The effect of high altitude (2500†m) on incremental cycling exercise in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a randomised controlled crossover trial.

BACKGROUND: Our objective was to investigate the effect of a day-long exposure to high altitude on peak exercise capacity and safety in stable patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: In a randomised controlled crossover trial, stable patients with PAH or distal CTEPH without resting hypoxaemia at low altitude performed two incremental exercise tests to exhaustion: one after 3-5 h at high altitude (2500 m) and one at low altitude (470 m). RESULTS: In 27 patients with PAH/CTEPH (44% females, mean±sd age 62±14 years), maximal work rate was 110±64 W at 2500 m and 123±64 W at 470 m (-11%, 95% CI -16- -11%; p<0.001). Oxygen saturation measured by pulse oximetry and arterial oxygen tension at end-exercise were 83±6% versus 91±6% and 6.1±1.9 versus 8.6±1.9 kPa (-8% and -29%; both p<0.001) at 2500 versus 470 m, respectively. Maximal oxygen uptake was 17.8±7.5 L·min-1·kg-1 at high altitude versus 20±7.4 L·min-1·kg-1 at low altitude (-11%; p<0.001). At end-exercise, the ventilatory equivalent for carbon dioxide was 43±9 at 2500 m versus 39±9 at 470 m (9%, 95% CI 2-6%; p=0.002). No adverse events occurred during or after exercise. CONCLUSIONS: Among predominantly low-risk patients with stable PAH/CTEPH, cycling exercise during the first day at 2500 m was well tolerated, but peak exercise capacity, blood oxygenation and ventilatory efficiency were lower compared with 470 m.

Effects of 5-Week Oral Acetazolamide on Incremental Cycling Exercise in Pulmonary Arterial and Chronic Thromboembolic Pulmonary Hypertension: A Randomized Placebo-Controlled, Double-Blinded, Crossover Trial.

INTRODUCTION: Acetazolamide (AZA) improves nocturnal and daytime blood oxygenation in patients with pulmonary vascular disease (PVD), defined as pulmonary arterial and distal chronic thromboembolic pulmonary hypertension (CTEPH), and may improve exercise performance. METHODS: We investigated the effect of 5 weeks of AZA (250 mg bid) versus placebo on maximal load during incremental cycling ramp exercise in patients with PVD studied in a randomized controlled, double-blind, crossover design, separated by > 2 weeks of washout. RESULTS: Twenty-five patients (12 pulmonary arterial hypertension, 13 CTEPH, 40% women, age 62 ± 15 years) completed the trial according to the protocol. Maximum load was similar after 5 weeks of AZA versus placebo (113 ± 9 vs. 117 ± 9 watts [W]), mean difference -4 W (95% CI: -9 to 1, p = 0.138). With AZA, maximum (max)-exercise partial pressure of O2 (PaO2) was significantly higher by 1.1 kPa (95% CI: 0.5-1.8, p = 0.003), while arterial pH and partial pressure of CO2 were significantly lower. Gas exchange threshold was reached at a higher load with AZA (108 ± 8 W vs. 97 ± 8 W) and was therefore delayed by 11 W (95% CI: 3-19, p = 0.013), while the ventilatory equivalent for O2 and CO2 were significantly higher at both the max-exercise and gas exchange threshold with AZA versus placebo. CONCLUSION: AZA for 5 weeks did not significantly change maximum exercise capacity in patients with PVD despite a significant increase in PaO2. The beneficial effects of increased blood oxygenation may have been diminished by increased ventilation due to AZA-induced metabolic acidosis and increased dyspnea.

Differential effects of high-altitude exposure on markers of oxidative stress, antioxidant capacity, and iron profiles.

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.

Alpine altitude climate treatment for severe and uncontrolled asthma: An EAACI position paper.

