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Clinica di Malattie dell' Apparato Respiratorio and Istituto di Radiologia Medica, Istituo di Recovero e Cura a Carattere Scientifico, 27100 Pavia, Italy; Servizio di Fisiopatologia Respiratoria, Azienda Ospedaliera S. Croce e Carle, 12100 Cuneo, Italy; Laboratorium voor Pneumologie, Universitaire Ziekenhuis Gasthuisberg, B-3000 Leuven, Belgium; and Cattedra di Fisiopatologia Respiratoria, Dipartimento di Scienze Motorie e Riabilitative, Università di Genova, 16132 Genoa, Italy
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We hypothesized that an altered effect of lung inflation on airway caliber may in part explain the isolated volume response to bronchodilators, i.e., an increase of forced vital capacity (FVC) without change in 1-s forced expiratory volume (FEV1). Small-airway caliber was measured by high-resolution computed tomography at functional residual capacity and total lung capacity in five chronic obstructive pulmonary disease patients with an isolated increase of FVC (FVC responders) and five with an increase of both FVC and FEV1 (FVC-FEV1 responders) after inhalation of salbutamol. In FVC-FEV1 responders, the airway diameter increased with the cube root of increase in lung volume but was unchanged or even decreased in four of five FVC responders. FVC responders had more severe emphysema, as inferred from lung function and imaging studies, than FVC-FEV1 responders. We speculate that longitudinal traction or space competition (Verbeken EK, Cauberghs M, and Van de Woestijne KP, J Appl Physiol 81: 2468-2480, 1996) are possible underlying mechanisms. We conclude that the isolated volume response to bronchodilators is associated with severe emphysema and likely results from an altered effect of lung inflation on airway caliber.
pulmonary emphysema; airway reversibility; 1-s forced expiratory volume; forced vital capacity; high-resolution computed tomography; chronic obstructive pulmonary disease
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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REVERSIBILITY OF AIRFLOW OBSTRUCTION is generally defined by an increment of the 1-s forced expiratory volume (FEV1) beyond its short-term natural variability after inhalation of a standard dose of a bronchodilator (3, 13). In a number of patients with severe chronic obstructive pulmonary disease (COPD), forced vital capacity (FVC) remarkably increases in response to bronchodilator administration whereas FEV1 remains substantially unchanged (4, 8, 12, 14). This isolated volume response is generally taken as an indisputable sign of bronchodilatation (3, 13), but the underlying mechanisms are still unknown.
In the normal lung, the airways and lung parenchyma are interdependent in such a way that airway caliber monotonically increases with increasing lung volume. In the emphysematous lung, the caliber of small airways changes less than in the normal lung during changes in lung volume (20), and peripheral airway resistance may paradoxically increase when lung volume increases (18). A lack of increase or even a decrease in airway caliber with lung inflation may be the result of longitudinal traction of airways not supported by the radial traction by parenchymal tethering. Furthermore, Verbeken et al. (19) advanced the hypothesis of space competition, by which enlarged emphysematous air spaces would compress the adjacent small airways more at high than at low lung volumes, thus blunting or even reversing the change in airway caliber during lung inflation. We hypothesized that these mechanisms may explain, at least in part, the isolated volume response to bronchodilators. We reasoned that, at high lung volume, flow cannot increase after bronchodilator administration because the caliber of small airways is mainly dependent on the effects of airway-to-parenchymal interdependence. During deflation, the airway caliber would become progressively more dependent on smooth muscle tone and, by inference, sensitive to bronchodilator drugs. As a consequence, the FEV1, which in the obstructed patients mainly reflects events occurring at relatively high lung volumes, would change very little, whereas FVC, which is dependent on the degree of flow limitation at low lung volume, would significantly increase.
