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.

Change in Right-to-Left Shunt Fraction in Patients with Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Endarterectomy.

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.

Pulmonary arterial wedge pressure increase during exercise in patients diagnosed with pulmonary arterial or chronic thromboembolic pulmonary hypertension.

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.

Hyperoxia improves exercise capacity in cardiopulmonary disease: a series of randomised controlled trials.

Background: The aim of this study was to investigate the overall and differential effect of breathing hyperoxia (inspiratory oxygen fraction (F IO2 ) 0.5) versus placebo (ambient air, F IO2 0.21) to enhance exercise performance in healthy people, patients with pulmonary vascular disease (PVD) with precapillary pulmonary hypertension (PH), COPD, PH due to heart failure with preserved ejection fraction (HFpEF) and cyanotic congenital heart disease (CHD) using data from five randomised controlled trials performed with identical protocols. Methods: 91 subjects (32 healthy, 22 with PVD with pulmonary arterial or distal chronic thromboembolic PH, 20 with COPD, 10 with PH in HFpEF and seven with CHD) performed two cycle incremental (IET) and two constant work-rate exercise tests (CWRET) at 75% of maximal load (Wmax), each with ambient air and hyperoxia in single-blinded, randomised, controlled, crossover trials. The main outcomes were differences in Wmax (IET) and cycling time (CWRET) with hyperoxia versus ambient air. Results: Overall, hyperoxia increased Wmax by +12 W (95% CI: 9-16, p<0.001) and cycling time by +6:13 min (4:50-7:35, p<0.001), with improvements being highest in patients with PVD (Wmax/min: +18%/+118% versus COPD: +8%/+60%, healthy: +5%/+44%, HFpEF: +6%/+28%, CHD: +9%/+14%). Conclusion: This large sample of healthy subjects and patients with various cardiopulmonary diseases confirms that hyperoxia significantly prolongs cycling exercise with improvements being highest in endurance CWRET and patients with PVD. These results call for studies investigating optimal oxygen levels to prolong exercise time and effects on training.

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

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

Oxygen Therapy in Pulmonary Vascular Disease: A Systematic Review, Meta-Analysis, and Comment.

Main pulmonary vascular diseases (PVD) with precapillary pulmonary hypertension (PH) are pulmonary arterial and chronic thromboembolic PH. Guidelines recommend supplemental oxygen therapy (SOT) for severely hypoxemic patients with PH, but evidence is scarce. The authors performed a systematic review and where possible meta-analyses on the effects of SOT on hemodynamics and exercise performance in patients with PVD. In PVD, short-term SOT significantly improved mean pulmonary artery pressure and exercise performance. There is growing evidence on the benefit of long-term SOT for selected patients with PVD regarding exercise capacity and maybe even survival.

Effects of Acute Hypoxia on Heart Rate Variability in Patients with Pulmonary Vascular Disease.

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 PaO2 ≥ 7.3 kPa) were exposed to ambient air (FiO2 = 21%) and normobaric hypoxia (FiO2 = 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) ms2; p < 0.01) and low-frequency (LF; 558.60 (746.10) vs. 203.90 (425.63) ms2; 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.

Clinician's Corner: Counseling Patients with Pulmonary Vascular Disease Traveling to High Altitude.

Ulrich, Silvia, Mona Lichtblau, Simon R. Schneider, Stéphanie Saxer, and Konrad E. Bloch, Clinician's corner: counseling patients with pulmonary vascular disease traveling to high altitude. High Alt Med Biol. 23:201-208, 2022.-Pulmonary vascular diseases (PVDs) with precapillary pulmonary hypertension (PH), such as pulmonary arterial or chronic thromboembolic PH, impair exercise performance and survival in patients. Vasodilators and other treatments improve quality of life and prognosis to an extent in patients who have PVDs as chronic disorders. Obviously, patients with PVD wish to participate in usual daily activities, including travel to popular settlements and mountainous regions located at high altitude. However, the pulmonary hemodynamic impairment due to PVD leads to blood and tissue hypoxia, particularly during exercise and sleep. It is thus of concern that alveolar hypoxia at higher altitude may exacerbate patients' symptoms and lead to decompensation. Current PH guidelines discourage high-altitude exposure for fear of altitude-related adverse health effects. However, several recent well-designed prospective and randomized trials show that despite altitude-induced hypoxemia, pulmonary hemodynamic changes and impairment of exercise performance in patients with PVD are similar to the responses in healthy people or in patients with mild chronic obstructive pulmonary disease. The vast majority of patients with PVD can tolerate short-term exposure to moderate altitudes up to 2,500 m. For the roughly 10% of patients with stable disease who develop severe hypoxemia when ascending to 2,500 m, they respond well to low-level supplemental oxygen support. The best low-altitude predictors for adverse health effects at high altitude are the known clinical risk factors for PVD such as symptoms, functional class, exercise capacity, and exertional oxygen desaturation, whereas hypoxia altitude simulation testing is of little additive value. In any case, patients should be instructed that altitude-related adverse health effects may be difficult to predict and that in case of worsening symptoms, immediate accompanied descent to lower altitude and oxygen therapy are required. Patients with severe hypoxemia near sea level may safely visit high-altitude regions up to 1,500-2,000 m while continuing oxygen therapy and avoiding strenuous exercise. All PH patients should be counseled before any high-altitude sojourn by doctors with experience in PVD and high-altitude medicine and have an action plan for the occurrence of severe hypoxemia and other altitude-related conditions such as acute mountain sickness.

