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The effect of long-acting dual bronchodilator therapy on exercise tolerance, dynamic hyperinflation, and dead space during constant work rate exercise in COPD.

ABSTRACT: We investigated whether dual bronchodilator therapy (glycopyrrolate/formoterol fumarate; GFF; Bevespi Aerosphere) would increase exercise tolerance during a high-intensity constant work rate exercise test (CWRET) and the relative contributions of dead space ventilation (V_D/V_T) and dynamic hyperinflation (change in inspiratory capacity) to exercise limitation in chronic obstructive pulmonary disease (COPD). In all, 48 patients with COPD (62.9 ± 7.6 yrs; 33 male; GOLD spirometry stage 1/2/3/4, n = 2/35/11/0) performed a randomized, double blind, placebo (PL) controlled, two-period crossover, single-center trial. Gas exchange and inspiratory capacity (IC) were assessed during cycle ergometry at 80% incremental exercise peak work rate. Transcutaneous [Formula: see text] (Tc[Formula: see text]) measurement was used for V_D/V_T estimation. Baseline postalbuterol forced expiratory volume in 1 s (FEV₁) was 1.86 ± 0.58 L (63.6% ± 13.9 predicted). GFF increased FEV₁ by 0.18 ± 0.21 L relative to placebo (PL; P < 0.001). CWRET endurance time was greater after GFF vs. PL (383 ± 184 s vs. 328 ± 115 s; difference 55 ± 125 s; P = 0.013; confidence interval: 20-90 s), a 17% increase. IC on GFF was above placebo IC at all time points and fell less with GFF vs. PL (P ≤ 0.0001). Isotime tidal volume (1.54 ± 0.50 vs. 1.47 ± 0.45 L; P = 0.022) and ventilation (52.9 ± 19.9 vs. 51.0 ± 18.9 L/min; P = 0.011) were greater, and respiratory rate was unchanged (34.9 ± 9.2 vs. 35.1 ± 8.0 br/min, P = 0.865). Isotime V_D/V_T did not differ between groups (GFF 0.28 ± 0.08 vs. PL 0.27 ± 0.09; P = 0.926). GFF increased exercise tolerance in patients with COPD, and the increase was accompanied by attenuated dynamic hyperinflation without altering V_D/V_T.NEW & NOTEWORTHY This study was a randomized clinical trial (NCT03081156) that collected detailed physiology data to investigate the effect of dual bronchodilator therapy on exercise tolerance in COPD, and additionally to determine the relative contributions of changes in dead space ventilation (V_D/V_T) and dynamic hyperinflation to alterations in exercise limitation. We utilized a unique noninvasive method to assess V_D/V_T (transcutaneous carbon dioxide, Tc[Formula: see text]) and found that dual bronchodilators yielded a moderate improvement in exercise tolerance. Importantly, attenuation of dynamic hyperinflation rather than change in dead space ventilation was the most important contributor to exercise tolerance improvement.

SUBMITTER: Stringer WW

PROVIDER: S-EPMC8526332 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bronchodilation with muscarinic antagonists, β2-agonists, and inhaled corticosteroids remains the foundation of pharmaceutical treatment for patients with stable COPD. These drugs are delivered from a variety of devices, including dry powder inhalers, pressurized metered-dose inhalers, soft-mist inhalers, or nebulizers. Nebulized delivery is often preferable in patients who are elderly, are cognitively impaired, are unable to generate sufficient inspiratory force to use their inhaler, have difficulty coordinating hand-breath activity, are too dyspneic to hold their breath for a sufficient time, and/or may be acutely ill. Revefenacin, a once-daily long-acting muscarinic antagonist for nebulization recently approved by the US FDA for the treatment of patients with COPD, was discovered and developed using "duration and lung selectivity-by-design." This strategy selected a molecule with a high lung-selective index to maximize bronchodilation and limit systemic anti-muscarinic side effects. In early-phase clinical studies, revefenacin for nebulization led to a rapid onset of bronchodilation that was sustained for 24 hrs in patients with moderate to severe COPD. Revefenacin also demonstrated minimal systemic exposure and good tolerability in these studies. Statistically and clinically significant improvements in lung function (ie, peak and/or trough FEV1) relative to placebo were observed with revefenacin in Phase III clinical trials of up to 3 months in patients with moderate to very severe COPD. Revefenacin was well tolerated in Phase III clinical trials with a low incidence of systemic antimuscarinic adverse events, which is consistent with its lung-selective design. There was no evidence of an increased risk of major cardiovascular events. Patient-reported outcome data from clinical trials indicated statistically significant improvements in several disease-specific measures. Revefenacin 175 μg for nebulization provides an effective once-daily treatment option for patients with moderate to very severe COPD who require or prefer nebulized therapy.

