Impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and idiopathic interstitial pneumonia: A post hoc subgroup analysis of the RISE-IIP study.

BACKGROUND: Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography, and associated clinical outcomes. METHODS: Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. RESULTS: Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance, and high forced vital capacity:DLCO ratio at baseline also appeared to be risk factors for mortality. CONCLUSIONS: High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.

Patient and disease characteristics of the first 500 patients with pulmonary arterial hypertension treated with selexipag in real-world settings from SPHERE.

BACKGROUND: Selexipag is a selective oral prostacyclin receptor agonist indicated for pulmonary arterial hypertension (PAH) treatment. SelexiPag: tHe usErs dRug rEgistry (SPHERE) (NCT03278002) is collecting data from selexipag-treated patients in real-world clinical practice to elucidate and describe the clinical characteristics, outcomes, and dosing/titration regimens of patients treated with selexipag in routine clinical practice. METHODS: SPHERE is a United States (US)-based, ongoing, multicenter, prospective observational study (target N = 800). This study enrolls patients who are either newly initiated on selexipag (≤60 days before enrollment) or were previously receiving selexipag with documentation of dose titration at study enrollment. Data collection for the study occurs at routine clinic visits. In this paper, we report on the first 500 patients enrolled. RESULTS: Median follow-up was 17.8 months; 77.6% of patients completed the planned 18 months follow-up, and 22.4% discontinued early from the study. At diagnosis, 94.8% of patients had PAH (World Health Organization [WHO] Group 1), most commonly idiopathic (49.2%) and connective tissue disease associated (26.4%). Most patients (72.4%) initiated selexipag more than 60 days before enrollment. At initiation, 31.0% of patients had WHO functional class (FC) II disease, and 49.6% had WHO FC II or III disease. In addition, 55.0% of patients were receiving double therapy (most commonly an endothelin receptor antagonist plus phosphodiesterase type 5 inhibitor [42.3%]), whereas 30.6% were receiving monotherapy. Despite most patients already receiving PAH-specific therapy, at selexipag initiation, 67.2% (336 of 500) were at intermediate risk, and 9.6% (48 of 500) were at high risk of 1-year mortality. Risk scores remained stable in ∼55% of patients and improved in ∼20% at the end of the study. In total, 72.2% of patients had at least 1 adverse event (AE), and 37.6% reported a serious AE. The median selexipag maintenance dose was 1,200 µg twice daily (interquartile range: 800-1,600 µg twice daily). CONCLUSIONS: Real-world, US-based patients with PAH initiating selexipag typically have WHO FC II/III disease and are at intermediate risk, despite receiving PAH-specific treatment. Selexipag was prescribed as part of a combination regimen in most patients. The study identified no unexpected adverse effects.

Relationship Between Time From Diagnosis and Morbidity/Mortality in Pulmonary Arterial Hypertension: Results From the Phase III GRIPHON Study.

BACKGROUND: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined. RESEARCH QUESTION: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH? STUDY DESIGN AND METHODS: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models. RESULTS: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction). INTERPRETATION: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov.

Phosgene inhalation toxicity: Update on mechanisms and mechanism-based treatment strategies.