Currently available European Alpine Altitude Climate Treatment (AACT) programs combine the physical characteristics of altitude with the avoidance of environmental triggers in the alpine climate and a personalized multidisciplinary pulmonary rehabilitation approach. The reduced barometric pressure, oxygen pressure, and air density, the relatively low temperature and humidity, and the increased UV radiation at moderate altitude induce several physiological and immunological adaptation responses. The environmental characteristics of the alpine climate include reduced aeroallergens such as house dust mites (HDM), pollen, fungi, and less air pollution. These combined factors seem to have immunomodulatory effects controlling pathogenic inflammatory responses and favoring less neuro-immune stress in patients with different asthma phenotypes. The extensive multidisciplinary treatment program may further contribute to the observed clinical improvement by AACT in asthma control and quality of life, fewer exacerbations and hospitalizations, reduced need for oral corticosteroids (OCS), improved lung function, decreased airway hyperresponsiveness (AHR), improved exercise tolerance, and improved sinonasal outcomes. Based on observational studies and expert opinion, AACT represents a valuable therapy for those patients irrespective of their asthma phenotype, who cannot achieve optimal control of their complex condition despite all the advances in medical science and treatment according to guidelines, and therefore run the risk of falling into a downward spiral of loss of physical and mental health. In the light of the observed rapid decrease in inflammation and immunomodulatory effects, AACT can be considered as a natural treatment that targets biological pathways.

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

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

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.

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

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

Effects of suboptimal adherence of CPAP therapy on symptoms of obstructive sleep apnoea: a randomised, double-blind, controlled trial.

INTRODUCTION: Continuous positive airway pressure (CPAP) is currently the treatment of choice for sleepiness in patients with obstructive sleep apnoea (OSA); however, adherence is often thought to be suboptimal. We investigated the effects of suboptimal CPAP usage on objective and subjective sleepiness parameters in patients with OSA. MATERIAL AND METHODS: In this 2-week, parallel, double-blind, randomised controlled trial we enrolled moderate-to-severe OSA patients with excessive pre-treatment daytime sleepiness (Epworth sleepiness scale (ESS) score >10 points) who had suboptimal CPAP adherence over ≥12 months (mean nightly usage time 3-4 h). Patients were allocated through minimisation to either subtherapeutic CPAP ("sham CPAP") or continuation of CPAP ("therapeutic CPAP"). A Bayesian analysis with historical priors calculated the posterior probability of superiority. RESULTS: Between May, 2016 and November, 2018, 57 patients (aged 60±8 years, 79% male, 93% Caucasian) were allocated in total, and 52 who completed the study (50% in each arm) were included in the final analysis. The unadjusted ESS score increase was 2.4 points (95% CI 0.6-4.2, p=0.01) in the sham-CPAP group when compared to continuing therapeutic CPAP. The probability of superiority of therapeutic CPAP over sham CPAP was 90.4% for ESS, 90.1% for systolic blood pressure and 80.3% for diastolic blood pressure. CONCLUSIONS: Patients with moderate-to-severe OSA and daytime sleepiness are still getting a substantial benefit from suboptimal CPAP adherence, albeit not as much as they might get if they adhered more. Whether a similar statement can be made for even lower adherence levels remains to be established in future trials.

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

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

Effect of Breathing Oxygen-Enriched Air on Exercise Performance in Patients with Chronic Obstructive Pulmonary Disease: Randomized, Placebo-Controlled, Cross-Over Trial.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) experience dyspnea and hypoxemia during exercise. OBJECTIVE: The aim of this study was to evaluate the effects of breathing oxygen-enriched air on exercise performance and associated physiological changes in patients with COPD. METHODS: In a randomized, placebo-controlled, single-blind, cross-over trial, 20 patients with COPD (11 women, age 65 ± 6 years, FEV1 64 ± 19% pred., resting SpO2 ≥90%) performed 4 cycle ergospirometries to exhaustion using an incremental exercise test (IET) and a constant work rate (at 75% maximal workload with air) exercise test (CWRET), each with ambient (FiO2 0.21) and oxygen-enriched (FiO2 0.5) air. The main outcomes were the change in maximal workload in the IET and the change in exercise duration in the CWRET with oxygen versus air. Electrocardiogram, pulmonary gas exchange, thoracic volumes by inductance plethysmography, arterial blood gases, and cerebral and quadriceps muscle tissue oxygenation (CTO and MTO) were additionally measured. RESULTS: In the IET, maximal workload increased from 96 ± 21 to 104 ± 28 W with oxygen. In the CWRET, exercise duration increased from 605 ± 274 to 963 ± 444 s with oxygen. At end-exercise with oxygen, CTO, MTO, PaO2, and PaCO2 were increased, while V'E/V'CO2 was reduced and thoracic volumes were similar. At the corresponding time to end of exercise with ambient air, oxygen decreased heart rate, respiratory rate, minute ventilation, and V'E/V'CO2, while oxygenation was increased. CONCLUSION: In COPD patients without resting hypoxemia, breathing oxygen-enriched air improves exercise performance. This relates to a higher arterial oxygen saturation promoting oxygen availability to muscle and cerebral tissue and an enhanced ventilatory efficiency. COPD patients may benefit from oxygen therapy during exercise training.

Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials.

BACKGROUND: The Epworth Sleepiness Scale (ESS) is a widely used tool for assessing sleepiness in patients with obstructive sleep apnoea (OSA). We aimed to estimate the minimal important difference (MID) in patients with OSA. METHODS: We used individual data from three randomised controlled trials (RCTs) in patients with OSA where the preintervention to postintervention change in ESS was used as a primary outcome. We used anchor-based linear regression and responder analysis approaches to estimate the MID. For anchors, we used the change in domains of the Functional Outcomes of Sleep Questionnaire and 36-Item Short Form Health Survey. We also used the distribution-based approaches Cohen's effect size, SE of measurement and empirical rule effect size to support the anchor-based estimates. The final MID was determined by triangulating all estimates to a single MID. FINDINGS: A total of 639 patients with OSA were included in our analyses across the three RCTs with a median (IQR) baseline ESS score of 10 (6-13). The median (IQR) ESS change score overall was -2 (-5 to 1). The anchor-based estimates of the MID were between -1.74 and -4.21 points and estimates from the responder analysis were between -1 and -3 points. Distribution-based estimates were smaller, ranging from -1.46 to -2.36. INTERPRETATION: We propose an MID for the ESS of 2 points in patients with OSA with a disease severity from mild to severe. This estimate provides the means to plan trials and interpret the clinical relevance of changes in ESS. TRIAL REGISTRATION NUMBER: Provent, NCT01332175; autoCPAP trial, NCT00280800; MOSAIC,ISRCTN (3416388).

Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial.

STUDY QUESTION: We investigated whether domiciliary oxygen therapy (DOXT) increases exercise capacity and quality of life in patients with pulmonary arterial or distal chronic thromboembolic pulmonary hypertension (PAH/CTEPH) presenting with mild resting hypoxaemia and exercise-induced oxygen desaturation. MATERIALS AND METHODS: 30 patients with PAH/CTEPH, mean±sd age 60±15 years, pulmonary artery pressure 39±11 mmHg, resting arterial oxygen saturation measured by pulse oximetry (S pO2 ) ≥90%, S pO2 drop during a 6-min walk test ≥4%, on pulmonary hypertension-targeted medication, were randomised in a double-blind crossover protocol to DOXT and placebo (ambient air) treatment, each over 5 weeks, at 3 L·min-1 via nasal cannula overnight and when resting during the day. Treatment periods were separated by 2 weeks of washout. Co-primary outcomes were changes in 6-min walk distance (6MWD, breathing ambient air) and physical functioning scale of the 36-item short-form medical outcome questionnaire during treatment periods. RESULTS: DOXT increased the 6MWD from baseline 478±113 m by a mean (95% CI) of 19 (6-32) m, and physical functioning from 52±29 by 4 (0-8) points. Corresponding changes with placebo were 1 (-11-13) m in 6MWD and -2 (-6-2) points in physical functioning. Between-treatment differences in changes were 6MWD 18 (1-35) m (p=0.042) and physical functioning 6 (1-11) points (p=0.029). DOXT significantly improved the New York Heart Association functional class versus placebo. ANSWER TO THE QUESTION: This first randomised trial in PAH/CTEPH patients with exercise-induced hypoxaemia demonstrates that DOXT improves exercise capacity, quality of life and functional class. The results support large long-term randomised trials of DOXT in PAH/CTEPH.

Frontiers in Clinical Practice of Long-Term Care of Chronic Ventilatory Failure.

