Arcangelo F. Carta

Background and aims: Exercise capacity is limited in patients with pulmonary vascular disease (PVD) exposed to high altitude. The PVD-drug sildenafil, a phospodiesterase-5 inhibitor, has improved exercise capacity and hemodynamics in healthy exposed to hypoxia. This study examined effects of additive sildenafil on pulmonary hemodynamics during rest and exercise in PVD exposed to normobaric hypoxia. Method: PVD-patients diagnosed as pulmonary arterial or chronic thromboembolic pulmonary hypertension underwent right heart catheterization assessed at rest and during mild exercise while breathing hypoxic air (FiO2 15%) in a sequence-randomized crossover design. Main outcomes were mean pulmonary artery pressure (mPAP), cardiac output (CO) and mPAP/CO-slope before and ∼60 min after additive sildenafil (50 mg oral). Results: 22 patients were included, 64% had PAH and 36% CTEPH; 41% were female with mean± sd age 54±14 y, and a BMI of 26.3±4.0 kg·m ⁻² . 73% received PH targeted therapy and 56% were on double or triple combination therapy. MPAP remained unchanged at rest, while it was significantly lower at end-exercise compared to the values without sildenafil. The mPAP/CO slope during exercise in hypoxia was reduced with additive sildenafil from 9.9±5.1 to 8.2±4.1 mmHg (mean difference (95% CI) of −1.9 (−3.8 to −0.1) mmHg, p=0.043). Conclusions: In PVD patients exposed to normobaric hypoxia, additional 50 mg of oral sildenafil improves exercise pulmonary hemodynamics. Whether the improved hemodynamics would translate into better tolerance or an enhancement in exercise capacity during hypoxia exposure needs to be studied further.

Aim: We investigated the effect of an overnight-stay at high altitude (HA, 2500 m) on constant work-rate exercise test (CWRET) time and cardiorespiratory function in patients with pulmonary vascular disease (PVD) and the impact of supplemental oxygen therapy (SOT) in case of severe altitude-induced hypoxemia. Methods: In a randomized crossover trial, stable patients diagnosed with pulmonary arterial or distal chronic thromboembolic pulmonary hypertension (PVD, PAH/CTEPH) performed a symptom-limited cycling CWRET at 470 m and after an overnight stay at 2500 m. For safety, patients with a SpO ₂ 30 min received SOT during the subsequent HA-stay. The primary outcome was CWRET-time, secondary outcomes were changes in ergospirometric parameters. Clinicaltrials.gov: NCT05107700 &NCT05112172. Results: Of 27 PVD-patients (44% female; mean age 62±14 y, 20 PAH, 7 distal CTEPH), 10 (37%) required SOT. Overall at HA versus 470 m, CWRET-time decreased to 292±181 s versus 454±411 s (mean difference −162 s, 95%CI −290 to −34 s; p=0.026), driven by patients without need for SOT (261±187 s versus 519±497 s; p=0.017), who revealed lower resting PaO ₂ (7.4±0.7 kPa versus 10.6±1.4 kPa, p2 -desaturation was not significantly different (−0.9%, 95%CI −3.9 to 2). In 10/27 patients needing SOT, SOT restored CWRET time to 470 m-values (344±170 s versus 345±167 s; p=0.990), corrected altitude-induced hypoxemia and attenuated hyperventilation. Conclusion: The majority of PVD-patients tolerated an overnight stay at 2500 m well. In those without need for SOT at HA, CWRET-time was reduced with increased hypoxemia and hyperventilation. In PVD-patients who received SOT due to severe nocturnal hypoxemia, SOT restored CWRET-time to 470 m levels and dampened the exercise-induced hypoxemia.

Background: In patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension (summarized as pulmonary vascular disease; PVD), it is unclear whether the brain is protected against acute hypoxia and whether acute pulmonary vascular dilatation by sildenafil would influence cerebral and muscle tissue oxygenation whilst breathing normoxia or hypoxia. Methods: Adult patients with PVD underwent right heart catheterization, while cerebral and muscular tissue oxygenation and tissue hemoglobin index were measured using near-infrared spectroscopy along with arterial and mixed-venous blood gases. Participants underwent a four-stage protocol in which they were blinded to breathing either normoxia (FiO₂ 0.21) or normobaric hypoxia (FiO₂ 0.15), both before and after a single oral dose of sildenafil (50 mg) according to a randomized, cross-over design. Results: In 22 PVD patients (9 women, age 54 ± 14 y) under hypoxia, mean cerebral tissue oxygenation decreased by −2% (95% CI −4 to 0%, p = 0.046), muscular tissue oxygenation by −1% (95% CI −3 to 0%, p = 0.011) and mean arterial partial pressure of oxygen by −2.3 kPa (95% CI −2.7 to −1.8 kPa, p < 0.0001). Sildenafil improved the cerebral tissue hemoglobin index under hypoxia compared to hypoxia without sildenafil by 0.12 (95% CI 0.00 to 0.23, p = 0.049), but not the muscular tissue hemoglobin index. Conclusions: In PVD patients, acute exposure to normobaric hypoxia leads to a reduction in arterial oxygenation as well as cerebral and muscular tissue oxygenation. Sildenafil improves cerebral blood flow but has no effect on arterial, cerebral or muscular oxygenation.