Phosgene (carbonyl dichloride) gas is an indispensable high-production-volume chemical intermediate used worldwide in numerous industrial processes. Published evidence of human exposures due to accidents and warfare (World War I) has been reported; however, these reports often lack specificity because of the uncharacterized exposure intensities of phosgene and/or related irritants. These may include liquid or solid congeners of phosgene, including di- and triphosgene and/or the respiratory tract irritant chlorine which are often collectively reported under the umbrella of phosgene exposure without any appreciation of their differences in causing acute lung injury (ALI). Among these irritants, phosgene gas is somewhat unique because of its poor water solubility. This prevents any appreciable retention of the gas in the upper airways and related trigeminal sensations of irritation. By contrast, in the pulmonary compartment, amphiphilic surfactant might scavenge this lipophilic gas. The interaction of phosgene and the surfactant may affect basic physiological functions controlled by Starling's and Laplace's laws, which can be followed by cardiogenic pulmonary edema. The phenotypic manifestations are dependent on the concentration × exposure duration (C × t); the higher the C × t is, the less time that is required for edema to appear. It is hypothesized that this type of edema is caused by cardiovascular and colloid osmotic imbalances to initial neurogenic events but not because of the injury itself. Thus, hemodynamic etiologies appear to cause imbalances in extravasated fluids and solute accumulation in the pulmonary interstitium, which is not drained away by the lymphatic channels of the lung. The most salient associated findings are hemoconcentration and hypoproteinemia. The involved intertwined pathophysiological processes coordinating pulmonary ventilation and cardiopulmonary perfusion under such conditions are complex. Pulmonary arterial catheter measurements on phosgene-exposed dogs provided evidence of 'cor pulmonale', a form of acute right heart failure produced by a sudden increase in resistance to blood flow in the pulmonary circulation about 20 h postexposure. The objective of this review is to critically analyze evidence from experimental inhalation studies in rats and dogs, and evidence from accidental human exposures to better understand the primary and secondary events causing cardiopulmonary dysfunction and an ensuing life-threatening lung edema. Mechanism-based diagnostic and therapeutic approaches are also considered for this form of cardiogenic edema.

Platelet dysfunction in a large-animal model of endotoxic shock; effects of inhaled nitric oxide and low-dose steroid.

OBJECTIVE: The role of inhaled nitric oxide in the treatment of shock remains controversial and further translational research is needed. Long-term observation studies using a model of endotoxin-induced shock to assess the effect of inhaled nitric oxide on platelet aggregation have not yet been reported. APPROACH AND RESULTS: The tests were carried out in an animal model of shock in two 10-h periods. During the first 10 h, endotoxin was infused and the inhibition of platelet aggregation was evaluated; following the termination of endotoxin infusion, the restoration of platelet aggregation was assessed for 10 h. A total of 30 pigs were used (NO group, N = 14; control, N = 16). In the NO group, nitric oxide inhalation (30 ppm) was started 3 h after endotoxin infusion and continued until the end of the study. Treatment with NO selectively decreased pulmonary artery pressure at 4 (p = 0.002) and 8 h (p = 0.05) of the experiment as compared to the control. Endotoxin significantly reduced platelet aggregation, as indicated by the decreased activity of platelet receptors: ASPI, ADP, collagen, and TRAP during the experiment (p < 0.001). Endotoxin had no significant effect on changes in the response of the receptor after ristocetin stimulation. After stopping endotoxin infusion, a significant restoration of receptor activity was observed for collagen and TRAP, while ASPI and ADP remained partially depressed. Inhaled nitric oxide did not cause additional inhibition of platelet aggregation, either during or after endotoxin challenge. CONCLUSIONS: A profound reduction in platelet aggregation was observed during endotoxic shock. After stopping endotoxin infusion a restoration of platelet receptor activity was seen. The inhibition of platelet aggregation induced by endotoxin infusion was not intensified by nitric oxide, indicating there was no harmful effect of inhaled nitric oxide on platelet aggregation.

Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Inhibition of the sodium-glucose cotransporter-2 (SGLT2i) improves outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but the mechanism by which they improve outcomes remains unclear. OBJECTIVES: This study aimed to investigate the effects of sodium-glucose cotransporter-2 inhibitor empagliflozin on central hemodynamics in patients with HF and HFrEF. METHODS: This investigator-initiated, double-blinded, placebo-controlled, randomized trial enrolled 70 patients with HFrEF from March 6, 2018, to September 10, 2019. Patients were assigned to empagliflozin of 10 mg or matching placebo once daily on guideline-driven HF therapy for 12 weeks. The primary outcome was ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise after 12 weeks. Patients underwent right-heart catheterization at rest and during exercise at baseline and 12-week follow-up. RESULTS: Patients with HFrEF, mean age of 57 years, mean left-ventricular ejection fraction, 26%, and 12 (17%) with type 2 diabetes mellitus were randomized. There was no significant treatment effect on peak PCWP/CI (-0.13 mm Hg/l/min/m2; 95% confidence interval: -1.60 to 1.34 mm Hg/l/min/m2; p = 0.86). Considering hemodynamics over the full range of exercise loads, PCWP was significantly reduced (-2.40 mm Hg; 95% confidence interval: -3.96 to -0.84 mm Hg; p = 0.003), but not CI (-0.09 l/min/m2; 95% confidence interval: -0.14 to 0.32 l/min/m2; p = 0.448) by empagliflozin. This was consistent among patients with and without type 2 diabetes. CONCLUSIONS: Among patients with stable HFrEF, empagliflozin for 12 weeks reduced PCWP compared with placebo. There was no significant improvement in neither CI nor PCWP/CI at rest or exercise.

