Time course of cerebral oxygenation and cerebrovascular reactivity in Kyrgyz highlanders. A five-year prospective cohort study.

Introduction: This prospective cohort study assessed the effects of chronic hypoxaemia due to high-altitude residency on the cerebral tissue oxygenation (CTO) and cerebrovascular reactivity. Methods: Highlanders, born, raised, and currently living above 2,500 m, without cardiopulmonary disease, participated in a prospective cohort study from 2012 until 2017. The measurements were performed at 3,250 m. After 20 min of rest in supine position while breathing ambient air (FiO2 0.21) or oxygen (FiO2 1.0) in random order, guided hyperventilation followed under the corresponding gas mixture. Finger pulse oximetry (SpO2) and cerebral near-infrared spectroscopy assessing CTO and change in cerebral haemoglobin concentration (cHb), a surrogate of cerebral blood volume changes and cerebrovascular reactivity, were applied. Arterial blood gases were obtained during ambient air breathing. Results: Fifty three highlanders, aged 50 ± 2 years, participated in 2017 and 2012. While breathing air in 2017 vs. 2012, PaO2 was reduced, mean ± SE, 7.40 ± 0.13 vs. 7.84 ± 0.13 kPa; heart rate was increased 77 ± 1 vs. 70 ± 1 bpm (p < 0.05) but CTO remained unchanged, 67.2% ± 0.7% vs. 67.4% ± 0.7%. With oxygen, SpO2 and CTO increased similarly in 2017 and 2012, by a mean (95% CI) of 8.3% (7.5-9.1) vs. 8.5% (7.7-9.3) in SpO2, and 5.5% (4.1-7.0) vs. 4.5% (3.0-6.0) in CTO, respectively. Hyperventilation resulted in less reduction of cHb in 2017 vs. 2012, mean difference (95% CI) in change with air 2.0 U/L (0.3-3.6); with oxygen, 2.1 U/L (0.5-3.7). Conclusion: Within 5 years, CTO in highlanders was preserved despite a decreased PaO2. As this was associated with a reduced response of cerebral blood volume to hypocapnia, adaptation of cerebrovascular reactivity might have occurred.

Effect of acetazolamide on pulmonary vascular haemodynamics in patients with COPD going to altitude: a randomised, placebo-controlled, double-blind trial.

Background: COPD may predispose to symptomatic pulmonary hypertension at high altitude. We investigated haemodynamic changes in lowlanders with COPD ascending to 3100 m and evaluated whether preventive acetazolamide treatment would attenuate the altitude-induced increase in pulmonary artery pressure (PAP). Methods: In this randomised, placebo-controlled, double-blind, parallel-group trial, patients with COPD Global Initiative for Chronic Obstructive Lung Disease grades 2-3 who were living <800 m and had peripheral oxygen saturation (S pO2 ) >92% and arterial carbon dioxide tension <6 kPa were randomised to receive either acetazolamide (125-250 mg·day-1) or placebo capsules, starting 24 h before ascent from 760 m and during a 2-day stay at 3100 m. Echocardiography, pulse oximetry and clinical assessments were performed at 760 m and after the first night at 3100 m. Primary outcome was PAP assessed by tricuspid regurgitation pressure gradient (TRPG). Results: 112 patients (68% men, mean±sd age 59±8 years, forced expiratory volume in 1 s (FEV1) 61±12% pred, S pO2 95±2%) were included. Mean±sd TRPG increased from 22±7 to 30±10 mmHg in 54 patients allocated to placebo and from 20±5 to 24±7 mmHg in 58 patients allocated to acetazolamide (both p<0.05) resulting in a mean (95% CI) treatment effect of -5 (-9 to -1) mmHg (p=0.015). In patients assigned to placebo at 760/3100 m, mean±sd S pO2 was 95±2%/88±3%; in the acetazolamide group, the respective values were 94±2%/90±3% (both p<0.05), resulting in a treatment effect of +2 (1 to 3)% (p=0.001). Conclusions: In lowlanders with COPD travelling to 3100 m, preventive acetazolamide treatment attenuated the altitude-induced rise in PAP and improved oxygenation.

