Responses of FEV₆, FVC, and FET to inhaled bronchodilator in the adult general population

In recent years forced expiratory volume in six seconds (FEV₆) has evolved as a novel parameter in flow-volume spirometry that has been suggested to replace forced vital capacity (FVC) for some clinical applications [1‐4]. A practical benefit of using FEV₆ would be easier performance by patients because maximal end-expiration can be avoided. This measure could especially lend itself for use in the primary care setting [1]. Reference values and data on reliability and utility in the diagnosis of obstructive and restrictive lung diseases are emerging for FEV₆ [2‐9].

Bronchodilation induced by pharmacological agents is an important feature of asthma, whereas chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation that is not fully reversible [10]. In COPD, bronchodilation response may be reflected as increase of FVC, as an indicator of relief of air trapping [11, 12]. The FVC manoeuvre is technically demanding, significantly affected by expiratory time in subjects with airflow limitation, and sensitive to the impact of tiring [13].

The joint American Thoracic Society (ATS) and European Respiratory Society (ERS) Task Force on Standardisation of Lung Function Testing recommended in 2005 that a 12% and 200 ml improvement in either FEV₁ or FVC from baseline would be considered a significant bronchodilation response [14]. Recently we have shown that FEV₁ response to bronchodilation by around 9% from the baseline in an adult urban population is significant [15]. If bronchodilation response is observed only in FVC, the concurrent change in forced expiratory time (FET) should be evaluated [14]. Based on the observed intra-session variability of FET in the general population, we have suggested that 3 seconds would constitute a significant change [16]. In subjects with airflow limitation the intra-session repeatability of FEV₆ was at least equal to the repeatability of FVC [16]. FEV₆ is the least variable of the FEVx [17]. Both FEV₃ and FEV₆ have been shown to increase significantly when the increase in FVC was not caused by longer exhalation time [18]. Standardisation of FET during bronchodilation testing is problematic. Since FEV₆ would offer better repeatability and an unequivocal end-of-test measure, it would be interesting to assess FEV₆ as a surrogate measure of FVC response in the bronchodilation test.

The aim of this study was to evaluate the concurrent changes in FEV₆, FVC, and FET in a standardized bronchodilation test and their association with airflow limitation in a general adult population sample using flow-volume spirometry. Furthermore, the role of FEV₆ as a surrogate of FVC in the bronchodilation test was evaluated.

Changes in FVC and FEV₆ in bronchodilation test were normally distributed. The concurrent changes in FEV₆, FVC and FET in the bronchodilation test are outlined in Table 2. FEV₆ decreased statistically significantly more in women both in absolute and in relative terms, whereas the gender difference was only significant in relative change in FVC. Change of FVC and FET in relation to their respective average values are shown in Figure 1 in a modified Bland-Altman plot. At higher FVC there were less bronchodilation changes, but at higher FET more frequent changes associated with both underlying airflow limitation and poorer repeatability of FET in comparison to FVC. In the bronchodilation test 23.1% of men and 33.2% of women had a decrease of FVC greater than 2.5% from the baseline. The mean change in FVC was -42.8 (95% CI -52.4 to -33.3) ml or -1.0% (-1.2% to -0.7%). The upper 95^th percentile for change in FVC was 137.0 ml and 4.0%. The mean change in FET was -0.2 (-0.4–0.0) seconds or 0.4% (-1.4%–2.3%), with a 95^th percentile of 3.4 seconds or 44.0%.

FEV₆ tended to decrease during bronchodilation test, but the mean reduction was less marked than in FVC (mean change -13.4 (-22.3 to -4.5) ml or -0.2% (-0.4%–0.0%)). The 95^th percentile for change in FEV₆ was 169.1 ml and 5.0%. The individual concurrent changes in FEV₆ and FVC are demonstrated in Figure 2. The intra-class correlation coefficient (ICC) for the concurrent absolute change in FEV₆ and FVC was 0.84 (0.82–0.87) and for the relative change 0.86 (0.83–0.88). The agreement between changes in FEV₆ and FVC was better in subjects with airways obstruction (FEV₁/FVC post-bronchodilator < LLN); ICC for the relative change in subjects with obstruction was 0.91 (0.84–0.95) and in those who were non-obstructed 0.80 (0.77–0.83). Age, height, weight or BMI did not correlate significantly with changes in FVC, FEV₆ or FET during the bronchodilation test.

There were four subjects with the increase of FVC from the baseline at least 12% and 200 ml, yielding a population prevalence of 0.6% for a significant improvement of FVC in the bronchodilation test. Using the same threshold values six subjects showed a significant change of FEV₆. The changes in FVC, FEV₆, FEV₁ and FET of these subjects are individually shown in Table 3. One subject had a significant increase in FVC, but an insignificant increase in FEV₆; for her the increase of FVC was associated with an increase of FET by 8 seconds and 71% relative to the baseline FET. Three subjects had a significant increase in FEV₆ but a smaller increase in FVC, which were associated to shorter FET in post-bronchodilator spirometry.

