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Dario Kohlbrenner,1,2 Maya Bisang,1 Sayaka S Aeschbacher,1 Emanuel Heusser,1 Silvia Ulrich,1,2 Konrad E Bloch,1,2 Michael Furian1,3 1Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland; 2Faculty of Medicine, University of Zurich, Zurich, Switzerland; 3Swiss University of Traditional Chinese Medicine, Bad Zurzach, SwitzerlandCorrespondence: Michael Furian, Department of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland, Email michael.furian@usz.chStudy Objectives: To assess the diagnostic accuracy of a purpose-designed QTc-scoring algorithm versus the established hand-scoring in patients with chronic obstructive pulmonary disease (COPD) undergoing sleep studies.Methods: We collected 62 overnight electrocardiogram (ECG) recordings in 28 COPD patients. QT-intervals corrected for heart rate (QTc, Bazett) were averaged over 1-min periods and quantified, both by the algorithm and by cursor-assisted hand-scoring. Hand-scoring was done blinded to the algorithm-derived results. Bland-Altman statistics and confusion matrixes for three thresholds (460, 480, and 500ms) were calculated.Results: A total of 32944 1-min periods and corresponding mean QTc-intervals were analysed manually and by computer. Mean difference between manual and algorithm-based QTc-intervals was − 1ms, with limits of agreement of − 18 to 16ms. Overall, 2587 (8%), 357 (1%), and 0 QTc-intervals exceeding the threshold 460, 480, and 500ms, respectively, were identified by hand-scoring. Of these, 2516, 357, and 0 were consistently identified by the algorithm. This resulted in a diagnostic classification accuracy of 0.98 (95% CI 0.98/0.98), 1.00 (1.00/1.00), and 1.00 (1.00/1.00) for 460, 480, and 500ms, respectively. Sensitivity was 0.97, 1.00, and NA for 460, 480, and 500ms, respectively. Specificity was 0.98, 1.00, and 1.00 for 460, 480, and 500ms, respectively.Conclusion: Overall, 8% of nocturnal 1-min periods showed clinically relevant QTc prolongations in patients with stable COPD. The automated QTc-algorithm accurately identified clinically relevant QTc-prolongations with a very high sensitivity and specificity. Using this tool, hospital sleep laboratories may identify asymptomatic patients with QTc-prolongations at risk for malignant arrhythmia, allowing them to consult a cardiologist before an eventual cardiac event.Keywords: QTc, long-QT syndrome, COPD, algorithm, validity, ECG

Konstantinos Bitos,1 Tobias Kuehne,1 Tsogyal D Latshang,1 Sayaka S Aeschbacher,1 Fabienne Huber,1 Deborah Flueck,1 Elisabeth D Hasler,1 Philipp M Scheiwiller,1 Mona Lichtblau,1 Silvia Ulrich,1 Konrad E Bloch,1 Michael Furian1,2 1University Hospital Zurich, Department of Respiratory Medicine, Zurich, Switzerland; 2Swiss University of Traditional Chinese Medicine, Research Department, Bad Zurzach, SwitzerlandCorrespondence: Michael Furian, University Hospital Zurich, Department of Pulmonology, Raemistrasse 100, Zurich, 8092, Switzerland, Email michael.furian@usz.chBackground: 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.Keywords: COPD, exercise, high altitude, hypoxia, hypoxemia, cardiopulmonary exercise testing

Saroj K Pradhan,1– 3 Felix Angst,2 Jie Xu,1,3 Andreas R Gantenbein,4 Susanne Lehmann,2 Peter S Sandor,4 Yiming Li,1– 3 Michael Furian1 1Research Department, Swiss University of Traditional Chinese Medicine, Bad Zurzach, Switzerland; 2Research Department, Rehaklinik Bad Zurzach, Bad Zurzach, Switzerland; 3TCM Ming Dao, Bad Zurzach, Switzerland; 4Neurorehabilitation & Research Department, Rehaklinik Bad Zurzach, Bad Zurzach, SwitzerlandCorrespondence: Michael Furian, Swiss University of Traditional Chinese Medicine, Langwiesstrasse 7, Bad Zurzach, 5330, Switzerland, Tel +41 79 403 75 86, Email michael.furian@tcmuni.chIntroduction: Chronic low back pain (CLBP) cannot sufficiently be treated by pharmacological therapy and generates substantial health-care costs worldwide. Acupuncture, a cost-effective, safe and non-pharmacological therapy, has shown promising results in relieving acute low back pain; however, the optimal acupuncture therapy for CLBP remains controversial. This study will compare two acupuncture methods for pain relief in CLBP.Methods and Analysis: This randomized, controlled, single-blind, parallel trial will be conducted in patients with clinically diagnosed CLBP with a disease duration ≥ 3 months and an average pain intensity of ≥ 4 points on an 11-point Pain Intensity Numerical Rating Scale (pain-NRS) on the previous 7 days. Patients will be randomized to 9-week acupuncture therapy using Jiu Gong Points (termed Swiss low back acupuncture, SLBA) or standard acupuncture (SA) therapy (weeks 1– 6: two sessions/week, weeks 7– 9: one session/week, 15 sessions/patient in total). Measurements will be conducted before the first session (T1), at the end of the 9-week therapy (T2) and after 3- and 6-month follow-up (T3 and T4). The primary hypothesis is that 9 weeks of SLBA will be superior in reducing the pain severity assessed by the pain-NRS compared to SA therapy for CLBP. Secondary outcomes will be derived from the Short-Form 36, Oswestry Disability Index, Multidimensional Pain Inventory questionnaire, Symptom Checklist-90 – Revised questionnaire and a daily pain diary. Assuming a minimal clinically important difference in the pain-NRS of 0.39 and an effect size of ≥ 0.6 between SLBA and SA, 80% power, 0.05 alpha level and 20% dropouts, a total of 55 patients/arm will be required. The primary outcome will be analyzed in the intention-to-treat population using chained linear regression models. Patients, outcome assessors and data analysts will be blinded to the treatment arm.Trial Registration: Clinicaltrials.gov Identifier: NCT05232487.Keywords: Chinese medicine, chronic disease, pain, Pain Intensity Numerical Rating Scale, Multidimensional Pain Inventory, Oswestry Disability Index, Randomized clinical trial