To test this hypothesis, we compared lung function with high-resolution and spiral computed tomography data in a group of COPD patients with isolated volume response to an inhaled bronchodilator. A group of patients with both FEV1 and FVC response to the bronchodilator served as controls. We predicted an association between the isolated volume response to the bronchodilator, the radiological extension of emphysema, and the lack (or reversal) of increase in small- airway caliber with lung inflation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Ten male patients affected by COPD took part in the study. The diagnosis was based on the criteria of the American Thoracic Society (2). All patients were familiar with pulmonary function tests. They were required to abstain from short-acting bronchodilators for at least 12 h, to be in stable clinical conditions, and not to have suffered from respiratory exacerbations in the previous 4 wk. To be included, patients had to respond to a standard dose of an inhaled bronchodilator (see Study design) with an increase of FVC alone (FVC responders, n = 5) or both FEV1 and FVC (FVC-FEV1 responders, n = 5) beyond their spontaneous variabilities. The study was approved by the local ethics committee, and the patients signed an informed consent.
Study design. The patients attended the clinic in the midafternoon of 3 separate days. On the first occasion, baseline spirometry and lung volumes were measured. These measurements plus single-breath diffusion capacity for carbon monoxide (DLCO) were repeated 30 min after inhalation of salbutamol (200 µg through a metered-dose inhaler with large spacer). Within a week, the patients returned to the lung function laboratory at the same time of the day to have the bronchodilatation response to salbutamol reassessed. On this occasion, lung elastic recoil was determined in those patients who consented. Finally, all patients attended the department of radiology for imaging studies.
Lung function measurements. A Vmax 22 system and an Autobox V6200 (SensorMedics, Yorba Linda, CA) were used to measure lung function.
For spirometry, mouth flow was measured through a mass flow sensor, and volume was obtained by numerical integration of the flow signal. After at least four stable tidal breaths, patients were asked to exhale slowly to residual volume (RV) and then to inspire forcefully to total lung capacity (TLC). This maneuver was immediately followed by a forced expiration to RV. The forced inspiratory flow at 50% of FVC (FIF50) and forced expiratory flows at 50% (FEF50) and 25% (FEF25) of FVC were measured on flow-volume curves. Forced expiratory maneuvers were repeated until reproducible values of FEV1 and FVC were obtained (3). Lung volumes were measured while the patients were sitting in a body plethysmograph and panting against a closed shutter at a frequency <1 Hz with their cheeks supported. TLC was obtained as the sum of thoracic gas volume and inspiratory capacity measured soon after the opening of the shutter. Predicted values for spirometry and lung volumes were from Quanjer et al. (13). Pleural pressure was estimated from the pressure measured (143PCO5D, Honeywell, Minneapolis, MN) in the lower third of the esophagus by a 10-cm-long latex balloon filled with ~1 ml of air while the patient was in a sitting position. Transpulmonary pressure (Ptp) was the difference between pleural pressure and mouth pressure. Placement of the balloon was considered correct if Ptp did not change when an expiratory effort was made against a partially closed airway and cardiac oscillations were minimal. Three satisfactory Ptp measurements were taken during breath hold at TLC, and their average was used as an estimate of lung elastic recoil pressure (PelTLC). Single-breath DLCO was measured by using the method described by Huang and MacIntyre (9) and predicted values were taken from Cotes et al. (6).Imaging techniques.
A third-generation, continuous-rotation computerized tomograph with
volume acquisition extendable to 24 s (Somaton Plus, Siemens, Erlangen,
Germany) was used. Qualitative evaluation of type and distribution of
emphysema was made by high-resolution computed tomography. During a
breath hold at TLC, three axial scans were taken at the levels of
aortic arch, tracheal carina, and pulmonary veins, respectively.
Quantitative evaluation of emphysema was based on three additional
scans, taken at the same levels as before while the patient was holding
his breath at RV. By using an appropriate software (Siemens) and the
"density mask" method, the percentage of pixels with density less
than 
900 Hounsfield units (HU) was calculated. This
percentage represents fairly well the proportion of lung tissue
affected by emphysema (11). Centrilobular emphysema was defined as a
prevalence of lucent holes within the lobules and panlobular emphysema
as the presence of widespread low-density areas with narrow vessels.
Statistical analysis. All values are presented as means ± SD. Differences between groups were tested by unpaired Student's t-test. Relationships between variables were tested by linear regression analysis and Pearson's correlation coefficient. Values of P < 0.05 were considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Pulmonary function.