The relationship of individual changes of FVC and the difference between changes in FEV₆ and FVC in bronchodilation test, to baseline FEV₁/FVC is demonstrated in Figure 3. Increase of FVC in the bronchodilation test associated inversely with FEV₁/FVC ratio and FEV₁. The changes in flow-volume spirometry variables stratified by FEV₁/FVC ratio at the baseline below or above lower limit of normal (LLN) are shown in Table 4. In subjects with airflow limitation the changes in FEV₆ and FVC were on the average +2.4% and +0.8%, respectively. In subjects with no airflow limitation the corresponding values were -0.7% and -1.3%. Conversely, there was no significant difference in FET between the subjects with or without airflow limitation at the baseline.

For healthy asymptomatic non-smokers (n = 219), the 95^th percentile of change in FEV₆ was 112.0 ml and 3.4%, change in FVC 92.0 ml and 2.5%, and change in FET 3.7 seconds and 50.0%.

The present study indicates that increase of FVC in response to inhaled salbutamol in the bronchodilation test in a general population sample is infrequent and is only rarely associated to increased expiratory time. Amongst subjects with baseline airflow limitation, FEV₆ response differentiated those individuals by whom increase of FVC was caused by longer exhalation time. This is important, because it implies that the use of FEV₆ would help to remove the need for standardization of exhalation time during standard bronchodilation testing. Decrease of FVC during the bronchodilation test was more frequent than previously reported, especially in healthy subjects. Therefore, the limit of significant increase of FVC might be lower than previously thought. However, the limits of any significant change are dependent of the inherent variability of the measures, like FVC, FEV₆ and FET.

Bronchodilation response in flow-volume spirometry is primarily assessed with FEV₁, but a significant response can also be seen in other measures, such as FVC [11‐13, 18, 30‐32]. It has been hypothesized that in patients with chronic airflow limitation combined with hyperinflation the potential increase of expiratory airflow due to bronchodilation may be attenuated in small airways due to airway-to-parenchymal interdependence [12]. The degree of obstruction in COPD has been found to modify the spirometric response to bronchodilation; FEV₁ response shown to dominate in mild obstruction (GOLD Stage I-II) and FVC response in severe obstruction (GOLD III-IV) [11]. Also in our material from general population FVC response to bronchodilator increased as the post-bronchodilator FEV₁/FVC ratio decreased as shown in Figure 3. However, especially in subjects with airflow limitation FVC has been found to depend on forced expiratory time; longer exhalations potentially created higher FVC values not necessarily due to actual bronchodilation [13]. At the present, FET is not routinely given in the reports of flow-volume spirometry and there is limited information on the concurrent changes of FET and FVC. It has been suggested, but not proved, that an increase in FET during bronchodilation testing in severely obstructed individuals could reflect bronchodilation in small airways [31, 33].

Since a positive response in FVC is most often seen in more severe COPD in a bronchodilation test, a large part of the bronchodilation studies assessing changes in lung volumes have been conducted in groups of patients with obstructive pulmonary diseases [12, 14, 18, 30‐32]. Bronchodilating medication, its dose and mode of delivery have varied making comparisons difficult. Most studies with large number of individuals have been conducted based on patient databases, where the exclusion of untreated asthmatics is nearly impossible [31].

Differing views have been voiced on the interpretation of FVC response. In patients with marked hyperinflation, bronchodilation response has been demonstrated to occur in inspiratory capacity (IC) and residual volume (RV) with better correlation to symptom relief than with other spirometric variables [31, 32]. Changes in vital capacity (VC) might in some individuals better correlate with symptomatic relief from bronchodilating medication and FVC can underestimate this volume response [34]. However, when assessing changes measured with flow-volume spirometry, FEV₆ would offer a measure that is not influenced by as many pathophysiological factors as FVC. Increase in FEV₆ may partially reflect flow changes also in small airways. Variables regarded to represent small airways (MEF50, MMEF) have greater inter- and intra-session variability than FEV₆ [35, 36] and are affected by concurrent changes in FVC. It is theoretically possible that in subjects with marked peripheral airways obstruction prolongation of FET after bronchodilation could imply decreased hyperinflation.

