A Systematic Review of the Effects of Bronchodilators on Exercise Capacity in Patients With COPD

doi:10.1378/chest.121.2.597

Chest

Volume 121, Issue 2, February 2002, Pages 597-608

https://doi.org/10.1378/chest.121.2.597 Get rights and content

One of the major goals of bronchodilator therapy in patients with COPD is to decrease airflow limitation in the airways and, as a consequence, improve dyspnea and exercise tolerance. The focus of this systematic review is to assess the effects of treatment with β-agonists, anticholinergics, and theophyllines on dyspnea, and steady-state and incremental exercise capacity. Thirty-three, double-blind, randomized, placebo-controlled studies written in English were selected. This review shows that approximately half of the studies showed a significant effect of bronchodilator therapy on exercise capacity. Anticholinergic agents have significant beneficial effects in the majority of studies, especially when measured by steady-state exercise protocols. There is a trend toward a better effect of high-dose compared to low-dose anticholinergics. Short-acting β₂-mimetics have favorable effects on exercise capacity in more than two thirds of the studies; surprisingly, the situation is less clear for long-acting β₂-agents. The majority of the results of the published reports on theophyllines and their effects on exercise are negative. Direct comparisons of different classes of bronchodilators have not been made in a sufficient number of studies for a rational preference. The addition of a second bronchodilator has no proven advantage for improving exercise test results, but this has not been studied extensively and not in sufficiently large studies. The majority of studies reporting a measure of dyspnea found improvements, even in the absence of improvement in exercise capacity.

Section snippets

Exercise Tests

To assess exercise capacity, different protocols are used depending on the aim of the study. The tests can be classified as steady-state tests and incremental tests, both measuring a different aspect of exercise capacity (Table 1). The term steady state is employed to indicate a more or less constant work rate during the test. Incremental exercise tests assess maximal exercise capacity in terms of peak exercise level, whereas steady-state tests explore the maximal capacity that can be endured

Materials and Methods

A systematic review of the literature searched with MEDLINE was performed including articles up to September 1999. Only randomized, controlled, double-blind trials written in English, were selected. Firstly, a database including all articles about obstructive lung diseases (key words: COPD, lung diseases, obstructive, plus all subheadings) was constructed. From this database, all articles that investigated patients with asthma were excluded (key-word strategy: database minus [asthma minus

Anticholinergics

Seventeen studies examining the effects of anticholinergics on exercise in patients with COPD were identified (Table 2). Ten studies applied ipratropium, 6 studies applied oxitropium, and 1 study applied atropine. At present, no tiotropium study is available. Twelve of 17 studies used a single-dose protocol; 16 of these studies primarily focusing on exercise testing showed a significant effect on FEV₁(Table 2).

Discussion

We identified 33 double-blind, randomized, controlled studies investigating the effects of bronchodilators on exercise capacity in patients with COPD. Only a few studies have been published with a head-to-head comparison between different types of bronchodilators. Bronchodilators are frequently prescribed to patients with COPD in order to improve exercise intolerance. Nevertheless, our systematic review shows that approximately half of the studies with bronchodilators do not show a significant

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Cited by (89)