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.

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.

Effect of acetazolamide on visuomotor performance at high altitude in healthy people 40 years of age or older-RCT.

OBJECTIVE: Altitude travel is increasingly popular also for middle-aged and older tourists and professionals. Due to the sensitivity of the central nervous system to hypoxia, altitude exposure may impair visuomotor performance although this has not been extensively studied. Therefore, we investigated whether a sojourn at moderately high altitude is associated with visuomotor performance impairments in healthy adults, 40y of age or older, and whether this adverse altitude-effect can be prevented by acetazolamide, a drug used to prevent acute mountain sickness. METHODS: In this randomized placebo-controlled parallel-design trial, 59 healthy lowlanders, aged 40-75y, were assigned to acetazolamide (375 mg/day, n = 34) or placebo (n = 25), administered one day before ascent and while staying at high altitude (3100m). Visuomotor performance was assessed at 760m and 3100m after arrival and in the next morning (post-sleep) by a computer-assisted test (Motor-Task-Manager). It quantified deviation of a participant-controlled cursor affected by rotation during target tracking. Primary outcome was the directional error during post-sleep recall of adaptation to rotation estimated by multilevel linear regression modeling. Additionally, adaptation, immediate recall, and correct test execution were evaluated. RESULTS: Compared to 760m, assessments at 3100m with placebo revealed a mean (95%CI) increase in directional error during adaptation and immediate recall by 1.9° (0.2 to 3.5, p = 0.024) and 1.1° (0.4 to 1.8, p = 0.002), respectively. Post-sleep recall remained unchanged (p = NS), however post-sleep correct test execution was 14% less likely (9 to 19, p<0.001). Acetazolamide improved directional error during post-sleep recall by 5.6° (2.6 to 8.6, p<0.001) and post-sleep probability of correct test execution by 36% (30 to 42, p<0.001) compared to placebo. CONCLUSION: In healthy individuals, 40y of age or older, altitude exposure impaired adaptation to and immediate recall and correct execution of a visuomotor task. Preventive acetazolamide treatment improved visuomotor performance after one night at altitude and increased the probability of correct test execution compared to placebo. CLINICALTRIALS.GOV IDENTIFIER: ClinicalTrials.gov NCT03536520.

Effect of altitude and acetazolamide on sleep and nocturnal breathing in healthy lowlanders 40 y of age or older. Data from a randomized trial.

STUDY OBJECTIVES: To assess altitude-induced sleep and nocturnal breathing disturbances in healthy lowlanders 40 y of age or older and the effects of preventive acetazolamide treatment. METHODS: Clinical examinations and polysomnography were performed at 760 m and in the first night after ascent to 3100 m in a subsample of participants of a larger trial evaluating altitude illness. Participants were randomized 1:1 to treatment with acetazolamide (375 mg/day) or placebo, starting 24 h before and while staying at 3100 m. The main outcomes were indices of sleep structure, oxygenation, and apnea/hypopnea index (AHI). RESULTS: Per protocol analysis included 86 participants (mean ± SE 53 ± 7 y old, 66% female). In 43 individuals randomized to placebo, mean nocturnal pulse oximetry (SpO2) was 94.0 ± 0.4% at 760 m and 86.7 ± 0.4% at 3100 m, with mean change (95%CI) -7.3% (-8.0 to -6.5); oxygen desaturation index (ODI) was 5.0 ± 2.3 at 760 m and 29.2 ± 2.3 at 3100 m, change 24.2/h (18.8 to 24.5); AHI was 11.3 ± 2.4/h at 760 m and 23.5 ± 2.4/h at 3100 m, change 12.2/h (7.3 to 17.0). In 43 individuals randomized to acetazolamide, altitude-induced changes were mitigated. Mean differences (Δ, 95%CI) in altitude-induced changes were: ΔSpO2 2.3% (1.3 to 3.4), ΔODI -15.0/h (-22.6 to -7.4), ΔAHI -11.4/h (-18.3 to -4.6). Total sleep time, sleep efficiency, and N3-sleep fraction decreased with an ascent to 3100 m under placebo by 40 min (17 to 60), 5% (2 to 8), and 6% (2 to 11), respectively. Acetazolamide did not significantly change these outcomes. CONCLUSIONS: During a night at 3100 m, healthy lowlanders aged 40 y or older revealed hypoxemia, sleep apnea, and disturbed sleep. Preventive acetazolamide treatment improved oxygenation and nocturnal breathing but had no effect on sleep duration and structure. TRIAL REGISTRATION: The trial is registered at Clinical Trials, https://clinicaltrials.gov, NCT03561675.

