The confounding effects of thoracic gas compression on measurement of acute bronchodilator response

Rationale: Improvement in FEV₁ is a main endpoint in clinical trials assessing the efficacy of bronchodilators. However, the effect of bronchodilators on maximal expiratory flow may be confounded by thoracic gas compression (TGC). Objective: To determine whether TGC confounds effect of albuterol on FEV₁. Methods: We evaluated the response to albuterol inhalation in 10 healthy subjects, 9 subjects with asthma, and 15 subjects with chronic obstructive pulmonary disease (COPD) with mean (SD) age in years of 38 (SD, 11), 45 (SD, 11), and 64 (SD, 8), respectively. Lung mechanics were measured at baseline and 20 minutes after inhalation of 180 μg of albuterol. We then applied a novel method to calculate FEV₁ corrected for the effect of TGC (NFEV₁). Results: Prior to albuterol administration, NFEV₁ was significantly higher than FEV₁. However, post-albuterol inhalation, FEV₁ increased more than NFEV₁ because of reduced TGC. In multiple regression analysis, the changes in TGC, inspiratory lung resistance, and ratio of residual volume to total lung capacity postalbuterol predicted more than 75% of FEV₁ improvement in patients with COPD. Conclusion: Improvements in FEV₁ after albuterol in patients with COPD are due to reduction of lung resistance, hyperinflation, and TGC. The latter is negligible during tidal breathing. Thus, although reduction of lung resistance and hyperinflation may result in improved dyspnea with a bronchodilator, the contribution of TGC reduction to improvement of FEV₁ may not exert any meaningful clinical effect during tidal breathing. This fact has to be taken into consideration when assessing the efficacy of new bronchodilators.