Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961 .).
Nebulized budesonide has been used successfully to treat acute asthma exacerbation, and we hypothesized that it could also be effective for exacerbations of chronic obstructive pulmonary disease (COPD). In this multicenter, double-blind, randomized, placebo-controlled trial, the efficacy of nebulized budesonide (Pulmicort Respules/Nebuamp), oral prednisolone, and placebo was compared in 199 patients with acute exacerbations of COPD requiring hospitalization. Patients received from randomization (H(0)) to 72 h (H(72)), 2 mg of budesonide every 6 h (n = 71), 30 mg of oral prednisolone every 12 h (n = 62), or placebo (n = 66). All received standard treatment, including nebulized beta(2)-agonists, ipratropium bromide, oral antibiotics, and supplemental oxygen. The mean change (95% confidence interval) in postbronchodilator FEV(1) from H(0) to H(72) was greater with active treatments than with placebo: budesonide versus placebo, 0.10 L (0.02 to 0.18 L); prednisolone versus placebo, 0.16 L (0.08 to 0.24 L). The difference in FEV(1) between budesonide and prednisolone was not significant, -0.06 L (-0.14 to 0.02 L). The occurrence of serious adverse events was similar for all groups. Budesonide had less systemic activity than prednisolone as indicated by a higher incidence of hyperglycemia observed with prednisolone. Both budesonide and prednisolone improved airflow in COPD patients with acute exacerbations when compared with placebo. Nebulized budesonide may be an alternative to oral prednisolone in the treatment of nonacidotic exacerbations of COPD but further studies should be done to evaluate its long-term impact on clinical outcomes after an initial episode of COPD exacerbation.
The phosphodiesterase-5 inhibitor sildenafil has been reported to improve hypoxic exercise capacity, but the mechanisms accounting for this observation remain incompletely understood. Sixteen healthy subjects were included in a randomized, double-blind, placebo-controlled, cross-over study on the effects of 50-mg sildenafil on echocardiographic indexes of the pulmonary circulation and on cardiopulmonary cycle exercise in normoxia, in acute normobaric hypoxia (fraction of inspired O2, 0.1), and then again after 2 weeks of acclimatization at 5000 m on Mount Chimborazo (Ecuador). In normoxia, sildenafil had no effect on maximum VO2 or O2 saturation. In acute hypoxia, sildenafil increased maximum VO2 from 27 +/- 5 to 32 +/- 6 mL/min/kg and O2 saturation from 62% +/- 6% to 68% +/- 9%. In chronic hypoxia, sildenafil did not affect maximum VO2 or O2 saturation. Resting mean pulmonary artery pressure increased from 16 +/- 3 mmHg in normoxia to 28 +/- 5 mmHg in normobaric hypoxia and 32 +/- 6 mmHg in hypobaric hypoxia. Sildenafil decreased pulmonary vascular resistance by 30% to 50% in these different conditions. We conclude that sildenafil increases exercise capacity in acute normobaric hypoxia and that this is explained by improved arterial oxygenation, rather than by a decrease in right ventricular afterload.
de Bisschop C, Martinot J, Leurquin-Sterk G, Faoro V, Guénard H, Naeije R. Improvement in lung diffusion by endothelin A receptor blockade at high altitude. J Appl Physiol 112: 20 -25, 2012. First published October 6, 2011 doi:10.1152/japplphysiol.00670.2011.-Lung diffusing capacity has been reported variably in high-altitude newcomers and may be in relation to different pulmonary vascular resistance (PVR). Twenty-two healthy volunteers were investigated at sea level and at 5,050 m before and after random double-blind intake of the endothelin A receptor blocker sitaxsentan (100 mg/day) vs. a placebo during 1 wk. PVR was estimated by Doppler echocardiography, and exercise capacity by maximal oxygen uptake (V O2 max). The diffusing capacities for nitric oxide (DLNO) and carbon monoxide (DLCO) were measured using a single-breath method before and 30 min after maximal exercise. The membrane component of DLCO (Dm) and capillary volume (Vc) was calculated with corrections for hemoglobin, alveolar volume, and barometric pressure. Altitude exposure was associated with unchanged DLCO, DLNO, and Dm but a slight decrease in Vc. Exercise at altitude decreased DLNO and Dm. Sitaxsentan intake improved V O2 max together with an increase in resting and postexercise DLNO and Dm. Sitaxsentan-induced decrease in PVR was inversely correlated to DLNO. Both DLCO and DLNO were correlated to V O2 max at sea level (r ϭ 0.41-0.42, P Ͻ 0.1) and more so at altitude (r ϭ 0.56 -0.59, P Ͻ 0.05). Pharmacological pulmonary vasodilation improves the membrane component of lung diffusion in high-altitude newcomers, which may contribute to exercise capacity. altitude; hypoxia; lung diffusion; gas exchange; exercise capacity; pulmonary vascular resistance; pulmonary capillary pressure; pulmonary hypertension BOTH THE MEMBRANE AND THE capillary components of lung diffusing capacity have been shown to be increased in highaltitude residents (10,13,15,25). Increased lung diffusing capacity at high altitude allows for the preservation of gas exchange in the presence of a decreased ventilatory response at exercise (15). High-altitude newcomers do not benefit from this adaptation (10,15,25) and, accordingly, depend on increased ventilation to maintain pulmonary gas exchange (15,45).Previous studies on lung diffusing capacity at high altitudes calculated the membrane and capillary components of alveolocapillary transfer of carbon monoxide (CO) using measurements at ambient air and increased inspired PO 2 (10,13,15,25). This approach rests on the PO 2 dependence of , the blood's specific transfer conductance of CO, in the Roughton and Forster equation, which states that 1/DL CO ϭ 1/Dm ϩ 1/ Vc where DL CO is the diffusing capacity of the lung for CO, Dm its membrane component, and Vc the capillary blood volume (37). Thus changing as by increasing or decreasing inspired PO 2 allows for the calculation of Dm and Vc from a simple system of two equations with two unknowns. However, changing inspired PO 2 might also change pulmonary vascular tone, cardiac output, ...