Acetazolamide to Prevent Adverse Altitude Effects in COPD and Healthy Adults.

Acetazolamide to Prevent Adverse Altitude Effects Furian and colleagues report on the results of two randomized controlled trials testing the use of acetazolamide to prevent the adverse effects of altitude on healthy older persons and in people with COPD. They find that acetazolamide decreased the incidence of altitude related adverse health events (primarily hypoxemia) in both populations with no evidence of adverse events.

Exercise Performance in Central Asian Highlanders: A Cross-Sectional Study.

Forrer, Aglaia, Philipp M. Scheiwiller, Maamed Mademilov, Mona Lichtblau, Ulan Sheraliev, Nuriddin H. Marazhapov, Stéphanie Saxer, Patrick Bader, Paula Appenzeller, Shoira Aydaralieva, Aybermet Muratbekova, Talant M. Sooronbaev, Silvia Ulrich, Konrad E. Bloch, and Michael Furian. Exercise performance in central Asian highlanders: A cross-sectional study. High Alt Med Biol. 22:386-394, 2021. Introduction: Life-long exposure to hypobaric hypoxia induces physiologic adaptations in highlanders that may modify exercise performance; however, reference data for altitude populations are scant. Methods: Life-long residents of the Tien Shan mountain range, 2,500 - 3,500 m, Kyrgyzstan, free of cardiopulmonary disease, underwent cardiopulmonary cycle exercise tests with a progressive ramp protocol to exhaustion at 3,250 m. ECG, breath-by-breath pulmonary gas exchange, and oxygen saturation by pulse oximetry (SpO2) were measured. Results: Among 81 highlanders, age (mean ± SD) 48 ± 10 years, 46% women, SpO2 at rest was 88% ± 2%, peak oxygen uptake (V'O2peak) was 21.6 ± 5.9 mL/kg/min (76% ± 15% predicted for a low-altitude reference population); peak work rate (Wpeak) was 117 ± 37 W (77% ± 17% predicted), SpO2 at peak was 84% ± 5%, heart rate reserve (220 - age - maximal heart rate) was 28 ± 17/min, ventilatory reserve (maximal voluntary ventilation - maximal minute ventilation) was 68 ± 32 l/min, and respiratory exchange ratio was 1.03 ± 0.09. Peak BORG-CR10 dyspnea and leg fatigue scores were 5.1 ± 2.0 and 6.3 ± 2.1. In multivariable linear regression analyses, age and sex were robust determinants of Wpeak, V'O2peak, and metabolic equivalent (MET) at peak, whereas body mass index, resting systolic blood pressure, and mean pulmonary artery pressure were not. Conclusions: The current study shows that V'O2peak and Wpeak of highlanders studied at 3,250 m, near their altitude of residence, were reduced by about one quarter compared with mean predicted values for lowlanders. The provided prediction models for V'O2peak, Wpeak, and METs in central Asian highlanders might be valuable for comparisons with other high altitude populations.

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 (S pO2 ) 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; S pO2 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; S pO2 96±1%) were studied. Highlanders had a lower resting S pO2 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.

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.

ECG changes at rest and during exercise in lowlanders with COPD travelling to 3100 m.

