INTRODUCTION

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Chronic obstructive pulmonary disease (COPD) represents a disease entity of increasing importance and prevalence worldwide (1). The pathophysiologic features of COPD involve two components: an inflammatory component (2) and a structural component comprising irreversible alterations of lung architecture that result in a gradual loss of lung and airway elasticity (3, 4). This process favors expiratory flow limitation and airway collapse as major pathophysiologic characteristics that ultimately occur even during tidal breathing (5, 6).

However, airway collapse might not affect baseline lung function alone, but might also interfere with measurements of changes in bronchial tone. In particular, it could be argued that expiratory airway collapse impairs or even prevents the detection of smooth-muscle relaxation after inhalation of bronchodilators if the effect of these drugs is assessed through forced expiratory maneuvers. In contrast, forced inspiratory maneuvers would not be hampered by airway collapse, owing to the negative intrapleural pressure that exists under these conditions, with the result that the effects of relaxation should be more apparent. These considerations suggest that in patients with COPD, the effect of inhaled bronchodilators might be more pronounced during forced inspiratory than during forced expiratory maneuvers. Such mechanisms might also help to explain the benefit of inhaled bronchodilators in many patients with COPD as judged from their symptoms, even though their bronchodilator response in terms of FEV₁ is weak (7).

On the basis of these premises we hypothesized that the effects of bronchodilation in patients with COPD would be more pronounced during forced inspiration than during forced expiration, and that accordingly, changes in the perception of dyspnea would be related to changes in forced inspiration and not in forced expiration. To this end, we assessed the effect of an inhaled ₂-adrenoceptor agonist through a standard dyspnea score, as well as through several indices of forced expiration and inspiration, including forced inspiratory volume in one second (FIV₁). We then utilized the statistical procedure of factor analysis, which has been used previously to analyze baseline conditions in patients with COPD (8), to delineate the relationships between the changes induced by the ₂-agonist, with particular emphasis on the correlation between dyspnea and lung function parameters.

	METHODS

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We studied 61 patients with COPD whose diagnosis was based on the guidelines of the American Thoracic Society (11) (Table 1). Patients were included on the basis of a history of gradual progression of dyspnea on exertion over many years, a positive smoking history, no history of atopy, FEV₁ of less than 80% predicted, a stable clinical condition, and absence of other major illnesses. Forty-one of the patients took theophylline, 51 took inhaled corticosteroids, and 36 took systemic corticosteroids. All patients inhaled ₂-adrenoceptor agonists and anticholinergics regularly and additionally on demand. Fifteen patients were receiving long-term oxygen therapy. According to their FEV₁ values and ATS criteria (11), 8, 27, and 26 patients had mild, moderate, or severe COPD, respectively.

Study Design

Before testing, inhaled short-acting bronchodilators were withheld for at least 6 h and long-acting bronchodilators for at least 12 h. Oral medication, including corticosteroids and theophylline, was not changed. Patients underwent lung function measurement in the morning, in the sitting position, before and 30 min after administration of 400 µg salbutamol through a metered-dose inhaler with an inhalation chamber. This dose was chosen to achieve a maximal effect of the inhaled bronchodilator. Changes in the perception of dyspnea were assessed immediately before the second lung function measurement, through use of a visual analogue scale (VAS) (12).

Lung Function Measurement

Lung function was measured in a body plethysmograph (Masterlab; Jaeger, Würzburg, Germany) with the capacity to quantitate forced expiratory and inspiratory volumes. Inspiratory vital capacity (IVC), expiratory specific airway resistance (SRaw_ex), inspiratory specific airway resistance (SRaw_in), TLC, intrathoracic gas volume (ITGV), RV, and inspiratory capacity (IC) were respectively determined according to ATS or ERS guidelines (13). Maximal expiratory and inspiratory flow volume curves were then generated, with short intervening periods of tidal breathing. For the measurement of forced expiratory volumes, patients inspired slowly from tidal breathing until TLC was reached, and then expired forcefully until RV was achieved. For the assessment of forced inspiratory volumes, patients expired slowly from tidal breathing until RV was achieved, with subsequent forceful inspiration until TLC was reached. At least two measurements of forced inspiratory and expiratory volumes were made. Measurements were repeated until the differences in FIV₁, as well as those in FEV₁, were less than 5% relative to the higher value. From two acceptable maneuvers (difference < 5%), as defined in analogy with ATS criteria (13, 14), the highest values of FIV₁, peak inspiratory flow rate (PIFR), FEV₁, and peak expiratory flow rate (PEFR) were chosen for analysis. With this approach, the coefficient of variation between acceptable measurements of FIV₁ was on average 3% before bronchodilation and 2.3% after bronchodilation. All other parameters were taken as mean values of at least two qualitatively acceptable measurements.

