Is sustained pharmacologic lung volume reduction now possible in COPD?

I nternational 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). 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. Studies3–7 have shown that substantial reductions in lung hyperinflation can occur after short-term treatment with shortacting 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.6,8,9 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 2-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.4,5 In patients with COPD, the smaller the resting IC, the closer that tidal volume is positioned to total lung CHEST Editorials