 2-Agonists, Improve the Perception of
Bronchoconstriction in Asthma
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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The relationship between asthma medication and the perception
of asthma symptoms is of interest for daily practice. Poor perception of asthma symptoms might influence patients' health care behavior and subsequently might lead to undertreatment and deterioration of their disease. This study investigated the influence of
the chronic use of short-acting and long-acting 
2-agonists, compared with the additional use of inhaled corticosteroids on the
perception of histamine-induced bronchoconstriction. Patients
with asthma (33 male and 31 female, mean age 35 ± 11 yr, FEV1
87 ± 14% of the reference value, PC20 geometric mean 1.08 mg/ml
(95% CI: 0.76-1.52) were selected and randomly allocated to the
use of either a short-acting 2-agonists (salbutamol, n = 22) or a
long-acting 2-agonists (formoterol, n = 22) or placebo (n = 20),
which has been used for 12 wk. This medication treatment was repeated exactly 1 yr later, with patients receiving the same medication plus an inhaled corticosteroid. Perception of histamine-induced
bronchoconstriction was measured at the start of each treatment
period and every 4 wk thereafter. Subjects quantified their sensation of respiratory discomfort during the challenge tests on a modified Borg scale. The perceptive "sensitivity" for changes in FEV1
was analyzed by the linear regression slope (
) "Borg versus percentage fall in FEV1." The "absolute perceptual magnitude" was
determined by the perception score at the 20% fall in FEV1 (PS20).
The additional use of inhaled corticosteroids during the second
year resulted in an improved perception of histamine-induced
bronchoconstriction (slope ) compared with the first year for
only the long-acting 2-agonists group (p value 0.036). This improvement was not observed for the "absolute perceptual magnitude" (PS20). The additional use of inhaled corticosteroids during
chronic use of long-acting 2-agonists improves the perceptive
"sensitivity" for changes in FEV1 during histamine-induced bronchoconstriction, which was not observed for short-acting bronchodilators. This result might indicate that the positive effects on
perception of airway obstruction might be another reason (besides the beneficial effects on the clinical condition) for prescribing a combination of long-acting 2-agonists and inhaled steroids.
Keywords: inhaled corticosteroids; long-acting beta 2 agonists; perception of bronchoconstriction; asthma
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Poor perception of asthma symptoms may be a major underlying cause of fatal or near fatal asthma attacks (1, 2). Those patients who perceive asthma symptoms poorly are at risk of underestimation and undertreatment of their disease. It is important to identify the determinants of the ability to perceive asthma symptoms (3, 4). In particular, the influence of asthma medication on the perception of asthma symptoms is of interest for daily practice. In the present study the effects of bronchodilators and inhaled corticosteroids on the perception of asthma symptoms are investigated. In Figure 1 we present the possible mechanisms underlying the relationship between the use of asthma medication and the perception of asthma symptoms.
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Bronchial hyperresponsiveness has been suggested to be a
negative factor in influencing the perception of asthma symptoms (5). Two different mechanisms for the relationship between bronchial hyperresponsiveness and perception of asthma
symptoms have been proposed. First, Burdon and coworkers
(5) suggested that those subjects who frequently develop acute
airflow obstruction acquire a degree of tolerance that reduces
the sensory intensity of the experience compared with that in
less reactive subjects. This mechanism is called temporal adaptation (dotted arrows in Figure 1). Second, it has been suggested that afferent nerves that participate in the perception
of bradykinin-induced bronchoconstriction may be impaired
by neurotoxins released by activated eosinophils in bronchial
hyperresponsive patients (double arrow in Figure 1) (7). This
is in agreement with in `t Veen and coworkers (8), who showed
that the degree of sputum eosinophilia is related with blunted
perception in patients with severe asthma. Both the use of inhaled corticosteroids and the chronic use of 2-agonists have
been shown to possibly have an effect on the degree of bronchial hyperresponsiveness (9). Some studies showed that
the chronic use of 2-agonists has detrimental effects, resulting
in increased bronchial hypperresponsiveness. It has been suggested that chronic use of short-acting 2-agonists leads to tolerance to its protective effects against bronchoconstrictor
stimuli, whereas its bronchodilator properties remained unchanged (11, 12). So the increased bronchial hyperresponsiveness after chronic use of 2-agonists might be a result of a
reduced protective effect against bronchoconstrictor stimuli.
Furthermore, several studies showed that regular, prolonged use of inhaled steroids can produce marked improvements in
airway hyperresponsiveness (13).