Martina Meszaros,1 Tsogyal D Latshang,1 Sayaka S Aeschbacher,1 Fabienne Huber,1 Deborah Flueck,1 Mona Lichtblau,1 Stefanie Ulrich,1 Elisabeth D Hasler,1 Philipp M Scheiwiller,1 Lukas Reinhard,1 Silvia Ulrich,1,2 Konrad E Bloch,1– 3 Michael Furian,1 Esther I Schwarz1,3 1Department of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Zurich, Switzerland; 2Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland; 3Centre of Competence Sleep & Health, University of Zurich, Zurich, SwitzerlandCorrespondence: Esther I SchwarzDepartment of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Zurich, SwitzerlandTel +41 44 255 11 11Fax +41 44 255 44 51Email estherirene.schwarz@usz.chPurpose: 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.Keywords: COPD, altitude, oxygen, hypoxia, blood pressure, blood pressure variability, baroreflex sensitivity

Esther I Schwarz,1 Tsogyal D Latshang,1 Michael Furian,1 Deborah Flück,1 Sebastian Segitz,1 Severine Müller-Mottet,1 Silvia Ulrich,1 Konrad E Bloch,1,2 Malcolm Kohler1,2 1Department of Pulmonology and Sleep Disorders Centre, University Hospital of Zurich, Zurich, Switzerland; 2Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland 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

Michael Furian,1,* Deborah Flueck,1,* Tsogyal D Latshang,1 Philipp M Scheiwiller,1 Sebastian Daniel Segitz,1 Séverine Mueller-Mottet,1 Christian Murer,1 Adrian Steiner,1 Silvia Ulrich,1 Thomas Rothe,2 Malcolm Kohler,1 Konrad E Bloch1 1Department of Respiratory Medicine, University Hospital of Zurich, Zurich, Switzerland; 2Zuercher RehaZentrum Davos, Davos Clavadel, Switzerland *These authors contributed equally to this work 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

Background: In patients with COPD, preventive treatment with acetazolamide reduces adverse health effects during altitude travel. We investigated whether preventive acetazolamide treatment modifies exercise performance in COPD patients going to high altitude., Methods: In this randomised, double-blind trial, lowlanders with COPD, forced expiratory volume in 1 s (FEV 1 ) 40-80% predicted, were assigned to acetazolamide (375 mg per 24 h) or placebo treatment starting 24 h before ascent and while staying at 3100 m. Patients performed progressive cycling exercise to exhaustion at 760 m, before taking the study drug, and within 4 h after arrival at 3100 m. The primary outcome was the maximal power output (W max )., Results: 103 patients (32 women), mean±sd age 57.2±8.1 years, FEV 1 66±11% predicted, were included in per-protocol analyses. In 53 patients receiving acetazolamide, W max and oxygen uptake ( V ' O 2 ) at 760 m and 3100 m were 105±27 and 91±25 W, and 18.0±4.8 and 15.5±3.7 mL·min max ) at 760 m and 3100 m were 105±27 and 91±25 W, and 18.0±4.8 and 15.5±3.7 mL·min -1 ·kg -1 (p<0.001, both changes). Corresponding W max and V ' O 2 max in 50 patients receiving placebo were 107±34 and 97±28 W, and 18.9±6.0 and 17.2±5.0 mL·min -1 ·kg -1 (p<0.001, both changes). Between-group differences (95% CI) in altitude-induced W max changes were -3.0 W (-8.7 to +2.7, p=0.305) and in V ' O 2 max by 0.7 kPa (0.1 to 1.3, p=0.016). At 3100 m, maximal work rate with respiratory exchange ratio ≤1 was greater with acetazolamide than with placebo by 10.1 W (4.0 to 16.2, p=0.022).-1 ·kg -1 (-2.1 to +0.5, p=0.213). Acetazolamide mitigated the altitude-induced reduction of P aO 2 by 0.7 kPa (0.1 to 1.3, p=0.016). At 3100 m, maximal work rate with respiratory exchange ratio ≤1 was greater with acetazolamide than with placebo by 10.1 W (4.0 to 16.2, p=0.022)., Conclusions: In lowlanders with COPD, preventive treatment with acetazolamide did not modify the altitude-induced reduction in maximal work rate. However, acetazolamide enhanced arterial oxygenation and submaximal, moderate-intensity work capacity compared with placebo., Competing Interests: Conflicts of interest: M. Lichtblau reports receiving honoraria for lectures and support for attending meetings from MSD, as well as participation in an advisory board for MSD, outside the submitted work. Conflicts of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2025.)

Häfliger, Alina, Aline Buergin, Laura C. Mayer, Maamed Mademilov, Mona Lichtblau, Talantbek Sooronbaev, Silvia Ulrich, Konrad E. Bloch, and Michael Furian. Sex-specific difference in health-related altitude-effects and their prevention by acetazolamide. Data from a randomized controlled trial. High Alt Med Biol. 00:00-00, 2024. Background: Women are underrepresented in studies on acute mountain sickness (AMS), altitude-induced sleep-disordered breathing and preventive acetazolamide use. Methods: We analyzed sex-specific altitude-effects in participants of a randomized, placebo-controlled, double-blind trial in healthy lowlanders >40 years. Participants took 375 mg/day acetazolamide or placebo starting 24 hours before ascent to and while staying 2 days at 3,100 m. Main outcomes of this analysis were sex-specific incidence of AMS (Lake Louise score ≥3), nocturnal pulse oximetry (SpO 2 ) and apnea-hypopnea index (AHI) at 3,100 m. Results: With placebo, 30 of 119 (25%) women and 4 of 51 (8%) men developed AMS ( p = 0.009 between sexes) at 3,100 m. Among women assigned to placebo, SpO 2 (mean ± SE 84 ± 0%) and AHI (16.9 ± 1.3/h) in night 1 at 3,100 m were lower compared to men (SpO 2 86 ± 0%; AHI 28.3 ± 1.9/h), despite similar baseline values at 760 m. Mean between-sex difference in altitude-effects (women-men) in SpO 2 was -1.4% (95% CI, -2.4 to -0.3%); AHI -10.7/h (95% CI, -15.7 to -5.7/h). The impact of acetazolamide on AMS was not significant for either sex but acetazolamide improved AHI in men (difference men-women, -9.8/h [95% CI, -16.8 to -2.7/h]). Conclusion: This study suggests sex-specific differences in altitude-induced hypoxemia, periodic breathing, AMS incidence, and in the response to preventive acetazolamide treatment.

