SARS-CoV-2 Transmission during High-Altitude Field Studies.

Grimm, Mirjam, Lucie Ziegler, Annina Seglias, Maamed Mademilov, Kamila Magdieva, Gulzada Mirzalieva, Aijan Taalaibekova, Simone Suter, Simon R. Schneider, Fiona Zoller, Vera Bissig, Lukas Reinhard, Meret Bauer, Julian Müller, Tanja L. Ulrich, Arcangelo F. Carta, Patrick R. Bader, Konstantinos Bitos, Aurelia E. Reiser, Benoit Champigneulle, Damira Ashyralieva, Philipp M. Scheiwiller, Silvia Ulrich, Talant M. Sooronbaev, Michael Furian, and Konrad E. Bloch. SARS-CoV-2 Transmission during High-Altitude Field Studies. High Alt Med Biol. 00:00-00, 2024. Background: Throughout the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, virus transmission during clinical research was of concern. Therefore, during high-altitude field studies performed in 2021, we took specific COVID-19 precautions and investigated the occurrence of SARS-CoV-2 infection. Methods: From May to September 2021, we performed studies in patients with chronic obstructive pulmonary disease (COPD) and in healthy school-age children in Kyrgyzstan in high-altitude facilities at 3,100 m and 3,250 m and at 760 m. The various implemented COVID-19 safety measures included systematic SARS-CoV-2 rapid antigen testing (RAT). Main outcomes were SARS-CoV-2-RAT-positive rate among participants and staff at initial presentation (prevalence) and SARS-CoV-2-RAT-positive conversion during and within 10 days after studies (incidence). Results: Among 338 participants and staff, SARS-CoV-2-RAT-positive prevalence was 15 (4.4%). During mean ± SD duration of individual study participation of 3.1 ± 1.0 day and within 10 days, RAT-positive conversion occurred in 1/237(0.4%) participants. Among staff working in studies for 31.5 ± 29.3 days, SARS-CoV-2-RAT-positive conversion was 11/101(10.9%). In all 338 individuals involved in the studies over the course of 15.6 weeks, the median SARS-CoV-2-RAT-positive incidence was 0.00%/week (quartiles 0.00; 0.64). Over the same period, the median background incidence among the total Kyrgyz population of 6,636 million was 0.06%/week (0.03; 0.11), p = 0.013 (Wilcoxon rank sum test). Conclusions: Taking precautions by implementing specific safety measures, SARS-CoV-2 transmission during clinical studies was very rare, and the SARS-CoV-2 incidence among participants and staff was lower than that in the general population during the same period. The results are reassuring and may help in decision-making on the conduct of clinical research in similar settings.

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.

Counseling Patients with Chronic Obstructive Pulmonary Disease Traveling to High Altitude.

Bloch, Konrad E., Talant M. Sooronbaev, Silvia Ulrich, Mona Lichtblau, and Michael Furian. Clinician's corner: counseling patients with chronic obstructive pulmonary disease traveling to high altitude. High Alt Med Biol. 24:158-166, 2023.-Mountain travel is increasingly popular also among patients with chronic obstructive pulmonary disease (COPD), a highly prevalent condition often associated with cardiovascular and systemic manifestations. Recent studies have shown that nonhypercapnic and only mildly hypoxemic lowlanders with moderate to severe airflow obstruction owing to COPD experience dyspnea, exercise limitation, and sleep disturbances when traveling up to 3,100 m. Altitude-related adverse health effects (ARAHE) in patients with COPD include severe hypoxemia, which may be asymptomatic but expose patients to the risk of excessive systemic and pulmonary hypertension, cardiac arrhythmia, and even myocardial or cerebral ischemia. In addition, hypobaric hypoxia may impair postural control, psycho-motor, and cognitive performance in patients with COPD during altitude sojourns. Randomized, placebo-controlled trials have shown that preventive treatment with oxygen at night or with acetazolamide reduces the risk of ARAHE in patients with COPD while preventive dexamethasone treatment improves oxygenation and altitude-induced excessive sleep apnea, and lowers systemic and pulmonary artery pressure. This clinical review provides suggestions for pretravel assessment and preparations and measures during travel that may reduce the risk of ARAHE and contribute to pleasant mountain journeys of patients with COPD.

