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.
Lung function is used to evaluate response to therapy. However, confounding factors, including thoracic gas compression, may affect change in lung function with therapy.
Thoracic gas compression may confound effect of bronchodilators on lung function. Improvements in FEV1 after inhaled β-adrenergic agents in COPD are due to reduction in lung resistance, hyperinflation, and thoracic gas compression.
Maximal expiratory airflow results from a unique flow–pressure–volume relationship, which reflects the mechanical properties of lungs and airways (5–7). It is determined by the lung elastic recoil pressure, the upstream frictional pressure loss, and the relationship between cross-sectional area and transmural pressure at the choke point (7, 8). Lung elastic recoil pressure depends on the absolute lung volume (9, 10).
During a forced expiratory maneuver in a subject with expiratory airflow limitation, the expired volume at the mouth (measured by a pneumotachograph) may differ considerably from the change in lung volume measured with a body plethysmograph. This difference in volume is primarily due to thoracic gas compression (TGC). TGC occurs at high and mid-lung volume (3, 11, 12) and is primarily affected by airway resistance, effort, and absolute lung volume (5, 13). TGC is high in subjects with large lung volume, strong expiratory muscles, and expiratory airflow limitation (14).
Bronchodilators improve expiratory airflow limitation by reducing lung resistance. This change in resistance can alter the amount of gas compression and thus results in altered flow–volume–pressure relationship and maximal expiratory airflow. Therefore, the reduction in TGC after inhalation of a bronchodilator may reduce the negative effect of TGC on forced expiratory airflow. Although both diminished lung resistance and TGC with a bronchodilator improve maximal expiratory airflow, only the diminished lung resistance affects expiratory airflow during tidal breathing. Thus, the presence of TGC may confound the effect of a bronchodilator on maximal expiratory airflow.
In this study, we investigated the mechanisms of improved maximal expiratory airflow subsequent to inhalation of albuterol to explore any confounding effects of TGC. We hypothesized that the improvement in FEV1 postalbuterol is due to the combined effect of reduced airway resistance and reduced gas compression.
We measured lung mechanics at baseline and 20 minutes after inhalation of albuterol (180 μg from a metered dose inhaler) in healthy subjects, subjects with asthma, and subjects with chronic obstructive pulmonary disease (COPD). The diagnoses of asthma and COPD were based on the American Thoracic Society criteria (15). All subjects had to be in stable clinical condition with no change in respiratory medications within the last 4 weeks of testing. Subjects with asthma and COPD were asked to withhold their short- and long-acting bronchodilators for 8 and 24 hours before the test, respectively. The study was approved by the local institutional review board, and each subject signed a written, informed consent form prior to participation in the study.
Lung mechanics were measured with the subject seated in a custom-made volume-displacement plethysmograph (16). During each session, we obtained at least three reproducible forced expiratory maneuvers. Quality control measures, as outlined by the American Thoracic Society, were used to select appropriate maneuvers (17). Inspiratory and expiratory lung resistances were measured during quiet breathing using the model reported before (18). Total lung capacity (TLC) and residual volume (RV) were also measured at baseline and 20 minutes after bronchodilator administration. We recorded esophageal pressure as an indicator of effort. Details of the measurements are provided in the online supplement.
We used a novel computational program in MATLAB environment to calculate the FEV1 corrected for the effect of TGC (NFEV1). First, the software generates a plot of the expiratory flow signal versus the box volume signal in an x–y graph (Figure 1A). This plot represents the forced expiratory flow volume loop with units of liters/second (L/s) on the y axis and liters (L) on the x axis. Subsequently, the software inverts the expiratory flow signal between TLC and RV, plots box volume signal (L) on the x axis and inverted expiratory flow signal (s/L) on the y axis, and generates a graph (Figure 1B). This new graph contains a very steep negative slope at the beginning of the maneuver that reverses to a positive shallow slope during the effort independent portion (<80% of TLC) of the FVC maneuver. Subsequently, the software uses the following algorithm to calculate the computed time (Z).
After generating the computed time, the software calculates the subject's NFEV1 (Figure 1C displayed as a solid line). The backward extrapolation technique is used to determine the start time for the NFEV1 calculation. The software uses the computed time for this determination instead of the standard linear time. The start time is determined by assuming that peak flow had begun since the expiration began at TLC. Volume–time curves are shown in Figure 1D. These curves are recorded at the mouth and are based on mouth-flow and box-volume measurements as described. To estimate the magnitude of gas compression, we used the following equation:
We used Stata version 9 (StataCorp, College Station, TX) for data analysis. Demographic and baseline lung function data were analyzed by descriptive statistics and are presented as means ± SD. We used analysis of variance to compare the values among normal subjects and patients with asthma and COPD. We used paired t test to compare lung parameters pre– and post–albuterol administration. The relationships between FEV1 improvement and other lung mechanics parameters were evaluated by stepwise multiple regression analysis. A p value of less than 0.05 was considered significant.