Background: Hypoxic pulmonary vasoconstriction leads to an increase in pulmonary artery pressure (PAP) and potentially right heart failure in healthy individuals and patients with respiratory diseases. Previous studies in patients with chronic obstructive pulmonary disease (COPD) exposed to hypobaric hypoxia have shown an increase in PAP, while traditional echocardiographic parameters revealed only minimal changes at high altitude. Speckle-tracking-derived analysis is potentially more sensitive to assess right ventricular (RV) function and we used this method to investigate the impact on RV function of patients with COPD ascending to high altitude and compared the results with the traditional echocardiographic parameters., Methods: This post hoc analysis evaluates echocardiographic RV free wall strain (RVFWS) in patients with COPD GOLD grade 1-3 travelling from 760 m to 3100 m for a 2-day stay. An RVFWS over -20% was considered as an indicator of RV dysfunction., Results: A total of 54 patients (57% men, mean±SD age 58±9 years, forced expiratory volume in 1 s (FEV 1 % predicted 77.3±22.5)) with echocardiographs of sufficient quality were included. The mean RVFWS worsened significantly from -26.0±4.9% at 760 m to -23.9±5.4% at 3100 m (p=0.02). The number of patients with relevant RV dysfunction based on RVFWS increased from 7.4% at 760 m to 25.9% at 3100 m (p=0.02), whereas the prevalence of RV dysfunction assessed by traditional indices remained unchanged., Conclusion: Exposure to hypoxia led to RVFWS impairment in more than one quarter of patients with COPD. Strain analysis is a promising, non-invasive method for evaluating RV dysfunction, even in subclinical cases and might be prognostically relevant in patients with lung diseases., Trial Registration Numbers: NCT02450968 and NCT03173508., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Stauffer, Emeric, François Caton, Raphael Marlu, Aurélien Pichon, Landry Seyve, Michael Furian, Aymeric Paillisser, Florence Berquet, Jeremy De Abreu, Blandine Deschamps, Benoit Polack, Philippe Connes, Paul Robach, Stéphane Doutreleau, Julien V Brugniaux, Samuel Verges, and Benoit Champigneulle.Acclimatized lowlanders exhibit a hypocoagulable profile after a passive ascent at high altitude. High Alt Med Biol. 00:00-00, 2024. Background: Discordant results have been previously reported regarding the impact of high-altitude (HA) exposure on coagulation. We aimed to investigate changes in coagulation parameters in lowlanders exposed to HA for 14 days using a combination of dynamic coagulation assays and conventional in vitro tests. Material and Methods: We assessed coagulation in 10 lowlanders using whole-blood rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) on poor-platelet plasma, and conventional coagulation tests. Tests were performed at low altitude (LA, 210 m) and at the end of a 14-day sojourn at HA, including passive ascents to 3,800 m for 6 days and then to 5,100 m for 8 days. Results: Conventional tests revealed significant changes in coagulation factors and inhibitors after HA exposure, although these changes remained within normal ranges. ROTEM assays demonstrated a delayed clot initiation in EXTEM/FIBTEM, without any alteration in clot firmness, in HA versus LA ( p < 0.01). TGA changes showed an increase in time to peak ( p < 0.01), a decrease in endogenous thrombin potential ( p < 0.05), and a decrease in thrombin peak ( p < 0.001). Conclusions: We found no evidence of hypercoagulability in lowlanders after a 14-day sojourn at HA. In contrast, dynamic coagulation assays (ROTEM and TGA) revealed a hypocoagulable pattern.