Impact of LABA/LAMA combination on exercise endurance and lung hyperinflation in COPD: A pair-wise and network meta-analysis
2017, Respiratory Medicine
Citation Excerpt :
In fact, as airway patency over time increases with longer duration of a more potent bronchodilator action, emptying of peripheral airways with trapped air is facilitated, thus reducing hyperinflation and improving breathing mechanics (“pharmacological lung volume reduction”) [34] and, consequently, enhancing the exercise capacity. The results of our study are a significant step forward compared to the review of Liesker and colleagues published in 2002 [35]. In particular, we have provided a pragmatic synthesis of the most recent available data concerning the effects of the so-called ‘‘dual bronchodilator therapy” on exercise capacity and lung hyperinflation in patients with COPD.
The ability to exercise is an important clinical outcome in COPD, and the improvement in exercise capacity is recognized to be an important goal in the management of COPD. Therefore, since the current interest in the use of bronchodilators in COPD is gradually shifting towards the dual bronchodilation, we carried out a meta-analysis to evaluate the impact of LABA/LAMA combination on exercise capacity and lung hyperinflation in COPD.
RCTs were identified after a search in different databases of published and unpublished trials. The aim of this study was to assess the influence of LABA/LAMA combinations on endurance time (ET) and inspiratory capacity (IC), vs. monocomponents.
Eight RCTs including 1632 COPD patients were meta-analysed. LABA/LAMA combinations were significantly (P < 0.05) more effective than the LABA or LAMA alone in terms of the improvement in ET (+43 s and +22 s, respectively) and IC (+107 ml and +87 ml, respectively). LABA/LAMA combinations showed the highest probability of being the best therapy with regard of both ET and IC (100% and 100%, respectively), followed by LAMA (66% and 64%, respectively) and LABA (32% and 36%, respectively), as indicated by the analysis of surface under the cumulative ranking curve (SUCRA). No publication bias was detected in this meta-analysis.
This meta-analysis clearly demonstrates that if the goal of the therapy is to enhance exercise capacity in patients with COPD, LABA/LAMA combinations consistently meet the putative clinically meaningful differences for both ET and IC and, in this respect, are superior to their monocomponents.
Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD
2013, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Bronchodilators are central to the symptomatic management of COPD, and inhaled β2-agonists and inhaled muscarinic antagonists are the most frequently used bronchodilators, including both short-acting and long-acting agents [1]. All categories of bronchodilators have been shown to improve lung function parameters [3–6] and increase exercise capacity in COPD [7–9]. Long-acting bronchodilators have also been shown to reduce the frequency of exacerbations [10–12] and to improve health status [10,12,13].
GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β₂-agonism (MABA) properties.
This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV₁) at 24 h on Days 1 and 14.
MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV₁ over 24 h. Mean (95% CI) 24 h trough FEV₁ (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only.
GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.
Left atrial compression and the mechanism of exercise impairment in patients with a large hiatal hernia
2011, Journal of the American College of Cardiology
The purpose of this study was to determine the association between cardiac compression and exercise impairment in patients with a large hiatal hernia (HH).
Dyspnea and exercise impairment are common symptoms of a large HH with unknown pathophysiology. Studies evaluating the contribution of cardiac compression to the pathogenesis of these symptoms have not been performed.
We collected clinical data from a consecutive series of 30 patients prospectively evaluated with resting and stress echocardiography, cardiac computed tomography, and respiratory function testing before and after laparoscopic HH repair. Left atrial (LA), inferior pulmonary vein, and coronary sinus compression was analyzed in relation to exercise capacity (metabolic equivalents [METs] achieved on Bruce treadmill protocol).
Exertional dyspnea was present in 25 of 30 patients (83%) despite normal mean baseline respiratory function. Moderate to severe LA compression was qualitatively present in 23 of 30 patients (77%) on computed tomography. Right and left inferior pulmonary vein and coronary sinus compression was present in 11 of 30 (37%), 12 of 30 (40%), and 26 of 30 (87%) patients, respectively. Post-operatively, New York Heart Association functional class and exercise capacity improved significantly (number of patients in New York Heart Association functional classes I, II, III, and IV: 6, 11, 11, and 2 vs. 26, 4, 0, and 0, respectively, p < 0.001; METs [percentage predicted]: 75 ± 24% vs. 112 ± 23%, p < 0.001) and resolution of cardiac compression was observed. Absolute change in LA diameter on the echocardiogram was the only independent cardiorespiratory predictor of exercise capacity improvement post-operatively (p = 0.006).
We demonstrate, for the first time, marked exercise impairment and cardiac compression in patients with a large HH and normal respiratory function. After HH repair, exercise capacity improves significantly and correlates with resolution of LA compression.
Acute administration of bronchodilators on exercise tolerance in treated COPD patients
2011, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Several studies have focused on the mechanisms that can induce exercise limitation in COPD: ventilatory constraints, pulmonary gas exchange abnormalities, peripheral muscle dysfunction, cardiac dysfunction, or any combination of the above [1–5]. Bronchodilator therapy may reduce dyspnoea and improve exercise tolerance, and several studies have been conducted in COPD, in order to describe the response to different classes of bronchodilators in terms of exercise capacity by using different methods of evaluation [6] but in particular the endurance time (ET) [7–9]. In addition to their regular pharmacologic treatment, COPD patients are often used to administer extra-doses of short-acting inhaled bronchodilators in presence of symptoms or in anticipation of making an effort.