Rational: Patients with pulmonary vascular disease often reveal nocturnal hypoxemia and sleep apnea. We investigated whether exposure to high altitude worsens those conditions. Methods and Objectives: In a randomized controlled crossover trial, stable patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension without resting hypoxemia (arterial oxygen pressure, >8 kPa at low altitude) underwent respiratory polygraphy at 470 meters and during an overnight stay at 2,500 meters. Patients with severe hypoxemia (oxygen saturation as measured by pulse oximetry [SpO2], 30 min) at 2,500 meters received supplemental oxygen therapy (SOT) according to safety criteria. The main outcomes were the number of patients who did not require SOT, the effect of high altitude on nocturnal SpO2, oxygen desaturation index (ΔSpO2, ⩾3%), apnea–hypopnea index, and the effect of SOT. Results: Of 27 patients (44% women; 20/7 pulmonary arterial hypertension/chronic thromboembolic pulmonary hypertension; mean ± standard deviation age, 62 ± 14 y), 10 (37%) required SOT during the course of the night (P = 0.008 vs. low altitude). At 2,500 meters versus 470 meters, mean nocturnal SpO2 on ambient air decreased from 91 ± 2% to 83 ± 4% (mean change [95% confidence interval], −8% [−9 to −6]; P < 0.001), time with SpO2 <90% increased from 29 ± 27% to 92 ± 15% (+63% [30 to 92]; P < 0.001), and the oxygen desaturation index increased from 17 ± 14 events/h to 42 ± 26 events/h (+24.8 events/h [12.8 to 36.5]; P < 0.001), but the apnea–hypopnea index remained unchanged. With SOT, SpO2 was restored to values at 470 meters. Conclusions: In stable, low-risk patients with pulmonary vascular disease, altitude worsened nocturnal hypoxemia but not sleep-disordered breathing. The majority of patients did not require SOT according to predefined safety criteria. When needed, SOT restored low-altitude indices of oxygenation. Clinical trial registered with www.clinicaltrials.gov (NCT05089487).

Background: The aim of this study was to investigate the acute effect of acetazolamide on pulmonary haemodynamics during exercise in patients with pulmonary vascular disease (PVD). Methods: Patients with PVD diagnosed as pulmonary arterial (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) underwent right-heart catheterisation with haemodynamic measurements at rest and during stepwise incremental cycling exercise 60 min after receiving intravenous acetazolamide (500 mg) or saline placebo in accordance with a double-blind, randomised-controlled, crossover design. The main outcomes were the difference between pulmonary vascular resistance (PVR) and its components mean pulmonary artery pressure (mPAP), cardiac output (CO) and pulmonary arterial wedge pressure (PAWP), during exercise, assessed by a mixed linear regression analysis. Results: A total of 24 patients (n=7 PAH, n=17 CTEPH; n=17 male) were included (mean± sd age 59±14 years). Treatment with acetazolamide compared with saline placebo showed the following average marginal effects during exercise: unchanged end-exercise power (mean difference −0.8 W, 95% CI −5.7–4.1 W; p=0.740), reduced mPAP (mean difference −1.7 mmHg, 95% CI −2.9– −0.5 mmHg; p=0.007), tendency to reduced CO (mean difference −0.3 L·min ⁻¹ , 95% CI −0.7–0.1 L·min ⁻¹ ; p=0.097), unchanged PVR (mean difference −0.1 Wood units (WU), 95% CI −0.3–0.2 WU; p=0.694), unchanged PAWP (mean difference 0.0 mmHg, 95% CI −0.2–0.3 mmHg; p=0.783) and unchanged mPAP/CO slope (mean difference 0.1 WU, 95% CI −1.0–1.3 WU; p=0.839). Conclusion: Intravenous acetazolamide was well tolerated and resulted in a significant but small decrease in mPAP, while CO, PVR and the pressure–flow slope during exercise were unchanged.