The chronic use of 2-agonists might also influence the perception of symptoms in a direct way, because the patients will have no warning against a possible deterioration of their disease. This reduced perception might have an effect on their health
care behavior (for instance, noncompliance with inhaled steroids), so that the protection against a potential progressive inflammatory airway disease with increasing bronchial hyperresponsiveness might be reduced (striped arrows in Figure 1). Chronic use
of bronchodilators also counteracts the bronchoconstriction, but
the negative consequence of chronic use of these drugs on bronchial responsiveness might eventually increase the airway inflammation and might have negative consequences for the degree of
bronchoconstriction in the long term (16).
We hypothesize that the chronic use of 2-agonists leads to
a decrease in the perception of airway obstruction, whereas
the additional use of inhaled corticosteroids will have a positive effect on the perception of bronchoconstriction. Therefore, we have studied the perception of bronchoconstriction
during chronic use of short-acting and long-acting 2-agonists
in comparison with the additional use of inhaled corticosteroids.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patient Selection
Patients, aged 16-60 yr, were selected for this study by their General Practitioner (GP). Criteria for selection included having bronchial symptoms or diagnosed asthma. Patients with asthma (FEV1 = 50% of predicted value; provocative concentration of an agonist causing a 20% fall in FEV1 [PC20] on histamine 8 mg/ml, and/or reversibility of obstruction at least 15% compared with baseline FEV1 after inhalation of 800 µg salbutamol; lower respiratory tract symptoms). In addition, patients selected used no inhaled corticosteroids (IC) or were able to cease this medication, in order to study the isolated effects of chronic bronchodilator use in the first year and the additional effects of inhaled corticosteroids in the second year. This selection procedure has been extensively described elsewhere (17).
Each histamine challenge test had to meet the following conditions to determine patient's "perceptiveness" during the study: baseline FEV1 50% of predicted value before the start of the bronchial provocation test, and during this test the PC20 value had to be established with at least two doubling doses of histamine. Patients were included in the analysis as they completed the study with at least four measurements (two baseline measurements and two follow-up measurements). Informed consent was obtained from each patient.
Study Design
The study started with an 8-wk washout period, in which patients
ceased all their pulmonary medication if used (inhaled corticosteroids, cromoglycates, bronchodilators) and were instructed to use only rescue medication on demand (Berodual [dpi], ipratropium bromide 40 µg, and fenoterol hydrobromide 100 µg). Selected patients were randomly allocated to three groups receiving either a short-acting (salbutamol [mdi], 2 × 100 µg four times a day), or a long-acting (formoterol [mdi], 1 × 12 µg twice a day) 2-agonist, or a placebo during
12 wk (double blind, double dummy). This study scheme is presented
in Figure 2. The study scheme was repeated exactly 1 yr later, with patients receiving the same blinded study medication plus an inhaled
corticosteroid (beclomethasone diproprionate [mdi], 2 × 200 µg twice
a day). Patients came to the laboratory at the start of each treatment
period (at the beginning of the first and second year) and received the
study medication. Patients were carefully instructed on how to use the
study medication (inhaler technique and time schedule) and this use
was checked every 4 wk thereafter. In case of an exacerbation patients
received a standardized treatment from their GP of an oral prednisone course (with antibiotics if necessary). The medication compliance was checked during every visit at the laboratory: used canisters
were collected and were weighed before and after.
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Methods
Histamine challenges were performed according to ERS standards (tidal breathing method) (18). Prior to testing, no study medication was used for at least 12 h. Doubling concentrations of histamine from 0.03 to 16 mg/ml were administered until PC20 was reached. The bronchial response to each dose of histamine was expressed as the reduction in FEV1 as percentage of baseline value (18).
The degree of respiratory discomfort was evaluated during the histamine challenge test, before each measurement of FEV1. Subjects were instructed to rate their degree of respiratory discomfort on a
modified Borg scale from 0 to 10 (19). The perception of bronchoconstriction during the histamine challenge test was analyzed by calculating the linear regression coefficient (slope ) between Borg scores
and the reduction in FEV1 as percentage of the baseline value in the
linear regression analysis of Borg = y + %
FEV1 indicating patient's perceptive "sensitivity" for changes in FEV1 (5, 7, 20). Furthermore, Borg scores corresponding to a reduction in FEV1 of 20% were
determined by interpolation (PS20), reflecting the "absolute perceptual magnitude" (6, 21, 22).
Analysis
To assess the influence on the perception of bronchoconstriction of
the chronic use of short-acting and long-acting 2-agonists compared
with the additional use of inhaled corticosteroids, the effects during
the first year (chronic use of 2-agonists alone) were compared with
the effects during the second year (chronic use of 2-agonists plus inhaled corticosteroids). A regression coefficient was calculated on the
data in the first year and the second year, both for the "sensitivity" index (slope ) and the "absolute perceptual magnitude" index (PS20).
