Influence of Beclomethasone and Salmeterol on the Perception of Methacholine-lnduced Bronchoconstriction

doi:10.1378/chest.114.2.373

Chest

Volume 114, Issue 2, August 1998, Pages 373-379

https://doi.org/10.1378/chest.114.2.373 Get rights and content

Background

Patient evaluation of asthma severity and medication needs is mostly based on respiratory symptoms and may be influenced by changes in perception of bronchoconstriction-induced sensations. However, the influence of asthma medication on the ability to perceive symptoms is still to be documented. This study evaluated the effects of short-term and regular use of salmeterol on the perception of methacholine-induced bronchoconstriction (MIB) in subjects with mild asthma, using inhaled salbutamol on an “as required” basis (n= 15), and in subjects with moderate asthma, using daily inhaled beclomethasone (mean daily dose, 640 μg; n=15) in addition to salbutamol to control their asthma.

Methods

Methacholine challenges (MC) were performed at entry into the study, and then before, 1, and 12 h following inhalation of 50 μg of salmeterol or a placebo, after a 15-day baseline period; and after 4 weeks of twice daily use of those treatments. The measurements were then repeated with the alternate treatment after a 15-day washout period. Finally, a last MC was performed after another 15-day washout period. For each MC, the perception score of bronchoconstriction-associated breathlessness at 20% fall in FEV₁ (PS₂₀) was evaluated on a modified Borg scale from 0 to 10.

Results

Subjects using regular beclomethasone had a higher baseline PS₂₀ than those using only salbutamol (means: 3.06±0.06 and 2.01 ±0.07, p=0.0001). Short- and long-term use of salmeterol did not change significantly the PS₂₀ compared with placebo (p>0.05) in either group (with or without corticosteroid). Although there were some intraindividual variations, mean PS₂₀ did not vary significantly throughout the study.

Conclusion

These observations show that the perception of bronchoconstriction-associated breathlessness is not influenced by regular use of salmeterol. Patients using inhaled corticosteroids show a greater perception of MIB.

Section snippets

Subjects

Thirty subjects with mild-to-moderate asthma (12 male and 18 female), nonsmokers, aged 18 to 62 years (mean±SEM: 39.1 ±2.9 years) took part in this study. Fifteen were using only bronchodilators to control their asthma (BD group) and 15 others were using a bronchodilator associated with inhaled corticosteroids (ICS group).

Inclusion Criteria

Patients were considered eligible for this study if they had a diagnosis of allergic or nonallergic asthma in accordance with the definition of the American Thoracic Society¹³

Demographics and Pulmonary Function Tests

At entry into the study, the two groups of subjects were comparable for gender and PC₂₀ (p>0.05; Table 1). Subjects in the BD group were younger than those in the ICS group (respective mean ages, 31 and 45 years; p=0.01) and showed a trend toward a shorter duration of asthma (9.5 vs 15.5 years; p>0.05). Fourteen subjects in the BD group and seven in the ICS group were atopic. At entry to the study, baseline FEV₁ was higher in the BD group than in the ICS group (87.1 ±3.8% predicted and

Discussion

This study shows that salmeterol did not significantly change perception of MIB compared with placebo, either short term or after a period of 4 weeks of daily use, in asthmatic subjects either using bronchodilators alone or using them with inhaled corticosteroids. To our knowledge, only one previous study looked at the perception of induced-broncho-constriction in asthmatic patients and the effect of corticosteroid treatment, and no other study specifically compared the effects of long-acting β₂

Acknowledgments

We would like to thank Lori Schubert for reviewing the manuscript.