We enrolled 10 healthy subjects, 9 patients with asthma, and 15 patients with COPD. All patients with COPD were male, whereas five of the normal subjects were females and five of the patients with asthma were female. Mean (SD) age in years for normal subjects and subjects with asthma or were 38 (SD, 11), 45 (SD, 11), and 64 (SD, 8) years, respectively. Mean heights in centimeters for normal subjects and patients with asthma or COPD were 170 (SD, 11), 172 (SD, 8), and 179 (SD, 6) cm, respectively. Only one of the normal subjects was a smoker, whereas none of the subjects with asthma had a smoking history of more than 10 pack-years. Five subjects with asthma were using short-acting bronchodilator on an as-needed basis, whereas the other four were receiving inhaled corticosteroid and/or long-acting β-agonist. All but five of the patients with COPD had stopped smoking more than a year before the study. All the patients with COPD were receiving inhaled bronchodilators and/or inhaled corticosteroid. Baseline and post-bronchodilator pulmonary function data are shown in Table 1. Mean FEV1 in subjects with asthma did not reverse to normal range; however, the reversibility was higher than in subjects with COPD who had severe disease with evidence of significant hyperinflation.
|FEV1, %||94 (3)||100 (4)*||57 (3)||65 (4)‡||33 (2)||38 (3)‡|
|FEV1, L||3.26 (0.60)||3.43 (0.67)*||1.97 (0.68)||2.23 (0.74)‡||1.17 (0.49)||1.36 (0.51)‡|
|NFEV1, L||3.61 (0.69)||3.80 (0.76)*||2.52 (0.65)||2.76 (0.64)‡||1.74 (0.50)||1.86 (0.52)‡|
|AFEV1||0.35 (0.06)||0.37 (0.08)||0.39 (0.07)||0.35 (0.09)||0.57 (0.08)||0.50 (0.07)†|
|%Compression||10% (4%)||10% (5%)||15% (10%)||12% (10)||32% (14%)||27% (13)‡|
|FVC, L||4.16 (0.7)||4.23 (0.8)||3.04 (0.9)||3.34 (0.9)‡||2.98 (0.9)||3.40(0.9)‡|
|FEV1/FVC, %||78 (5)||81 (6)||65 (8)||69 (9)||39 (7)||39 (7)|
|TLC, L||6.5 (0.44)||6.8 (0.47)†||7.7 (0.52)||7.6 (1.3)||8.9 (1.32)||9.0 (1.4)|
|RV/TLC, %||31 (6)||32 (6)||37 (14)||38 (4)||60 (7)||58 (6)‡|
|Rle, cm H2O/L/s||3.2 (0.7)||3.5 (1.7)||15.0 (12.5)||10.9 (9.8)†||17.1 (8.7)||12 (7.1)‡|
|Rli, cm H2O/L/s||1.6 (0.5)||1.2 (0.4)†||7.8 (5.6)||5.3 (3.5)†||4.8 (1.8)||3.4 (1.4)*|
|PEF, L/s||7.4 (1.9)||8.3 (2.4)*||5.2 (1.4)||5.9 (1.5)‡||3.4 (1.1)||3.7 (1.1)†|
|EPpeak, cm H2O||80 (21)||86 (19)||129 (44)||132 (53)||133 (62)||132 (55)|
Baseline mean FEV1 and NFEV1 as well as baseline FVC, TLC, RV/TLC ratio, expiratory lung resistance (Rle), inspiratory lung resistance (Rli), PEF, and maximal esophageal pressure during forced maneuver (EPpeak) differed significantly among the three study groups (p < 0.05). FEV1 as well as peak expiratory airflow significantly increased with albuterol inhalation. Furthermore, in patients with asthma and COPD, FVC increased, whereas Rle, Rli, RV, and RV/TLC decreased significantly (for p values, see Table 1).