This was done for each medication group independently. Regression
coefficients of the first year were compared with regression coefficients of the second year with a paired t test. Finally, to compare the
change in effect (between the first and the second year) between active medication and placebo an unpaired t test was used. All analyses were corrected for baseline perception score and baseline bronchial responsiveness (PC20). All data are presented as mean (±SEM).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients
During the first year, 128 patients participated in the study. Between the first and the second study year 64 subjects dropped out, mainly because of lack of motivation. The baseline characteristics of the 64 patients included in the analysis are presented in Table 1. The drop out between the first and second year was not selective, so there was no recruitment bias.
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Histamine Challenge Test
The mean value of the FEV1 as percentage of the predicted value was 86% (SD 14%) at the beginning of the histamine challenge test. The median value of the maximum fall in FEV1 was 25% of the baseline value (25-75th percentile: 22%- 29%). The mean values of the Borg scores at baseline and at the end of the histamine challenge test were 1.3 (SD 1.3) and 4.5 (SD 2.1), respectively.
Baseline Perception Scores
Baseline perceptive sensitivity for changes in FEV1 (slope )
were not significantly different among the three medication groups at the start of both medication treatment periods (Table 1). Baseline perception values at 20% reduction in FEV1
(PS20) were not significantly different among the three medication groups at the start of both medication treatment periods (Table 1).
Bronchial Hyperresponsiveness
There was a significant difference in baseline bronchial responsiveness among the three medication groups, which disappeared largely at the start of the second year (Table 1). The
courses of bronchial hyperresponsiveness during the 12 wk of
the first and second medication treatment period (chronic
bronchodilator use with and without inhaled corticosteroids)
are both shown in Figure 3. There were no significant differences in the degree of bronchial hyperresponsiveness between
baseline and after 12 wk of medication treatment in all three
medication groups. The bronchial hyperresponsiveness during
the second treatment period (chronic bronchodilator use with
additionally inhaled corticosteroids) increased significantly in
the group using chronic long-acting 2-agonists with additional
use of inhaled corticosteroids from 0.87 mg/ml (95% CI: 0.51-
1.49) to 1.60 mg/ml (95% CI: 0.90-2.86) (p value = 0.001).
Also, the PC20 in the group using placebo with inhaled corticosteroids increased significantly from 1.09 mg/ml (95% CI:
0.69-1.72) to 1.79 mg/ml (95% CI: 1.14-2.81) (p value = 0.025).
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Perceptive Sensitivity for Changes in FEV1
Only the regression coefficients for the perceptual sensitivity
(slope ) in the long-acting 2-agonists group were significantly different between the first and second year (p = 0.036).
The regression coefficient in the first year was 
0.0074 (± 0.0045) "Borg/% fall in FEV1"/4 wk and 0.0065 (± 0.0036)
"Borg/% fall in FEV1"/4 wk in the second year (Figure 4). This
result indicates that the perceptual sensitivity improves in the
long-acting 2-agonists group when additional inhaled corticosteroids were used. The change in course of the perceptual
sensitivity between the first and the second year for the long-acting 2-agonists group was not different from the change in
course in the placebo group (p = 0.424). The regression coefficients between the first and the second year were not significantly different in the short-acting 2-agonists and the placebo
group. So the additional use of inhaled corticosteroids did not
improve the perceptual sensitivity in the short-acting 2-agonists or placebo group.
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Absolute Perceptual Magnitude
There were no significant differences between the regression coefficient for the PS20 in the first year and the second year for all the three medication groups (Figure 5). The additional use of inhaled corticosteroids did not change the absolute perceptual magnitude in any of the three medication groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We hypothesized earlier that chronic use of 2-agonists might increase bronchial hyperresponsiveness (23), resulting in more
airway inflammation. We assume that increased bronchial responsiveness might lead eventually to a reduction of the perception of bronchoconstriction. We also suggested that the additional use of inhaled corticosteroids would reduce the possible
detrimental effect of chronic use of bronchodilators on bronchial hyperresponsiveness, possibly resulting in an improvement
of the perception of bronchoconstriction. These hypotheses can
only partially be confirmed by the results of the present study.
The present study showed that additional use of inhaled corticosteroids caused a decrease in bronchial hyperresponsiveness in
the group using long-acting 2-agonists and placebo. This improvement in bronchial hyperresponsiveness was not present
in combination with a short-acting 2-agonists. The additional use
of inhaled corticosteroids resulted only in an improvement of
the perceptual sensitivity when long-acting 2-agonists were used
and not during the use of inhaled steroids alone. However, the
change in course of perceptual sensitivity between the first and
the second year for the long-acting 2-agonists group was not
different from the change in course in the placebo group. These
findings might be explained by the relatively low reduction in
perceptual sensitivity in the first year in the placebo group
compared with the relatively high decline in perception in the
long-acting 2-agonists group, with the improvement in perceptual sensitivity being almost the same for both groups in
the second year when additional steroids were used (Figure 4).