Stable-treated patients with pulmonary vascular disease (PVD) defined as pulmonary arterial or distal chronic thromboembolic pulmonary hypertension (PAH/CTEPH) wish to participate in daily activities including travel to high altitude or by air, but may be at increased risk of adverse events at high altitude (AE_HA).^1,2 Thus, pulmonary hypertension (PH) guidelines recommend that symptomatic PVD patients should not travel >1500 m or fly without supplemental oxygen therapy (SOT),³ but evidence is scarce and ambiguous.⁴

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.

Background: We previously showed that COPD patients can timely detect impending altitude-related adverse health effects (ARAHE) by structured self-monitoring (SSM) of symptoms and pulse oximetry (SpO2). In the current trial, we investigated whether acetazolamide therapy started in COPD patients testing SSM positive during altitude travel prevents ARAHE. Methods: This randomized, placebo-controlled, double blind, parallel trial included COPD patients, FEV1 40-80%pred, SpO2≥92%, PaCO2<6kPa at altitude of residence (<800m). Patients traveled by bus to a clinic at 3100m and stayed there for 2 days. At 3100m, patients performed SSM (4 times/day). Those testing SSM positive (based on predefined symptoms and/or SpO2<85%) were randomized to subsequent placebo or acetazolamide (375mg/d) therapy. The incidence of ARAHE (primary outcome, defined as severe acute mountain sickness, SpO230min, or need of medical treatment for other reason) was observed during the further stay at 3100m. ClinicalTrials.gov NCT04913389. Results: Of 241 COPD patients travelling to 3100m, 157 (72 women), mean±SD age 59±9y, FEV1 61±12%pred, turned SSM positive and were randomized. During the subsequent stay at 3100m, ARAHE occurred in 60 of 81 (74%) patients taking placebo and in 38 of 76 (50%) patients taking acetazolamide (P=0.002), number needed to treat 3.9 (95%CI 2.5 to 10.5); odds ratio 0.35 (95%CI 0.18 to 0.68). Acetazolamide was well tolerated, no serious adverse event occurred. Conclusion: In lowlanders with COPD, travelling to 3100m, SSM-guided preventive acetazolamide therapy reduced the incidence of ARAHE. This novel approach may allow to restrict the use of preventive acetazolamide therapy to patients at risk.

Investigation of pulmonary gas exchange efficacy usually requires arterial blood gas analysis (aBGA) to determine arterial partial pressure of oxygen (mPaO₂) and compute the Riley alveolar-to-arterial oxygen difference (A-aDO₂); that is a demanding and invasive procedure. A noninvasive approach (AGM100), allowing the calculation of PaO₂ (cPaO₂) derived from pulse oximetry (SpO₂), has been developed, but this has not been validated in a large cohort of chronic obstructive pulmonary disease (COPD) patients. Our aim was to conduct a validation study of the AG100 in hypoxemic moderate-to-severe COPD. Concurrent measurements of cPaO₂ (AGM100) and mPaO₂ (EPOC, portable aBGA device) were performed in 131 moderate-to-severe COPD patients (mean ±SD FEV₁: 60 ± 10% of predicted value) and low-altitude residents, becoming hypoxemic (i.e., SpO₂ < 94%) during a short stay at 3100 m (Too-Ashu, Kyrgyzstan). Agreements between cPaO₂ (AGM100) and mPaO₂ (EPOC) and between the O₂-deficit (calculated as the difference between end-tidal pressure of O₂ and cPaO₂ by the AGM100) and Riley A-aDO₂ were assessed. Mean bias (±SD) between cPaO₂ and mPaO₂ was 2.0 ± 4.6 mmHg (95% Confidence Interval (CI): 1.2 to 2.8 mmHg) with 95% limits of agreement (LoA): −7.1 to 11.1 mmHg. In multivariable analysis, larger body mass index (p = 0.046), an increase in SpO₂ (p < 0.001), and an increase in PaCO₂-PETCO₂ difference (p < 0.001) were associated with imprecision (i.e., the discrepancy between cPaO₂ and mPaO₂). The positive predictive value of cPaO₂ to detect severe hypoxemia (i.e., PaO₂ ≤ 55 mmHg) was 0.94 (95% CI: 0.87 to 0.98) with a positive likelihood ratio of 3.77 (95% CI: 1.71 to 8.33). The mean bias between O₂-deficit and A-aDO₂ was 6.2 ± 5.5 mmHg (95% CI: 5.3 to 7.2 mmHg; 95%LoA: −4.5 to 17.0 mmHg). AGM100 provided an accurate estimate of PaO₂ in hypoxemic patients with COPD, but the precision for individual values was modest. This device is promising for noninvasive assessment of pulmonary gas exchange efficacy in COPD patients.