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2-agonists on lung
function in chronic obstructive pulmonary disease
1 Laboratorio di Fisiopatologia Respiratoria, Clinica Malattie Apparato Respiratorio, Università di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, 27100 Pavia; 2 Servizio di Fisiopatologia Respiratoria, Azienda Ospedaliera S. Croce e Carle, 12100 Cuneo; and 3 Fisiopatologia Respiratoria, Dipartimento di Medicina Interna, 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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The effects of inhaled bronchodilators at rest and during exercise were studied in 15 subjects with chronic obstructive pulmonary disease. In a crossover study against placebo, albuterol caused a significant increase in expiratory flow and reduced lung hyperinflation and dyspnea at rest, but this was not associated with differences in symptoms with exercise or any relevant parameter of physical performance. Dynamic hyperinflation occurred during exercise similarly after placebo or albuterol and was associated with a reduction of forced expiratory flows. This, in turn, was correlated with the bronchoconstrictor effect of deep inhalation determined at rest. In a parallel group study, expiratory flow was increased by 3-wk treatment with salmeterol (n = 9) but not with placebo (n = 6). However, in neither group was the response to exercise different from baseline. These results suggest that in chronic obstructive pulmonary disease effective pharmacological bronchodilation at rest may not be predictive of benefits of exercise tolerance. This may be related to the occurrence of airway narrowing during exercise, particularly when a deep inhalation at rest is followed by a decrease in expiratory flow.
lung hyperinflation; maximal and partial flow-volume loops; deep inhalation; dyspnea
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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DYSPNEA OCCURS DURING EXERCISE in subjects with chronic obstructive pulmonary disease (COPD), presumably because they must breathe at increased lung volume due to excessive flow limitation in the operative volume range (22). Accordingly, in subjects with reversible airway obstruction, bronchodilators decrease dyspnea during exercise, and this is associated with a decrease in functional residual capacity (FRC). In a number of COPD subjects, FRC decreases after a bronchodilator even in the absence of significant changes in forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC) (21, 25). The lack of sensitivity of FEV1 and FVC to the effect of bronchodilators has been attributed to a bronchoconstrictor effect of the deep inhalation preceding the forced expiratory maneuver, which is often observed in chronic airway obstruction (8, 13, 25, 26, 31, 37). It has therefore been postulated that the beneficial effect of bronchodilator treatments on symptoms and exercise tolerance may be overlooked by standard reversibility tests (21), and the reduction of lung hyperinflation at rest may be a better predictor of benefits on exercise tolerance (22). This may hold true if the bronchodilator effect is maintained during exercise. However, in subjects in whom a deep breath decreases flow, it may be expected that the increase of tidal volume (VT) during exercise also causes bronchoconstriction. This may offset the effect of pharmacological bronchodilatation, thus hindering its beneficial effects on airway hyperinflation and exercise tolerance.
This study was undertaken to investigate whether changes in airway caliber occur during exercise in COPD subjects and whether they modulate the effects of acute or chronic bronchodilator treatment.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Fifteen male subjects affected by moderate to severe COPD (1) took part in the study (Table 1). All were familiar with pulmonary function tests, because they had already participated in previous studies, were in stable clinical condition, and had not suffered from respiratory exacerbations in the previous 4 wk. No subject had a recent history of myocardial infarction or refractory heart failure or unstable arrhythmias that required treatment. The study protocol was approved by the local Ethics Committee, and informed consent was obtained from each participating subject.
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Study Design
The following tests were made on a prestudy screening day: standard spirometry, absolute lung volumes, single-breath lung carbon monoxide diffusion capacity, arterial blood gases, airway response to albuterol (200 µg by metered dose inhaler and spacer), 12-lead electrocardiogram, dyspnea score (modified Medical Research Council scale), and maximal incremental exercise test.The study consisted of a crossover phase and a subsequent parallel-group phase. In the crossover phase, subjects attended the laboratory on two separate occasions at the same time of day to have their resting lung function and response to exercise measured after treatment with placebo (day 1) or 200 µg of albuterol (day 2) in a double-blind random sequence. Subjects were then randomized to a 3-wk double-blind treatment with salmeterol (50 µg bid, by metered dose inhaler) or placebo and attended the laboratory on a third occasion (day 3), within 3 h from the morning dose of treatment, to have resting lung function and response to exercise measured again.
