENTION: Two-day sojourns at 490 m, 1,650 m, and 2,590 m in randomized order. OUTCOME MEASURES: Six-minute walk distance (6MWD), cardiopulmonary exercise tests, symptoms, and other health effects. RESULTS: At 490 m, days 1 and 2, median (quartiles) 6MWD were 558 m (477; 587) and 577 m (531; 629). At 2,590 m, days 1 and 2, mean changes in 6MWD from corresponding day at 490 m were -41 m (95% CI -51 to -31) and -40 m (-53 to -27), n=40, P<0.05, both changes. At 1,650 m, day 1, 6MWD had changed by -22 m (-32 to -13), maximal oxygen uptake during bicycle exercise by -7% (-13 to 0) vs 490 m, P<0.05, both changes. At 490 m, 1,650 m, and 2,590 m, day 1, resting PaO2 were 9.0 (8.4; 9.4), 8.1 (7.5; 8.6), and 6.8 (6.3; 7.4) kPa, respectively, P<0.05 higher altitudes vs 490 m. While staying at higher altitudes, nine patients (24%) experienced symptoms or adverse health effects requiring oxygen therapy or relocation to lower altitude. CONCLUSION: During sojourns at 1,650 m and 2,590 m, lowlanders with moderate to severe COPD experienced a mild reduction in exercise performance and nearly one quarter required oxygen therapy or descent to lower altitude because of adverse health effects. The findings may help to counsel COPD patients planning altitude travel. REGISTRATION: ClinicalTrials.gov: NCT01875133.

Postural Control in Lowlanders With COPD Traveling to 3100 m: Data From a Randomized Trial Evaluating the Effect of Preventive Dexamethasone Treatment.

Objective: To evaluate the effects of acute exposure to high altitude and preventive dexamethasone treatment on postural control in patients with chronic obstructive pulmonary disease (COPD). Methods: In this randomized, double-blind parallel-group trial, 104 lowlanders with COPD GOLD 1-2 age 20-75 years, living near Bishkek (760 m), were randomized to receive either dexamethasone (2 × 4 mg/day p.o.) or placebo on the day before ascent and during a 2-day sojourn at Tuja-Ashu high altitude clinic (3100 m), Kyrgyzstan. Postural control was assessed with a Wii Balance BoardTM at 760 m and 1 day after arrival at 3100 m. Patients were instructed to stand immobile on both legs with eyes open during five tests of 30 s each, while the center of pressure path length (PL) was measured. Results: With ascent from 760 to 3100 m the PL increased in the placebo group from median (quartiles) 29.2 (25.8; 38.2) to 31.5 (27.3; 39.3) cm (P < 0.05); in the dexamethasone group the corresponding increase from 28.8 (22.8; 34.5) to 29.9 (25.2; 37.0) cm was not significant (P = 0.10). The mean difference (95% CI) between dexamethasone and placebo groups in altitude-induced changes (treatment effect) was -0.3 (-3.2 to 2.5) cm, (P = 0.41). Multivariable regression analysis confirmed a significant increase in PL with higher altitude (coefficient 1.6, 95% CI 0.2 to 3.1, P = 0.031) but no effect of dexamethasone was shown (coefficient -0.2, 95% CI -0.4 to 3.6, P = 0.925), even when controlled for several potential confounders. PL changes were related more to antero-posterior than lateral sway. Twenty-two of 104 patients had an altitude-related increase in the antero-posterior sway velocity of >25%, what has been associated with an increased risk of falls in previous studies. Conclusion: Lowlanders with COPD travelling from 760 to 3100 m revealed postural instability 24 h after arriving at high altitude, and this was not prevented by dexamethasone. Trial Registration: clinicaltrials.gov Identifier: NCT02450968.

Efficacy of Dexamethasone in Preventing Acute Mountain Sickness in COPD Patients: Randomized Trial.

BACKGROUND: Patients with COPD may experience acute mountain sickness (AMS) and other altitude-related adverse health effects (ARAHE) when traveling to high altitudes. This study evaluated whether dexamethasone, a drug used for the prevention of AMS in healthy individuals, would prevent AMS/ARAHE in patients with COPD. METHODS: This placebo-controlled, double-blind, parallel-design trial included patients with COPD and Global Initiative for Obstructive Lung Disease grade 1 to 2 who were living below 800 m. Patients were randomized to receive dexamethasone (8 mg/d) or placebo starting on the day before ascent and while staying in a high-altitude clinic at 3,100 m for 2 days. The primary outcome assessed during the altitude sojourn was the combined incidence of AMS/ARAHE, defined as an Environmental Symptoms Questionnaire cerebral score evaluating AMS ≥ 0.7 or ARAHE requiring descent or an intervention. RESULTS: In 60 patients randomized to receive dexamethasone (median [quartiles] age: 57 years [50; 60], FEV1 86% predicted [70; 104]; PaO2 at 760 m: 9.6 kPa [9.2; 10.0]), the incidence of AMS/ARAHE was 22% (13 of 60). In 58 patients randomized to receive placebo (age: 60 y [53; 64]; FEV1 94% predicted [76; 103]; PaO2: 10.0 kPa [9.1; 10.5]), the incidence of AMS/ARAHE was 24% (14 of 58) (χ2 statistic vs dexamethasone, P = .749). Dexamethasone mitigated the altitude-induced PaO2 reduction compared with placebo (mean between-group difference [95% CI], 0.4 kPa [0.0-0.8]; P = .028). CONCLUSIONS: In lowlanders with mild to moderate COPD, the incidence of AMS/ARAHE at 3,100 m was moderate and not reduced by dexamethasone treatment. Based on these findings, dexamethasone cannot be recommended for the prevention of AMS/ARAHE in patients with COPD undertaking high-altitude travel, although the drug mitigated the altitude-induced hypoxemia. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02450968; URL: www.clinicaltrials.gov.