BACKGROUND: The incidence and magnitude of cardiac ischemia and arrhythmias in patients with chronic obstructive pulmonary disease (COPD) during exposure to hypobaric hypoxia is insufficiently studied. We investigated electrocardiogram (ECG) markers of ischemia at rest and during incremental exercise testing (IET) in COPD-patients travelling to 3100 m. STUDY DESIGN AND METHODS: Lowlanders (residence <800 m) with COPD (forced volume in the first second of expiration (FEV1) 40-80% predicted, oxygen saturation (SpO2) ≥92%, arterial partial pressure of carbon dioxide (PaCO2) <6 kPa at 760 m) aged 18 to 75 years, without history of cardiovascular disease underwent 12­lead ECG recordings at rest and during cycle IET to exhaustion at 760 m and after acute exposure of 3 h to 3100 m. Mean ST-changes in ECGs averaged over 10s were analyzed for signs of ischemia (≥1 mm horizontal or downsloping ST-segment depression) at rest, peak exercise and 2-min recovery. RESULTS: 80 COPD-patients (51% women, mean ± SD, 56.2 ± 9.6 years, body mass index (BMI) 27.0 ± 4.5 kg/m2, SpO2 94 ± 2%, FEV1 63 ± 10% prEd.) were included. At 3100 m, 2 of 53 (3.8%) patients revealed ≥1 mm horizontal ST-depression during IET vs 0 of 64 at 760 m (p = 0.203). Multivariable mixed regression revealed minor but significant ST-depressions associated with altitude, peak exercise or recovery and rate pressure product (RPP) in multiple leads. CONCLUSION: In this study, ECG recordings at rest and during IET in COPD-patients do not suggest an increased incidence of signs of ischemia with ascent to 3100 m. Whether statistically significant ST changes below the standard threshold of clinical relevance detected in multiple leads reflect a risk of ischemia during prolonged exposure remains to be elucidated.

Cardiac function and pulmonary hypertension in Central Asian highlanders at 3250†m.

THE QUESTION ADDRESSED BY THE STUDY: Chronic exposure to hypoxia increases pulmonary artery pressure (PAP) in highlanders, but the criteria for diagnosis of high-altitude pulmonary hypertension (HAPH) are debated. We assessed cardiac function and PAP in highlanders at 3250 m and explored HAPH prevalence using different definitions. PATIENTS AND METHODS: Central Asian highlanders free of overt cardiorespiratory disease, permanently living at 2500-3500 m compared to age-matched lowlanders living <800 m. Participants underwent echocardiography close to their altitude of residence (at 3250 m versus 760 m). RESULTS: 173 participants (97 highlanders, 76 lowlanders), mean±sd age 49±9 years (49% females) completed the study. Results in lowlanders versus highlanders were systolic PAP (23±5 versus 30±10 mmHg), right ventricular fractional area change (42±6% versus 39±8%), tricuspid annular plane systolic excursion (2.1±0.3 versus 2.0±0.3 cm), right atrial volume index (20±6 versus 23±8 mL·m-2), left ventricular ejection fraction (62±4% versus 57±5%) and stroke volume (64±10 versus 57±11 mL); all between-group comparisons p<0.05. Depending on criteria, HAPH prevalence varied between 6% and 35%. THE ANSWER TO THE QUESTION: Chronic exposure to hypoxia in highlanders is associated with higher PAP and slight alterations in right and left heart function compared to lowlanders. The prevalence of HAPH in this large highlander cohort varies between 6% according to expert consensus definition of chronic high-altitude disease to 35% according to the most recent definition of pulmonary hypertension proposed for lowlanders.

Effect of High-Flow Oxygen on Exercise Performance in COPD Patients. Randomized Trial.

