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 (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 [Formula: see text] (Tc[Formula: see text]) 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[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.

Keywords: COPD; CPET; VD/VT; exercise intolerance; hyperinflation.

Conflict of interest statement

AstraZeneca also provided the medications and a placebo inhaler for the study. Dr. S. Rennard and S. Siddiqui were paid employees of AstraZeneca at the time the project was designed and performed. Dr. R. Casaburi has been a consultant for AstraZeneca.

Figures

Figure 1.

Protocol and visit designation for this single-center, randomized, double-blind, placebo-controlled, two-period, crossover clinical trial. CPET, cardiopulmonary exercise testing; CT, computed tomography; CWR, constant work rate; LABA, long-acting beta agonists; LAMA, long-acting muscarinic antagonists; PFT, pulmonary function testing; V, visit.

Figure 2.

A–P: physiologic responses to constant work rate exercise testing in patients with COPD receiving LAMA/LAMA therapy (closed circles) vs. Placebo (open circles). Description of visits is given in text. All data points are for 48 subjects, except the 4.5 minute time point, in which only 22 subjects completed this duration in both tests. *P < 0.05, **P = 0.01, ***P ≤ 0.001 by rmANOVA. V̇E (L/min), pulmonary ventilation; VT (L), tidal volume; RR (breaths/min), respiratory rate; V̇E/MVV (%), pulmonary ventilation divided by maximum voluntary ventilation; V̇o2 (L/min), oxygen uptake; V̇co2 (L/min), carbon dioxide output; HR (beats/min), heart rate; V̇o2/HR (mL/beat), oxygen pulse; V̇E/V̇co2, pulmonary ventilation divided by carbon dioxide output; PETCO2 (mmHg), end-tidal carbon dioxide partial pressure; TcPCO2 (mmHg), transcutaneous carbon dioxide partial pressure; VD/VT, dead space to tidal volume ratio; IRV (L), inspiratory reserve volume; IC (L), inspiratory capacity; SpO2 (%), oxygen saturation by pulse oximetry. COPD, chronic obstructive pulmonary disease; LAMA, long-acting muscarinic antagonists.

Figure 3.

Perceptual responses to constant work rate exercise in patients with COPD receiving LAMA/LAMA therapy (closed circles) vs. Placebo (open circles). All data points are for 48 subjects except the 4.5-min time point, in which only 22 subjects completed this duration in both tests. There were no statistical differences in the Borg scores for either dyspnea (A) or leg fatigue (B). COPD, chronic obstructive pulmonary disease; CR10, Category and Ratio Scale of 10; LAMA, long-acting muscarinic antagonists.

Figure 4.

Constant work rate exercise duration while receiving dual bronchodilator vs. placebo for 48 individual subjects with COPD. COPD, chronic obstructive pulmonary disease; CWRET, constant work rate exercise time; placebo versus GFF, dual LABA/LAMA bronchodilator; GFF, glycopyrrolate/formoterol fumarate; LABA, long-acting beta agonists; LAMA, long-acting muscarinic antagonists.