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Background: Pure oxygen breathing (hyperoxia) may improve hemodynamics in patients with pulmonary hypertension (PH) and allows to calculate right-to-left shunt fraction (Qs/Qt), whereas breathing normobaric hypoxia may accelerate hypoxic pulmonary vasoconstriction (HPV). This study investigates how hyperoxia and hypoxia affect mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with PH and whether Qs/Qt influences the changes of mPAP and PVR., Study Design and Methods: Adults with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) underwent repetitive hemodynamic and blood gas measurements during right heart catheterization (RHC) under normoxia [fractions of inspiratory oxygen (FiO 2 ) 0.21], hypoxia (FiO 2 0.15), and hyperoxia (FiO 2 1.0) for at least 10 min., Results: We included 149 patients (79/70 PAH/CTEPH, 59% women, mean ± SD 60 ± 17 years). Multivariable regressions (mean change, CI ) showed that hypoxia did not affect mPAP and cardiac index, but increased PVR [0.4 (0.1-0.7) WU, p = 0.021] due to decreased pulmonary artery wedge pressure [-0.54 (-0.92 to -0.162), p = 0.005]. Hyperoxia significantly decreased mPAP [-4.4 (-5.5 to -3.3) mmHg, p < 0.001] and PVR [-0.4 (-0.7 to -0.1) WU, p = 0.006] compared with normoxia. The Qs/Qt (14 ± 6%) was >10 in 75% of subjects but changes of mPAP and PVR under hyperoxia and hypoxia were independent of Qs/Qt., Conclusion: Acute exposure to hypoxia did not relevantly alter pulmonary hemodynamics indicating a blunted HPV-response in PH. In contrast, hyperoxia remarkably reduced mPAP and PVR, indicating a preserved vasodilator response to oxygen and possibly supporting the oxygen therapy in patients with PH. A high proportion of patients with PH showed increased Qs/Qt, which, however, was not associated with changes in pulmonary hemodynamics in response to changes in FiO 2 ., Competing Interests: SU reports grants from Johnson and Johnson SA, Switzerland, during the conduct of the study; grants from the Swiss National Science Foundation, grants from Zurich Lung, grants from Orpha Swiss, personal fees from Actelion SA, Switzerland, personal fees from MSD Switzerland, outside the submitted work. The remaining 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 Carta, Lichtblau, Berlier, Saxer, Schneider, Schwarz, Furian, Bloch and Ulrich.)

Background: Exact and simultaneous measurements of mean pulmonary artery pressure (mPAP) and cardiac output (CO) are crucial to calculate pulmonary vascular resistance (PVR), which is essential to define pulmonary hypertension (PH). Simultaneous measurements of mPAP and CO are not feasible using the direct Fick (DF) method, due to the necessity to sample blood from the catheter-tip. We evaluated a modified DF method, which allows simultaneous measurement of mPAP and CO without needing repetitive blood samples. Methods: Twenty-four patients with pulmonary arterial or chronic thromboembolic PH had repetitive measurements of CO at rest and end-exercise during three phases of a crossover trial. CO was assessed by the original DF method using oxygen uptake, measured by a metabolic unit, and arterial and mixed venous oxygen saturations from co-oximetry of respective blood gases served as reference. These CO measurements were then compared with a modified DF method using pulse oximetry at the catheter- and fingertip. Results: The bias among CO measurements by the two DF methods at rest was -0.26 L/min with limits of agreement of ±1.66 L/min. The percentage error was 28.6%. At the end-exercise, the bias between methods was 0.29 L/min with limits of agreement of ±1.54 L/min and percentage error of 16.1%. Conclusion: Direct Fick using a catheter- and fingertip pulse oximetry (DFp) is a practicable and reliable method for assessing CO in patients with PH. This method has the advantage of allowing simultaneous measurement of PAP and CO, and frequent repetitive measurements are needed during exercise. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02755259, identifier: NCT02755259., Competing Interests: None of the authors reports any conflict of interest in direct relation to this manuscript. SU reports grants from the Swiss National Science Foundation and Zurich Lung related to this work. She reports a grant from the Swiss Lung League, Janssen SA, Switzerland, Orpha Swiss, personal fees from Actelion SA, MSD, Orpha Swiss and Novartis, Switzerland, outside of the submitted work. The remaining 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 © 2021 Duknic, Lichtblau, Saxer, Berlier, Schneider, Schwarz, Carta, Furian, Bloch and Ulrich.)