The Clinical Efficacy of Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension.

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.

Ambrisentan in portopulmonary hypertension: A multicenter, open-label trial.

BACKGROUND: Ambrisentan has shown effectiveness in the treatment of Group 1 pulmonary arterial hypertension (PAH). Although portopulmonary hypertension (PoPH) is a subset of Group 1 PAH, few clinical trials have been testing PAH therapies in patients with PoPH. The objective of this study is to evaluate the efficacy and safety of ambrisentan in PoPH. METHODS: This study is a prospective, multicenter, open-label trial in which treatment-naive patients with PoPH with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks). The primary end-points were change in pulmonary vascular resistance (PVR) and 6-minutes walk distance (6MWD) at 24 weeks, whereas secondary end-points included safety, World Health Organization (WHO) functional class (FC) and echocardiographic assessments. RESULTS: Of the 31 patients, 23 finished 24 weeks of ambrisentan therapy and 19 finished the extension. PVR decreased significantly (mean ± SD) (7.1 ± 5 vs 3.8 ± 1.8 Wood units, p < 0.001), whereas 6MWD remained unchanged (314 ± 94 vs 336 ± 108 m). Other hemodynamic parameters such as right atrial pressure (13 ± 8 vs 9 ± 4 mm Hg, p < 0.05), mean pulmonary arterial pressure (46 ± 13 vs. 38 ± 8 mm Hg, p < 0.01), cardiac index (2.6 ± 0.6 vs. 3.5 ± 0.7 liter/min/m2, p < 0.001) showed improvement, whereas pulmonary capillary wedge pressure remained unchanged. Of the 22 patients with WHO FC assessments at baseline and 24 weeks, WHO FC improved significantly (p = 0.005). Most frequent drug-related adverse events were edema (38.7%) and headache (22.5%). One episode of leg edema resulted into the permanent discontinuation of ambrisentan. CONCLUSIONS: Ambrisentan monotherapy in PoPH improves hemodynamics and FC at 24 weeks; however, it did not show any improvement in 6MWD. These preliminary outcomes should be interpreted with caution (Clinicaltrials.Gov:NCT01224210).

Risk assessment in pulmonary arterial hypertension: Insights from the GRIPHON study.

BACKGROUND: Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. METHODS: GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide <300 ng/liter) and REVEAL 2.0 risk category. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazard models. RESULTS: Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score. CONCLUSIONS: These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile.

Cocaine Use and Pulmonary Hypertension.

Evidence linking cocaine to the risk of pulmonary hypertension (PH) is limited and inconsistent. We examined whether cocaine use, in the absence of other known causes of PH, was associated with elevated systolic pulmonary artery pressure (sPAP) and increased probability of PH. We compared patients with documented cocaine use to a randomly selected age, sex, and race-matched control group without history of cocaine use. All participants had no known causes of PH and underwent echocardiography for noninvasive estimation of sPAP. We used routinely reported echocardiographic parameters and contemporary guidelines to grade the probability of PH. In 88 patients with documented cocaine use (mean age ± standard deviation 51.7 ± 9.5 years), 33% were women and 89% were of Black race. The commonest route of cocaine use was smoking (74%). Cocaine users compared with the control group had significantly higher sPAP (mean ± standard deviation, 30.1 ± 13.1 vs 22.0 ± 9.8 mm Hg, p <0.001) and greater likelihood of PH (25% vs 10%, p = 0.012). In multivariable analyses adjusted for potential confounders including left ventricular diastolic dysfunction, cocaine use conferred a fivefold greater odds of echocardiographic PH (p = 0.006). Additionally, a stepwise increase in the likelihood of PH was noted across cocaine users with negative or no drug screen on the day of echocardiography to cocaine users with a positive drug screen (multivariable p for trend = 0.008). In conclusion, cocaine use was associated with a higher sPAP and an increased likelihood of echocardiographic PH with a probable acute-on-chronic effect.