Resting Lung Function Measurements
A Vmax 22 system and an Autobox V6200 (SensorMedics, Yorba Linda, CA) were used to measure lung function. Mouth flow was measured by a mass flow sensor, and volume was obtained by numerical integration of the flow signal. Partial and maximal flow-volume curves were obtained as follows. After at least four regular breaths, subjects forcefully expired from end-tidal inspiration to residual volume (RV), which was immediately followed by a fast inspiration to total lung capacity (TLC) and a second forced expiration to RV. The maneuvers were performed at least in triplicate until the reproducibility criteria for FEV1 and FVC were met (2). Flows at 30% of control FVC were measured on both maximal (
max30) and partial flow-volume curves (part30), and their
ratio (M/P) was calculated to quantify the effects of deep inhalation
on airway caliber.
Thoracic gas volume was measured with subjects seated in the body plethysmograph and panting against a closed shutter at a frequency slightly <1 Hz with their cheeks supported. TLC was obtained as the sum of thoracic gas volume and the inspiratory capacity (IC) measured soon after reopening the shutter; RV was calculated as the difference between TLC and a slow expiratory vital capacity. FRC was obtained from thoracic gas volume corrected for any difference between the volume at which the shutter was closed and the average end-expiratory volume of the four preceding regular tidal breaths.
Single-breath carbon monoxide diffusion capacity was measured by using the method described by Huang and MacIntyre (17). Blood samples were drawn from the radial artery, and gas tensions were measured by a Ciba Corning 855 gas analyzer (Ciba Corning Diagnostic, Medfield, MA).
Predicted values were from Quanjer et al. (32) for spirometry and lung volumes, and from Cotes et al. (11) for carbon monoxide diffusion capacity.
Exercise Test
A symptom-limited incremental exercise test was performed on an electronically braked cycle ergometer (Ergometrics 800, Ergoline, Bitz, Germany) with subjects wearing nose clips and breathing through a mass flow sensor (dead space = 75 ml) connected to a saliva trap. Heart rate was continuously recorded (Archimed 4210, Esaote, Genoa, Italy). Oxygen uptake (O2) and carbon dioxide output were measured breath by breath with rapid gas analyzers (Vmax,
SensorMedics). Flow was continuously measured during inspiration and
expiration and numerically integrated to obtain volumes. After a 5-min
resting measurements period and a 3-min warm-up, exercise load was
increased by 10 W every minute until the load could no longer be
sustained; subjects pedaled at 50-60 revolutions/min. Special care
was taken to maintain the position of the trunk fairly constant during
the test. Predicted values were from Jones et al. (19).
Sets of at least four to six regular tidal breaths immediately followed
by a partial forced expiratory maneuver and an inspiration to TLC were
obtained in triplicate at rest and individually over the last 30 s
of each load step. Flow-volume curves were superimposed at TLC, which
was assumed to remain constant throughout the test. This allowed
changes in FRC, end-inspiratory lung volume, and part30 to be assessed during exercise. Changes of
airway caliber on exercise were estimated by calculating the slope of
the linear regression of all part30 values against
minute ventilation (E). VT,
inspiratory and expiratory times, heart rate, carbon dioxide output,
and O2 were recorded over the last
30 s of each load step before recording the partial forced
expiratory maneuver. The first three variables allowed breathing
frequency (f), E, and the ratio of inspiratory time
to total respiratory cycle duration to be computed. The severity of
breathlessness was assessed by using a modified Borg scale and a visual
analog scale.
Statistical Analysis
The relationship between variables was tested by linear regression analysis and by Pearson's coefficient of correlation. Differences within groups were tested by paired Student's t-test. A two-factor repeated-measure analysis of variance with Duncan's post hoc test was used to compare the effect of treatments between groups. P values of <0.05 were considered statistically significant. Values are presented as means ± SD.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Crossover Phase
Resting lung function.
After albuterol treatment (day 2), mean FEV1 was
slightly but significantly larger than after placebo treatment
(day 1) (Table 2). This was
associated with significant increments of max30, part30, IC, and inspiratory vital capacity, and with
significant decrements of FRC and RV, which is suggestive of effective
bronchodilation. The M/P ratio at rest was significantly <1
(P < 0.01) on both days 1 and 2,
indicating a bronchoconstrictor effect of deep inhalation. Respiratory
symptoms also improved after albuterol, as documented by a decrease of
both Borg (P < 0.05) and visual analog scale (P < 0.05) scores.
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Response to exercise.
After placebo treatment (day 1), both maximum workload and
O2 were well below the predicted normal
values (Table 3). Peak E was 72 ± 16% of maximum voluntary
ventilation, as assessed by
FEV1 · 35, and heart rate was below
the lower predicted values. In general, maximum exercise was variably
limited by ventilation, physical deconditioning, and cardiovascular
response. Exercise hyperpnea was achieved by increasing both
VT and f. The slope of part30 vs.
E could be reliably determined in 13 subjects and
was insignificantly different from zero (
0.008 ± 0.015)
but negative in 10 cases, which suggests that further airway narrowing occurred during exercise in most subjects.