Aims: More than 220 Mio people live at altitudes above 2000 m, many of whom have pre-existing chronic diseases, including pulmonary vascular diseases (PVDs) such as pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). We investigated the acute effects of high-dose supplemental oxygen on pulmonary haemodynamics assessed by echocardiography in patients with PVD permanently living at 2850 m., Methods and Results: In a randomized, single-blind, placebo-controlled crossover trial, patients with PVD diagnosed with PAH or CTEPH were allocated to receive 10 L/min supplemental oxygen (FiO 2 ≈ 95%) and placebo air administered via a facial mask with reservoir near their living altitude in Quito at 2850 m (FiO 2 0.21, PiO 2 ≈ 60% of sea level) in random order with a washout period of >2 h. After >15 min of breathing the respective FiO 2 , systolic pulmonary artery pressure (sPAP), cardiac output (CO), and other parameters were assessed by echocardiography. Furthermore, radial arterial blood gases were analysed. Twenty-eight patients with PVD (24 females, 26 PAH, age 45 ± 12 years) treated with phosphodiesterase-5 inhibitors ( n = 28) and endothelin receptor antagonists ( n = 9) were included. With oxygen vs. placebo air, sPAP was 57 ± 23 vs. 68 ± 24 mmHg, mean difference -11 mmHg (-15 to -6 mmHg, P < 0.001), CO was 3.2 ± 0.9 vs. 3.9 ± 1.1 L/min; -0.7 L/min (-0.9 to -0.4 L/min, P < 0.001), while sPAP/CO was unchanged, and the right ventriculo-arterial coupling was increased. PaO 2 was 22.5 ± 9.7 vs. 7.6 ± 1.5 kPa; 14.9 kPa (11.4-18.4 kPa, P < 0.001)., Conclusion: High-dose oxygen therapy in prevalent patients with PVD living near 2850 m significantly lowered sPAP but also CO by a reduced heart rate, resulting in an unchanged pulmonary resistance. Whether longer-term oxygen therapy would improve pulmonary vascular resistance requires further investigation., Registration: NCT06084559 URL: https://clinicaltrials.gov/study/NCT06084559., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Hypoxia is a trigger for sympathetic activation and autonomic cardiovascular dysfunction. Pulmonary vascular disease (PVD) is associated with hypoxaemia, which increases with altitude. The aim was to investigate how exposure of patients with PVD to hypobaric hypoxia at altitude affects autonomic cardiovascular regulation., Methods: In a randomised crossover study, patients with PVD were studied for 1 day and one night at an altitude of 2500 m (hypobaric hypoxia) and low altitude at 470 m in a random order. Outcomes were heart rate variability (HRV) in the time domain and in the frequency domain (low frequency (LF)/high frequency (HF) and LF/HF) and heart rate (HR) during day and night and baroreflex sensitivity (BRS)., Results: In 25 patients with PVD (72% pulmonary arterial hypertension and 28% distal chronic thromboembolic pulmonary hypertension; mean±sd age 60.7±13.6 years), exposure to altitude resulted in significant increases in awake HR by 9.4 bpm (95% confidence interval (CI) 6.3-12.4, p<0.001) and nocturnal HR by 9.0 bpm (95% CI 6.6-11.4, p<0.001) and significant changes in awake and particularly nocturnal HRV indicating decreasing parasympathetic and increasing sympathetic activity (change in daytime LF/HF 1.7 (95% CI 0.6-2.8), p=0.004; nocturnal LF/HF 1.9 (95% CI 0.3-3.4), p=0.022) and a significant decrease in BRS (-2.4·mmHg -1 (95% CI -4.3- -0.4, p=0.024))., Conclusion: Exposure of PVD patients to altitude resulted in a significant change in HRV indicating an increase in sympathetic activity and a decrease in BRS. The relative change in HRV at altitude was more pronounced during sleep., Competing Interests: Conflict of interest: S. Ulrich reports grants or contracts from Swiss National Science Foundation, Zurich, and Swiss Lung League; unrestricted grants from Orpha Swiss and MSD, outside the submitted work; consulting fees from Orpha Swiss, MSD SA and Janssen SA, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events for Orpha Swiss, MSD SA, Janssen SA and Novartis SA, outside the submitted work; support for attending meetings and/or travel from Orpha Swiss, MSD SA, Janssen SA and Novartis SA, outside the submitted work; participation on a data safety monitoring or advisory board for Orpha Swiss, MSD SA and Janssen SA, outside the submitted work; leadership or fiduciary roles for the Swiss Society of Pulmonology, European Respiratory Society and Swiss Society of Pulmonary Hypertension, outside the submitted work. Conflict of interest: M. Lichtblau reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from MSD SA, outside the submitted work; support for attending meetings and/or travel from Orpha Swiss, Janssen and MSD, outside the submitted work; and participation on a data safety monitoring or advisory board for MSD SA, outside the submitted work. Conflict of interest: E.I. Schwarz reports receiving lecture fees from ResMed outside the submitted work and is Secretary of Assembly 4 of the European Respiratory Society (unpaid) outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

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 . 25:197-204, 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.

Importance: Prior study in healthy subjects has shown a reduction of partial pressure of arterial oxygen (PaO 2 ) by -1.60 kPa/kilometre of altitude gain. However, the association of altitude-related change in PaO 2 and altitude-related adverse health effects (ARAHE) in patients with chronic obstructive pulmonary disease (COPD) remain unknown., Objective: To provide an effect size estimate for the decline in PaO 2 with each kilometre of altitude gain and to identify ARAHE in relation to altitude in patients with COPD. www.crd.york.ac.uk/prospero: CRD42020217938., Data Sources: A systematic search of PubMed and Embase was performed from inception to May 30, 2023., Study Selection: Peer-reviewed and prospective studies in patients with COPD staying at altitudes >1500 m providing arterial blood gases within the first 3 days at the target altitude., Data Extraction and Synthesis: Aggregate data (AD) on study characteristics were extracted, and individual patient data (IPD) were requested. Estimates were pooled using random-effects meta-analysis., Main Outcome and Measures: Relative risk estimates and 95 % confidence intervals for the association between PaO 2 and altitude in patients with COPD., Results: Thirteen studies were included in the AD analysis, of which 6 studies (222 patients, 45.2 % female) provided IPD, thus were included in the quantitative analysis. The estimated effect size of PaO 2 was -0.84 kPa [95 %CI, -0.92 to -0.76] per 1000 m of altitude gain (I 2 =65.0 %, P < 0.001). In multivariable regression analysis, COPD severity, baseline PaO 2 , age and time spent at altitude were predictors for PaO 2 at altitude. Overall, 37.8 % of COPD patients experienced an ARAHE, whereas older age, female sex, COPD severity, baseline PaO 2, and target altitude were predictors for the occurrence of ARAHE (area under ROC curve: 0.9275, P < 0.001)., Conclusions and Relevance: This meta-analysis, providing altitude-related decrease in PaO 2 and risk of ARAHE in patients with COPD ascending to altitudes >1500 m, revealed a lower altitude-related decrease in PaO 2 in COPD patients compared with healthy. However, these findings might improve patient care and facilitate decisions about initiating preventive measures against hypoxaemia and ARAHE in patients with COPD planning an altitude sojourn or intercontinental flight, i.e. supplemental oxygen or acetazolamide., Competing Interests: Conflicts of interest The authors declare no conflict of interest concerning this work., (Copyright © 2024 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE-). Blood samples were collected from 30 EE+ and 15 EE- in La Rinconada (Peru, 5100-5300 m a.s.l.), with special attention given to the sampling pre-analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet-poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE- and LL (all P < 0.01). At normalized haematocrit, clotting times were normalized in most individuals. Conversely, maximal clot firmness was normalized only in FIBTEM and not in EXTEM/INTEM assays, suggesting abnormal platelet activity. Thrombin generation, levels of plasma clotting factors and inhibitors, and standard coagulation assays were mostly normal in all groups. No highlanders reported a history of venous thromboembolism based on the dedicated survey. Collectively, these results indicate that EE+ do not present a hypercoagulable profile potentially favouring thrombosis., (© 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

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 (SpO 2 ) 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 SpO 2 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 SpO 2 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 SpO 2 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mutschler, Furian, Lichtblau, Buergin, Schneider, Appenzeller, Mayer, Muralt, Mademilov, Abdyraeva, Aidaralieva, Muratbekova, Akylbekov, Shabykeeva, Sooronbaev, Ulrich and Bloch.)