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.

Effect of altitude and acetazolamide on postural control in healthy lowlanders 40 years of age or older. Randomized, placebo-controlled trial.

Background: Hypoxia and old age impair postural control and may therefore enhance the risk of accidents. We investigated whether acetazolamide, the recommended drug for prevention of acute mountain sickness, may prevent altitude-induced deterioration of postural control in older persons. Methods: In this parallel-design trial, 95 healthy volunteers, 40 years of age or older, living <1,000 m, were randomized to preventive therapy with acetazolamide (375 mg/d) or placebo starting 24 h before and during a 2-day sojourn at 3,100 m. Instability of postural control was quantified by a balance platform with the center of pressure path length (COPL) as primary outcome while pulse oximetry (SpO2) was monitored. Effects of altitude and treatment on COPL were evaluated by ordered logistic regression. www.ClinicalTrials.gov NCT03536429. Results: In participants taking placebo, ascent from 760 m to 3,100 m increased median COPL from 25.8 cm to 27.6 cm (odds ratio 3.80, 95%CI 2.53-5.70) and decreased SpO2 from 96% to 91% (odds ratio 0.0003, 95%CI 0.0002-0.0007); in participants taking acetazolamide, altitude ascent increased COPL from 24.6 cm to 27.3 cm (odds ratio 2.22, 95%CI 1.57-3.13), while SpO2 decreased from 96% to 93% (odds ratio 0.007, 95%CI 0.004-0.012). Altitude-induced increases in COPL were smaller with acetazolamide vs. placebo (odds ratio 0.58, 95%CI 0.34-0.99) while drops in SpO2 were mitigated (odds ratio 19.2, 95%CI 9.9-37.6). Conclusion: In healthy individuals, 40 years of age or older, postural control was impaired after spending a night at 3,100 m. The altitude-induced deterioration of postural control was mitigated by acetazolamide, most likely due to the associated improvement in oxygenation.

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.)

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.

Prevalence and Population-Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

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.

Asthma rehabilitation at high vs. low altitude and its impact on exhaled nitric oxide and sensitization patterns: Randomized parallel-group trial.

BACKGROUND: Allergens and pollution are reduced at high altitude. We investigated the effect of asthma rehabilitation at high altitude (HA, 3100 m) compared to low altitude (LA, 760 m) on exhaled nitric oxide (FeNO) and on specific IgE levels for house dust mites (HDM,d1) and common pollen (sx1). METHODS: For this randomized controlled trial adult asthmatics living <1000 m were randomly assigned to a 3-week in-hospital-rehabilitation (education, physical- and breathing-exercises) at either LA or HA. Changes in FeNO, d1 and sx1 from baseline to end-rehabilitation were measured. RESULTS: 50 asthmatics (34 females) were randomized [mean ± standard deviation LA: n = 25, 44 ± 11 years, total IgE 267 ± 365kU/l; HA: n = 25, 43 ± 13 years, total IgE 350 ± 445kU/l]. FeNO significantly improved at HA from 69 ± 56 ppb at baseline to the first day at altitude 23 ± 19 ppb and remained decreased until end-rehabilitation with 37 ± 23 ppb, mean difference 95%CI -31(-50 to -13, p = 0.001) whereas at LA FeNO did not change. A significant decrease in d1 and sx1 at end-rehabilitation was observed in the LA-group [mean difference 95%CI -10.2 kUA/l (-18.9 to -1.4) for d1 and -4.95 kUA/l(-9.69 to -0.21) for sx1] but not in the HA-group. No significant difference between groups [d1 5.9 kUA/l(-4.2 to 16.2) and sx1 4.4 kUA/l(-3.5 to 12.4)] was found. CONCLUSION: Rehabilitation at HA led to significant FeNO reduction starting from the first day until end-rehabilitation despite unchanged levels of specific IgE. The significant decrease in d1 and sx1 at end-rehabilitation in the LA group might be explained by less HDM in the hospital and/or reduced seasonal pollen, as this decrease was not observed at HA.

