Effect of twice daily inhaled albuterol on cardiopulmonary exercise outcomes, dynamic hyperinflation, and symptoms in secondhand tobacco-exposed persons with preserved spirometry and air trapping: a randomized controlled trial

Abstract

Background: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping.

Methods: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO₂) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed.

Results: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV₁] = 103 ± 16% predicted; FEV₁ to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO₂ (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity.

Conclusions: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction.

Keywords: Air trapping; Bronchodilation; Exercise capacity; Pre-COPD; Secondhand tobacco smoke; Spirometric obstruction; Tobacco-exposed person.

Fig. 1

Study design. Abbreviations: PFT: pulmonary function test; CPET: cardiopulmonary exercise testing; DH: dynamic hyperinflation

Fig. 2

Participants flow through the study

Fig. 3

Associations of Albuterol and outcomes in all participants. The effect of Albuterol on the outcome variables was examined with a repeated measure design using mixed-effect linear regression modeling with the random subject effect and fixed effect variables including age, sex, height, weight, and the corresponding baseline measure of the outcome variable. The number of participants (N), the summary statistics (mean ± standard deviation) for each outcome variables measured in the placebo visit and the albuterol visit as well as the resulted parameter estimate (PE) representing the adjusted difference and the corresponding 95% confidence interval (CI) are shown. In this intention-to-treat analysis, N represents the number of participants who completed each (albuterol or placebo) arm of the study. The dot-and-whisker plots represent the PE and 95% CI with colors black (scaled on the top) and red (scaled on the bottom) to distinguish outcomes in which higher versus lower values are preferable. The PE and 95% CI for the statistically significant associations were shown in bold. Abbreviations: VO₂: oxygen uptake; Watts: work stage completed in watts; V_E: minute ventilation value; RR: respiratory rate; V_T: tidal volume; VCO₂: carbon dioxide production; SpO₂: oxygen saturation; O₂-Pulse: oxygen uptake per heartbeat; EELV: end-expiratory lung volume; VFL: volume of the tidal breath that is flow limited on expiration; EFL: expiratory flow limitation; SF12: Short Form 12-Item Health Survey; IPAQ: International Physical Activity Questionnaire; MET: metabolic equivalent: MVPA: moderate to vigorous physical activities; PE: parameter estimate; CI: confidence interval

Fig. 4

Associations of Albuterol and outcomes in subgroup analysis. The effect of Albuterol on the outcome variables was examined with a repeated measure design using mixed-effect linear regression modeling with the random subject effect and fixed effect variables including age, sex, height, weight, and the corresponding baseline measure of the outcome variable. The analysis was separately done within the whole group of participants and the subgroups based on RV/TLC and/or adherence. The number of participants (N), the summary statistics (mean ± standard deviation) for each outcome variables measured in the placebo visit and the albuterol visit as well as the resulted parameter estimate (PE) representing the adjusted difference and the corresponding 95% confidence interval (CI) are shown. In these subgroup analyses, N represents the number of participants in both arms of the study who met the air trapping and/or adherence criteria. The dot-and-whisker plots represent the PE and 95% CI with colors black (scaled on the top) and red (scaled on the bottom) to distinguish outcomes in which higher versus lower values are preferable. Abbreviations: VO_2Peak: oxygen uptake in peak exercise; V_TPeak: tidal volume in peak exercise; VFL: volume of the tidal breath that is flow limited on expiration; PE: parameter estimate; CI: confidence interval

Fig. 5

Associations of Albuterol and outcomes in the subgroup with RV/TLC > 0.35 and ≥ 90% adherence. The effect of Albuterol on the outcome variables was examined with a repeated measure design using mixed-effect linear regression modeling with the random subject effect and fixed effect variables including age, sex, height, weight, and the corresponding baseline measure of the outcome variable. The number of participants (N), the summary statistics (mean ± standard deviation) for each outcome variables measured in the placebo visit and the albuterol visit as well as the resulted parameter estimate (PE) representing the adjusted difference and the corresponding 95% confidence interval (CI) are shown. In this subgroup analysis, N represents the number of participants in each arm of the study who met the adherence criteria of ≥ 90%. The dot-and-whisker plots represent the PE and 95% CI with colors black (scaled on the top) and red (scaled on the bottom) to distinguish outcomes in which higher versus lower values are preferable. The PE and 95% CI for the statistically significant associations were shown in bold. Abbreviations: VO₂: oxygen uptake; Watts: work stage completed in watts; V_E: minute ventilation value; RR: respiratory rate; V_T: tidal volume; VCO₂: carbon dioxide production; SpO₂: oxygen saturation; O₂-Pulse: oxygen uptake per heartbeat; EELV: end-expiratory lung volume; VFL: volume of the tidal breath that is flow limited on expiration; EFL: expiratory flow limitation; SF12: Short Form 12-Item Health Survey; IPAQ: International Physical Activity Questionnaire; MET: metabolic equivalent: MVPA: moderate to vigorous physical activities; PE: parameter estimate; CI: confidence interval