Red blood cell (RBC) metabolic reprogramming upon exposure to high altitude contributes to physiological human adaptations to hypoxia, a multifaceted process critical to health and disease. To delve into the molecular underpinnings of this phenomenon, first, we performed a multi-omics analysis of RBCs from six lowlanders after exposure to high-altitude hypoxia, with longitudinal sampling at baseline, upon ascent to 5,100 m and descent to sea level. Results highlighted an association between erythrocyte levels of 2,3-bisphosphoglycerate (BPG), an allosteric regulator of hemoglobin that favors oxygen off-loading in the face of hypoxia, and expression levels of the Rhesus blood group RHCE protein. We then expanded on these findings by measuring BPG in RBCs from 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. These data informed a genome-wide association study using BPG levels as a quantitative trait, which identified genetic polymorphisms in the region coding for the Rhesus blood group RHCE as critical determinants of BPG levels in erythrocytes from healthy human volunteers. Mechanistically, we suggest that the Rh group complex, which participates in the exchange of ammonium with the extracellular compartment, may contribute to intracellular alkalinization, thus favoring BPG mutase activity., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background and aims: Chinese herbal medicine (CHM) was used to prevent and treat coronavirus disease 2019 (COVID-19) in clinical practices. Many studies have demonstrated that the combination of CHM and Western medicine can be more effective in treating COVID-19 compared to Western medicine alone. However, evidence-based studies on the prevention in undiagnosed or suspected cases remain scarce. This systematic review and meta-analysis aimed to investigate the effectiveness of CHM in preventing recurrent, new, or suspected COVID-19 diseases. Methods: We conducted a comprehensive search using ten databases including articles published between December 2019 and September 2023. This search aimed to identify studies investigating the use of CHM to prevent COVID-19. Heterogeneity was assessed by a random-effects model. The relative risk (RR) and mean differences were calculated using 95% confidence intervals (CI). The modified Jadad Scale and the Newcastle-Ottawa Scale (NOS) were employed to evaluate the quality of randomized controlled trials and cohort studies, respectively. Results: Seventeen studies with a total of 47,351 patients were included. Results revealed that CHM significantly reduced the incidence of COVID-19 (RR = 0.24, 95% CI = 0.11-0.53, p = 0.0004), influenza (RR = 0.37, 95% CI = 0.18-0.76, p = 0.007), and severe pneumonia exacerbation rate (RR = 0.17, 95% CI = 0.05-0.64, p = 0.009) compared to non-treatment or conventional control group. Evidence evaluation indicated moderate quality evidence for COVID-19 incidence and serum complement components C3 and C4 in randomized controlled trials. For the incidence of influenza and severe pneumonia in RCTs as well as the ratio of CD4 + /CD8 + lymphocytes, the evidence quality was low. The remaining outcomes including the disappearance rate of symptoms and adverse reactions were deemed to be of very low quality. Conclusion: CHM presents a promising therapeutic option for the prevention of COVID-19. However, additional high-quality clinical trials are needed to further strengthen evidential integrity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hu, Luo, Zhu, Pan, Chen, Furian, Harkare, Sun, Fansa, Wu, Yu, Ma, Wang and Shi.)

Background: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (CTEPH) with accessible lesions. Breathing pure oxygen (hyperoxia) during right heart catheterization (RHC) allows for the calculation of the right-to-left shunt fraction (Qs/Qt). In the absence of intracardiac shunt, Qs/Qt can be used as a marker of ventilation-perfusion mismatch in patients with CTEPH. This study involved investigating Qs/Qt after PEA and its relation to other disease-specific outcomes., Study Design and Methods: This study is a retrospective study that focuses on patients with operable CTEPH who had Qs/Qt assessment during RHC before and 1 year after PEA. Additionally, 6 min walking distance (6MWD), WHO functional class (WHO-FC), and NT-proBNP were assessed to calculate a four-strata risk score., Results: Overall, 16 patients (6 females) with a median age of 66 years (quartiles 55; 74) were included. After PEA, an improvement in mean pulmonary artery pressure (38 [32; 41] to 24 [18; 28] mmHg), pulmonary vascular resistance (5.7 [4.0; 6.8] to 2.5 [1.4; 3.8] WU), oxygen saturation (92 [88; 93]% to 94 [93; 95]%), WHO-FC, and risk score was observed (all p < 0.05). No improvement in median Qs/Qt could be detected (13.7 [10.0; 17.5]% to 13.0 [11.2; 15.6]%, p = 0.679). A total of 7 patients with improved Qs/Qt had a significant reduction in risk score compared to those without improved Qs/Qt., Conclusion: PEA did not alter Qs/Qt assessed after 1 year in operable CTEPH despite an improvement in hemodynamics and risk score, potentially indicating a persistent microvasculopathy. In patients whose shunt fraction improved with PEA, the reduced shunt was associated with an improvement in risk score.

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 (FiO 2 0.21) or oxygen (FiO 2 1.0) in random order, guided hyperventilation followed under the corresponding gas mixture. Finger pulse oximetry (SpO 2 ) 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, P aO 2 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, SpO 2 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 SpO 2 , 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 P aO 2 . As this was associated with a reduced response of cerebral blood volume to hypocapnia, adaptation of cerebrovascular reactivity might have occurred., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luyken, Appenzeller, Scheiwiller, Lichtblau, Mademilov, Muratbekova, Sheraliev, Abdraeva, Marazhapov, Sooronbaev, Ulrich, Bloch and Furian.)

Background: The course of pulmonary arterial wedge pressure (PAWP) during exercise in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH), further abbreviated as pulmonary vascular disease (PVD), is still unknown. The aim of the study was to describe PAWP during exercise in patients with PVD., Methods: In this cross-sectional study, right heart catheter (RHC) data including PAWP, recorded during semi-supine, stepwise cycle exercise in patients with PVD, were analysed retrospectively. We investigated PAWP changes during exercise until end-exercise., Results: In 121 patients (59 female, 66 CTEPH, 55 PAH, 62±17 years) resting PAWP was 10.2±4.1 mmHg. Corresponding peak changes in PAWP during exercise were +2.9 mmHg (95% CI 2.1-3.7 mmHg, p<0.001). Patients ≥50 years had a significantly higher increase in PAWP during exercise compared with those <50 years (p<0.001). The PAWP/cardiac output (CO) slopes were 3.9 WU for all patients, and 1.6 WU for patients <50 years and 4.5 WU for those ≥50 years., Conclusion: In patients with PVD, PAWP increased slightly but significantly with the onset of exercise compared to resting values. The increase in PAWP during exercise was age-dependent, with patients ≥50 years showing a rapid PAWP increase even with minimal exercise. PAWP/CO slopes >2 WU are common in patients with PVD aged ≥50 years without exceeding the PAWP of 25 mmHg during exercise., Competing Interests: Conflict of interest: E. Grünig has received fees for lectures and/or consultations from Actelion, Bayer/MSD, Ferrer, GEBRO, GSK, Janssen and OMT. Research grants to his institution have been received from Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, GSK, Janssen, Novartis, OMT, Pfizer, REATE and United Therapeutics. Conflict of interest: None of the other authors have any conflicts of interest in the context of this manuscript., (Copyright ©The authors 2023.)

