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

Abstract

Rationale: Improvement in FEV(1) 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 FEV(1).

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 micro g of albuterol. We then applied a novel method to calculate FEV(1) corrected for the effect of TGC (NFEV(1)).

Results: Prior to albuterol administration, NFEV(1) was significantly higher than FEV(1). However, post-albuterol inhalation, FEV(1) increased more than NFEV(1) 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 FEV(1) improvement in patients with COPD.

Conclusion: Improvements in FEV(1) 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 FEV(1) 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.

Figure 1.

The steps taken to obtain FEV₁ using no compression method (NFEV₁). (A) A flow–volume loop and associated gas compression in a patient with expiratory flow limitation (chronic obstructive pulmonary disease) measured using a plethysmograph. (B) A curve generated by plotting inverse flow (s/L) against volume. The crowding of the data points at the end of this curve is due to compression of the time scale, related to the very low flows. Integrating the area under the curve in B produces the computed time. (C) The volume change measured with plethysmograph versus this computed time. (D) Regular volume versus time (thin line) and NFEV₁ (thick line). Reprinted by permission from Reference 19.

Figure 2.

Effect of bronchodilator administration on FEV₁ (dashed line) and NFEV₁ (solid line) in a subject with chronic obstructive pulmonary disease. A and B show the flow–volume loop at (A) baseline (prebronchodilator) and (B) after bronchodilator inhalation. A shows that the volume measured with plethysmograph is appreciably different from the volume measured from exhaled volume. B demonstrates that the difference between the two volumes is smaller after inhalation of albuterol. The difference between volume for PEF from expired flow and volume for PEF from plethysmograph flow diminished with bronchodilator. Similarly, the difference between volumes at RV between mouth-expired volume and plethysmograph volume change diminished with inhalation of albuterol.

Figure 2.

Effect of bronchodilator administration on FEV₁ (dashed line) and NFEV₁ (solid line) in a subject with chronic obstructive pulmonary disease. A and B show the flow–volume loop at (A) baseline (prebronchodilator) and (B) after bronchodilator inhalation. A shows that the volume measured with plethysmograph is appreciably different from the volume measured from exhaled volume. B demonstrates that the difference between the two volumes is smaller after inhalation of albuterol. The difference between volume for PEF from expired flow and volume for PEF from plethysmograph flow diminished with bronchodilator. Similarly, the difference between volumes at RV between mouth-expired volume and plethysmograph volume change diminished with inhalation of albuterol.

Figure 3.

Plot of lost volume (L) against time (s) before (thin line) and after (thick line) inhalation of albuterol. A and B show that the lost volume difference before and after albuterol inhalation is not appreciably different in (A) a normal subject and (B) a subject with asthma. In contrast, C shows that the lost volume was significantly less after inhalation of albuterol in a subject with chronic obstructive pulmonary disease (COPD).

Figure 3.

Plot of lost volume (L) against time (s) before (thin line) and after (thick line) inhalation of albuterol. A and B show that the lost volume difference before and after albuterol inhalation is not appreciably different in (A) a normal subject and (B) a subject with asthma. In contrast, C shows that the lost volume was significantly less after inhalation of albuterol in a subject with chronic obstructive pulmonary disease (COPD).

Figure 3.

Plot of lost volume (L) against time (s) before (thin line) and after (thick line) inhalation of albuterol. A and B show that the lost volume difference before and after albuterol inhalation is not appreciably different in (A) a normal subject and (B) a subject with asthma. In contrast, C shows that the lost volume was significantly less after inhalation of albuterol in a subject with chronic obstructive pulmonary disease (COPD).