Abstract
There is the possibility that during treatment with inhaled long-acting β2-agonists that a loss of perception of dyspnoea might occur and that the forced expiratory volume in one second (FEV1) might fall precipitously during bronchial provocation. This study investigated these possibilities during methacholine provocation, continued until there was ≥30% fall in FEV1, mimicking a moderate asthma attack.
Nineteen asthmatic patients were asked to score their dyspnoea as a Borg score during provocation with methacholine. One hour prior to this provocation, the patients used the last morning dose of 14 days treatment with either formoterol (twice daily 24 µg by Turbuhaler®), salmeterol (twice daily 100 µg by DiskhalerTM) and placebo in a double-blind, randomized, double-dummy, cross-over design.
The perception of dyspnoea, expressed as the Borg score divided by the change in FEV1 at ≥30% fall in FEV1, was similar on the three test days at 0.067, 0.076 and 0.074%−1 after formoterol, salmeterol and placebo treatment, respectively (p=0.16). The slope of the methacholine dose response curve did not differ (p=0.52).
In conclusion, no suggestion was found for an abnormal perception of dyspnoea or an exaggerated fall in forced expiratory volume in one second during provocation with methacholine under long-acting β2-agonist treatment.
This work was supported by a research grant from AstraZeneca, the Netherlands.
In the treatment of asthma, the inhaled long-acting β2-agonists formoterol and salmeterol have obtained an important role due to their excellent bronchodilating and bronchoprotective effects 1. This excellent bronchodilating effect could have a negative influence; patients may be unable to perceive a deterioration of the effects of airway inflammation 2. It may be possible this is partly a result of a change in perception of dyspnoea due to the β2-agonist. Furthermore, the suggestion has been made that after prior administration of a bronchodilator, there may be an exaggerated fall in forced expiratory volume in one second (FEV1) when the bronchial provocation test is continued 3. Therefore, this study investigated whether poor perception of dyspnoea may be caused by long-acting β2-agonist treatment, by assessing dyspnoea scores during a provocation test performed after maximal bronchodilation from inhaled long-acting β2-agonists. In addition the slope of the methacholine dose response curve was measured to see if it was increased.
Materials and methods
Patients
Nineteen nonsmoking patients aged 18–50 yrs with a diagnosis of asthma according to the American Thoracic Society Guidelines 4 were invited to participate in the study (table 1⇓). Eligible patients had an FEV1 >1.5 L and >60% of predicted 5, a 20% fall in FEV1 after provocation with methacholine ⪕4 mg·mL−1 and a fall of ≥30% in FEV1 on continuing the test. Exclusion criteria were: concomitant diseases that might interfere with the study; use of long-acting β2-agonists, oral antihistamines or oral bronchodilators from 24 h before the enrolment visit until study completion; changes in inhaled glucocorticosteroid treatment dose or use of oral steroids in the 6 weeks prior to the initial visit and pregnancy. The study was approved by the Medical Ethics Committee of the Martini Hospital, Groningen and was conducted according to Good Clinical Practice guidelines. Written informed consent was obtained from all patients before enrolment.
Characteristics of the patients at enrolment.
Study design and procedures
The study had a single centre, cross-over, randomized, double-blind, placebo-controlled, double-dummy design. The enrolment visit and the three test days were separated by the three consecutive treatment periods of two weeks each. Patients were treated twice daily with two doses of formoterol (Oxis® Turbuhaler®, 12 µg formoterol fumarate per metered dose, equivalent with 9 µg delivered dose), salmeterol (SereventTM DiskhalerTM, 50 µg salmeterol xinafoate per dose) or corresponding placebos (all provided by AstraZeneca R&D, Lund, Sweden).
On the three test days the last dose of study medication was inhaled in the morning in the clinic. Exactly 1 h later, the FEV1 was measured and the methacholine provocation test was performed in a standardized manner and continued until there was a reduction of at least 30% in FEV1 as described elsewhere 6. In brief, doubling concentrations of methacholine bromide from 0.125 to 64 mg·mL−1 dissolved in saline were inhaled at 5-min intervals during 2 min of tidal breathing. Nebulizer output was 0.1 mL·min−1. FEV1 was measured with a daily-calibrated dry spirometer (Schiller SP-100, Schiller, Baar, Switzerland). The same technician performed all provocation tests. If dyspnoea became too severe during the test day, as judged by the subject or the technician, a bronchodilator was given and the test-day was repeated.
The patients reported the Borg score for dyspnoea, ranging from 0–10, at all time points where lung function was assessed 7.
