| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
Kingston, ON, Canada
Dr. O’Donnell is Professor, Departments of Medicine and Physiology, and Head, Division of Respiratory and Critical Care Medicine, Queen’s University.
Correspondence to: Denis O’Donnell, MD, 102 Stuart St, Kingston, ON, Canada K7L 2V6; e-mail: odonnell{at}post.queensu.ca
International guidelines1 have correctly highlighted dyspnea alleviation and improvement in exercise tolerance as being among the most important management goals in patients with COPD. Bronchodilator therapy is the first step in achieving these goals, and, in this respect, the advent of therapy with newer long-acting bronchodilators represents a significant clinical advance. Historically, the airflow limitation that characterizes COPD, at least in its later stages, has been thought to be largely "irreversible," and this may have contributed to a pervasive attitude of therapeutic nihilism. This view has changed, however, and most current consensus documents on the subject acknowledge that the airway obstruction of COPD is indeed "partially reversible."1
Bronchodilator reversibility criteria still rely exclusively on the detection of an arbitrary increase in spirometric maximal expiratory flow rates (ie, FEV1).2 The recognition that bronchodilator therapy can be associated with clinically important improvements in desired patient-centered outcomes such as dyspnea, exercise endurance, and health status, in the presence of little or no change in maximal expiratory flow rates, has prompted a search for additional physiologic markers of improved dynamic airway function. The increase in FEV1 after therapy with a bronchodilator mainly reflects improved conductance in the larger airways and increased expired flow rates in alveolar units with relatively fast time constants for emptying. Improvements in small airway function after bronchodilator therapy are more difficult to measure, but reduced lung volumes as a consequence of enhanced gas emptying in alveolar units with slower time constants provide us with indirect evidence of a positive effect. Studies34567 have shown that substantial reductions in lung hyperinflation can occur after short-term treatment with short-acting and long-acting bronchodilators in the presence of only modest improvements in FEV1. Patients who show expiratory flow limitation during spontaneous resting breathing and those with the most severe resting lung hyperinflation have demonstrated the greatest acute lung volume reduction with bronchodilator therapy.689 Moreover, reductions in lung hyperinflation have been shown to correlate better with improved exertional dyspnea ratings and exercise endurance time than traditional spirometric parameters.3 These data, together with the known benefits of surgical lung volume reduction,10 have provided us with a solid physiologic rationale for the clinical benefits of pharmacologic lung volume reduction in COPD patients.
In this issue of CHEST (see page 509), van Noord and colleagues11 report the effect of combined therapy with long-acting anticholinergic and ß2-agonist bronchodilators on airway function and resting lung hyperinflation over a 24-h period in patients with moderate-to-severe COPD. This study confirmed that the combination therapy of tiotropium every day and formoterol twice a day was associated with an average increase in FEV1 (0 to 24 h) of 0.198 L, which was significantly greater in magnitude than the improvements with therapy using either tiotropium alone or tiotropium and formoterol in combination each taken once daily. This is the first study to chart the time course of resting inspiratory capacity (IC), which is an indirect measure of lung hyperinflation, over a 24-h period. Clearly, IC in such patients is a continuous dynamic variable, which, in conjunction with FEV1, has a pronounced circadian variation with lowest values (greatest hyperinflation) evident in the early hours of the morning. This study showed that combined bronchodilator treatment improves, but does not abolish, this nocturnal worsening of expiratory airway obstruction and lung hyperinflation. The average increase in IC (0 to 24 h) after combined treatment with tiotropium and formoterol twice a day was 0.215 L, with an impressive peak effect within 2 h of dosing of 0.552 L and an average increase of 0.294 L during waking hours (0 to 12 h). Improvements of this magnitude are arguably clinically important and should translate into an important reduction in activity-related dyspnea and an increase in exercise endurance.45
In patients with COPD, the smaller the resting IC, the closer that tidal volume is positioned to total lung capacity and the upper noncompliant extreme of the respiratory systems pressure volume relationship where there is increased elastic loading of the inspiratory muscles. Small increases in IC after bronchodilator therapy, which signify a reduction in end-expiratory lung volume, are associated with reduced mechanical loading and increased functional strength of the inspiratory muscles, resulting in a reduced work and oxygen cost of breathing. Furthermore, an increased resting IC (on the order of 0.3 L or 10% predicted) means a greater ability to expand tidal volume during exercise with a resultant increase in ventilatory capacity.345 Reduced operating lung volumes during exercise enhance neuromechanical coupling of the respiratory system (ie, the relation between neural drive and mechanical response), thereby relieving respiratory discomfort. The net effect of all of these physiologic benefits is to improve the patients’ capacity to engage in exercise.
This study raises a number of questions. To the extent that the peak lung deflation achievable with therapy with combined long-acting bronchodilators in this study exceeded 0.5 L, is it possible (or clinically advantageous) to sustain this maximal level over 24 h by using additional bronchodilators or possibly inhaled corticosteroids? What are the mechanisms of this circadian variation, which persists despite effective anticholinergic therapy? Would abolition of the nocturnal dip in airway function result in improved sleep quality and daytime function in COPD patients?
The most intriguing question, in my view, is whether maximal sustained bronchodilation in COPD patients results in positive long-term effects? It now appears that we have the capability of achieving lung volume reduction by pharmacologic means that is comparable in magnitude to that obtained by lung volume reduction surgery. Can we expect a similar survival advantage, and if so, will this be confined to specific subsets of patients? Specifically, do health status and survival improve in response to therapy with combined long-acting bronchodilators in patients with severe COPD and diffuse homogeneous emphysema in whom lung volume reduction surgery is contraindicated?
To date, therapy with long-acting bronchodilators has been studied in relative isolation but has nevertheless shown consistent improvements in airway function and hyperinflation, dyspnea, exercise capacity, the number and severity of exacerbations, and overall health status compared with placebo.121314 The results of the study by van Noord and colleagues11 lend support to the hypothesis that combined long-acting bronchodilator therapies will have a greater impact on measures of impairment, disability, and handicap than has previously been reported in clinical trials of single bronchodilators. Since each of the above-listed outcome parameters are independent predictors of survival in COPD patients,15161718 it is tempting to speculate that modern pharmacotherapy will, in an unprecedented manner, positively influence the natural history of this devastating disease.
Footnotes
Dr. O’Donnell has no real or potential financial or personal conflict of interest on this topic.
References
This article has been cited by other articles:
|
|
 |
|
  H. A. M. Kerstjens, T. A. Bantje, P. B. Luursema, H. E. J. Sinninghe Damste, J. W. de Jong, A. Lee, S. P. C. Wijker, and P. J. G. Cornelissen Effects of Short-Acting Bronchodilators Added to Maintenance Tiotropium Therapy Chest, November 1, 2007; 132(5): 1493 - 1499. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