The positive effect of inhaled steroids on bronchial hyperresponsiveness has been observed by many other studies (13, 24, 25). Two other studies investigating the effect of bronchodilators and inhaled corticosteroids on the perception of airway obstruction showed no effect of bronchodilators and a positive effect of inhaled corticosteroids on the perception of induced airway obstruction (7, 22). Roisman and coworkers (7) showed that corticosteroid treatment is associated with improved perception of bronchoconstriction induced by bradykinin. Boulet and coworkers (22) also found that patients using inhaled corticosteroids showed a greater perception of methacholine-induced bronchoconstriction. This latter study demonstrated also that short- and long-term use of salmeterol did not significantly change the perception of bronchoconstriction. In contrast, Higgs and coworkers (26) showed that beclomethasone reduced perception in most patients. This result might be a consequence of the fact that the study was done in the first week after treatment, before there was much improvement in lung function. We did not investigate the suggested mechanisms of the influence of bronchial hyperresponsiveness on the perception of bronchoconstriction as presented in Figure 1. Roisman and coworkers (7) suggested that activated eosinophils in inflammatory airways may impair afferent nerves that participate in the perception of induced bronchoconstriction. In `t Veen and coworkers (8) showed that the degree of sputum eosinophilia is indeed related to blunted perception in patients with severe asthma. Burdon and coworkers (5) suggested that subjects who frequently develop acute airflow obstruction due to inflammation in the airways acquire a degree of tolerance. This tolerance reduces the sensory intensity. Both statements are in agreement with the results of this study.
The study population showed a relatively high mean intensity of respiratory discomfort following 20% reduction in
FEV1 (mean values of 3.4, 3.8, and 4.5 in the short-acting,
long-acting, and placebo group) compared with previous similar studies (usually 3 or slightly less) (6). Possibly the relatively
high baseline bronchoconstriction (mean value 
88% of predicted FEV1) and the mean bronchial responsiveness (mean
value < 2 mg/ml) of this study population result in substantially greater absolute bronchoconstriction, which might be
the reason for the difference in intensity of respiratory discomfort.
The perception of airway obstruction was measured during the histamine challenge test in the laboratory. Assessment of the perception of respiratory sensation during laboratory tests may help to identify poor perceivers. However, the similarity of respiratory sensation induced by histamine challenge and by a spontaneous asthmatic attack has not been established. Boudreau and coworkers (27) found no relationship between the ability to sense breathlessness during induced and "spontaneous" bronchoconstriction. So the results of the present study cannot automatically be extrapolated to the effect of asthma medication on the perception of asthma symptoms in daily life.
Patients' sensitivity toward changes in airway obstruction is best measured by the threshold detection plus the increase in magnitude with equally appearing increments in stimulus magnitude. However, it is not possible to insert fixed sequence stimulus intensity by a histamine challenge test. Therefore, the linear regression slope of the Borg score versus the present fall in FEV1 was chosen as an alternative index for sensitivity.
This study indicates that the combined use of long-acting
2-agonists and inhaled corticosteroids has a positive effect on the perceptual sensitivity for bronchoconstriction compared
with long-acting 2-agonists alone, whereas the additional use
of inhaled steroids combined with short-acting 2-agonists had
no positive effect on perception. This might indicate that if a
combination of 2-agonists and inhaled steroids is needed, the
use of long-acting 2-agonists is to be preferred. Apart from
the positive effect that long-acting 2-agonists in combination
with inhaled corticosteroids has on the clinical condition of
patients with asthma, the positive effects on perception of airway obstruction might be another argument for using this
combination of these drugs, especially because nonperceivers
seem to have an increased risk of an asthma attack.
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Footnotes |
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Correspondence and requests for reprints should be addressed to I.D. Bijl-Hofland, Department of General Practice and Social Medicine, CEHM 229, University of Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: Ingrid.Bijl{at}zon.nl
(Received in original form October 25, 1999 and in revised form January 3, 2001).
Acknowledgments: The authors gratefully acknowledge the cooperation of Mrs. M. Habes, Mrs. I. v.d. Heuvel, Mrs. E. Snakenburg, and Mrs. M. Thies in measuring lung function, bronchial hyperresponsiveness, and breathlessness of the patients.
This study was supported by the Dutch Asthma Foundation, by 3M Pharma Industries, by Novartis Pharma, and by Boehringer Ingelheim.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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