Dasatinib-Induced Pulmonary Arterial Hypertension.

A 73-year-old woman with chronic myeloid leukemia developed severe pulmonary arterial hypertension (PAH) and pleural effusions after treatment with dasatinib. During workup, partial anomalous pulmonary venous connection and a sinus venosus atrial septal defect were found; these anomalies may have predisposed her to developing this rare and life-threatening condition. Fortunately, her PAH was completely reversible by discontinuation of dasatinib. This case highlights dasatinib's ability to cause PAH in patients predisposed to pulmonary vascular disease.

Pulmonary vasodilator therapy for patients after Fontan procedure: A protocol for a systematic review and meta-analysis.

BACKGROUND: The Fontan circulation is fragile, which is easily broken down. For now, there is no consensus on the drug treatment for the prevention of failure of the Fontan circulation. METHODS: Studies comparing pulmonary vasodilator and control in Fontan patients were identified by searching the PubMed, EMBASE, Clinical Trials, and the Cochrane Library databases until March 20, 2019. The assessed variables included the change of pulmonary resistance, heart function, exercise capacity, life of quality, mortality, and serials of adverse events before and after drug administration. A random-effect/fixed-effect model was used to summarize the estimates of the mean difference (MD)/risk ratio (RR) with 95% confidence interval (CI). Subgroup analysis stratified by drug was performed. RESULTS: This study will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will assess the efficacy and safety of pulmonary vasodilators for patients after Fontan procedure, and provide more evidence-based guidance in clinical practice. PROSPERO REGISTRATION NUMBER: CRD42019132135.

Transition from intravenous treprostinil to enteral selexipag in an infant with pulmonary arterial hypertension.

Selexipag is an enteral, selective prostacyclin IP receptor agonist approved for pulmonary hypertension in adults. There are few reports of its use in children and none in infants. We report the first transition of an infant (11.5 months, 8.6 kg) from intravenous treprostinil (40 ng/kg/minute) to enteral selexipag (400 mcg twice daily) with a good response and no adverse effects.

Balloon pulmonary angioplasty vs riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension: A systematic review and meta-analysis.

BACKGROUNDS: No previous meta-analyses have compared the efficacy and safety of BPA with riociguat therapy in inoperable CTEPH patients. METHODS: Relevant published studies were searched in the PubMed, Embase and ClinicalTrial.gov databases. RESULTS: Twenty-three clinical trials including 1454 patients (631 underwent BPA; 823 underwent riociguat therapy) were analyzed. BPA was associated with a greater improvement in RAP (mean difference (MD) = -3.53 mmHg, 95% CI: [-4.85, -2.21] vs MD = -1.05 mmHg, 95% CI: [-1.82, -0.29]); mPAP (MD = -15.02 mmHg, 95% CI: [-17.32, -12.71] vs MD = -4.19 mmHg, 95% CI: [-5.58, -2.80]); PVR (standard MD = -1.32 woods, 95% CI: [-1.57, -1.08] vs standard MD = -0.65 woods, 95% CI: [-0.79, -0.50]); NYHA functional class (RR = 6.78, 95% CI: [3.14, 14.64] vs RR = 1.49, 95% CI: [1.07, 2.07]); and 6MWD (MD = 71.66 m, 95% CI: [58.34, 84.99] vs MD = 45.25 m, 95% CI: [36.51, 53.99]) than riociguat treatment. However, the increase in CO was greater with riociguat (MD = 0.78 L/min, 95% CI: [0.61, 0.96]) than with BPA (MD = 0.33 L/min, 95% CI: [0.06, 0.59]). No significant difference in cardiac index (CI) was found between BPA (MD = 0.40 L/min/m2 , 95% CI: [0.21, 0.58]) and riociguat (MD = 0.40 L/min/m2 , 95% CI: [0.26, 0.54]). The most common complications of BPA were pulmonary injury (0.3%-5.6%) and pulmonary edema (0.8%-28.6%). The most common adverse events of riociguat were headache, dizziness, hypotension and nasopharyngitis. CONCLUSIONS: Our meta-analysis indicates that BPA might be associated with greater improvements in exercise tolerance and pulmonary hemodynamics except for cardiac output and cardiac index than riociguat therapy. However, both of them were well tolerated.

