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 (VD/VT) 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 (Tc) measurement was used for VD/VT 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 VD/VT 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 VD/VT.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 (VD/VT) and dynamic hyperinflation to alterations in exercise limitation. We utilized a unique noninvasive method to assess VD/VT (transcutaneous carbon dioxide, Tc) 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.
Highlights
Patients with chronic obstructive pulmonary disease (COPD) experience expiratory flow limitation, breathlessness, dyspnea, and reduced exercise tolerance relative to age and sex matched controls [1,2,3,4]
The effects of dynamic hyperinflation on dyspnea and exercise intolerance are amplified in COPD by an increased ventilatory requirement for exercise, related to increased dead space to tidal volume ratio (VD/VT) [7, 8]
Treatment with bronchodilators (BD) are partially effective at reducing expiratory flow limitation, and the optimal regimen in COPD appears to be achieved with a fixed dose, long-acting inhaled combination medications (LABA/LAMA, long-acting beta agonists and long-acting muscarinic antagonists) [1, 2, 9,10,11]
Summary
Patients with chronic obstructive pulmonary disease (COPD) experience expiratory flow limitation, breathlessness, dyspnea, and reduced exercise tolerance relative to age and sex matched controls [1,2,3,4]. A prominent mechanism responsible for exercise intolerance in COPD is thought to be dynamic hyperinflation (DH) during exercise due to end expiratory lung volume increase, usually assessed by a commensurate decrease in inspiratory capacity (IC) [5, 6]. The effects of dynamic hyperinflation on dyspnea and exercise intolerance are amplified in COPD by an increased ventilatory requirement for exercise, related to increased dead space to tidal volume ratio (VD/VT) [7, 8]. In patients with COPD, LABA/LAMA bronchodilator therapy reduces DH and increases exercise tolerance [12]. Short-acting bronchodilator therapy in COPD does not influence estimated VD/VT, long-acting bronchodilation, which increases ventilation to both well- and poorly perfused lung
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