Exercise intolerance is a major feature in patients with Chronic Obstructive Pulmonary Disease (COPD). Bronchodilators increase endurance time (ET) and reduce dynamic hyperinflation (DH). We evaluated whether a single-dose of salbutamol/ipratropium + flunisolide (BD + ICS), added on top of the regular treatment, may improve ET in COPD patients. In a single-blind randomized crossover pilot trial, nebulised BD + ICS or placebo (PL) was administered 30 min before a constant load cardiopulmonary test, in 22 moderate-to-severe COPD patients (FEV₁: 53.9% pred). ET was the primary outcome measured. BD + ICS did not improve ET or VO₂ peak with respect to PL. BD + ICS increased pre-test FEV₁ and pre-test Inspiratory Capacity but did not modify DH. In a retrospective analysis, patients were divided in Improvers (N = 11) and Non-Improvers (N = 11) according to the difference in ET between BD + ICS and PL (>25 s). Improvers had a worst BODE index, a higher static hyperinflation and poorer Vd/Vt ratio at peak of exercise with respect to Non-Improvers. Improvers only had a significant increase from BD + ICS on pre-test FEV₁ and IC. In conclusion, although a single-dose BD + ICS did not improve ET in COPD patients under regular treatment, a subgroup of more severe patients may have some benefit from that.
Dyspnea and handicap in chronic obstructive pulmonary disease: Interaction of their mechanisms
2009, Presse Medicale
La dyspnée de la bronchopneumopathie chronique obstructive (BPCO) est clairement attribuée à la distension thoracique secondaire à l’obstruction bronchique et à l’hyperventilation. Elle survient inévitablement au cours de l’exercice même chez les patients peu obstructifs mais capables de développer des puissances élevées et prolongées nécessitant une hyperventilation importante.
L’intolérance à l’exercice est majoritairement due à la dyspnée, mais la fatigabilité musculaire est aussi déterminante, notamment chez les patients atteints de BPCO et dénutris.
La dégradation de la fonction musculaire est secondaire à la réduction considérable des activités physiques de la vie quotidienne, mais on évoque chez les sujets dénutris et hypoxémiques la responsabilité de divers processus biologiques aggravants dus à l’inflammation chronique de bas grade et à l’accentuation du stress oxydant.
La diminution drastique de l’activité physique est la conséquence des déficiences ventilatoires et musculaires et des symptômes qui rendent pénibles les déplacements. Néanmoins, l’amélioration de ces déficiences ne permet pas de récupérer une activité physique hebdomadaire suffisante.
La spirale du désengagement, processus psychodynamique morbide, est l’apanage des affections chroniques affectant davantage les patients qui n’ont pas eu avant leur maladie une culture de l’activité physique.
L’amélioration du handicap nécessite donc une prise en charge globale du patient qui ne se cantonne pas à la prescription d’une activité physique médicalisée, mais qui vise à travers les diverses propositions thérapeutiques, un changement de comportement durable du patient.
Today, dyspnea in chronic obstructive pulmonary disease (COPD) is attributed to thoracic distention secondary to bronchial obstruction and hyperventilation. It inevitably occurs during exercise, even in patients with little obstruction, when they are capable of the elevated and prolonged power output that necessitates substantial hyperventilation.
Exercise intolerance is due mainly to dyspnea, but muscle fatigue is also involved, especially in COPD patients who are malnourished.
Deterioration of muscle function follows a substantial reduction in daily physical activity. In malnourished and hypoxemic subjects, however, responsibility for this is attributed to diverse aggravating biological processes related to chronic low-grade inflammation and to accentuated oxidative stress.
The drastic diminution of physical activity results from ventilatory and muscle impairment and from symptoms that make movement painful. Improvement of ventilatory and muscle function, however, does not lead to recovery that allows sufficient physical activity.
The spiral of disengagement, a morbid, psychodynamic process, accompanies chronic diseases and has the strongest effect in patients who were not highly physically active before becoming ill.
Improvement of this handicap therefore requires a comprehensive management of patients, not confined to the prescription of physical activity under medical supervision. The aim is to offer diverse treatment propositions that can produce sustainable behavioral change.
Use of 6-min and 12-min walking test for assessing the efficacy of formoterol in COPD
2008, Respiratory Medicine
Citation Excerpt :
Improvements in performance are, therefore, achieved differently for the two tests.8 Patients have to increase walking speed to cover more distance on the 6-MWT, while they have to increase endurance time to achieve the same outcome on the endurance shuttle walk.8 It has been highlighted that patients usually start walking at a faster pace before settling to a remarkably constant speed.9
Exercise tolerance is an important outcome measure in patients with COPD, mostly because there is evidence that exercise testing is superior to other functional measurements obtained at rest in demonstrating the positive effect of a specific intervention. We assessed the effect of a 5-day treatment with formoterol 12 μg twice daily on lung function, exercise capacity and dyspnea in 22 stable COPD patients, and compared 6-MWT with 12-MWT in evaluating formoterol efficacy. All subjects entered a crossover design. They underwent 6-MWT or 12-MWT in a randomised order and soon after started the 5-day treatment. After a 3-day washout, patients who had first performed 6-MWT, underwent 12-MWT, and the contrary. Formoterol induced a progressively significant increase in pre-drug FEV1 and IC and also significant changes in these parameters 2 h after its inhalation at each test day. Moreover, it increased the walked distance by 53.6 m at the end of 6-MWT and 59.9 m at the end of 12-MWT. Formoterol also induced a significant change in Borg score for dyspnea caused by the 6-MWT when compared with the pre-treatment values, whereas it significantly changed dyspnea induced by 12-MWT only after the first dose. Our study not only strengthens the importance of walking tests as a useful tool for evaluating the impact of a bronchodilator on some COPD patient-centred outcomes, but also indicates that 6-MWT seems to be a more appropriate instrument than 12-MWT for assessing the exercise response to a bronchodilator in COPD.