Hemodynamic Response to Rapid Saline Infusion Compared with Exercise in Healthy Participants Aged 20-80 Years.

BACKGROUND AND OBJECTIVE: Rapid saline infusion and exercise has been proposed as methods to unmask cardiovascular disease. However, the normal hemodynamic response to rapid saline infusion has not been compared to exercise nor is it known whether the responses are age-dependent.We assessed the hemodynamic response to rapid saline infusion in healthy participants over a wide age-range and compared it to exercise in the same participants. METHODS AND RESULTS: Fifty healthy participants (young <40 years, n = 16, middle-aged 40-59 years, n = 15, elderly 60-80 years, n = 19) underwent right heart catheterization at rest, during semisupine ergometer exercise at three exercise levels (25%, 50%, and 75% of peak VO2) and after rapid saline infusion (10 ml/kg at a rate of 150 ml/min). Rapid saline infusion significantly increased pulmonary capillary wedge pressure (PCWP) similarly across all age groups (∆PCWP 6 ±â€¯2; 7 ±â€¯2; 6 ±â€¯4 mmHg for the young, middle-aged and elderly respectively) with no correlation between age and ∆PCWP (r = 0.05; p = 0.74). However, there was a negative correlation between age and ∆stroke volume (SV) as elderly participants had a lower increase in SV following rapid saline infusion (r = 0.44; p = 0.002). On the contrary, exercise-induced significantly larger and age-dependent increases in PCWP (r = 0.58; p < 0.0001). Exercise also caused a larger increase in SV compared with rapid fluid loading (p = 0.0003) CONCLUSION: Unlike exercise, rapid saline infusion caused an age-independent increase in PCWP in healthy adults. Suggesting that age-related impairments beyond passive stiffness have a greater impact on exercise-induced increase in PCWP. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01974557.

Dexamethasone improves pulmonary hemodynamics in COPD-patients going to altitude: A randomized trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) may predispose to symptomatic pulmonary hypertension at high altitude. We investigated hemodynamic changes in lowlanders with COPD ascending rapidly to 3100 m and evaluated whether preventive dexamethasone treatment would mitigate the altitude-induced increase in pulmonary artery pressure. METHODS: In this placebo-controlled, double-blind trial, non-hypercapnic COPD patients living <800 m, were randomized to receive either dexamethasone (8 mg/day) or placebo tablets one day before ascent from 760 m and during a 3-day-stay at 3100 m. Echocardiography was performed at 760 m and after the first night at 3100 m. The trans-tricuspid pressure gradient (RV/RA, main outcome), cardiac output (Q) by velocity-time integral of left ventricular outflow, indices of right and left heart function, blood gases and pulse-oximetry (SpO2) were compared between groups. RESULTS: 95 patients, 79 men, mean ±â€¯SD age 57 ±â€¯8y FEV1 89 ±â€¯21% pred, SpO2 95 ±â€¯2% were included in the analysis. In 52 patients receiving dexamethasone, RV/RA, Q and SpO2 at 760 and 3100 m were 19 ±â€¯5 mm Hg and 26 ±â€¯7 mm Hg, 4.9 ±â€¯0.7 and 5.7 ±â€¯1.1 l/min, SpO2 95 ±â€¯2% and 90 ±â€¯3% (P < 0.05 all changes). In 43 patients receiving placebo the corresponding values were 20 ±â€¯4 mm Hg and 31 ±â€¯9 mm Hg, 4.7 ±â€¯0.9 l/min and 95 ±â€¯3% and 89 ±â€¯3% (P < 0.05 all changes) between group differences of altitude-induced changes were (mean, 95% CI): RV/RA -4.8 (-7.7 to -1.8) mm Hg, Q 0.13 (-0.3 to 0.6) l/min and SpO2 1 (-1 to 2) %. CONCLUSIONS: In lowlanders with COPD travelling to 3100 m preventive dexamethasone treatment mitigates the altitude-induced rise in RV/RA potentially along with a reduced pulmonary vascular resistance and improved oxygenation.