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.

Importance: With increasing altitude, the partial pressure of inspired oxygen decreases and, consequently, the Pao2 decreases. Even though this phenomenon is well known, the extent of the reduction as a function of altitude remains unknown., Objective: To calculate an effect size estimate for the decrease in Pao2 with each kilometer of vertical gain among healthy unacclimatized adults and to identify factors associated with Pao2 at high altitude (HA)., Data Sources: A systematic search of PubMed and Embase was performed from database inception to April 11, 2023. Search terms included arterial blood gases and altitude., Study Selection: A total of 53 peer-reviewed prospective studies in healthy adults providing results of arterial blood gas analysis at low altitude (<1500 m) and within the first 3 days at the target altitude (≥1500 m) were analyzed., Data Extraction and Synthesis: Primary and secondary outcomes as well as study characteristics were extracted from the included studies, and individual participant data (IPD) were requested. Estimates were pooled using a random-effects DerSimonian-Laird model for the meta-analysis., Main Outcomes and Measures: Mean effect size estimates and 95% CIs for reduction in Pao2 at HA and factors associated with Pao2 at HA in healthy adults., Results: All of the 53 studies involving 777 adults (mean [SD] age, 36.2 [10.5] years; 510 men [65.6%]) reporting 115 group ascents to altitudes between 1524 m and 8730 m were included in the aggregated data analysis; 13 of those studies involving 305 individuals (mean [SD] age, 39.8 [13.6] years; 185 men [60.7%]) reporting 29 ascents were included in the IPD analysis. The estimated effect size of Pao2 was -1.60 kPa (95% CI, -1.73 to -1.47 kPa) for each 1000 m of altitude gain (τ2 = 0.14; I2 = 86%). The Pao2 estimation model based on IPD data revealed that target altitude (-1.53 kPa per 1000 m; 95% CI, -1.63 to -1.42 kPa per 1000 m), age (-0.01 kPa per year; 95% CI, -0.02 to -0.003 kPa per year), and time spent at an altitude of 1500 m or higher (0.16 kPa per day; 95% CI, 0.11-0.21 kPa per day) were significantly associated with Pao2., Conclusions and Relevance: In this systematic review and meta-analysis, the mean decrease in Pao2 was 1.60 kPa per 1000 m of vertical ascent. This effect size estimate may improve the understanding of physiological mechanisms, assist in the clinical interpretation of acute altitude illness in healthy individuals, and serve as a reference for physicians counseling patients with cardiorespiratory disease who are traveling to HA regions.

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 pO 2 ) 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).-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 (FEV 1 ) 61±12% pred, S 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 pO 2 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 pO 2 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., Competing Interests: Conflict of interest: M. Lichtblau received funding from the Swiss Lung League for this study. S. Ulrich reports grants from the Swiss National Science Foundation and Lung Zuerich. K.E. Bloch was supported by Swiss National Science Foundation (grant ID: 172980). S. Saxer, L. Mayer, U. Sheraliev, M. Mademilov, M. Furian, A. Buergin, P.M. Schweiwiller, S.R. Schneider, F.C. Tanner and T. Sooronbaev have nothing to declare., (Copyright ©The authors 2023.)

Background/aims: Amongst numerous travellers to high altitude (HA) are many with the highly prevalent COPD, who are at particular risk for altitude-related adverse health effects (ARAHE). We then investigated the hypoxia-altitude simulation test (HAST) to predict ARAHE in COPD patients travelling to altitude., Methods: This prospective diagnostic accuracy study included 75 COPD patients: 40 women, age 58±9 years, forced expiratory volume in 1 s (FEV 1 ) 40-80% pred, oxygen saturation measured by pulse oximetry ( S pO 2 ) ≥92% and arterial carbon dioxide tension ( P ) of 15%) for 15 min, at low altitude (760 m). Cut-off values for a positive HAST were set according to British Thoracic Society (BTS) guidelines (arterial oxygen tension ( aCO 2 ) <6 kPa. Patients underwent baseline evaluation and HAST, breathing normobaric hypoxic air (inspiratory oxygen fraction ( F <85%). The following day, patients travelled to HA (3100 m) for two overnight stays where ARAHE development including acute mountain sickness (AMS), Lake Louise Score ≥4 and/or AMS score ≥0.7, severe hypoxaemia ( IO 2 ) of 15%) for 15 min, at low altitude (760 m). Cut-off values for a positive HAST were set according to British Thoracic Society (BTS) guidelines (arterial oxygen tension ( P aO 2 ) <6.6 kPa and/or S pO 2 <85%). The following day, patients travelled to HA (3100 m) for two overnight stays where ARAHE development including acute mountain sickness (AMS), Lake Louise Score ≥4 and/or AMS score ≥0.7, severe hypoxaemia ( S pO 2 <80% for >30 min or 75% for >15 min) or intercurrent illness was observed., Results: ARAHE occurred in 50 (66%) patients and 23 out of 75 (31%) were positive on HAST according to S pO 2 , and 11 out of 64 (17%) according to P aO 2 . For S pO 2 / P aO 2 we report a sensitivity of 46/25%, specificity of 84/95%, positive predictive value of 85/92% and negative predictive value of 44/37%., Conclusion: In COPD patients ascending to HA, ARAHE are common. Despite an acceptable positive predictive value of the HAST to predict ARAHE, its clinical use is limited by its insufficient sensitivity and overall accuracy. Counselling COPD patients before altitude travel remains challenging and best focuses on early recognition and treatment of ARAHE with oxygen and descent., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2023.)