VAS

Thirty minutes after the administration of bronchodilator, patients were asked whether they felt less short of breath, equally short of breath, or shorter of breath than at the start of measurements, and they were invited to rate the change on a VAS (16). The VAS used was a 20-cm-long horizontal line labeled "very much worse" at the left end, "very much better" at the right end, and "no change" in the middle (17). It was ensured that the patients understood the scale and the three possibilities of improvement, no change, and worsening of breathlessness. Each subject was instructed to mark the VAS line at any point at which he or she wished to do so. Ratings were expressed as percents of the full VAS line length, the range being from 100% (very much worse) to +100% (very much better). Patients were carefully advised to rate only shortness of breath, and to ignore other sensations such as cough or chest tightness.

Statistical Analysis

Mean values and SD or SEM were computed. Values measured before and after bronchodilation were compared with each other through use of the paired t test. Pearson's linear correlation coefficients were computed for factor analysis (18). Statistical significance was assumed for p < 0.05.

Correlation coefficients were analyzed by principal component factor analysis and subsequent rotation according to the standard varimax criterion (19). In this type of analysis, the correlation between parameters is attributed to their common dependence on independent entities called "factors." The coefficients that link parameters to factors are called "factor loadings," and are the correlation coefficients between parameters and factors. The varimax procedure aims to find optimal loadings, such that they are either high or low. Ideally, each variable would have a high loading on one factor, whereas its loadings on all other factors would be low. Thus, in essence, parameters are separated into independent subgroups, and the correlation of parameters within subgroups is due to their common factor. The number of factors that are necessary is chosen to be as small as possible but large enough to account for most of the variation within the data. Following the common approach (19), we derived the number of factors from the number of eigenvalues of the correlation matrix whose magnitude was more than 1.

	RESULTS

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Basic Statistics

VAS scores and changes in lung function parameters at 30 min after inhalation of salbutamol are given in Table 2. IVC, FVC, FEV₁, FIV₁, IC, PIFR, and PEFR increased significantly (p < 0.001 each), whereas ITGV, RV, SRaw_ex, and SRaw_In decreased significantly (p < 0.001 each). No significant change was seen in TLC. Mean FIV₁ increased by 0.357 L, which was significantly greater than the 0.157 L increase in FEV₁ (p < 0.001). Regarding relative changes from baseline, the mean increase in FIV₁ was 18.2%, and was not significantly different from the 14.9% increase in FEV₁ (p = 0.093). In accordance with ATS criteria, which require an increase in FEV₁ of both  12% and  200 ml, 17 patients (28%) were classified as responders to bronchodilation. With application of the same criterion of FIV₁, 37 patients (61%) would have been responders.

Correlation between VAS Score and Changes in Lung Function Parameters

VAS scores correlated significantly with both absolute and relative changes in FIV₁ (r = 0.715 and 0.730, respectively; p < 0.001 each; Figure 1A), PIFR (r = 0.456 and 0.495; p < 0.001 each), SRaw_in (r = 0.568 and 0.395; p < 0.01 each), SRaw_ex (r = 0.510 and 0.347, p < 0.01 each), IVC (r = 0.541 and 0.570, p < 0.001 each), and IC (r = 0.265 and 0.254, p < 0.05 each; Figure 1B). Only the percent change (r = 0.389; p < 0.01; Figure 1C), and not the absolute change in these variables (r = 0.213; p = NS) in FEV₁, showed a significant correlation with VAS score. No statistically significant correlation was found between VAS score and absolute or relative changes in TLC (r = 0.039 and 0.069), RV (r = 0.208 and 0.181), or ITGV (r = 0.216 and 0.219; Figure 1D).

View larger version (9K): [in this window] [in a new window]   View larger version (10K): [in this window] [in a new window]   View larger version (9K): [in this window] [in a new window]   View larger version (10K): [in this window] [in a new window]   Figure 1.   Relationship between VAS score and percent changes in FIV1 (A), IC (B), FEV1 (C), and ITGV (D). IC = inspiratory capacity; ITGV = intrathoracic gas volume; VAS = visual analogue scale. For corresponding correlation coefficients see RESULTS. The correlation coefficients, part of which are shown here, formed the basis for factor analysis.