Background: High-flow oxygen therapy (HFOT) provides oxygen-enriched, humidified, and heated air at high flow rates via nasal cannula. It could be an alternative to low-flow oxygen therapy (LFOT) which is commonly used by patients with chronic obstructive pulmonary disease (COPD) during exercise training. Research Question: We evaluated the hypothesis that HFOT improves exercise endurance in COPD patients compared to LFOT. Methods: Patients with stable COPD, FEV1 40-80% predicted, resting pulse oximetry (SpO2) ≥92%, performed two constant-load cycling exercise tests to exhaustion at 75% of maximal work rate on two different days, using LFOT (3 L/min) and HFOT (60 L/min, FiO2 0.45) in randomized order according to a crossover design. Primary outcome was exercise endurance time, further outcomes were SpO2, breath rate and dyspnea. Results: In 79 randomized patients, mean ± SD age 58 ± 9 y, FEV1 63 ± 9% predicted, GOLD grades 2-3, resting PaO2 9.4 ± 1.0 kPa, intention-to-treat analysis revealed an endurance time of 688 ± 463 s with LFOT and 773 ± 471 s with HFOT, mean difference 85 s (95% CI: 7 to 164, P = 0.034), relative increase of 13% (95% CI: 1 to 28). At isotime, patients had lower respiratory rate and higher SpO2 with HFOT. At end-exercise, SpO2 was higher by 2% (95% CI: 2 to 2), and Borg CR10 dyspnea scores were lower by 0.8 points (95% CI: 0.3 to 1.2) compared to LFOT. Interpretation: In mildly hypoxemic patients with COPD, HFOT improved endurance time in association with higher arterial oxygen saturation, reduced respiratory rate and less dyspnea compared to LFOT. Therefore, HFOT is promising for enhancing exercise performance in COPD. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03955770.

Right-to-left shunts in lowlanders with COPD traveling to altitude: a randomized controlled trial with dexamethasone.

Right-to-left shunts (RLS) are prevalent in patients with chronic obstructive pulmonary disease (COPD) and might exaggerate oxygen desaturation, especially at altitude. The aim of this study was to describe the prevalence of RLS in patients with COPD traveling to altitude and the effect of preventive dexamethasone. Lowlanders with COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1-2, oxygen saturation assessed by pulse oximetry (SpO2) >92%] were randomized to dexamethasone (4 mg bid) or placebo starting 24 h before ascent from 760 m and while staying at 3,100 m for 48 h. Saline-contrast echocardiography was performed at 760 m and after the first night at altitude. Of 87 patients (81 men, 6 women; mean ± SD age 57 ± 9 yr, forced expiratory volume in 1 s 89 ± 22% pred, SpO2 95 ± 2%), 39 were assigned to placebo and 48 to dexamethasone. In the placebo group, 19 patients (49%) had RLS, of which 13 were intracardiac. In the dexamethasone group 23 patients (48%) had RLS, of which 11 were intracardiac (P = 1.0 vs. dexamethasone). Eleven patients receiving placebo and 13 receiving dexamethasone developed new RLS at altitude (P = 0.011 for both changes, P = 0.411 between groups). RLS prevalence at 3,100 m was 30 (77%) in the placebo and 36 (75%) in the dexamethasone group (P = not significant). Development of RLS at altitude could be predicted at lowland by a higher resting pulmonary artery pressure, a lower arterial partial pressure of oxygen, and a greater oxygen desaturation during exercise but not by treatment allocation. Almost half of lowlanders with COPD revealed RLS near sea level, and this proportion significantly increased to about three-fourths when traveling to 3,100 m irrespective of dexamethasone prophylaxis.NEW & NOTEWORTHY The prevalence of intracardiac and intrapulmonary right-to-left shunts (RLS) at altitude in patients with chronic obstructive pulmonary disease (COPD) has not been studied so far. In a large cohort of patients with moderate COPD, our randomized trial showed that the prevalence of RLS increased from 48% at 760 m to 75% at 3,100 m in patients taking placebo. Preventive treatment with dexamethasone did not significantly reduce the altitude-induced recruitment of RLS. Development of RLS at 3,100 m could be predicted at 760 m by a higher resting pulmonary artery pressure and arterial partial pressure of oxygen and a more pronounced oxygen desaturation during exercise. Dexamethasone did not modify the RLS prevalence at 3,100 m.

Asthma rehabilitation at high vs. low altitude: randomized parallel-group trial.