Exercise Performance of Lowlanders with COPD at 2,590 m: Data from a Randomized Trial.

BACKGROUND: Effects of hypobaric hypoxia at altitude on exercise performance of lowlanders with chronic obstructive pulmonary disease (COPD) have not been studied in detail. OBJECTIVES: To quantify changes in exercise performance and associated physiologic responses in lowlanders with COPD travelling to moderate altitude. METHODS: A total of 31 COPD patients with a median age (quartiles) of 66 years (59; 69) and FEV1 of 56% predicted (49; 69) living below 800 m performed a constant-load bicycle exercise to exhaustion at 60% of the maximal work rate at 490 m (Zurich) and at an identical work rate at 2,590 m (Davos) in randomized order. Pulmonary gas exchange, pulse oximetry (SpO2), cerebral tissue oxygenation (CTO; near-infrared spectroscopy), and middle cerebral artery peak blood flow velocity (MCAv) by Doppler ultrasound during 30 s at end exercise were compared between altitudes. RESULTS: With ascent from 490 to 2,590 m, the median endurance time (quartiles) was reduced from 500 s (256; 795) to 205 s (139; 297) by a median (95% CI) of 303 s (150-420) (p < 0.001). End exercise SpO2 decreased from 92% (89; 94) to 81% (77; 84) and CTO from 62% (56; 66) to 55% (50; 60); end exercise minute ventilation increased from 40.6 L/min (35.5; 47.8) to 47.2 L/min (39.6; 58.7) (p < 0.05; all comparisons 2,590 vs. 490 m). MCAv increased similarly from rest to end exercise at 490 m (+25% [17; 36]) and at 2,590 m (+21% [14; 30]). However, the ratio of MCAv increase to SpO2 drop during exercise decreased from +6%/% (3; 12) at 490 m to +3%/% (2; 5) at 2,590 m (p < 0.05). CONCLUSIONS: In lowlanders with COPD travelling to 2,590 m, exercise endurance is reduced by more than half compared to 490 m in association with reductions in systemic and cerebral oxygen availability.

Autoadjusted versus fixed CPAP for obstructive sleep apnoea: a multicentre, randomised equivalence trial.

BACKGROUND: The obstructive sleep apnoea syndrome (OSAS) is conventionally treated by continuous positive airway pressure set at a fixed level (fCPAP). Automatic mask pressure adjustment (autoCPAP) is increasingly used during home therapy. We investigated whether autoCPAP is equivalent to fCPAP in improving sleepiness in patients with OSAS in the long-term. METHODS: In this multicentre equivalence trial, 208 patients with OSAS, with median Epworth sleepiness score (ESS) 13, apnoea/hypopnoea index 48.4/hour, were randomised to treatment with autoCPAP (5-15 mbar) or fCPAP (pressure set at the 90th percentile applied by autoCPAP during 2-4 weeks adaptation). Coprimary outcomes were changes in subjective and objective sleepiness from baseline to 2 years after treatment. Equivalence ranges were ±2 points in ESS and ±3 min sleep resistance time evaluated by recording responses to light signals. RESULTS: At 2 years, in the intention to treat analysis, the reduction in sleepiness versus pretreatment baseline was similar in patients using autoCPAP (n=113, mean ESS-change -6.3, 95% CI -7.1 to -5.5; sleep resistance time +8.3 min, +6.9 to +9.7) and fCPAP (n=95, mean ESS-change -6.2, 95% CI -7.0 to -5.3; sleep resistance time +6.3 min, +4.7 to +7.8). The 95% CI of difference in ESS-reduction between autoCPAP and fCPAP was -0.9 to +1.4 and the 95% CI of difference in increase in sleep resistance time was -2.6 to +1.0 min. Blood pressure reduction and OSAS-related costs were similar between groups. CONCLUSIONS: AutoCPAP and fCPAP are equivalent within prespecified ranges in improving subjective and objective sleepiness in patients with OSAS over the course of 2 years. Costs of these treatments are similar. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00280800.