Exercise intolerance in COPD is associated with dyspnea, reduced inspiratory capacity (IC) and occurs with a neuromuscular "power reserve" i.e. an acute ability to increase isokinetic locomotor power. This power reserve is associated with resting FEV1/FVC suggesting that treatments to target pulmonary function may protect neuromuscular performance and extend whole-body exercise in COPD. We, therefore, tested whether combination long-acting β-agonist and muscarinic antagonist bronchodilator therapy (LAMA+LABA; Stiolto Respimat®) would ameliorate the decline in neuromuscular performance and increase endurance time during constant power cycling at 80% peak incremental power. Fourteen COPD patients (4 female; 64[58,72] years; FEV1 67[56,75]% predicted; median[25th,75th percentile]), participated in a randomized, placebo-controlled cross-over trial (NCT02845752). Pulmonary function and cardiopulmonary exercise responses were assessed before and after 1 week of treatment, with 2 weeks washout between conditions. Performance fatigue was assessed using a ~4-second maximal isokinetic cycling effort at pre-exercise, isotime and intolerance. Isotime was the shorter exercise duration of the two treatment conditions. Significance was assessed using ANOVA with treatment as fixed factor and subject as random factor. FEV1 was greater with LAMA+LABA vs. placebo (1.81[1.58,1.98] L vs 1.72[1.29,1.99] L; P=0.006), but IC at isotime, performance fatigue at isotime and constant power endurance time were not different between condition (each P>0.05). A modest (~95 mL) FEV1 increase in following 1 week of combination LAMA+LABA treatment did not alleviate neuromuscular performance fatigue or enhance cycle exercise tolerance in mild to severe COPD patients with largely preserved "static" lung volumes.

A 26-year-old man presented to the ED with dizziness and gait imbalance. He noted dizziness for 3 months, but symptoms progressed more rapidly over the last 3 weeks when he began experiencing nausea, vomiting, and "wobbly legs." These symptoms would worsen with physical exertion, especially when lifting heavy objects. On review of systems, he also reported subjective fevers and chills. He had no appreciable dyspnea, cough, chest pain, or increased sputum production. The patient recalled a history of "brain surgery" approximately 4 years prior to his presentation, but no further details could be provided at the time.

RATIONALE Exercise intolerance in COPD patients is associated with reduced inspiratory reserve volume (IRV) and dyspnea. The mechanisms by which exercise is limited are unknown. Intolerance may occur due to: limiting symptoms (e.g. pain, dyspnea); reduced neural motor activation and/or excitability (activation fatigue, AF); reduced muscular power for a given muscle activation (muscle fatigue, MF). The sum of activation and muscle fatigue describes overall exercise‐induced reduction in neuromuscular performance, and is termed performance fatigue (PF; watts). In moderate to severe COPD, PF is associated negatively with resting FEV1/FVC and positively with peak exercise VE/MVV. We postulated that this was due to greater activation fatigue when IRV was low. Thus, this study determined the effect of bronchodilation on mechanisms limiting cycling exercise in COPD. We hypothesized that, compared with placebo, combination LAMA+LABA therapy would increase pre‐exercise FEV1, increase isotime IRV during exercise, leading to reduced performance fatigue and prolonged exercise endurance. METHODS Fourteen COPD patients (4 female) volunteered for this single center, randomized, placebo controlled, double blind, crossover trial of once‐daily Stiolto Respimat (tiotropium bromide and olodaterol) (ClinicalTrials.gov: NCT02845752). Pulmonary function and cardiopulmonary exercise responses were assessed before and after 1 week of treatment, with 2 weeks washout between treatment periods. PF (and its subcomponents, AF and MF) were assessed using a 4‐second maximal isokinetic cycling effort (Cannon et al. J Appl Physiol 121:1365–1373, 2016) at baseline, isotime and intolerance during a constant work rate exercise test at 80% peak incremental power. Isotime was the shorter exercise duration of the two treatment conditions. Muscle activity was assessed by surface EMG on 5 leg muscles. Significance was assessed in Box‐Cox transformed data using a univariate general linear model ANOVA with treatment as fixed factor and subject as random factor. RESULTS Patients were 64[58,72] years old with FEV1 67[56,75]% predicted at baseline (median[IQR]). Peak incremental exercise responses included: 79[70,99] W; VO2peak 14.0[12.9,18.0] mL.min−1.kg−1; IRV 0.59[0.34,0.95] L. Pre‐exercise FEV1 was significantly greater with LAMA+LABA vs placebo (1.81[1.58,1.98] vs. 1.72[1.29,1.99] L; p=0.006). However, IRV at isotime (0.54[0.23,0.90] vs. 0.46[0.29,0.85] L; p=0.391), PF at isotime (76.1[45.9,103.7] vs 68.5[54.0,116.6] W; p=0.248) and constant work rate endurance time (297[253,351] vs 274[222,326] s; p=0.228) were not significantly different between LAMA+LABA vs. placebo. CONCLUSION A modest (~95 mL) FEV1 increase in following 1 week of combination LAMA+LABA treatment did not detectably alleviate neuromuscular performance fatigue or enhance cycle exercise tolerance in moderate to severe COPD patients. Support or Funding Information Boehringer Ingelheim, Investigator Initiated Study 1237.55