BACKGROUND: To investigate the effect of asthma rehabilitation at high altitude (3100 m, HA) compared to low altitude (760 m, LA). METHODS: For this randomized parallel-group trial insufficiently controlled asthmatics (Asthma Control Questionnaire (ACQ) > 0.75) were randomly assigned to 3-week in-hospital rehabilitation comprising education, physical-&breathing-exercises at LA or HA. Co-primary outcomes assessed at 760 m were between group changes in peak expiratory flow (PEF)-variability, and ACQ) from baseline to end-rehabilitation and 3 months thereafter. RESULTS: 50 asthmatics were randomized [median (quartiles) LA: ACQ 2.7(1.7;3.2), PEF-variability 19%(14;33); HA: ACQ 2.0(1.6;3.0), PEF-variability 17%(12;32)]. The LA-group improved PEF-variability by median(95%CI) -7%(- 14 to 0, p = 0.033), ACQ - 1.4(- 2.2 to - 0.9, p < 0.001), and after 3 months by - 3%(- 18 to 2, p = 0.103) and - 0.9(- 1.3 to - 0.3, p = 0.002). The HA-group improved PEF-variability by - 10%(- 21 to - 3, p = 0.004), ACQ - 1.1(- 1.3 to - 0.7, p < 0.001), and after 3 months by - 9%(- 10 to - 3, p = 0.003) and - 0.2(- 0.9 to 0.4, p = 0.177). The additive effect of HA vs. LA directly after the rehabilitation on PEF-variability was - 6%(- 14 to 2), on ACQ 0.3(- 0.4 to 1.1) and after 3 months - 5%(- 14 to 5) respectively 0.4(- 0.4 to 1.1), all p = NS. CONCLUSION: Asthma rehabilitation is highly effective in improving asthma control in terms of PEF-variability and symptoms, both at LA and HA similarly. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02741583, Registered April 18, 2016.

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.

Dexamethasone improves pulmonary hemodynamics in COPD-patients going to altitude: A randomized trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) may predispose to symptomatic pulmonary hypertension at high altitude. We investigated hemodynamic changes in lowlanders with COPD ascending rapidly to 3100 m and evaluated whether preventive dexamethasone treatment would mitigate the altitude-induced increase in pulmonary artery pressure. METHODS: In this placebo-controlled, double-blind trial, non-hypercapnic COPD patients living <800 m, were randomized to receive either dexamethasone (8 mg/day) or placebo tablets one day before ascent from 760 m and during a 3-day-stay at 3100 m. Echocardiography was performed at 760 m and after the first night at 3100 m. The trans-tricuspid pressure gradient (RV/RA, main outcome), cardiac output (Q) by velocity-time integral of left ventricular outflow, indices of right and left heart function, blood gases and pulse-oximetry (SpO2) were compared between groups. RESULTS: 95 patients, 79 men, mean ±â€¯SD age 57 ±â€¯8y FEV1 89 ±â€¯21% pred, SpO2 95 ±â€¯2% were included in the analysis. In 52 patients receiving dexamethasone, RV/RA, Q and SpO2 at 760 and 3100 m were 19 ±â€¯5 mm Hg and 26 ±â€¯7 mm Hg, 4.9 ±â€¯0.7 and 5.7 ±â€¯1.1 l/min, SpO2 95 ±â€¯2% and 90 ±â€¯3% (P < 0.05 all changes). In 43 patients receiving placebo the corresponding values were 20 ±â€¯4 mm Hg and 31 ±â€¯9 mm Hg, 4.7 ±â€¯0.9 l/min and 95 ±â€¯3% and 89 ±â€¯3% (P < 0.05 all changes) between group differences of altitude-induced changes were (mean, 95% CI): RV/RA -4.8 (-7.7 to -1.8) mm Hg, Q 0.13 (-0.3 to 0.6) l/min and SpO2 1 (-1 to 2) %. CONCLUSIONS: In lowlanders with COPD travelling to 3100 m preventive dexamethasone treatment mitigates the altitude-induced rise in RV/RA potentially along with a reduced pulmonary vascular resistance and improved oxygenation.

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.