It has been suggested that increased pulmonary vascular reserve, as defined by reduced pulmonary vascular resistance (PVR) and increased pulmonary transit of agitated contrast measured by echocardiography, might be associated with increased exercise capacity. Thus, at altitude, where PVR is increased because of hypoxic vasoconstriction, a reduced pulmonary vascular reserve could contribute to reduced exercise capacity. Furthermore, a lower PVR could be associated with higher capillary blood volume and an increased lung diffusing capacity. We reviewed echocardiographic estimates of PVR and measurements of lung diffusing capacity for nitric oxide (DL(NO)) and for carbon monoxide (DL(CO)) at rest, and incremental cardiopulmonary exercise tests in 64 healthy subjects at sea level and during 4 different medical expeditions at altitudes around 5000 m. Altitude exposure was associated with a decrease in maximum oxygen uptake (VO2max), from 42±10 to 32±8 mL/min/kg and increases in PVR, ventilatory equivalents for CO2 (V(E)/VCO2), DL(NO), and DL(CO). By univariate linear regression VO2max at sea level and at altitude was associated with V(E)/VCO2 (p<0.001), mean pulmonary artery pressure (mPpa, p<0.05), stroke volume index (SVI, p<0.05), DL(NO) (p<0.02), and DL(CO) (p=0.05). By multivariable analysis, VO2max at sea level and at altitude was associated with V(E)/VCO2, mPpa, SVI, and DL(NO). The multivariable analysis also showed that the altitude-related decrease in VO2max was associated with increased PVR and V(E)/VCO2. These results suggest that pulmonary vascular reserve, defined by a combination of decreased PVR and increased DL(NO), allows for superior aerobic exercise capacity at a lower ventilatory cost, at sea level and at high altitude.
Tibetans have been reported to present with a unique phenotypic adaptation to high altitude characterized by higher resting ventilation and arterial oxygen saturation, no excessive polycythemia, and lower pulmonary arterial pressures (Ppa) compared with other high-altitude populations. How this affects exercise capacity is not exactly known. We measured aerobic exercise capacity during an incremental cardiopulmonary exercise test, lung diffusing capacity for carbon monoxide (DL(CO)) and nitric oxide (DL(NO)) at rest, and mean Ppa (mPpa) and cardiac output by echocardiography at rest and at exercise in 13 Sherpas and in 13 acclimatized lowlander controls at the altitude of 5,050 m in Nepal. In Sherpas vs. lowlanders, arterial oxygen saturation was 86 ± 1 vs. 83 ± 2% (mean ± SE; P = nonsignificant), mPpa at rest 19 ± 1 vs. 23 ± 1 mmHg (P < 0.05), DL(CO) corrected for hemoglobin 61 ± 4 vs. 37 ± 2 ml · min(-1) · mmHg(-1) (P < 0.001), DL(NO) 226 ± 18 vs. 153 ± 9 ml · min(-1) · mmHg(-1) (P < 0.001), maximum oxygen uptake 32 ± 3 vs. 28 ± 1 ml · kg(-1) · min(-1) (P = nonsignificant), and ventilatory equivalent for carbon dioxide at anaerobic threshold 40 ± 2 vs. 48 ± 2 (P < 0.001). Maximum oxygen uptake was correlated directly to DL(CO) and inversely to the slope of mPpa-cardiac index relationships in both Sherpas and acclimatized lowlanders. We conclude that Sherpas compared with acclimatized lowlanders have an unremarkable aerobic exercise capacity, but with less pronounced pulmonary hypertension, lower ventilatory responses, and higher lung diffusing capacity.
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