Pulmonary vascular diseases (PVDs), defined as arterial or chronic thromboembolic pulmonary hypertension, are associated with autonomic cardiovascular dysregulation. Resting heart rate variability (HRV) is commonly used to assess autonomic function. Hypoxia is associated with sympathetic overactivation and patients with PVD might be particularly vulnerable to hypoxia-induced autonomic dysregulation. In a randomised crossover trial, 17 stable patients with PVD (resting PaO 2 ≥ 7.3 kPa) were exposed to ambient air (FiO 2 = 21%) and normobaric hypoxia (FiO 2 = 15%) in random order. Indices of resting HRV were derived from two nonoverlapping 5-10-min three-lead electrocardiography segments. We found a significant increase in all time- and frequency-domain HRV measures in response to normobaric hypoxia. There was a significant increase in root mean squared sum difference of RR intervals (RMSSD; 33.49 (27.14) vs. 20.76 (25.19) ms; p < 0.01) and RR50 count divided by the total number of all RR intervals (pRR50; 2.75 (7.81) vs. 2.24 (3.39) ms; p = 0.03) values in normobaric hypoxia compared to ambient air. Both high-frequency (HF; 431.40 (661.56) vs. 183.70 (251.25) ms 2 ; p < 0.01) and low-frequency (LF; 558.60 (746.10) vs. 203.90 (425.63) ms 2 ; p = 0.02) values were significantly higher in normobaric hypoxia compared to normoxia. These results suggest a parasympathetic dominance during acute exposure to normobaric hypoxia in PVD.

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.

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Reiser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Investigation of pulmonary gas exchange efficacy usually requires arterial blood gas analysis (aBGA) to determine arterial partial pressure of oxygen (mPaO 2 ) and compute the Riley alveolar-to-arterial oxygen difference (A-aDO 2 ); that is a demanding and invasive procedure. A noninvasive approach (AGM100), allowing the calculation of PaO 2 (cPaO 2 ) derived from pulse oximetry (SpO 2 ), 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 cPaO 2 (AGM100) and mPaO 2 (EPOC, portable aBGA device) were performed in 131 moderate-to-severe COPD patients (mean ±SD FEV 1 : 60 ± 10% of predicted value) and low-altitude residents, becoming hypoxemic (i.e., SpO 2 < 94%) during a short stay at 3100 m (Too-Ashu, Kyrgyzstan). Agreements between cPaO 2 (AGM100) and mPaO 2 (EPOC) and between the O 2 -deficit (calculated as the difference between end-tidal pressure of O 2 and cPaO 2 by the AGM100) and Riley A-aDO 2 were assessed. Mean bias (±SD) between cPaO 2 and mPaO 2 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 SpO 2 ( p < 0.001), and an increase in PaCO 2 -PETCO 2 difference ( p < 0.001) were associated with imprecision (i.e., the discrepancy between cPaO 2 and mPaO 2 ). The positive predictive value of cPaO 2 to detect severe hypoxemia (i.e., PaO 2 ≤ 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 O 2 -deficit and A-aDO 2 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 PaO 2 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.

Maximal values of aerobic power (VO 2 max) and peripheral oxygen saturation (SpO 2 max) decline in parallel with gain in altitude. Whereas this relationship has been well investigated when acutely exposed to high altitude, potential benefits of acclimatization on SpO 2 and related VO 2 max in healthy and diseased individuals have been much less considered. Therefore, this narrative review was primarily aimed to identify relevant literature reporting altitude-dependent changes in determinants, in particular SpO 2 , of VO 2 max and effects of acclimatization in athletes, healthy non-athletes, and patients suffering from cardiovascular, respiratory and/or metabolic diseases. Moreover, focus was set on potential differences with regard to baseline exercise performance, age and sex. Main findings of this review emphasize the close association between individual SpO 2 and VO 2 max, and demonstrate similar altitude effects (acute and during acclimatization) in healthy people and those suffering from cardiovascular and metabolic diseases. However, in patients with ventilatory constrains, i.e., chronic obstructive pulmonary disease, steep decline in SpO 2 and V̇O 2 max and reduced potential to acclimatize stress the already low exercise performance. Finally, implications for prevention and therapy are briefly discussed.

High-altitude (HA) exposure may stimulate significant physiological and molecular changes, resulting in HA-related illnesses. HA may impact oxidative stress, antioxidant capacity, and iron homeostasis, yet it is unclear how both repeated exposure and HA acclimatization may modulate such effects. Therefore, we assessed the effects of weeklong repeated daily HA exposure (2,900-5,050 m) in altitude-naïve individuals ( n = 21 individuals, 13 females, mean ± SD, 25.3 ± 3.7 yr) to mirror the working schedule of HA workers ( n = 19 individuals, all males, 41.1 ± 9.4 yr) at the Atacama Large Millimeter Array (ALMA) Observatory (San Pedro de Atacama, Chile). Markers of oxidative stress, antioxidant capacity, and iron homeostasis were measured in blood plasma. Levels of protein oxidation ( P < 0.001) and catalase activity ( P = 0.023) increased and serum iron ( P < 0.001), serum ferritin ( P < 0.001), and transferrin saturation ( P < 0.001) levels decreased with HA exposure in both groups. HA workers had lower levels of oxidative stress, and higher levels of antioxidant capacity, iron supply, and hemoglobin concentration as compared with altitude-naïve individuals. On a second week of daily HA exposure, changes in levels of protein oxidation, glutathione peroxidase, and nitric oxide metabolites were lower as compared with the first week in altitude-naïve individuals. These results indicate that repeated exposure to HA may significantly alter oxidative stress and iron homeostasis, and the degree of such changes may be dependent on if HA is visited naïvely or routinely. Further studies are required to fully elucidate differences in HA-induced changes in oxidative stress and iron homeostasis profiles among visitors of HA.