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O2),
breathing pattern (E, VT, f, FRC,
end-inspiratory lung volume), and respiratory symptom scores recorded
at maximum exercise were not significantly different from day
1. The slope of part30 vs. E
could be reliably determined in 12 subjects and was significantly
different from zero (0.016 ± 0.016; P < 0.05).
The slope of part30 vs. E was
significantly correlated with the M/P ratio at rest (Fig.
1) both on day 1 (r = 0.71, P < 0.01) and day
2 (r = 0.63, P < 0.05),
suggesting that the greater the bronchoconstrictor effect of deep
inhalation at rest the greater the airway narrowing during exercise.
Furthermore, the slope of part30 vs. VT,
but not vs. f, was significantly correlated with the M/P ratio at rest
both on day 1 (r = 0.65, P < 0.05) and day 2 (r = 0.61, P < 0.05). In most individuals, FRC increased with E after either placebo or albuterol
treatment, and this increase was significantly correlated with the
part30 vs. E slope
(Fig. 2) both on day 1 (r = 0.62, P < 0.05) and day 2 (r = 0.69, P < 0.05). Partial and
tidal flow-volume loops of a representative subject at rest and during
exercise are shown in Fig. 3.
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Parallel-Group Phase
Resting lung function.
Treatment for 3 wk with salmeterol in nine patients was associated with
a significant increase in part30 (P < 0.05) (Table 4). Both Borg and visual
analog scale tended to decrease, although this did not achieve
statistical significance. None of the lung function variables was
significantly changed after placebo treatment compared with day
1.
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Response to exercise.
Despite an increase in part30 and/or IC beyond the
limits of spontaneous variability (25) in four of nine
subjects treated with salmeterol, no difference was observed in any
parameter of physical performance, breathing pattern, or respiratory
symptoms compared with day 1 (Table
5). The average slope of
part30 vs. E was
still negative with salmeterol treatment (0.011 ± 0.030),
although it was not significantly different from zero and from placebo
treatment (0.016 ± 0.019), suggesting that the long-term
bronchodilator effect of salmeterol was also offset by
bronchoconstriction that occurred during exercise.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of this study are that 1) airway narrowing occurs during exercise in a number of COPD subjects, and the magnitude of this effect is related to the bronchoconstrictor effect of deep inhalation at rest; 2) the reduction of expiratory flows during exercise contributes to lung hyperinflation with hyperpnea; and 3) the bronchoconstrictor effect of exercise may offset pharmacologically induced bronchocodilatation.
Comments on Methodology
In the present study, changes in airway caliber during exercise were assessed by measuring partial forced expiratory flows at various steps of exercise, according to a technique previously used (5, 27) and based on two assumptions. First, partial flows reflect changes in airway caliber relevant to each step of exercise better than maximal flows because they are not affected by the effect of lung inflation (8-10, 26, 27). Second, with the assumption that TLC remains constant with exercise (38), a full inflation taken soon after the maneuver allows the tidal flow-volume loops to be superimposed on the volume axis; thus assessment of flow at constant lung volume, namely 30% of control FVC in this study, was allowed.Maximal and partial flow volume curves were obtained by plotting flow against expired volume, thus the effects of thoracic gas compression were not taken into account. In theory, more thoracic gas compression on maximal than on partial expiratory maneuver could result in M/P ratios of <1, and this effect should be greater in the more hyperinflated subjects. However, there are reasons to be confident that this phenomenon was unimportant in this study. In asthma, thoracic gas compression was found to be similar (24) on maximal and partial flow-volume curves or slightly greater on the former (14), but by an amount that is unlikely to be appreciable when the downslope of the flow-volume curves is flat, as in the severely obstructed subjects of this study. Moreover, in asthma, changes in flow and airway resistance after a deep breath occur in the same direction and proportion (28, 30). Finally, in this study, no correlation was found between baseline M/P ratio and indexes of lung hyperinflation, namely FRC and TLC as a percent of predicted values.
