Cao Min, Calmelat Robert A, Kierstead Peter, Carraro Nicolo, Stringer William W, Porszasz Janos, Casaburi Richard, Rossiter Harry B
Rehabilitation Clinical Trials Center, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California.
Department of Respiratory and Critical Care Medicine, Beijing Chest Hospital, Capital Medical University, Beijing, China.
J Appl Physiol (1985). 2022 May 1;132(5):1145-1153. doi: 10.1152/japplphysiol.00332.2021. Epub 2022 Mar 24.
Exercise intolerance in chronic obstructive pulmonary disease (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 forced expiratory volume in 1 s (FEV)/forced vital capacity (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 [long-acting muscarinic antagonist (LAMA) + long-acting β-agonist (LABA); Stiolto Respimat] would ameliorate the decline in neuromuscular performance and increase endurance time during constant power cycling at 80% peak incremental power. Fourteen patients with COPD (4 female; 64 [58, 72] yr; FEV 67% [56%, 75%] predicted; median [25th, 75th percentile]) participated in a randomized, placebo-controlled crossover trial (NCT02845752). Pulmonary function and cardiopulmonary exercise responses were assessed before and after 1 wk of treatment, with 2 wk washout between conditions. Performance fatigue was assessed using an ∼4-s maximal isokinetic cycling effort at preexercise, 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. FEV was greater with LAMA + LABA versus placebo (1.81 [1.58, 1.98] L vs. 1.72 [1.29, 1.99] L; = 0.006), but IC at isotime, performance fatigue at isotime, and constant power endurance time were not different between conditions (each > 0.05). A modest (∼95 mL) increase in FEV following 1 wk of combination LAMA + LABA treatment did not alleviate neuromuscular performance fatigue or enhance cycle exercise tolerance in patients with mild-to-severe COPD with largely preserved "static" lung volumes. Bronchodilation is known to increase forced expiratory volume in 1 s (FEV) and reduce hyperinflation in COPD. In a randomized controlled trial, we investigated whether combined inhaled long-acting β-agonist and muscarinic antagonist would alleviate maximal voluntary neuromuscular performance fatigue or enhance maximal muscle activation during cycling in patients with COPD. Despite increased FEV, combination bronchodilator therapy did not reduce neuromuscular performance fatigue or enhance muscle activity or exercise tolerance in patients with mild-to-severe COPD.
慢性阻塞性肺疾病（COPD）患者的运动不耐受与呼吸困难、吸气能力（IC）降低有关，且与神经肌肉“功率储备”相关，即增加等速运动功率的急性能力。这种功率储备与静息1秒用力呼气容积（FEV）/用力肺活量（FVC）相关，这表明针对肺功能的治疗可能会保护神经肌肉功能，并延长COPD患者的全身运动时间。因此，我们测试了长效β受体激动剂和毒蕈碱拮抗剂联合支气管扩张剂治疗[长效毒蕈碱拮抗剂（LAMA）+长效β受体激动剂（LABA）；思力华能倍乐]是否能改善神经肌肉功能的下降，并在80%峰值递增功率的恒定功率骑行过程中增加耐力时间。14例COPD患者（4例女性；64[58,72]岁；FEV为预测值的67%[56%，75%]；中位数[第25，第75百分位数]）参与了一项随机、安慰剂对照交叉试验（NCT02845752）。在治疗1周前后评估肺功能和心肺运动反应，两种治疗条件之间有2周的洗脱期。使用运动前、等时和不耐受时约4秒的最大等速骑行努力来评估运动疲劳。等时是两种治疗条件下较短的运动持续时间。使用以治疗为固定因素、受试者为随机因素的方差分析评估显著性。与安慰剂相比，LAMA+LABA治疗组的FEV更高（1.81[1.58,1.98]L对1.72[1.29,1.99]L；P=0.006），但等时的IC、等时的运动疲劳和恒定功率耐力时间在两种治疗条件之间没有差异（均P>0.05）。在轻度至重度COPD且“静态”肺容积基本保留的患者中，联合LAMA+LABA治疗1周后FEV适度增加（约95 mL），但并未减轻神经肌肉功能疲劳或提高骑行运动耐受性。已知支气管扩张可增加COPD患者的1秒用力呼气容积（FEV）并减少肺过度充气。在一项随机对照试验中，我们研究了联合吸入长效β受体激动剂和毒蕈碱拮抗剂是否能减轻COPD患者在骑行过程中的最大自主神经肌肉功能疲劳或增强最大肌肉激活。尽管FEV增加，但联合支气管扩张剂治疗并未减轻轻度至重度COPD患者的神经肌肉功能疲劳或增强肌肉活动或运动耐受性。