Prediction of maximal oxygen uptake from 6-min walk test in pulmonary hypertension.

Maximal oxygen uptake (V'O2 max), assessed by cardiopulmonary exercise testing (CPET), is an important parameter for risk assessment in patients with pulmonary hypertension (PH). However, CPET may not be available for all PH patients. Thus, we aimed to test previously published predictive models of V'O2 max from the 6-min walk distance (6MWD) for their accuracy and to create a new model. We tested four models (two by Ross et al. (2010), one by Miyamoto et al. (2000) and one by Zapico et al. (2019)). To derive a new model, data were split into a training and testing dataset (70:30) and step-wise linear regression was performed. To compare the different models, the standard error of the estimate (SEE) was calculated and the models graphically compared by Bland-Altman plots. Sensitivity and specificity for correct prediction into low-risk classification (V'O2 max >15 mL/min/kg) was calculated for all models. A total of 276 observations were included in the analysis (194/82 training/testing dataset); 6MWD and V'O2 max were significantly correlated (r=0.65, p<0.001). Linear regression showed significant correlation of 6MWD, weight and heart rate response (HRR) with V'O2 max and the best fitting prediction equation was: V'O2 max = 1.83 + 0.031 × 6MWD (m) - 0.023 × weight (kg) - 0.015 × HRR (bpm). SEEs for the different models were 3.03, 3.22, 4.36 and 3.08 mL/min/kg for the Ross et al., Miyamoto et al., Zapico et al. models and the new model, respectively. Predicted mean V'O2 max was 16.5 mL/min/kg (versus observed 16.1 mL/min/kg). 6MWD and V'O2 max reveal good correlation in all models. However, the accuracy of all models is inadequate for clinical use. Thus, CPET and 6MWD both remain valuable risk assessment tools in the management of PH.

Cardiorespiratory Adaptation to Short-Term Exposure to Altitude vs. Normobaric Hypoxia in Patients with Pulmonary Hypertension.

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).

Disease characteristics and clinical outcome over two decades from the Swiss pulmonary hypertension registry.

Pulmonary hypertension (PH), especially pulmonary arterial and chronic thromboembolic pulmonary hypertension (PAH/CTEPH), are rare and progressive conditions. Despite recent advances in treatment and prognosis, PH is still associated with impaired quality of life and survival. Long-term PH-registry data provide information on the changing PH-epidemiology and may help to direct resources to patient's needs. This retrospective analysis of the Swiss Pulmonary Hypertension Registry includes patients newly diagnosed with PH (mainly PAH/CTEPH) registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient characteristics (age, body mass index, gender, diagnosis), hemodynamics at baseline, treatment, days of follow-up, and events (death, transplantation, pulmonary endarterectomy, or loss to follow-up) at last visit were analyzed. Patients were stratified into four time periods according to their date of diagnosis. Survival was analyzed overall and separately for PAH/CTEPH and time periods. 1427 PH patients were included (thereof 560 PAH, 383 CTEPH). Over the years, age at baseline (mean ± SD) significantly increased from 59 ± 14 years in 2001-2005 to 66 ± 14 years in 2016-2019 (p < 0.001) while the gender distribution tended toward equality. Mean pulmonary artery pressure and pulmonary vascular resistance significantly decreased over time (from 46 ± 15 to 41 ± 11 mmHg, respectively, 9 ± 5 to 7 ± 4 WU, p < 0.001). Three-year survival substantially increased over consecutive periods from 69% to 91% (for PAH 63%-95%, for CTEPH 86%-93%) and was poorer in PAH than CTEPH independently of time period (p < 0.001). Most patients were treated with mono- or combination therapy and an increasing number of CTEPH underwent pulmonary endarterectomy (40% 2016-2019 vs. 15% 2001-2005). This long-term PH registry reveals that over two decades of observation, newly diagnosed patients are older, less predominantly female, have less impaired hemodynamics and a better survival.

The Impact of Breathing Hypoxic Gas and Oxygen on Pulmonary Hemodynamics in Patients With Pulmonary Hypertension.