Objective: To evaluate the effects of breathing oxygen-enriched air (oxygen) on exercise performance in patients with pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). Methods: Ten patients with PH-HFpEF (five women, age 60 ± 9 y, mPAP 37 ± 14 mmHg, PAWP 18 ± 2 mmHg, PVR 3 ± 3 WU, resting SpO 2 98 ± 2%) performed two-cycle incremental exercise tests (IET) and two constant-work-rate exercise test (CWRET) at 75% maximal work-rate ( W max ), each with ambient air (FiO 2 0.21) and oxygen (FiO 2 0.5) in a randomized, single-blinded, cross-over design. The main outcomes were the change in W max (IET) and cycling time (CWRET) with oxygen vs. air. Blood gases at rest and end-exercise, dyspnea by Borg CR10 score at end-exercise; continuous SpO 2 , minute ventilation (V'E), carbon dioxide output (V'CO 2 ), and cerebral and quadricep muscle tissue oxygenation (CTO and QMTO) were measured. Results: With oxygen vs. air, W max (IET) increased from 94 ± 36 to 99 ± 36 W, mean difference (95% CI) 5.4 (0.9-9.8) W, p = 0.025, and cycling time (CWRET) from 532 ± 203 to 680 ± 76 s, +148 (31.8-264) s, p = 0.018. At end-exercise with oxygen, Borg dyspnea score and V'E/V'CO 2 were lower, whereas PaO 2 and end-tidal PaCO 2 were higher. Other parameters were unchanged. Conclusion: Patients with PH-HFpEF not revealing resting hypoxemia significantly improved their exercise performance while breathing oxygen-enriched air along with less subjective dyspnea sensation, a better blood oxygenation, and an enhanced ventilatory efficiency. Future studies should investigate whether prolonged training with supplemental oxygen would increase the training effect and, potentially, daily activity for PH-HFpEF patients. Clinical Trial Registration: [clinicaltrials.gov], identifier [NCT04157660]., 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 © 2021 Müller, Lichtblau, Saxer, Calendo, Carta, Schneider, Berlier, Furian, Bloch, Schwarz and Ulrich.)

Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertension (PH) under ambient air and hypoxia. Methods: Patients with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) undergoing right heart catheterization were included in this randomized, placebo-controlled, double-blinded, crossover trial. The main outcome, pulmonary vascular resistance (PVR), further hemodynamics, blood- and cerebral oxygenation were measured 1 h after intravenous administration of 500 mg acetazolamide or placebo-saline on ambient air (normoxia) and at the end of breathing hypoxic gas (F I O 2 0.15, hypoxia) for 15 min. Results: 24 PH-patients, 71% men, mean ± SD age 59 ± 14 years, BMI 28 ± 5 kg/m 2 , PVR 4.7 ± 2.1 WU participated. Mean PVR after acetazolamide vs. placebo was 5.5 ± 3.0 vs. 5.3 ± 3.0 WU; mean difference (95% CI) 0.2 (-0.2-0.6, p = 0.341). Heart rate was higher after acetazolamide (79 ± 12 vs. 77 ± 11 bpm, p = 0.026), pH was lower (7.40 ± 0.02 vs. 7.42 ± 0.03, p = 0.002) but PaCO 2 and PaO 2 remained unchanged while cerebral tissue oxygenation increased (71 ± 6 vs. 69 ± 6%, p = 0.017). In acute hypoxia, acetazolamide decreased PVR by 0.4 WU (0.0-0.9, p = 0.046) while PaO 2 and PaCO 2 were not changed. No adverse effects occurred. Conclusions: In patients with PAH/CTEPH, i.v. acetazolamide did not change pulmonary hemodynamics compared to placebo after 1 hour in normoxia but it reduced PVR after subsequent acute exposure to hypoxia. Our findings in normoxia do not suggest a direct acute pulmonary vasodilator effect of acetazolamide. The reduction of PVR during hypoxia requires further corroboration. Whether acetazolamide improves PH when given over a prolonged period by stimulating ventilation, increasing oxygenation, and/or altering vascular inflammation and remodeling remains to be investigated., Competing Interests: SU reports grants from Johnson and Johnson SA, Switzerland, during the conduct of the study; grants from Zurich Lung, grants from Orpha Swiss, personal fees from Actelion SA, Switzerland, personal fees from MSD Switzerland, outside the submitted work. The remaining 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 © 2021 Lichtblau, Berlier, Saxer, Carta, Mayer, Groth, Bader, Schneider, Furian, Schwarz, Swenson, Bloch and Ulrich.)