Home mechanical ventilation (HMV) is an effective long-term treatment for chronic hypercapnic respiratory failure. In addition to the established practice of providing HMV for the treatment of chronic ventilatory failure in slowly progressive neuromuscular and chest wall disease, there is accumulating evidence for improvement of quality of life and prolongation of survival by HMV in highly prevalent diseases like chronic obstructive pulmonary disease and ever-increasing obesity hypoventilation syndrome as well as rapidly progressive neuromuscular disease. The key concepts for successful HMV are an experienced team selecting the right patients, timely initiation of adequate ventilation via an appropriate interface, and monitoring effectiveness during regular long-term follow-up. Coaching of patients with chronic respiratory failure on long-term HMV within a dedicated service and collaborations with community services for home care are essential. The current review describes various important practical aspects of HMV that remain frontiers in the implementation of the current knowledge in clinical practice and may help in providing effective HMV to all those in need.

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

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

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

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

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

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

Nocturnal cerebral hypoxia in obstructive sleep apnoea: a randomised controlled trial.

Cerebral hypoxia may promote cerebral damage in patients with obstructive sleep apnoea (OSA). We investigated whether OSA patients experience nocturnal cerebral hypoxia that is prevented by continuous positive airway pressure (CPAP).OSA patients using CPAP underwent sleep studies including pulse oximetry (arterial oxygen saturation (SpO2 )) and near-infrared spectroscopy to monitor cerebral tissue oxygenation (CTO) at baseline and after 2 weeks on either subtherapeutic or therapeutic CPAP according to randomised allocation. Changes in oxygenation at end of the 2-week intervention were compared between groups.Among 21 patients (mean apnoea/hypopnoea index 50.3 events·h-1), OSA recurred in all nine patients using subtherapeutic CPAP and in none of the patients using therapeutic CPAP: mean (95% CI) between-group differences in changes of oxygen desaturation index from baseline to 2 weeks +40.7 (31.1-50.4) events·h-1 for SpO2 and +37.0 (25.3-48.7) events·h-1 for CTO (both p<0.001). Mean nocturnal SpO2 and CTO decreased more in patients using subtherapeutic versus therapeutic CPAP: -2.4 (-3.4--1.1)% and -3.8 (-7.4--0.1)%, respectively; both p<0.03. Severe CTO drops ≥13% associated with cerebral dysfunction in previous studies occurred in four out of nine patients using subtherapeutic CPAP, but in none out of 12 patients using therapeutic CPAP (p=0.01).In patients with OSA, CPAP withdrawal resulted in nocturnal cerebral deoxygenation, suggesting a role of cerebral hypoxia in predisposing untreated OSA patients to cerebral damage.

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

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

Effect of breathing oxygen-enriched air on exercise performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over trial.

Aims: The purpose of the current trial was to test the hypothesis that breathing oxygen-enriched air increases exercise performance of patients with pulmonary arterial or chronic thrombo-embolic pulmonary hypertension (PAH/CTEPH) and to investigate involved mechanisms. Methods and results: Twenty-two patients with PAH/CTEPH, eight women, means ± SD 61 ± 14 years, resting mPAP 35 ± 9mmHg, PaO2 ambient air >7.3 kPa, underwent four bicycle ergospirometries to exhaustion on different days, while breathing oxygen-enriched (FiO2 0.50, hyperoxia) or ambient air (FiO2 0.21, normoxia) using progressively increased or constant load protocols (with 75% maximal work rate under FiO2 0.21), according to a randomized, sham-controlled, single-blind, cross-over design. ECG, pulmonary gas-exchange, arterial blood gases, cerebral and quadriceps muscle tissue oxygenation (CTO and QMTO) by near-infrared spectroscopy were measured. In ramp exercise, maximal work rate increased from 113 ± 38 W with normoxia to 132 ± 48 W with hyperoxia, mean difference 19.7 (95% CI 10.5-28.9) W, P < 0.001. Constant load exercise endurance increased from 571 ± 443 to 1242 ± 514 s, mean difference 671 (95% CI 392-951) s, P < 0.001. At end-exercise with hyperoxia PaO2, CTO, QMTO, and PaCO2 were increased, and ventilatory equivalents for CO2 were reduced while the physiological dead space/tidal volume ratio remained unchanged. Conclusion: In patients with PAH/CTEPH, breathing oxygen-enriched air provides major increases in exercise performance. This is related to an improved arterial oxygenation that promotes oxygen availability in muscles and brain and to a reduction of the excessive ventilatory response to exercise thereby enhancing ventilatory efficiency. Patients with PAH/CTEPH may therefore benefit from oxygen therapy during daily physical activities and training. Trial registration: clinicaltrials.gov Identifier: NCT01748474.