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 (FiO2) 0.21], hypoxia (FiO2 0.15), and hyperoxia (FiO2 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 FiO2.

Influence of Upright Versus Supine Position on Resting and Exercise Hemodynamics in Patients Assessed for Pulmonary Hypertension.

Background The aim of the present work was to study the influence of body position on resting and exercise pulmonary hemodynamics in patients assessed for pulmonary hypertension (PH). Methods and Results Data from 483 patients with suspected PH undergoing right heart catheterization for clinical indications (62% women, age 61±15 years, 246 precapillary PH, 48 postcapillary PH, 106 exercise PH, 83 no PH) were analyzed; 213 patients (main cohort, years 2016-2018) were examined at rest in upright (45°) and supine position, such as under upright exercise. Upright exercise hemodynamics were compared with 270 patients (historical cohort) undergoing supine exercise with the same protocol. Upright versus supine resting data revealed a lower mean pulmonary artery pressure 31±14 versus 32±13 mm Hg, pulmonary artery wedge pressure 11±4 versus 12±5 mm Hg, and cardiac index 2.9±0.7 versus 3.1±0.8 L/min per m2, and higher pulmonary vascular resistance 4.1±3.1 versus 3.9±2.8 Wood P<0.001. Exercise data upright versus supine revealed higher work rates (53±26 versus 33±22 watt), and adjusting for differences in work rate and baseline values, higher end-exercise mean pulmonary artery pressure (52±19 versus 45±16 mm Hg, P=0.001), similar pulmonary artery wedge pressure and cardiac index, higher pulmonary vascular resistance (5.4±3.7 versus 4.5±3.4 Wood units, P=0.002), and higher mean pulmonary artery pressure/cardiac output (7.9±4.7 versus 7.1±4.1 Wood units, P=0.001). Conclusions Body position significantly affects resting and exercise pulmonary hemodynamics with a higher pulmonary vascular resistance of about 10% in upright versus supine position at rest and end-exercise, and should be considered and reported when assessing PH.

Effect of oxygen therapy on exercise performance in patients with cyanotic congenital heart disease: Randomized-controlled trial.

BACKGROUND: Patients with unrepaired cyanotic congenital heart disease (CHD) suffer from aggravated hypoxemia during exercise. We tested the hypothesis that supplemental oxygen improves exercise performance in these patients. METHODS: In this randomized, sham-controlled, single-blind, cross-over trial cyanotic CHD-patients underwent four cycle exercise tests to exhaustion, while breathing either oxygen-enriched (FiO2 0.50, oxygen) or ambient air (FiO2 0.21, air) using incremental (IET) or constant work-rate (CWRET) exercise test protocols (75% of maximal work rate achieved under FiO2 0.21). Pulmonary gas-exchange, electrocardiogram, arterial blood gases, oxygen saturation (SpO2), cerebral and quadriceps muscle tissue oxygenation (CTO and QMTO) by near-infrared spectroscopy were measured. RESULTS: We included seven patients with cyanotic CHD (4 Eisenmenger syndrome, 3 unrepaired cyanotic defects, 4 women) median (quartiles) age 36 (32;50) years, BMI 23 (20;26) kg/m2 and SpO2 at rest 87 (83;89) %. When comparing supplemental oxygen with air during exercise, maximal work-rate in IET increased from 76 (58;114) Watts to 83 (67;136) Watts, median difference 9 (0;22) W (p = 0.046) and CWRET-time increased from 412 s (325;490) to 468 s (415;553), median increase 56 (39;126) s (p = 0.018). In both IET and CWRET SpO2 was significantly higher and ventilatory equivalent for carbon dioxide significantly lower at end-exercise with oxygen compared to air, whereas CTO and QMTO did not significantly differ. CONCLUSIONS: Patients with cyanotic CHD significantly improved their exercise performance, in terms of maximal work-rate and endurance time along with an improved arterial oxygenation and ventilatory efficiency with supplemental oxygen compared to air.

Comparison of Repetitive Cardiac Output Measurements at Rest and End-Exercise by Direct Fick Using Pulse Oximetry vs. Blood Gases in Patients With Pulmonary Hypertension.

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.

Effect of a day-trip to altitude (2500†m) on exercise performance in pulmonary hypertension: randomised crossover trial.