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: Dr. Liesker received research stipendium from AstraZeneca BV, Zoetermeer, the Netherlands.

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Chest

ReviewsA Systematic Review of the Effects of Bronchodilators on Exercise Capacity in Patients With COPD

Section snippets

Exercise Tests

Materials and Methods

Anticholinergics

Discussion

Lancet

Clin Chest Med

Prim Care

Am J Cardiol

Chest

Chest

Br J Dis Chest

Chest

Respir Med

Chest

Chest

Respir Med

Respir Med

Chest

Chest

Chest

Chest

Chest

Gender differences in smoking cessation after 3 years in the Lung Health Study

Am J Public Health

BTS guidelines for the management of chronic obstructive pulmonary disease: the COPD Guidelines Group of the Standards of Care Committee of the BTS

Thorax

Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Optimal assessment and management of chronic obstructive pulmonary disease (COPD): the European Respiratory Society Task Force

Eur Respir J

A test to determine parameters of aerobic function during exercise

J Appl Physiol

Development of a shuttle walking test of disability in patients with chronic airways obstruction

Thorax

Development of a single-stage submaximal treadmill walking test

Med Sci Sports Exerc

Principles of exercise testing and interpretation

Clinical exercise testing

Stress testing

Optimizing the exercise protocol for cardiopulmonary assessment

J Appl Physiol

Comparison of oxygen uptake during a conventional treadmill test and the shuttle walking test in chronic airflow limitation

Eur Respir J

Reviews
A Systematic Review of the Effects of Bronchodilators on Exercise Capacity in Patients With COPD