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Clinical Investigations: COPD |

Improvement in Resting Inspiratory Capacity and Hyperinflation With Tiotropium in COPD Patients With Increased Static Lung Volumes* FREE TO VIEW

Bartolome Celli; Richard ZuWallack; Susan Wang; Steven Kesten
Author and Funding Information

*From the Pulmonary and Critical Care Division (Dr. Celli), St. Elizabeth’s Medical Center, Boston. MA; Division of Pulmonary Medicine (Dr. ZuWallack), St. Francis Hospital and Medical Center, Hartford, CT; and Boehringer Ingelheim (Drs. Wang and Kesten), Ridgefield, CT.

Correspondence to: Bartolome Celli, MD, FCCP, St. Elizabeth’s Medical Center, 36 Cambridge St, Boston, MA 02135; e-mail: bcelli@cchcs.org



Chest. 2003;124(5):1743-1748. doi:10.1378/chest.124.5.1743
Text Size: A A A
Published online

Background: In patients with COPD, changes in inspiratory capacity (IC) have shown a higher correlation to patient-focused outcomes, such as dyspnea with exercise, than other standard spirometric measurements. Changes in IC reflect changes in hyperinflation. Tiotropium is a once-daily inhaled anticholinergic that has its effect through prolonged M3 muscarinic receptor antagonism and has demonstrated sustained improvements in spirometric and health outcomes. We sought to evaluate changes in resting IC and lung volumes after long-term administration of tiotropium.

Methods: To evaluate the effect of tiotropium, 18 μg/d, on IC, a 4-week, randomized, double-blind, placebo-controlled study was conducted in 81 patients with stable COPD. At each of the visits (weeks 0, 2, and 4) FEV1, FVC, IC, slow vital capacity (SVC), and thoracic gas volume (TGV) were measured prior to study drug (- 60 and - 15 min) and after study drug (30 min, 60 min, 120 min, and 180 min).

Results: Mean age was 64 years; 62% were men. Mean baseline FEV1 was 1.12 L (43% predicted). The mean differences (tiotropium − placebo) in FEV1 trough (morning before drug), peak, and area under the curve over 3 h values (adjusted for baseline and center differences) at week 4 were 0.16 L, 0.22 L, and 0.22 L, respectively (p < 0.01 for all); differences in IC for these variables were 0.22 L, 0.35 L, and 0.30 L (p < 0.01 for all). Differences in TGV were − 0.54 L, − 0.60 L, and − 0.70 L, respectively (p < 0.01 for all). The percentage improvement in area under the curve above baseline with tiotropium was similar among FEV1 and lung volumes (FEV1, 18%; FVC, 20%; SVC, 16%; IC, 16%; TGV, 14%).

Conclusions: Observed improvements in IC and reductions in TGV with once-daily tiotropium reflect improvements in hyperinflation that are maintained over 24 h.

Figures in this Article

COPD is a disease characterized by progressive airflow limitation along with changes in lung compliance and elastic recoil that are manifested by hyperinflation.1 Therefore, an understanding of the efficacy for a bronchodilator in patients with COPD should include assessments of lung volumes. The measurement of resting lung volumes and capacities can provide additional information regarding hyperinflation and its implications for clinical outcomes such as dyspnea.

It is now accepted that following the administration of a bronchodilator agent, the changes in FEV1 do not necessarily reflect changes in dyspnea.26 To this end, it has been shown that dynamic hyperinflation5 and hyperinflation at rest are key determinants of dyspnea in patients with COPD.7 Among static flow and volume measurements, the highest correlation of dyspnea was observed with inspiratory capacity (IC). To this end, the evaluation of FEV1 in response to bronchodilator therapy may point toward improvements in airflow obstruction; however, the results may not properly gauge the potential for a bronchodilator to improve on patient-focused outcomes such as dyspnea.

Tiotropium is a once-daily inhaled anticholinergic that has its effect through prolonged M3 muscarinic receptor antagonism.89 In 1-year clinical trials1011 in patients with COPD, tiotropium has demonstrated sustained improvements in spirometric outcomes as well as improvements in dyspnea and health status. In these long-term studies,1011 lung volume assessments were limited to FVC. Therefore, in the present study, the acute and chronic bronchodilator response to tiotropium in patients with COPD was assessed through measurements of IC, slow vital capacity (SVC), and thoracic gas volume (TGV) as measured by body plethysmography.