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Symptoms and perception of airway obstruction in asthmatic patients: Clinical implications for use of reliever medications
2019, Journal of Allergy and Clinical Immunology
Citation Excerpt :
In another study, although inhalation of albuterol reduced airway obstruction and reduced Borg scale scores for dyspnea, it paradoxically increased Borg scores in response to an external resistive load.31 There is evidence that ICSs can restore or improve perception of airway obstruction,41-44,64 most likely by preventing or ameliorating airway epithelial and receptor damage caused by inflammatory cells. Boulet et al41 showed that patients using twice-daily beclomethasone dipropionate (BDP; mean daily dose, 640 ± 60 μg) plus albuterol as a reliever had a greater perception of bronchoconstriction induced by methacholine challenge than patients treated with albuterol alone in a 14-week crossover study.
Asthma causes the unpleasant sensation of breathlessness (dyspnea) caused by airway obstruction. Patients with poor perception of airway obstruction are at risk of delay in seeking medical attention and undertreatment, which can lead to avoidable deaths. Conversely, those with heightened perception are at risk of overtreatment and iatrogenic adverse effects with reliever medications, anxiety, and unnecessary use of health care resources.
We sought to review evidence about symptom misperception in asthmatic patients and how to identify and manage affected patients, particularly with regard to reliever medications.
We conducted a systematic literature search for studies of perception of airway function in asthmatic patients. We searched the OVID (Medline and Medline [R] in process [PubMed]), Embase, and Adisearch/Odyssey databases, restricting our search to human studies published in English from 1990–2018, with no restrictions on age, sex, or racial origin.
We found that both underperception and overperception assessed during induced bronchoconstriction or bronchodilation or during changes in airway resistance were common across all age groups and that aging, disease severity, smoking, sex, ethnicity, psychologic factors, and medication are all associated with differences in perception. Importantly, airway inflammation was associated with impaired perception and a history of severe or near-fatal asthma. We also identified knowledge gaps, such as whether an individual patient's perception varies over time and the influence perception has on patients' use of reliever medication.
We found that abnormal perception of airway obstruction has important clinical implications for the management of patients with asthma.
The relationship between inflammation and symptoms in asthma
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Les symptômes d’asthme sont le motif principal de recours aux soins, constituant un élément essentiel de l’évaluation du contrôle de la maladie. L’asthme est défini comme une maladie inflammatoire chronique. Les asthmatiques non contrôlés ont une augmentation des polynucléaires éosinophiles de l’expectoration induite et une production accrue de NO exhalé. Cette majoration de l’inflammation éosinophilique peut précéder l’apparition des symptômes, la diminution du VEMS et le développement d’une exacerbation. Le contrôle de l’asthme par le traitement anti-inflammatoire s’accompagne d’une diminution de ces marqueurs. Les symptômes d’asthme résultent de mécanismes complexes, leur perception est parfois altérée par l’inflammation éosinophilique et améliorée par la corticothérapie inhalée. Difficilement applicables en pratique, les stratégies de suivi basées sur l’évaluation de l’inflammation semblent plus efficaces pour réduire les exacerbations que les stratégies habituellement recommandées basées sur l’évaluation rétrospective des symptômes et l’analyse séquentielle de la fonction respiratoire. L’ajustement immédiat selon les symptômes de la corticothérapie inhalée est une stratégie efficace pour éviter les exacerbations et permet de réduire les doses totales de corticothérapie inhalée. Un groupe d’expert français a entrepris d’étudier les relations entre l’inflammation et les symptômes d’asthme à partir d’une lecture critique de la littérature internationale.
D. Montani, I. Tillie-Leblond, B. Crestani, J. de Blic, M. Humbert, M. Tunon-de-Lara, A. Magnan, N. Roche, S. Gati, P. Chanez
In asthma, symptoms are the main reason for recourse to healthcare and are a fundamental parameter for the evaluation of asthma control. Currently, asthma is defined as a chronic inflammatory disease. Uncontrolled asthmatics have an increased number of eosinophils in induced sputum and an increased production of exhaled NO. Control by anti-inflammatory treatment is accompanied by a reduction in bronchial eosinophilia and exhaled NO. Asthma symptoms are the result of complex mechanisms and many factors modify their perception. Experimental data suggests that there is a relationship between the perception of symptoms and eosinophilic inflammation, and that inhaled corticoid therapy improves this perception. Although they are still not applicable in routine practice, follow-up strategies based on the evaluation of inflammation are thought to be more effective in reducing exacerbations than those usually recommended based on retrospective evaluation of symptoms and sequential analysis of respiratory function. Inhaled corticosteroid therapy is the reference maintenance therapy for persistent asthma and adjustment of anti-inflammatory treatment based on symptoms is an effective strategy to prevent exacerbations and reduce the total dose of inhaled corticosteroids. A French expert group has undertaken a study of the association between inflammation and asthma symptoms by carrying out a critical review of the international literature.
The influence of corticosteroids on the perception of dyspnea in asthma
2007, Respiratory Medicine
Citation Excerpt :
In turn, this may reduce intraepithelial nerve injury or increase the production of epithelial-derived mediators being involved in the activation of airway sensory receptors.12 Because epithelial cells in particular may be a major cellular target for ICS,11 the restoration of the airway epithelial structure has been suggested as another mechanism by which corticosteroids might improve the perception of dyspnea10,12 (see Fig. 1). In addition to the intentional anti-inflammatory effects and known adverse physiologic side effects of corticosteroids, many adverse psychological effects have been reported in children and adults, including symptoms of depression, mania, psychosis and behavioral and cognitive deficits.14–16
Corticosteroids are effective anti-inflammatory medications that are recommended for the control of persistent asthma. Little, however, is known about their influence on the perception of dyspnea, which, in turn, is important to the successful self-management of asthma. This paper provides a synopsis of available studies examining the impact of corticosteroids on the sensitivity to perceive dyspnea and presents possible mechanisms underlying this relationship. The results of these investigations are conflicting with some studies showing improved perception and other studies showing worsened perception of dyspnea after corticosteroid treatment. Thus, firm conclusions cannot be derived from the currently available data. Implications for future research, which is required to increase our understanding of potential influences of corticosteroids on the perception of dyspnea, are provided.
Dynamic hyperinflation during bronchoconstriction in asthma: Implications for symptom perception
2006, Chest
Citation Excerpt :
It was reported in < 30% of subjects even at maximum response and appears to be distinct from the other clusters. Chronicity and reversibility of airway obstruction and prior use of ICS are several factors reported to affect symptom perception in asthma.38,39,40 In this study, we found no difference in dyspnea intensity or quality throughout MCT between mild and severe asthma or between individuals who were and were not receiving ICS.
The objective of this study was to examine the relationship between respiratory symptom intensity and quality and dynamic lung hyperinflation (DH) during induced bronchoconstriction in asthma.
Subjects with asthma (n = 116) underwent baseline spirometry and lung volume measurement followed by high-dose methacholine challenge testing (MCT) [maximum decrease in FEV₁ of 50% from baseline]. Dyspnea intensity (Borg scale) was measured after each dose of methacholine. Qualitative descriptors of breathlessness and functional residual capacity (FRC) were measured at the doses nearest to the provocative concentration of methacholine causing a 20% fall in FEV (PC₂₀) and at the highest dose of methacholine (maximum response).
FEV₁ decreased by 24.7 ± 0.7% (mean ± SEM) at the dose nearest to PC₂₀ and by 46.1 ± 1.1% at maximum response. Inspiratory capacity decreased by 0.62 ± 0.04 L at the dose nearest to PC₂₀ and 1.06 ± 0.06 L at maximum response. The descriptor clusters “inspiratory difficulty,” “chest tightness,” “unsatisfied inspiration,” and “work” were selected at the dose nearest to PC₂₀ but were more frequently selected at maximum response (p < 0.0001). Individuals who reported chest tightness at maximum response had greater airflow obstruction and higher FRC (percentage of predicted) than those who did not report chest tightness.
Four dominant qualities of dyspnea in asthma (inspiratory difficulty, chest tightness, unsatisfied inspiration, and work) were reported early in the course of MCT and evolved in parallel, becoming more prevalent at maximum response. Significant DH accompanied even mild bronchoconstriction during MCT in asthma, making it difficult to separate mechanisms of chest tightness from other dominant respiratory sensations.
Effects of anti-asthma therapy on dyspnea perception in acute asthma patients
2006, Respiratory Medicine
Blunted perception of dyspnea may predispose patients to fatal asthma attacks. To examine whether this impaired perception of dyspnea in patients with acute asthma could be corrected by anti-asthma therapy, the medical records of 104 consecutive asthma patients who had been hospitalized as a result of asthma attacks were analyzed retrospectively. During the course of treatment with conventional asthma medications, the forced expiratory volume in 1 s (FEV₁) and the Borg scale-based dyspnea perception scores during breathing through an inspiratory muscle trainer were measured at least twice. The baseline Borg score measured just before discharge was significantly lower than from that measured initially, regardless of improvement in FEV₁. In contrast, the Borg score at the highest resistance (HR; 3.12±0.26 vs. 5.03±0.53; P<0.01) and the HR-induced ΔBorg score (1.68±0.20 vs. 4.47±0.54, P<0.001) were increased significantly in the Poor Perceivers (Borg score ⩽ 5 at HR and HR-induced ΔBorg score ⩽3). Patient age (r=0.363, P<0.001), blood eosinophil counts (r=−0.285, P<0.01), and serum total IgE levels (r=−0.213, P<0.05), but not FEV₁, were significantly related to the effect of the treatment on the HR-induced ΔBorg scores. These findings suggest that anti-asthma treatments decrease dyspnea even without a concomitant improvement in lung function and correct the impaired perception of inspiratory resistive load in acute asthma, and that age and allergy influence the effect of treatment on impaired perception.
Symptom perception and respiratory sensation: Clinical applications
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: Supported by Glaxo Wellcome Canada, Bureau d'affaires du Québec and the Fonds de la Recherche en Santé du Québec (FRSQ-Industry program).