At baseline (Table 1), the
degree of airflow obstruction was markedly greater in FVC responders
than in FVC-FEV1 responders. FEF50 was lower in
FVC responders than in FVC-FEV1 responders (P < 0.02), whereas FIF50 was not significantly different in the two groups. This resulted in a significantly (P < 0.02) greater FIF50-to-FEF50 ratio in FVC
responders (11.6 ± 3.0) than in FVC-FEV1 responders (5.7 ± 0.5); one patient of each group was not able to perform correctly
the forced inspiratory maneuver. The duration of forced expiration was
similar in both groups. Also similar were TLC, FRC, and RV.
PelTLC was determined in three FVC responders (14.9 ± 2.04 cmH2O, or 64 ± 12% of predicted) and in only one FVC-FEV1 responder (18 cmH2O, or 81% of
predicted); the remaining subjects did not tolerate the esophageal
balloon. DLCO was significantly lower in FVC
responders than in FVC-FEV1 responders; one FVC responder and two FVC-FEV1 responders were not able to perform the
correct maneuver.
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Imaging data.
The extent of emphysema was significantly greater in FVC responders
than in FVC-FEV1 responders (Table
4). The diameter of the small airways was
similar in the two groups at FRC but significantly smaller (P < 0.05) in FVC responders than in FVC-FEV1 responders at
TLC. With lung inflation from FRC to TLC, the caliber of small airways
increased in all FVC-FEV1 responders and in one FVC
responder, whereas in the remaining four FVC responders it remained
unchanged (2 cases) or decreased (2 cases). Typical spiral computed
tomography scans of small airways at FRC and TLC for one FVC responder
and one FVC-FEV1 responder are shown in Fig.
2.
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Relationships among variables.
Salbutamol-induced changes in FEV1 (Fig.
3) were negatively correlated with the
extent of emphysema (r = 0.89; P < 0.001) and
the ratio FIF50/FEF50 (r = 0.92; P < 0.01) but positively correlated with
DLCO (r = 0.96; P < 0.001),
PelTLC (r = 0.95; P = 0.054), and the absolute
increment in small-airway diameter between FRC and TLC (r = 0.63; P < 0.05). The caliber of small airways increased
proportionally to the cube root of the increase in lung volume from FRC
to TLC in FVC-FEV1 responders (r = 0.90; P < 0.05) but not in FVC responders (Fig.
4). The extent of emphysema was
significantly correlated with both DLCO
(r = 0.85; P < 0.05) and PelTLC
(r = 0.97; P < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The hypothesis tested in the present study was that the isolated volume response to bronchodilators is a characteristic of severe emphysema and may be in part explained by abnormal effects of lung inflation on airway caliber. The findings seem to support this hypothesis because 1) there was an inverse relationship between salbutamol-induced increments in FEV1 and various indexes of emphysema, in spite of conspicuous increments of FVC, and 2) the airway caliber increased with lung volume in all FVC-FEV1 responders but decreased or remained unchanged in most FVC responders.
Comments on methodology.
The extent of emphysema was inferred from the percent area in the six
hemislices with attenuation values less than 900 HU at the end
of full expiration. Although we might have missed some areas of the
lungs where the disease was more diffuse and severe, we believe that
our estimate of emphysema was fairly good because it correlated well
with both PelTLC and DLCO.
Comments on results. The isolated volume response to bronchodilators has been recognized for a long time (3, 4, 8, 12, 14), but the underlying mechanisms have never been completely elucidated. The FEV1 is determined by airflow at high to medium lung volumes, whereas the FVC is determined by airway closure or extreme flow limitation at low lung volumes. Therefore, a change of FVC without a concomitant change of FEV1 after administration of a bronchodilator agent suggests that the airway smooth muscle tone is a major determinant of airway caliber at low but not at high lung volumes.