Background: High-flow oxygen therapy (HFOT) provides oxygen-enriched, humidified, and heated air at high flow rates via nasal cannula. It could be an alternative to low-flow oxygen therapy (LFOT) which is commonly used by patients with chronic obstructive pulmonary disease (COPD) during exercise training. Research Question: We evaluated the hypothesis that HFOT improves exercise endurance in COPD patients compared to LFOT. Methods: Patients with stable COPD, FEV 1 40-80% predicted, resting pulse oximetry (SpO 2 ) ≥92%, performed two constant-load cycling exercise tests to exhaustion at 75% of maximal work rate on two different days, using LFOT (3 L/min) and HFOT (60 L/min, FiO 2 0.45) in randomized order according to a crossover design. Primary outcome was exercise endurance time, further outcomes were SpO 2 , breath rate and dyspnea. Results: In 79 randomized patients, mean ± SD age 58 ± 9 y, FEV 1 63 ± 9% predicted, GOLD grades 2-3, resting PaO 2 9.4 ± 1.0 kPa, intention-to-treat analysis revealed an endurance time of 688 ± 463 s with LFOT and 773 ± 471 s with HFOT, mean difference 85 s (95% CI: 7 to 164, P = 0.034), relative increase of 13% (95% CI: 1 to 28). At isotime, patients had lower respiratory rate and higher SpO 2 with HFOT. At end-exercise, SpO 2 was higher by 2% (95% CI: 2 to 2), and Borg CR10 dyspnea scores were lower by 0.8 points (95% CI: 0.3 to 1.2) compared to LFOT. Interpretation: In mildly hypoxemic patients with COPD, HFOT improved endurance time in association with higher arterial oxygen saturation, reduced respiratory rate and less dyspnea compared to LFOT. Therefore, HFOT is promising for enhancing exercise performance in COPD. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03955770., Competing Interests: KEB reports grants to his institution from the Swiss National Science Foundation, and the Bockhoff Foundation. The high-flow equipment was provided by Fisher & Paykel Healthcare, Switzerland; the oxygen concentrators were provided by Philips AG Respironics, Switzerland. The remaining 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 © 2021 Bitos, Furian, Mayer, Schneider, Buenzli, Mademilov, Sheraliev, Marazhapov, Abdraeva, Aidaralieva, Muratbekova, Sooronbaev, Ulrich and Bloch.)

Introduction: The purpose of the study was to establish spirometric reference values for a Central Asian population of highlanders and lowlanders. Methods: Spirometries from a population-based cross-sectional study performed in 2013 in rural areas of Kyrgyzstan were analyzed. Using multivariable linear regression, Global Lung Function Initiative (GLI) equations were fitted separately for men and women, and altitude of residence (700-800 m, 1,900-2,800 m) to data from healthy, never-smoking Kyrgyz adults. The general GLI equation was applied: Predicted value = e a 0 + a 1 ×  ln ( Height ) + a 2 ×  ln ( Age ) + b 1 ×  ln ( Age 100 ) + b 2 ×  ln ( Age 100 ) 2 + b 3 ×  ln ( Age 100 ) 3              + b 4 ×  ln ( Age 100 ) 4 + b 5 ×  ln ( Age 100 ) 5 Results: Of 2,784 screened Kyrgyz, 448 healthy, non-smoking highlanders (379 females) and 505 lowlanders (368 females), aged 18-91 years, were included. Predicted FVC in Kyrgyz fit best with GLI "North-East Asians," predicted FEV 1 fit best with GLI "Other/Mixed." Predicted FEV 1 /FVC was lower than that of all GLI categories. Age- and sex-adjusted mean FVC and FEV 1 were higher in highlanders (+0.138l, +0.132l) than in lowlanders ( P < 0.001, all comparisons), but FEV 1 /FVC was similar. Conclusion: We established prediction equations for an adult Central Asian population indicating that FVC is similar to GLI "North-East Asian" and FEV 1 /FVC is lower than in all other GLI population categories, consistent with a relatively smaller airway caliber. Central Asian highlanders have significantly greater dynamic lung volumes compared to lowlanders, which may be due to environmental and various other effects., (Copyright © 2020 Ulrich, Furian, Estebesova, Toktogulova, Beishekeeva, Ulrich, Burney, Sooronbaev and Bloch.)