QUESTION ADDRESSED BY THE STUDY: To investigate exercise performance and hypoxia-related health effects in patients with pulmonary hypertension (PH) during a high-altitude sojourn. PATIENTS AND METHODS: In a randomised crossover trial in stable (same therapy for >4 weeks) patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) with resting arterial oxygen tension (P aO2 ) ≥7.3 kPa, we compared symptom-limited constant work-rate exercise test (CWRET) cycling time during a day-trip to 2500 m versus 470 m. Further outcomes were symptoms, oxygenation and echocardiography. For safety, patients with sustained hypoxaemia at altitude (peripheral oxygen saturation <80% for >30 min or <75% for >15 min) received oxygen therapy. RESULTS: 28 PAH/CTEPH patients (n=15/n=13); 13 females; mean±sd age 63±15 years were included. After >3 h at 2500 m versus 470 m, CWRET-time was reduced to 17±11 versus 24±9 min (mean difference -6, 95% CI -10 to -3), corresponding to -27.6% (-41.1 to -14.1; p<0.001), but similar Borg dyspnoea scale. At altitude, P aO2 was significantly lower (7.3±0.8 versus 10.4±1.5 kPa; mean difference -3.2 kPa, 95% CI -3.6 to -2.8 kPa), whereas heart rate and tricuspid regurgitation pressure gradient (TRPG) were higher (86±18 versus 71±16 beats·min-1, mean difference 15 beats·min-1, 95% CI 7 to 23 beats·min-1) and 56±25 versus 40±15 mmHg (mean difference 17 mmHg, 95% CI 9 to 24 mmHg), respectively, and remained so until end-exercise (all p<0.001). The TRPG/cardiac output slope during exercise was similar at both altitudes. Overall, three (11%) out of 28 patients received oxygen at 2500 m due to hypoxaemia. CONCLUSION: This randomised crossover study showed that the majority of PH patients tolerate a day-trip to 2500 m well. At high versus low altitude, the mean exercise time was reduced, albeit with a high interindividual variability, and pulmonary artery pressure at rest and during exercise increased, but pressure-flow slope and dyspnoea were unchanged.

Effect of Breathing Oxygen-Enriched Air on Exercise Performance in Patients With Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction: A Randomized, Placebo-Controlled, Crossover Trial.

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 SpO2 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 (FiO2 0.21) and oxygen (FiO2 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 SpO2, minute ventilation (V'E), carbon dioxide output (V'CO2), 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'CO2 were lower, whereas PaO2 and end-tidal PaCO2 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].

Acute Hemodynamic Effect of Acetazolamide in Patients With Pulmonary Hypertension Whilst Breathing Normoxic and Hypoxic Gas: A Randomized Cross-Over Trial.

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 (FIO2 0.15, hypoxia) for 15 min. Results: 24 PH-patients, 71% men, mean ± SD age 59 ± 14 years, BMI 28 ± 5 kg/m2, 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 PaCO2 and PaO2 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 PaO2 and PaCO2 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.

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

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

Effect of Nocturnal Oxygen Therapy on Daytime Pulmonary Hemodynamics in Patients With Chronic Obstructive Pulmonary Disease Traveling to Altitude: A Randomized Controlled Trial.

INTRODUCTION: We investigated whether nocturnal oxygen therapy (NOT) mitigates the increase of pulmonary artery pressure in patients during daytime with chronic obstructive pulmonary disease (COPD) traveling to altitude. METHODS: Patients with COPD living below 800 m underwent examinations at 490 m and during two sojourns at 2,048 m (with a washout period of 2 weeks < 800 m between altitude sojourns). During nights at altitude, patients received either NOT (3 L/min) or placebo (ambient air 3 L/min) via nasal cannula according to a randomized crossover design. The main outcomes were the tricuspid regurgitation pressure gradient (TRPG) measured by echocardiography on the second day at altitude (under ambient air) and various other echocardiographic measures of the right and left heart function. Patients fulfilling predefined safety criteria were withdrawn from the study. RESULTS: Twenty-three COPD patients [70% Global Initiative for Chronic Obstructive Lung Disease (GOLD) II/30% GOLD III, mean ± SD age 66 ± 5 years, FEV1 54% ± 13% predicted] were included in the per-protocol analysis. TRPG significantly increased when patients traveled to altitude (from low altitude 21.7 ± 5.2 mmHg to 2,048 m placebo 27.4 ± 7.3 mmHg and 2,048 m NOT 27.8 ± 8.3 mmHg) difference between interventions (mean difference 0.4 mmHg, 95% CI -2.1 to 3.0, p = 0.736). The tricuspid annular plane systolic excursion was significantly higher after NOT vs. placebo [2.6 ± 0.6 vs. 2.3 ± 0.4 cm, mean difference (95% confidence interval) 0.3 (0.1 - 0.5) cm, p = 0.005]. During visits to 2,048 m until 24 h after descent, eight patients (26%) using placebo and one (4%) using NOT had to be withdrawn because of altitude-related adverse health effects (p < 0.001). CONCLUSION: In lowlanders with COPD remaining free of clinically relevant altitude-related adverse health effects, changes in daytime pulmonary hemodynamics during a stay at high altitude were trivial and not modified by NOT. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02150590.