During a forced expiratory maneuver, flow limitation occurs at the point (choke point) at which the velocity of air matches the velocity of wave propagation in the airway wall (7). The magnitude of maximal flow is directly related to airway caliber and to the elastance of the airway wall at choke point. A reduction of airway smooth muscle tone after inhalation of a bronchodilator can increase airway caliber, but it may also decrease airway wall stiffness. In emphysema, airway stiffness may be decreased (10), and a further decrease of it by removal of airway smooth muscle tone could prevent flow from increasing after bronchodilatation. Although no inference about airway compressibility is possible with the present data, the higher ratio of FIF50 to FEF50 in FVC responders than in FVC-FEV1 responders and the significant negative correlation between this ratio and the percent increase of FEV1 suggest a role for this mechanism. Another reason for an isolated volume response may be related to an abnormal effect of lung inflation on airway caliber. In emphysema, the distending force acting on the small airway walls may not be sufficient to fully dilate them so that expiratory flow may be limited in peripheral airways even at high lung volumes, irrespective of airway smooth muscle tone. Under these conditions, the airway smooth muscle tone may not be the major determinant of flow at high lung volume, thus making bronchodilator agents ineffective. With lung emptying, the effect of airway-to-parenchymal interdependence becomes progressively less important, and flow will be mainly dependent on airway caliber as determined by airway smooth muscle tone. In the present study, the caliber of small airways increased proportionally to the cube root of lung volume, as theoretically predicted for normal lung (16), in all FVC-FEV1 responders, but it remained unchanged or decreased in FVC responders. A decrease in airway caliber with lung inflation may be the result of longitudinal traction in the absence of the radial support provided by the lung elastic recoil on airway walls. Furthermore, Verbeken et al. (17, 19) recently proposed a theory according to which the airways, which are located within interlobular septa, can be compressed by enlarged air spaces. The precise mechanism for such a space competition is unknown, but small noncartilaginous airways might be compressed because the two layers of the septa containing them get too close when stretched or because they are squeezed by the abutting emphysematous air spaces (19). If airway caliber decreases with lung inflation in most of the lung, then we may assume that expiratory flow can be limited in the small airways even at high lung volume either before or after bronchodilatation. If elastic recoil does not change after salbutamol inhalation, then such a constant high-flow resistance could explain the lack of increase in flow after bronchodilatation over the first liter below TLC. In FVC responders, there was a small but significant increase in the duration of the forced expiratory maneuver after bronchodilatation, but its magnitude was such that it could explain only a minor part (~30%) of the observed increase of FVC. Another hypothetical cause for flow to be prevented from increasing at high lung volumes after bronchodilatation could be an excess of thoracic gas compression occurring during forced expiration. This explanation, however, should assume a larger lung volume or an increase of the force of the expiratory muscles in FVC responders than in FVC-FEV1 responders. Although we have no data to reject this mechanism, we feel that it is unlikely because TLC was not significantly different in the two groups yet tended to be larger in FVC-FEV1 responders than in FVC responders.Conclusions. The results of the present study suggest that isolated volume response to bronchodilators is a characteristic of severe emphysema involving more than 40% of lung parenchyma. An altered effect of lung inflation on airway caliber, due either to loss of lung elastic recoil or to space competition, may be the mechanism making airway caliber independent of airways smooth muscle tone at high lung volume, thus explaining at least in part the lack of sensitivity to bronchodilatation as assessed by changes in FEV1.
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ACKNOWLEDGEMENTS |
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This study was supported in part by a research grant from Ministero dell' Università e della Ricerca Scientifica e Tecnologica, Rome, Italy.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: V. Brusasco, Dipartimento di Scienze Motorie e Riabilitative, Università di Genova, Largo R. Benzi 10, 16132 Genova, Italy (E-mail: brusasco{at}dism.unige.it).
Received 27 October 1999; accepted in final form 30 January 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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FEV1) and emphysema
extent (A), single-breath diffusion capacity
(DLCO, B), lung elastic recoil at TLC
(PelTLC, C), change in diameter of the small
airways from FRC to TLC (airway caliber TLC-FRC, D), and ratio
between forced inspiratory and expiratory flows at 50% of FVC
(FIF50/FEF50, E). 
, FVC responders;
, FVC-FEV1 responders. Regression lines for pooled
patients are presented. All correlations were statistically significant
(see text for r and P values). Some data are missing
because of poor cooperation by patients.