The frequent negative changes in FVC during bronchodilation test have to date been largely neglected. However, it greatly affects the distribution of values and the assessment of upper limit of normal change. We found 23% of men and 33% of women to have greater than 2.5% reduction in FVC in the bronchodilation test. One reason for reduction of FVC after the bronchodilator in healthy subjects could be the increased collapsibility of the airways as a result of the reduced airway smooth muscle tone with β2-agonists [37]. On the contrary, those subjects with markedly reduced FEV₁/FVC ratio indicating bronchial obstruction showed increased FVC after bronchodilation in our population study (Figure 3, Table 4). In this population, the upper 95^th percentiles for change in FEV₆ and FVC were around 5% and 4% from baseline, respectively. The corresponding values for the subgroup of healthy asymptomatic non-smokers were 3.4% and 2.5%.

When considering significant changes in bronchodilation testing, it is necessary to evaluate also the inherent measurement variability. In a large patient sample, the intra-session repeatability of FVC has been shown to have a 95^th percentile of 7.0% or 180 ml [38] although that study didn't control concurrent variations in FET either. In our earlier report from the present population sample the 95^th percentiles of the intra-session repeatability of FEV₆ and FVC were 3.3% or 117 ml and 3.2% or 119 ml, respectively [16]. Concurrently FET varied on average -0.0 (2.0) seconds with a 95^th percentile of 2.7 seconds. Earlier, Pennock and coworkers have concluded that the within-day repeatability of FVC is 6.7% and FEV₁ 8.1% in obstructive subjects [36]. Although our results imply that an increase in FVC due to bronchodilation is statistically significant at a lower level than given in the current standards [14], the limit for significant change cannot be lower than the repeatability of the measurement.

In our study, very few positive FEV₆ or FVC bronchodilation responses were detected in the unselected population sample, which limits the possibilities of further analysis in this study. This can partially be caused by the fact that regular medication was not discontinued for the study and hence subjects with asthma were on appropriate treatment. Since the number of subjects with positive responses was this limited in the population, concurrent changes in FEV₆, FVC, and FET should be further evaluated in subjects with varying degrees of obstruction. However, it is clear from this unselected population study that FVC tends to decrease in the healthy subjects and thus positive changes – most likely in those with airflow obstruction – are significant at a lower level than previously thought. No differences were detected between different age-groups, but the negative changes were slightly more common in women. However, men had more airflow limitation, which was associated with more frequent positive changes in FEV₆ and FVC during the bronchodilation test.

FEV₆ performed in this study comparably with FVC, suggesting that it could be considered a surrogate for FVC in the bronchodilation test. FVC might underestimate changes in vital capacity (VC) in subjects with severe airflow limitation and air trapping, which has been suggested to partially account for their subjective benefit of bronchodilating medication in clinical practice [34]. In subjects with airflow limitation, change in FEV₆ was significant in three subjects that had shorter exhalations in post-bronchodilation spirometry, which resulted in changes in FVC remaining below significant change limits (Table 3). We chose to replace FEV₆ with FVC when FET was under 6 seconds, because the exclusion of these subjects would have created a selection bias. In subjects with FET < 6 seconds, most often healthy young adults, FVC is not dependent on FET [39]. The intra-class correlation coefficient showed good agreement between changes in FEV₆ and FVC especially in subjects with airflow limitation in spirometry. Earlier Girard & Light have also shown that timed expiratory flows (FEV₃ and FEV₆) generally increase if the increase in FVC is not being caused by longer FET [13]. Previously it has been reported that FEV₆ has the least within-session variability of the FEVx values [17] when exhalation times are over 10 seconds. It is suggested that the use of FEV₆ would preclude the need to standardize FET and could act as a measure of bronchodilation especially in the primary care. The current standard states that FET should be analysed from those curves where the sum of FVC and FEV₁ is the greatest [25]. Since FET varies within test session more than FVC and FEV₁ [16], we suggest that in the bronchodilation test FET should be analysed from those curves with the largest FVC values. FEV₆ is more repeatable than FVC also in subjects with reduced FEV₁/FVC [15]. Earlier it has been disputed that the use of FEV₆ could more easily misclassify subjects with borderline obstruction [4, 5, 7, 8, 40], but since positive changes in FVC in the bronchodilation test are more likely to occur in more severe airflow limitation, this should not become a problem for the use of FEV₆ as a measure of bronchodilation in lieu of FVC.

In conclusion, we found that in a general population sample, positive FVC and FEV₆ response to bronchodilation in flow-volume spirometry was infrequent occurring almost solely in subjects with bronchial airflow limitation. In subjects with normal FEV₁/FVC ratio both FVC and FEV₆, on the average, decreased. We suggest that FEV₆ could be used in assessment of bronchodilation response in flow-volume spirometry instead of FVC; significant increase of FEV₆ would seem to be around 6%. By using FEV₆ for assessment of bronchodilator effect instead of FVC would remove the need for regulation of forced exhalation time during a bronchodilation test.