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Chest

Clinical Investigations: AsthmaInfluence of Beclomethasone and Salmeterol on the Perception of Methacholine-lnduced Bronchoconstriction

Background

Methods

Results

Conclusion

Section snippets

Subjects

Inclusion Criteria

Demographics and Pulmonary Function Tests

Discussion

Acknowledgments

Chest

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

Lancet

Perception of breathlessness during early and late asthmatic responses

Am Rev Respir Dis

Poorly perceived asthma

Thorax

Perception of airflow obstruction and associated breathlessness in normal and asthmatic subjects: correlation with anxiety and bronchodilator needs

Thorax

Perception of bronchial obstruction in asthmatic patients: relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteroid treatment

J Clin Invest

Long- versus short-term β2-agonists: implications for asthma management

Drugs

Long-acting β2-adrenoreceptor antagonists: a new perspective in the treatment of asthma

Eur Respir J

Inhaled salmeterol and salbutamol in asthmatic patients

Am Rev Respir Dis

Clinical Investigations: Asthma
Influence of Beclomethasone and Salmeterol on the Perception of Methacholine-lnduced Bronchoconstriction

Long- versus short-term β₂-agonists: implications for asthma management

Long-acting β₂-adrenoreceptor antagonists: a new perspective in the treatment of asthma