Background: Effects of prolonged and repeated high-altitude exposure on oxygenation and control of breathing remain uncertain. We hypothesized that prolonged and repeated high-altitude exposure will improve altitude-induced deoxygenation and breathing instability. Methods: 21 healthy lowlanders, aged 18-30y, underwent two 7-day sojourns at a high-altitude station in Chile (4-8 hrs/day at 5,050 m, nights at 2,900 m), separated by a 1-week recovery period at 520 m. Respiratory sleep studies recording mean nocturnal pulse oximetry (SpO 2 ), oxygen desaturation index (ODI, >3% dips in SpO 2 ), breathing patterns and subjective sleep quality by visual analog scale (SQ-VAS, 0-100% with increasing quality), were evaluated at 520 m and during nights 1 and 6 at 2,900 m in the 1st and 2nd altitude sojourn. Results: At 520 m, mean ± SD nocturnal SpO 2 was 94 ± 1%, ODI 2.2 ± 1.2/h, SQ-VAS 59 ± 20%. Corresponding values at 2,900 m, 1st sojourn, night 1 were: SpO 2 86 ± 2%, ODI 23.4 ± 22.8/h, SQ-VAS 39 ± 23%; 1st sojourn, night 6: SpO 2 90 ± 1%, ODI 7.3 ± 4.4/h, SQ-VAS 55 ± 20% ( p < 0.05, all differences within corresponding variables). Mean differences (Δ, 95%CI) in acute effects (2,900 m, night 1, vs 520 m) between 2nd vs 1st altitude sojourn were: ΔSpO 2 0% (-1 to 1), ΔODI -9.2/h (-18.0 to -0.5), ΔSQ-VAS 10% (-6 to 27); differences in acclimatization (changes night 6 vs 1), between 2nd vs 1st sojourn at 2,900 m were: ΔSpO 2 -1% (-2 to 0), ΔODI 11.1/h (2.5 to 19.7), ΔSQ-VAS -15% (-31 to 1). Conclusion: Acute high-altitude exposure induced nocturnal hypoxemia, cyclic deoxygenations and impaired sleep quality. Acclimatization mitigated these effects. After recovery at 520 m, repeated exposure diminished high-altitude-induced deoxygenation and breathing instability, suggesting some retention of adaptation induced by the first altitude sojourn while subjective sleep quality remained similarly impaired., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Furian, Bitos, Hartmann, Muralt, Lichtblau, Bader, Rawling, Ulrich, Poulin and Bloch.)

Importance: To date, there is no established evidence of sex-specific differences in altitude-induced sleep-disordered breathing (SDB) during polysomnography-confirmed sleep. Objective: The aim of this study was to investigate whether differences in sex play a pivotal role in incidences of SDB and acute mountain sickness (AMS) when staying overnight at high altitude. Design: This was a prospective cohort study. Setting: Participants underwent overnight polysomnography (PSG) and clinical assessment in a sleep laboratory at 500 m and two consecutive days at 3270 m. Participants: The participants comprised 28 (18 women) healthy, young, low-altitude residents with a median (interquartile range) age of 26.0 (25.0, 28.0) years. Exposures: Altitude exposure. Main outcomes and Measures: The primary outcome was altitude-induced change in the PSG-confirmed apnea−hypopnea index (AHI) at 3270 m compared to 500 m between men and women. Secondary outcomes included sex differences in other parameters related to SDB, sleep structure, AMS, psychomotor vigilance test reaction time and parameters from arterial and venous blood analyses. Results: The median (interquartile range) AHIs at 500 m and 3270 m on night 1 and on night 2 were 6.5/h (3.6, 9.1), 23.7/h (16.2, 42.5) and 15.2/h (11.8, 20.9) in men, respectively, and 2.2/h (1.0, 5.5), 8.0/h (5.3, 17.0) and 7.1/h (4.9, 11.5) in women, respectively (p < 0.05 nights 1 and 2 at 3270 m vs. 500 m in men and women). The median difference (95% CI) of altitude-induced change in AHI (3270 m night 1 compared to 500 m) between men and women was 11.2/h (1.9 to 19.6) (p < 0.05). Over the time course of 2 days at 3270 m, 9 out of 18 (50%) women and 1 out of 10 (10%) men developed AMS (p < 0.05 women versus men). Conclusions and Relevance: This prospective cohort study showed that men were more susceptible to altitude-induced SDB but that they had a lower AMS incidence when staying for 2 days at 3270 m than women. These findings indicate that sex-related prevention and intervention strategies against SDB and AMS are highly warranted. Trial Registration: This trial was registered at the Chinese Clinical Trial Registry; No. ChiCTR1800020155.

Prediction of adverse health effects at altitude or during air travel is relevant, particularly in pre-existing cardiopulmonary disease such as pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH, PH). A total of 21 stable PH-patients (64 ± 15 y, 10 female, 12/9 PAH/CTEPH) were examined by pulse oximetry, arterial blood gas analysis and echocardiography during exposure to normobaric hypoxia (NH) (FiO2 15% ≈ 2500 m simulated altitude, data partly published) at low altitude and, on a separate day, at hypobaric hypoxia (HH, 2500 m) within 20−30 min after arrival. We compared changes in blood oxygenation and estimated pulmonary artery pressure in lowlanders with PH during high altitude simulation testing (HAST, NH) with changes in response to HH. During NH, 4/21 desaturated to SpO2 < 85% corresponding to a positive HAST according to BTS-recommendations and 12 qualified for oxygen at altitude according to low SpO2 < 92% at baseline. At HH, 3/21 received oxygen due to safety criteria (SpO2 < 80% for >30 min), of which two were HAST-negative. During HH vs. NH, patients had a (mean ± SE) significantly lower PaCO2 4.4 ± 0.1 vs. 4.9 ± 0.1 kPa, mean difference (95% CI) −0.5 kPa (−0.7 to −0.3), PaO2 6.7 ± 0.2 vs. 8.1 ± 0.2 kPa, −1.3 kPa (−1.9 to −0.8) and higher tricuspid regurgitation pressure gradient 55 ± 4 vs. 45 ± 4 mmHg, 10 mmHg (3 to 17), all p < 0.05. No serious adverse events occurred. In patients with PH, short-term exposure to altitude of 2500 m induced more pronounced hypoxemia, hypocapnia and pulmonary hemodynamic changes compared to NH during HAST despite similar exposure times and PiO2. Therefore, the use of HAST to predict physiological changes at altitude remains questionable. (ClinicalTrials.gov: NCT03592927 and NCT03637153).