Data analysis
Spirometry values are expressed as ΔFEV1, the percentage change from baseline on that test day, baseline being the FEV1 1 h after inhaling the morning dose of the study treatments. Dyspnoea perception was defined as the quotient of Borg score and Δ FEV1 at the point of reaching the ≥30% fall in FEV1. The cumulative methacholine “dose” administered, needed for the ≥30% fall (PD30), was calculated from the nebulizer output and duration of nebulization. The slope in the ΔFEV1 versus methacholine-dose response curve was calculated as described by Prieto 8.
A two-way fixed effect analysis of variance (ANOVA) was used to determine treatment differences with patient, period and treatment as factors. When treatment was statistically significant in the ANOVA, confidence intervals were calculated from the least-squares means. A two-sided p-value <0.05 was considered significant.
Results
Four patients were withdrawn from the study due to intercurrent airway infections. Baseline FEV1 was higher after active pretreatment. The actual methacholine-induced fall in FEV1 was almost 40% on all three test days (table 2⇓). After active treatment a significantly higher PD30 was observed than after placebo. The PD30 after formoterol pretreatment was significantly higher than after salmeterol (p<0.05).
forced expiratory volume in one second FEV1 and Borg score at baseline and at reaching a methacholine induced ≥30% fall in FEV1
The Borg-scores and ΔFEV1 measured after the final dose of methacholine are shown in figure 1⇓. The perception of dyspnoea did not differ significantly between all treatments and was not related to the methacholine dose administered (p=0.16; table 2⇑). Neither was there a significant difference in the mean slope in the curve of ΔFEV1 versus log cumulative methacholine concentration which were 10.2% for formoterol, 10.2% for salmeterol and 8.4% for placebo (p=0.52).
Mean Borg scores (open symbols) and forced expiratory volume in one second (FEV1; closed symbols) during the final doses of methacholine after placebo (squares), or pretreatment with salmeterol (circles) or formoterol (triangles).
Discussion
The present study shows that the perception of dyspnoea was unaltered after prior treatment with the long-acting β2-agonists formoterol and salmeterol, and that the slope of the methacholine concentration curves does not differ compared with placebo.
Due to the administration of the β2-agonist, the patients had a higher baseline FEV1 and higher doses of methacholine had to be given before a 30% fall in FEV1 occurred: a 3.4-fold higher methacholine dose had to be given in the formoterol period and a 2.2-fold higher dose in the salmeterol period. The actual fall of 40% indicated that a moderate asthma attack was simulated.
This study confirms the observation by Boulet et al. 9 that inhaled salmeterol does not influence perception of dyspnoea during methacholine provocation. However, a lower dose of salmeterol was used in their study and provocation was stopped after a 20% fall in FEV1, raising the possibility that the study lacked sensitivity. One long-term study on the effect of added formoterol therapy revealed a similar course of the exacerbation whether or not inhaled formoterol was administered, also indicating that there was no loss of perceived dyspnoea 10.
The observed change in Borg score in the present study may seem small on a 10 point-scale, but it confirms studies with a similar design where ∼2 points difference was observed 9. A Borg score of 3 represents “moderate”, indicating that a noticeable dyspnoea was induced. In other studies, using a visual analogue scale, ∼20% of the maximal score was observed at reaching a 20% fall by different stimuli 11. An alternative way of investigating the perception of dyspnoea involves the measurement of dyspnoea during inhalation against different resistances. With this methodology, the perception of dyspnoea was improved slightly after prior inhalation of salbutamol 12.
In the present study, the slope of the methacholine dose-response curve did not show a difference between placebo and long acting β2-agonist pretreatment, confirming similar studies investigating the slope of the dose response curves for both histamine and adenosine monophosphate after formoterol 13 and salmeterol treatment 14. These results differ from the previous report by Bel et al. 3 when the protective effect of salbutamol was followed by a sudden fall in FEV1. It is speculated that this may have been a consequence of the short duration of action of salbutamol and not to a true increased reactivity of the airways.
In conclusion, the results of the present study show that during maintenance treatment with long-acting β2-agonists at a high dose, there is neither a different perception of dyspnoea nor an increased reactivity of the airways during methacholine provocation as compared to placebo.
Acknowledgments
The authors thank T.H. Winter for performing all the methacholine challenges, AstraZeneca R&D Lund for preparing blinded medication, M. Boorsma for his help in monitoring the study and assistance in editing the manuscript, P.P.H.M. Gobbens for assistance in the statistical analysis and G.D. Nossent, L.H. Steenhuis, W.J. Snoek, C.G. Tol and S.H. Wills for their contribution to the clinical part of the study.
- Received September 28, 2000.
- Accepted April 4, 2001.
- © ERS Journal Ltd
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