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.

Validation of a Portable Blood Gas Analyzer for Use in Challenging Field Conditions at High Altitude.

BACKGROUND: Novel, portable blood gas analyzers (BGAs) may serve as essential point-of-care tools in remote regions, during air travel or in ambulance services but they have not been extensively validated. RESEARCH QUESTION: We compared accuracy of a portable BGA to a validated stationary device. METHODS: In healthy individuals and patients with chronic obstructive pulmonary disease participating in clinical field studies at different altitudes, arterial blood samples were obtained at rest and during exercise in a hospital at 760 m and in a high altitude clinic at 3100 m. Paired measurements by a portable BGA (EPOC, Siemens Healthcare) and a stationary BGA (Rapidpoint500, Siemens Healthcare) were performed to compute bias (mean difference) and limits of agreement (95% CI of bias). RESULTS: Of 105 individuals, 248 arterial blood samples were analyzed, 108 at 760 m, 140 at 3100 m. Ranges of values measured by portable BGA were: pH 7.241-7.473, PaCO2 21.5-52.5 mmHg, and PaO2 45.5-107.1 mmHg. Bias (95% CI) between devices were: pH 0.007 (-0.029 to 0.044), PaCO2 -0.3 mmHg (-4.8 to 4.2), and PaO2 -0.2 mmHg (-9.1 to 4.7). For pH, agreement between devices was improved by the equation to correct pH by portable BGA = -1.37 + pH measured × 1.19; bias after correction -0.007 (-0.023 to 0.009). The portable BGA was easily handled and worked reliably. INTERPRETATION: Accuracy of blood gas analysis by the portable BGA in comparison to the reference BGA was adequate for clinical use. Because of portability and ease of handling, portable BGA are valuable diagnostic tools for use in everyday practice as well as under challenging field conditions.

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.

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.

Spirometry in Central Asian Lowlanders and Highlanders, a Population Based Study.

Introduction: The purpose of the study was to establish spirometric reference values for a Central Asian population of highlanders and lowlanders. Methods: Spirometries from a population-based cross-sectional study performed in 2013 in rural areas of Kyrgyzstan were analyzed. Using multivariable linear regression, Global Lung Function Initiative (GLI) equations were fitted separately for men and women, and altitude of residence (700-800 m, 1,900-2,800 m) to data from healthy, never-smoking Kyrgyz adults. The general GLI equation was applied: Predicted value = e a 0 + a 1 ×  ln ( Height ) + a 2 ×  ln ( Age ) + b 1 ×  ln ( Age 100 ) + b 2 ×  ln ( Age 100 ) 2 + b 3 ×  ln ( Age 100 ) 3              + b 4 ×  ln ( Age 100 ) 4 + b 5 ×  ln ( Age 100 ) 5 Results: Of 2,784 screened Kyrgyz, 448 healthy, non-smoking highlanders (379 females) and 505 lowlanders (368 females), aged 18-91 years, were included. Predicted FVC in Kyrgyz fit best with GLI "North-East Asians," predicted FEV1 fit best with GLI "Other/Mixed." Predicted FEV1/FVC was lower than that of all GLI categories. Age- and sex-adjusted mean FVC and FEV1 were higher in highlanders (+0.138l, +0.132l) than in lowlanders (P < 0.001, all comparisons), but FEV1/FVC was similar. Conclusion: We established prediction equations for an adult Central Asian population indicating that FVC is similar to GLI "North-East Asian" and FEV1/FVC is lower than in all other GLI population categories, consistent with a relatively smaller airway caliber. Central Asian highlanders have significantly greater dynamic lung volumes compared to lowlanders, which may be due to environmental and various other effects.

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.