%Compression was defined as (NFEV1 − FEV1)/NFEV1. We used %Compression as an index of TGC. %Compression was significantly larger in patients with COPD compared with normal subjects (p < 0.0001). In univariate regression analysis, prealbuterol %Compression was significantly predicted by Rle, Rli, TLC, RV/TLC ratio, and PEF (all p values < 0.05). In a stepwise multiple regression analysis, %Compression correlated significantly only with Rli, RV/TLC ratio, and EPpeak (Rli, p < 0.05; RV/TLC ratio, p < 0.01; EPpeak, p < 0.0001; adjusted R2 = 0.75).
We defined the absolute and percent difference between FEV1 and NFEV1 as AFEV1 and %Compression, respectively (see Methods). AFEV1 and %Compression diminished significantly in subjects with COPD post–albuterol inhalation (p < 0.03 and p < 0.005, respectively) but did not reach statistical significance in subjects with asthma or in normal subjects.
In univariate analyses, absolute and percent FEV1 improvement postalbuterol significantly correlated with the reduction of %Compression, RV/TLC ratio, and Rli (%Compression: p < 0.001, adjusted R2 = 0.75; RV/TLC: p < 0.0001, adjusted R2 = 0.71; Rli: p < 0.01, adjusted R2 = 0.39) in subjects with asthma and COPD. In multiple regression analysis, FEV1 improvement correlated significantly with change in Rli and RV/TLC ratio (Rli, p < 0.004; RV/TLC ratio, p < 0.05; adjusted R2= 0.56). Addition of change in %Compression improved the regression (p for %compression change < 0.0001, adjusted R2 = 0.79). This predicts that 23% of FEV1 improvement was predicted by reduction of gas compression.
In subjects with COPD, FEV1 increased 190 ml (SD, 150) and 19% (SD, 15) from baseline, whereas NFEV1 increased only 120 ml (SD, 110) and 7% (SD, 7) from baseline. Both absolute and percentage changes from baseline were significantly different between FEV1 and NFEV1 (p < 0.05). In subjects with asthma, FEV1 increased 260 ml (SD, 270) and 15% (SD, 16) from baseline, whereas NFEV1 increased 240 ml (SD, 216) and 11% (SD, 11) from baseline.
FVC also improved significantly after albuterol inhalation. Reduction in %Compression and RV/TLC ratio significantly predicted FVC improvement in subjects with asthma and COPD (p < 0.0001 and p < 0.0001, respectively; adjusted R2 = 0.93).
A representative set of data from a subject with COPD before and after albuterol inhalation is presented in Figure 2. Figures 2A and 2B show the flow volume loop before and after inhalation of albuterol. The volume measured with the plethysmograph was appreciably different from the volume measured from integration of mouth flow at baseline and after albuterol. However, after albuterol inhalation, the flow difference at each volume point of FVC between the loops diminished (TGC). The volume at PEF obtained from mouth airflow diminished from 170 to 100 ml with albuterol inhalation. The volume at PEF obtained from plethysmograph flow diminished from 340 to 240 ml with albuterol inhalation. The difference in PEF volume for mouth and plethysmograph flow diminished from 170 to 140 ml. Figures 2A and 2B also show similar reduction in volume difference at residual volume between mouth airflow and plethysmograph airflow with inhalation of albuterol.
Data in Figure 3 represent lost volume due to gas compression against time in three study subjects before (thin line) and after (thick line) inhalation of albuterol. AFEV1 was appreciably higher in patients with COPD compared with patients with asthma and normal subjects. Furthermore, in all three examples, AFEV1 was larger before inhalation of albuterol. Figure 3A is from a normal subject. As expected, in this normal subject, lost volume was not appreciably different before and after albuterol. Figure 3B is from a subject with asthma. In this subject, lost volume did not change significantly with albuterol. In contrast, the lost volume in a patient with COPD (Figure 3C) was significantly diminished with albuterol inhalation. In all three subjects (before and after inhalation of albuterol), the lost volume was more at the beginning of the forced maneuver compared with the end of the maneuver.
In this study, we explored the mechanisms of maximal expiratory airflow improvement after bronchodilator administration by studying the effect of albuterol inhalation on lung mechanics. Our data show that inhalation of albuterol improves maximal expiratory airflow by reducing lung resistance (Rli and Rle), hyperinflation (RV/TLC ratio), and TGC (AFEV1 and %Compression). This phenomenon was more pronounced in subjects with more severe airflow obstruction, such as those with COPD. Our finding suggests that, in subjects with COPD, improvement in FEV1 after a bronchodilator inhalation is confounded by reduction in TGC. Reduction of lung resistance and hyperinflation improve expiratory airflow during both forced and nonforced exhalation and thus may correlate with improvement in symptoms and exercise capacity. However, TGC is negligible during nonforced expiration and occurs mainly with forced expiration and thus its reduction may not have any meaningful clinical effect during nonforced expiration. Our data suggest that more than 20% of FEV1 improvement is in fact due to TGC reduction.