Project description:The dissociation between constant work rate of O2 uptake (V?o2) and ramp V?o2 at a given work rate might be mitigated during slowly increasing ramp protocols. This study characterized the V?o2 dynamics in response to five different ramp protocols and constant-work-rate trials at the maximal metabolic steady state (MMSS) to characterize 1) the V?o2 gain (G) in the moderate, heavy, and severe domains, 2) the mean response time of V?o2 (MRT), and 3) the work rates at lactate threshold (LT) and respiratory compensation point (RCP). Eleven young individuals performed five ramp tests (5, 10, 15, 25, and 30 W/min), four to five time-to-exhaustions for critical power estimation, and two to three constant-work-rate trials for confirmation of the work rate at MMSS. G was greatest during the slowest ramp and progressively decreased with increasing ramp slopes (from ~12 to ~8 ml·min-1·W-1, P < 0.05). The MRT was smallest during the slowest ramp slopes and progressively increased with faster ramp slopes (1?±?1, 2?±?1, 5?±?3, and 10?±?4, 15?±?6 W, P < 0.05). After "left shifting" the ramp V?o2 by the MRT, the work rate at LT was constant regardless of the ramp slope (~150 W, P > 0.05). The work rate at MMSS was 215?±?55 W and was similar and highly correlated with the work rate at RCP during the 5 W/min ramp (P > 0.05, r?=?0.99; Lin's concordance coefficient?=?0.99; bias?=?-3 W; root mean square error?=?6 W). Findings showed that the dynamics of V?o2 (i.e., G) during ramp exercise explain the apparent dichotomy existing with constant-work-rate exercise. When these dynamics are appropriately "resolved", LT is constant regardless of the ramp slope of choice, and RCP and MMSS display minimal variations between each other.NEW & NOTEWORTHY This study demonstrates that the dynamics of V?o2 during ramp-incremental exercise are dependent on the characteristics of the increments in work rate, such that during slow-incrementing ramp protocols the magnitude of the dissociation between ramp V?o2 and constant V?o2 at a given work rate is reduced. Accurately accounting for these dynamics ensures correct characterizations of the V?o2 kinetics at ramp onset and allows appropriate comparisons between ramp and constant-work-rate exercise-derived indexes of exercise intensity.

Project description:BackgroundExercise tolerance is an important endpoint in chronic obstructive pulmonary disease (COPD) clinical trials. Little is known about the comparative measurement properties of constant work rate cycle ergometry (CWRCE) and the endurance shuttle walking test (ESWT). The objective of this sub-analysis of the TORRACTO® study was to directly compare the endurance measurement properties of CWRCE and ESWT in patients with COPD in a multicentre, multinational setting. We predicted that both tests would be similarly reliable, but that the ESWT would be more responsive to bronchodilation than CWRCE.MethodsThis analysis included 151 patients who performed CWRCE and ESWT at baseline and week 6 after receiving once-daily placebo, tiotropium/olodaterol (T/O) 2.5/5 μg or T/O 5/5 μg. Reproducibility was assessed by comparing their respective performance at baseline and week 6 in the placebo group. Responsiveness to bronchodilation was assessed by comparing endurance time at week 6 with T/O with baseline values and placebo. The locus of symptom limitation and end-exercise Borg scales for breathing and leg discomfort for both tests were also analysed.ResultsThe intraclass correlation coefficients for CWRCE and ESWT were 0.56 [95% confidence interval (CI) 0.37-0.71] and 0.75 (95% CI 0.63-0.84). More patients were limited by breathing discomfort during the ESWT than during CWRCE, whereas more patients were limited by leg discomfort or breathing/leg discomfort during CWRCE than the ESWT (p <0.0001). Both tests were responsive to bronchodilator treatment: there was a 19% increase in endurance time from baseline at week 6 (p = 0.0006) assessed with CWRCE, and a 20% increase in endurance time assessed with ESWT (p = 0.0013).ConclusionsBoth exercise tests performed well in a multicentre clinical trial. Although the locus of symptom limitation differed between the two tests, both were reliable and responsive to bronchodilation. For future clinical trials, the choice of test should depend on the study requirements.Clinicaltrials.gov identifierNCT01525615. The reviews of this paper are available via the supplemental material section.

Project description:Lung hyperinflation and exercise intolerance are hallmarks of chronic obstructive pulmonary disease (COPD). However, their relationship remains uncertain. A combined analysis of two placebo-controlled, randomized studies examined the effects of the long-acting muscarinic antagonist umeclidinium (UMEC) and long-acting ?2-agonist vilanterol (VI) separately and in combination on static hyperinflation, exercise endurance time (EET), and their relationship in patients with COPD.Patients with moderate-to-severe stable COPD and resting functional residual capacity >120% predicted were randomized to UMEC/VI 62.5/25 ?g, UMEC 62.5 ?g, VI 25 ?g, or placebo for 12 weeks. Inspiratory capacity (IC), residual volume (RV), total lung capacity (TLC), and EET in an endurance shuttle-walk test were measured. In this post hoc analysis, IC/TLC, RV/TLC, and IC were used as hyperinflation markers.After 12 weeks, UMEC/VI and UMEC and VI showed significant improvements in hyperinflation versus placebo when measured by absolute change from baseline in IC/TLC (trough and 3 hours postdose [P?0.011]). UMEC/VI showed significant improvements versus UMEC and VI in absolute changes in IC/TLC (trough and 3 hours postdose [P?0.001]). Statistical significance for comparisons with placebo and between treatments for absolute changes in IC and percentage changes in RV/TLC followed similar patterns to those for absolute changes in IC/TLC. UMEC/VI showed significant improvements in EET versus placebo at day 2 and week 12, measured as change from baseline in seconds (P?0.002) and as a percentage from baseline (P?0.005). There was a lack of evidence to suggest a correlation between improvements in static hyperinflation and EET at any time point.Although the dual bronchodilator UMEC/VI demonstrated greater improvements in static hyperinflation markers than UMEC or VI and significant improvements in exercise endurance, no direct relationship was observed between static hyperinflation and exercise endurance.

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The effect of long-acting dual bronchodilator therapy on exercise tolerance, dynamic hyperinflation, and dead space during constant work rate exercise in COPD.

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