Comments on Results
Bronchodilatation generally occurs during physical exercise not only in healthy subjects but also in those with bronchial asthma or mild COPD (3, 16, 18, 27, 34), thus widening the flow-volume loop and ultimately increasing the expiratory flow reserve. As a result, the breathing constraints mostly represented by the occurrence of expiratory airflow limitation and dynamic hyperinflation disappear or occur at higher levels of ventilation. Although unknown, mechanisms such as continuous stretching imposed by the lung on the airway wall, release of bronchodilator mediators (adrenaline, nitric oxide, etc.), and decrement in vagal tone may contribute to increase airway caliber possibly acting at the smooth muscle level (3, 12, 16, 18, 27, 34). In the present study, exercise hyperpnea was associated with airway narrowing, especially after inhalation of a regular dose of albuterol, which suggests that the above bronchodilator mechanisms were not operative in these subjects or were counteracted by some bronchoconstrictor mechanisms.Bronchoconstriction may also occur during exercise in subjects with exercise-induced asthma (6, 35, 36), which has been attributed to a series of mechanisms, such as local release of mediators, osmotic changes at the airways level (4), and myogenic reflexes of the airway smooth muscles (29). Whether these bronchoconstrictor mechanisms are also operative in COPD is unknown, but the absence of sustained bronchoconstriction after the repeated deep inhalations used to assess baseline lung function in these subjects makes it unlikely that constriction during exercise was mediated by a release of mediators or myogenic reflexes.
In subjects with chronic airflow obstruction, further airway narrowing
is often observed after a deep inhalation is taken (8, 13, 25,
31). Potential physiological explanations for this phenomenon
are a reduced volume excursion due to lung hyperinflation, low elastic
recoil, stress relaxation, altered airway-to-parenchymal
interdependence, relative predominance of parenchymal hysteresis over
airway hysteresis, and inhomogeneity of lung emptying during forced
expiration (15, 20, 26). Whatever the underlying
mechanisms, whose discussion is beyond the scope of this paper, it is a
fact that airflow obstruction occurs after taking a full lung inflation
in many COPD patients (8, 13, 25, 26). The positive
correlation between the slope of part30 vs.
E and the M/P ratio at rest observed in this study
suggests that, in those subjects in whom deep inhalation causes
bronchoconstriction, the increase in E with exercise may also cause airway narrowing. The large variability in both part30 vs. E and M/P ratio may be
accounted for by the heterogeneous nature of COPD (23).
The failure of bronchodilator treatments to reduce airflow limitation
and symptoms during exercise can be explained by two mechanisms. First,
a greater bronchoconstrictor effect of deep inhalation was observed in
most individuals after albuterol, as indicated by further reduction in
part30 vs. E slope, which became
significantly <0. This was possibly due to a decrease in airway
hysteresis as a consequence of a pharmacologically induced reduction in
airway smooth muscle tone (33, 37) or to a decrease in
airway wall stiffness. These findings may appear at variance with those
of Belman et al. (7) and O'Donnell et al.
(22), who reported an increase in exercise performance and
a reduction in dyspnea during exercise after treatment with
bronchodilators. A possible explanation for this difference is that the
researchers mostly studied subjects in whom the negative effect of
volume history on airway caliber was absent or minimal, as was the case with some of the subjects of the present study. Moreover, with partial
flows that remained low during exercise, FRC had to increase similarly
with and without bronchodilators (Fig. 2), which was likely to meet the
ventilatory demands or act as a reaction to airway dynamic compression
(5, 18, 27). In agreement with Belman et al. and
O'Donnell et al., the lack of benefit from bronchodilators on
respiratory symptoms at maximum workload could be explained by the same
degree of lung hyperinflation achieved during exercise with and without bronchodilators.
The findings of the present study raise the question of whether the severity of the disease is based on the response to deep inhalations. The data would indicate that the COPD patients in whom a deep breath at rest evokes airflow obstruction may still take advantage of bronchodilator drugs at rest, which was suggested by improvement of respiratory symptoms and lung function (decrease in FRC and increase in partial flows), but this cannot be seen with parameters preceded by full lung inflation (FEV1 and/or FVC). However, because of the negative effect of volume history, subjects may show airflow obstruction during exercise, which would thus make pharmacologically induced bronchodilatation ineffective. In contrast, COPD patients without bronchoconstriction induced by deep inhalation may take advantage of bronchodilator treatments equally at rest and during exercise.
In conclusion, the present study indicates that airflow obstruction may occur during exercise in COPD subjects and is related to the bronchoconstrictor effect of the deep inhalation at rest. This effect may be sufficient in a number of subjects to offset the beneficial effect of bronchodilator drugs revealed at rest by using lung function measurements not affected by volume history.
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ACKNOWLEDGEMENTS |
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This study was supported in part by a grant from the Ministero dell'Università e delle Ricerca Scientifica e Tecnologica, Rome, Italy
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FOOTNOTES |
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Address for reprint requests and other correspondence: I. Cerveri, Clinica Malattie Apparato Respiratorio, IRCCS Policlinico S. Matteo, Via Taramelli, 5, 27100 Pavia, Italy (E-mail: i.cerveri{at}libero.it).
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. Section 1734 solely to indicate this fact.
September 6, 2002;10.1152/japplphysiol.00490.2002
Received 4 June 2002; accepted in final form 27 August 2002.
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METHODS
RESULTS
DISCUSSION
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