Eur Respir J 2001; 18: 914–920 Copyright #ERS Journals Ltd 2001 DOI: 10.1183/09031936.01.00216501 European Respiratory Journal Printed in UK – all rights reserved ISSN 0903-1936 Evaluation of bronchodilator responses in patients with "irreversible" emphysema D.E. O9Donnell, L. Forkert, K.A. Webb Evaluation of bronchodilator responses in patients with 0irreversible0 emphysema. D.E. Respiratory Investigation Unit, Dept O9Donnell, L. Forkert, K.A. Webb. #ERS Journals Ltd 2001. of Medicine, Queen9s University, King- ABSTRACT: Given the emerging physiological and clinical rationale for pharmaco- ston, Ontario, Canada. logical lung-volume reduction, assessment of volume responses to bronchodilators is Correspondence: D.E. O9Donnell likely to be highly relevant in chronic obstructive pulmonary disease (COPD). The Richardson House authors examined the magnitude of lung-volume reduction after acute bronchodilator 102 Stuart Street treatment in patients with advanced emphysema. c/o Kingston General Hospital Eighty-four stable patients with emphysema (mean¡SEM forced expiratory volume Kingston in one second (FEV1): 32¡1% predicted) performed spirometry and body plethysmo- Ontario graphy before and 15–30 min after 200 mg salbutamol. Only irreversible patients with a Canada postbronchodilator change in FEV1 v10% pred were considered in this study. K7L 2V7 Postsalbutamol, the majority of subjects (83%) had significant improvements in one Fax: 1 6135491459 or more lung volumes: on average, residual volume (RV), functional residual capacity Keywords: Bronchodilators (FRC), inspiratory capacity (IC), forced vital capacity and slow vital capacity changed ¡ ¡ ¡ ¡ ¡ chronic obstructive pulmonary disease by -18 2, -10 1, 8 1, 9 1 and 7 1% pred (pv0.0005 each). Total lung capacity emphysema (TLC) decreased 0.12¡0.04 L (pv0.01). Change in IC reflected change in FRC inspiratory capacity (r=-0.60, pv0.0005), but more strongly in the 57% of patients with no significant change lung hyperinflation in TLC (r=-0.93, pv0.0005). The magnitude and frequency of volume responses were reversibility criteria greatest in patients with the most severe COPD; for example, RV decreased by 0.51¡0.09 L (23¡4% pred) and 0.27¡0.04 L (14¡2% pred) in severe and moderate Received: February 19 2001 subgroups, respectively. Accepted after revision July 11 2001 Significant reductions in lung hyperinflation occurred in the absence of a change in This work was supported by the forced expiratory volume in one second after low-dose salbutamol in a majority of Ontario Ministry of Health. patients with advanced emphysema; the greatest changes occurred in those with the most severe disease. Eur Respir J 2001; 18: 914–920. The relatively diminished bronchodilator response dynamic lung hyperinflation, which is arguably a in chronic obstructive pulmonary disease (COPD) relevant measure of impairment in severely flow- (compared with asthma) has led to its designation as limited patients [9, 10]. Symptom relief and improved an irreversible airways disease and has, consequently, exercise performance, following both b2-agonist and promoted a general attitude of therapeutic nihilism. anticholinergic bronchodilators, correlate well with Although the measurement of maximal flow rates e.g. reduced resting and exercise operational lung volumes the forced expiratory volume in one sec (FEV1)is in the presence of only minimal changes in the FEV1 of unquestionable diagnostic utility, and has become [1, 2]. Therefore, the purpose of this study was to an acceptable (albeit imprecise) measure of disease examine the frequency and magnitude of lung-volume severity in COPD, recent studies have shown that this reduction in response to salbutamol in patients with measurement has definite limitations as a clinical irreversible emphysema. The authors were particularly outcome measure for the evaluation of bronchodilator interested in evaluating whether improved inspiratory efficacy [1–4]. In advanced COPD, forced expiratory capacity (IC) accurately reflected reduced lung hyper- manoeuvres initiated from total lung capacity (TLC) inflation in this population. The resting IC may be a are fraught with measurement artefact (e.g. gas and clinically relevant outcome measure because it has airway compression effects) that underestimate the recently been shown to correlate well with symptom- true maximal expiratory flows available over the limited peak oxygen uptake in COPD [10, 11]. More- operating tidal volume range [5]. Therefore, FEV1, over, there is mounting evidence that small increases only crudely reflects the degree of expiratory-flow in IC (in the order of y10 % predicted or 0.3 L), limitation (EFL), which is the true pathophysiological following bronchodilator therapy are associated with hallmark of COPD [6]. The FEV1 correlates weakly, important improvements in dyspnoea and exercise or not at all, with symptom intensity and exercise performance in COPD [1, 3, 12, 13]. The behaviour of capacity in COPD [7–9]. TLC following salbutamol was also studied, since this A major consequence of EFL is air trapping and is essential to the evaluation of the potential utility of PHARMACOLOGICAL VOLUME REDUCTION IN EMPHYSEMA 915 measuring changes in spirometric IC and vital capa- Linda, CA, US). Prebronchodilator only, single- city (VC) to accurately reflect changes in plethysmo- breath DL,CO was also measured (6200 Autobox DL graphic functional residual capacity (FRC) and or Vmax229). Predicted normal values for spirometry, residual volume (RV), respectively. Finally, the lung volumes, and diffusing capacity were those of authors compared volume responses in patients with MORRIS et al. [19], CRAPO et al. [20], and BURROWS moderate (Stage II) and severe (Stage III) COPD, et al. [21], respectively. Predicted normal values for stratified by recent Global Initiative for Chronic IC were calculated as predicted TLC minus predicted Obstructive Lung Disease (GOLD) criteria [14]. FRC. In this study, the authors examined responses to 200 mg of salbutamol in a large population of patients with well-characterized, stable, advanced COPD, who Evaluation of bronchodilator responses had clinical and physiological features of emphysema. The analysis was confined to those patients who had a To establish eligibility for the study, bronchodilator minimal or absent FEV1 response during reversibility responsiveness was first judged against FEV1 criteria testing. recommended by the ERS [15]. To avoid bias from differences in baseline lung function [15], changes in various lung volumes were assessed and compared as Methods % pred normal. A change of ¢10% pred was felt to represent a Subjects significant bronchodilator response for IC or VC, since this amount falls outside the 95% confidence The present authors studied 84 clinically-stable interval (CI) for each of these measurements in this patients with advanced COPD, who did not meet group and in other severe COPD populations [2, 22]. the European Respiratory Society (ERS) reversibility Based on the results from a previous study of patients criteria for a positive bronchodilator response [15]. with severe COPD, a change of this magnitude also Specific inclusion criteria included: 1) a clinical pro- fell outside the coefficient of variation for repeated file of emphysema [16]; 2) a long history of cigarette measurements in this population [2]. In addition, it smoking (¢20 pack-yrs); 3) FEV1 ¡50% pred and was estimated that an increase in IC of 10% pred, FEV1/forced vital capacity (FVC) v70%; 4) lung or y0.3 L, resulted in clinically important improve- hyperinflation (FRC w120% pred); 5) a reduced ments in exertional dyspnoea intensity (i.e. reductions carbon monoxide diffusing capacity of the lung of y0.5 Borg Scale units) and in exercise endurance (DL,CO) ¡50% pred); and 6) a postbronchodilator (i.e. increases of y25%) in severe COPD. FEV1 response v10% pred. Subjects were further Similarly, the proportion of patients with plethys- stratified with respect to COPD severity based on mographic FRC and RV responses w10% pred was FEV1 criteria [14]: moderate (Stage II, FEV1 ¢30% evaluated. Finally, changes in TLC were also eval- pred and ¡50% pred) and severe (Stage III, FEV1 uated, and a significant change was assessed as a v30% pred). change outside the 95% CI of the within-group baseline measurement. Study design Statistical analysis Subjects were selected from a database of COPD Results are means¡SEM. Pre- and postbroncho- patients, who had performed reversibility testing dilator comparisons were made using paired t-tests. during assessment before pulmonary rehabilitation Unpaired t-tests were used for subgroup compari- or as part of the screening process prior to entering sons. Nonparametric frequency statistics were ana- various clinical-research studies. All subjects signed lysed using Chi-squared analysis. Interrelationships written informed consent at the time of their origi- between postbronchodilator changes (D) in lung func- nal assessments and were aware that their test data tion measurements were evaluated using Pearson9s might be used in future analyses. Prior to reversibility correlations. For subgroup comparisons and regres- testing, patients were required to withdraw from all sion analyses, pulmonary function measurements short-acting and long-acting bronchodilators for ¢4 were standardized as % pred normal values. and ¢12 h, respectively. Results Procedures Subject characteristics Pulmonary function testing was conducted with subjects seated at rest, before and 15–30 min after Subjects had significant