Factor Analysis

The factor analysis of percent changes in lung function parameters yielded three factors, with eigenvalues of 4.46, 2.91, and 1.23, which accounted for 71.6% of total variance. VAS score and changes in FIV₁, PIFR, and IVC loaded predominantly on one common factor; changes in TLC, ITGV, and RV loaded largely on a second factor; and changes in FEV₁, PEFR, SRaw_ex, and SRaw_in loaded largely on a third factor (Table 3). When the analysis was repeated with absolute changes in lung function parameters, the first and second factors did not change essentially. However, factor three comprised only FEV₁ and PEFR, whereas a fourth factor contained SRaw_ex and SRaw_in. In this analysis, the first three factors accounted for only 63.4% of variance, and all four factors accounted for 79.9% of variance; the third and fourth eigenvalues were 1.24 and 1.08, respectively.

Results were not altered when the subgroup of patients with severe airflow obstruction (FEV₁ < 35% predicted, n = 26) was analyzed separately. Again, three factors resulted, which explained 78.1% of variance. The pattern of factor loadings was unchanged, and VAS was again associated with percent changes in FIV₁, PIFR, and IVC, but not with those in ITGV, IC, and FEV₁. In the subgroup of patients with FEV₁  35% predicted (n = 35), three factors also resulted, which explained 71.5% of variance. The one factor comprising VAS accounted for 43.9% of variance, and again loaded predominantly on changes in FIV₁ (loading = 0.840) and IVC (loading = 0.842). In addition, however, this factor was associated with high loadings on changes in ITGV (0.714) and FEV₁ (0.673). When gender was included, it led to a fourth independent factor, whereas the other three factors showed the same pattern with regard to dyspnea, FIV₁, FEV₁, and lung hyperinflation as in the analysis without gender. The pattern was also the same in the group of male patients (n = 43) analyzed separately, whereas the group of female patients was considered too small (n = 18) for analysis.

	DISCUSSION

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This study demonstrates that in patients with COPD, changes in the perception of dyspnea at rest after inhalation of a ₂-adrenoceptor agonist are primarily related to changes in parameters that describe forced inspiration, such as FIV₁, and PIFR, and not to changes in parameters of forced expiration or lung hyperinflation.

The aim of the study was a detailed analysis of the bronchodilator response in patients with COPD. In particular, we wondered whether forced inspiration would show greater improvements than forced expiration, and whether these improvements would correlate with dyspnea ratings. In patients with asthma, it is known that changes in the perception of dyspnea after inhalation of a ₂-adrenoceptor agonist (16), or after bronchoconstriction induced by exercise (20) or histamine (21), are related to changes in FEV₁. In patients with COPD, on the other hand, changes in FEV₁ after inhalation of ₂-agonists do not correlate with the perception of dyspnea (16, 22, 23).

Noseda and coworkers (16) identified patients with COPD who showed a high perception or a low perception of dyspnea after bronchodilation; patients in the high-perception group showed significantly larger increases in inspiratory airway resistance, IVC, and maximal inspiratory flow (MIF₅₀) than did those in the low-perception group. In the present study, low and high dyspnea ratings as measured with the VAS also occurred, and these ratings were much more closely related to changes in FIV₁ (Figure 1A), PIFR, and IVC than to changes in FEV₁ (Figure 1C). We did not include MIF₅₀ in our analysis, since its values were similar to those of PIFR. Among the parameters of inspiration, FIV₁, which was not reported in previous studies, correlated best with VAS ratings. Although IC, IVC, and inspiratory airway resistance, all of which have been studied previously, improved in terms of both absolute and relative changes (Table 2), they correlated much less with dyspnea than did changes in FIV₁ (Figure 1). Therefore, our data are consistent with those of Noseda and coworkers (16), and provide additional evidence that the discrepancy between high and low perceivers of dyspnea in relation to functional changes is much reduced when the perception of dyspnea is related to inspiratory rather than expiratory parameters.

On average, absolute values of improvements were significantly higher with FIV₁ than with FEV₁, but there was considerable heterogeneity between individual responses (Table 2). VAS ratings also showed considerable heterogeneity, but were strongly correlated with the absolute and relative changes in FIV₁, particularly as compared with other variables (Figure 1). That FEV₁ also showed an association with VAS in patients with less severe airway obstruction, although a weaker association than with FIV₁, suggests that in mild to moderate COPD, forced expiration yields more information, just as in the case of asthma (16), at least with regard to the perception of dyspnea. Therefore, for the assessment of bronchodilation, FEV₁ appears to be less useful, the greater the degree of structural alterations that are typical of COPD.

