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

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 P-CO2, (TcPCO2) 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 +/- 184s vs. 328 +/- 115 s; difference 55 +/- 125s; P = 0.013; confidence interval: 20-90s), 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 Umin; 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, TcPCO2) 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.