Theoretically, gas compression could occur in (1) gas trapped with no access to an open airway (which will include abdominal gas) and (2) gas with open access to an airway but with an axial expiratory velocity greater than 0.3 of the wave speed in that airway at that time so that the air upstream can now act as a compressible fluid. This velocity may be achieved at high lung volume when the flow is high. As is shown in Figures 3A–3C, the lost volume is larger earlier in the forced maneuver than close to the end of the maneuver especially in the patients with COPD. This finding indicates that the gas compression is in part due to the second (2) mechanism mentioned previously because the lost volume is more at the beginning of the breathing maneuver.
Clinical trials use FEV1 to assess response to bronchodilators. This is despite its insensitivity and inability to predict improvement in symptoms or exercise tolerance (4, 20, 21). Several studies show that improvement in other lung mechanic parameters may correlate better with improvement in symptoms and exercise capacity (4, 21, 22). Available data in the literature show that FEV1 response to a bronchodilator may underestimate the effect of the bronchodilator (20, 22). In contrast, our data for the first time show that the improvement of FEV1 may overestimate effect of a bronchodilator on expiratory flow limitation.
In patients with expiratory airflow obstruction, FEV1 can be negatively affected with effort due to gas compression (23, 24). TGC negatively affects the flow–pressure–volume relationship and maximal expiratory flow by reducing lung volume (24). The data in Figure 1 are similar to those reported by Pedersen and colleagues on the effect of addition of external resistance on maximal expiratory airflow (24). TGC is affected by several factors, including expiratory airflow limitation, lung volume, and strong expiratory muscles (13, 14). Our data, consistent with previous studies, showed that TGC increased with rise in lung resistance, effort, absolute lung volume, and hyperinflation. In normal subjects at baseline, the FEV1 was less than NFEV1. However, the percentage difference between FEV1 and NFEV1 in normal subjects was appreciably less than patients with COPD. This finding was expected because airflow limitation and hyperinflation are required to cause appreciable gas compression (13). Normal individuals can generate significant gas compression despite normal lung resistance if both effort and the flow speed that is generated are large. However, we did not observe this condition in our normal subjects.
In subjects with COPD, expiratory and inspiratory lung resistances were significantly higher than in normal subjects. All our subjects with COPD with expiratory airflow limitation generated a significant amount of positive intrathoracic pressure during forced expiratory maneuvers. Furthermore, TLC and RV/TLC were considerably higher in subjects with COPD compared with normal subjects. In the patients with COPD, high lung resistance, large lung volume, and large intrathoracic pressure appear to explain the relatively high values of TGC at baseline measurement. On average, our subjects with COPD had 70 ml less gas compression with inhalation of albuterol. This reduction mostly stemmed from reduced resistance and lung hyperinflation. In contrast to forced expiration, due to its dependence on effort, TGC is negligible during nonforced expiration.
The effects of increasing resistance on maximal expiratory flow and TGC were studied by Pedersen and colleagues (24). They showed that addition of various external resistances increased the amount of compressed gas and reduced peak expiratory airflow in proportion to the amount of added resistance (24). TGC reduced the absolute lung volume, and thus negatively influenced the maximal expiratory airflow. This concept is also supported by data reported by Krowka and colleagues demonstrating that the highest values for FEV1 were associated with forced expiratory maneuvers performed with submaximal effort (14). Consistent with Pedersen and colleagues' study, our data showed that reduction of airway resistance and hyperinflation results in less TGC.
In summary, we demonstrate that the effect of albuterol on maximal expiratory flow is confounded by TGC reduction. Improvement in FEV1 after albuterol administration is partly explained by the reduction in airway resistance and hyperinflation but also by the reduction in TGC. Although TGC is large during forced maneuver, it is small during tidal breathing. TGC reduction during a forced expiration may not necessarily result in improvement in expiratory flow and thus symptoms and exercise capacity during nonforced breathing. This may in part explain the fact that, in subjects with severe airway obstruction such as COPD, FEV1 improvement measured using the traditional methods may not always correlate with improvement in symptoms and exercise. A more accurate way of determining a bronchodilator response during forced expiration has to take into account the change in TGC.
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