After inhalation of salbutamol, IC turned out to be of minor importance (Figure 1B) with respect to dyspnea at rest, in contrast to results obtained during exercise (24). Furthermore, SRaw_in was not related to FIV₁, possibly owing to the limited amplitude of tidal breathing as compared with that of forced maneuvers. These findings suggest that in COPD, the increase in the volume of air that can be inspired (IC), or the reduction in expiratory obstruction (FEV₁) and hyperinflation (ITGV), are minor determinants of the reduction in dyspnea after inhalation of a ₂-agonist. It is noteworthy that the preponderance of FIV₁ as an indicator of reduced dyspnea after such therapy matches the frequently heard description by patients of the sensation after bronchodilator inhalation as the ability "to get air more easily."

We followed standard procedures of factor analysis with respect to the selection of eigenvalues and the method of factor rotation. The analysis was done in an analogous manner for absolute and percent changes in lung function parameters. That the use of percent and absolute changes yielded similar results in terms of the association between VAS, FIV₁, and PIFR indicates the consistency of the analysis. This is also supported by inspection of Figure 1, which illustrates that the correlation between VAS and changes in FIV₁ was better than the correlation between VAS and changes in any other lung function parameter.

Previous studies used factor analysis for assessing baseline conditions in COPD (8). Various quality-of-life and symptom scores were assessed, and all were found to be unrelated to lung hyperinflation or expiratory obstruction. However, the scores correlated with 6-min walking distance, which may therefore be considered an objective measure of these scores in patients with COPD. In the present study, an additional factor analysis of baseline values of FEV₁, FIV₁, IVC, IC, ITGV, RV, PIFR, and PEFR yielded results similar to those of previous studies (8) (data not shown). Two factors were found, and lung hyperinflation was not associated with airway obstruction as described by expiratory parameters. Furthermore, inspiratory parameters were much more closely associated with expiratory parameters than with lung hyperinflation. All of these data are consistent in the sense that they prove indices of airway obstruction to be independent of indices of lung hyperinflation.

We used an experimental design comparable with the common procedure for bronchodilator testing, which is done under resting conditions. Several studies have suggested that inspiratory parameters at rest (23, 25) and during exercise (26, 27) are useful for assessing bronchodilation in COPD. Accordingly, IC has been proposed as a surrogate marker of lung hyperinflation that is linked to changes in the perception of exertional dyspnea and exercise endurance (26, 27). The present findings indicate that IC is not closely related to the reduction in dyspnea at rest after bronchodilator inhalation (Figure 1B). In contrast to dynamic measurements during exercise, IC might be more variable under resting conditions, particularly since it depends on hyperinflation as well as on expiratory and inspiratory obstruction. This argument is reflected in our finding that the factor loadings of IC were distributed over all of the three factors that we extracted, in contrast to the case for FIV₁ (Table 3; Figures 1A and 1B). It is conceivable that, as compared with the variability inherent in resting ventilation, the ventilatory demands of exercise lead to a stabilization of end-expiratory ITGV. This is also suggested by the finding that after bronchodilation with ipratropium bromide, changes in IC assessed under resting conditions were less correlated with changes in exertional dyspnea than were changes in IC assessed during exercise (28). Since FIV₁ depends on the end-expiratory lung volume preceding the FIV₁ maneuver, as well as on the effectiveness of the respiratory system in generating inspiratory flows under resting conditions, the dynamic aspect of the forced inspiratory maneuver might also reflect conditions that are relevant during exercise. Because forced inspiration has not so far been widely utilized as an evaluative maneuver in patients with COPD, the relationship between functional effects of bronchodilators and dyspnea during rest as opposed to exercise in COPD deserves further study.

In summary, our data indicate that in patients with COPD, forced inspiration, and particularly the assessment of FIV₁, yields objective information that correlates closely with subjective ratings of dyspnea after bronchodilator inhalation. These effects might help to explain why many patients with COPD show a benefit from bronchodilator treatment despite their relatively weak bronchodilator response as assessed through FEV₁. The advantage of forced inspiration as compared with forced expiration could depend on the masking effect of airway collapse on the effects of smooth-muscle relaxation during expiration but not during inspiration.