Study Design

This was a randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the efficacy of tiotropium in patients with COPD. The first clinic visit was for screening of patients. Qualified patients were asked to return within 2 weeks for the baseline visit. If they continued to meet inclusion/exclusion criteria, they were randomized to receive one capsule daily of tiotropium, 18 μg, or placebo through the HandiHaler device (Boehringer Ingelheim; Ridgefield, CT) for 28 days.12 Clinic visits were scheduled at 2 weeks and at 4 weeks. A final visit was scheduled approximately 1 week after completion of study medication to ensure that patients were in stable condition.

Patient Demographics

All patients had a diagnosis of COPD as defined by American Thoracic Society.13 Patients were at least 40 years of age and had a smoking history of at least 10 pack-years. Patients were required to meet the following spirometric and static lung volume criteria: FEV1 > 30% but < 65% of predicted values, and lung hyperinflation demonstrated by TGV ≥ 120% of predicted value. Patients with a history of asthma, allergic rhinitis or atopy, an elevated total eosinophil count, or a recent respiratory tract infection were excluded. Patients were required to discontinue all previous inhaled anticholinergic and long-acting β-agonist use. The protocol was approved by Institutional Review Boards, and written informed consent was obtained before any study procedure was undertaken.

Spirometry

Pulmonary function testing was performed at all clinic visits. Measurements were performed according to American Thoracic Society criteria.13 Spirometry was conducted in triplicate, while the patient was in a seated position. The largest FEV1 and FVC were recorded after examining all of the acceptable curves, even if they were not from the same curve. SVC was taken as a slow expiration from total lung capacity. The largest SVC was recorded in a maneuver prior to the forced expiratory flow-volume loops. IC, SVC, FVC, and FEV1 measurements were performed at 1 h and again 15 min before study drug administration at the randomization visit and at 2 weeks and 4 weeks following randomization. After study drug administration, measurements were performed at 30 min, 60 min, 2 h, and 3 h. Short-acting theophyllines were withheld at least 24 h, long-acting theophyllines at least 48 h, and short-acting β2-agonists 8 h before spirometry.

To obtain IC, the patient quietly breathed into the spirometer, so that several reproducible readings of tidal volume were obtained. The patient was then asked to take a maximum inspiration, and slowly and completely exhale (SVC). Expiratory reserve volume was determined from the maneuver. IC was calculated as SVC - expiratory reserve volume.

Body Plethysmography

Airway resistance (Raw) and TGV were measured using a constant-volume variable pressure body plethysmograph at each visit according to the methods described by Coates et al.14 These measurements were collected at the same time intervals as the spirometric assessments. TGV was determined as a mean of three satisfactory readings.

Data Analysis

The trough measurement was defined as the average of the two measurements taken at the end of the drug administration period, at approximately 23 to 25 h after drug administration. The area under the curve over 3 h (AUC0–3) of the drug administration period was calculated using the trapezoidal rule and divided by three. The statistical model was an analysis of covariance. The terms included in the analysis of covariance model were treatment, center, and baseline covariate. The baseline value was included in the analysis of covariance model as a covariate to adjust for any baseline differences between treatment groups. The predose data collected at visit 2 was defined as baseline. In a report by O’Donnell et al,5 the SD of the postdose change in IC was estimated to be 0.4 L. Thirty-seven patients per treatment group (total 74 patients) were needed to detect a 0.3-L difference in resting IC between tiotropium and placebo at 5% level of significance with 90% of power based on a two-tailed t test.

A total of 128 patients were screened and signed informed consent, and 81 patients were randomized and entered the study. Of the 81 randomized patients, 75 patients completed the study. Of the six patients withdrawn after randomization, one patient from each treatment group withdrew due to worsening COPD. The other withdrawals were due to protocol violations.

Patient Demographics

Age, smoking history, COPD duration, and race were similar between the tiotropium and placebo groups (Table 1 ). The mean age was approximately 64 years (overall range, 42 to 75 years). Approximately 72% of patients were ex-smokers. The overall mean COPD duration was 8.7 years. There were more men in the tiotropium group than the placebo group (70% vs 54%). The mean FEV1 values at baseline were greater (p < 0.05) in the tiotropium group (1.23 L; 46% predicted) compared with the placebo group (1.01 L; 41% predicted). Similarly, the mean FVC and TGV in the tiotropium group were increased compared with placebo, although only the FVC was statistically significant. The FEV1/FVC ratio and TGV percentage of predicted and mean age were similar between the groups.

Spirometry

Patients treated with tiotropium had significant increases in AUC0–3 and trough IC in comparison to placebo patients (Fig 1 ). The differences between the tiotropium and placebo groups in AUC0–3 and trough IC were 0.30 and 0.22 L, respectively, on day 28 (p < 0.001). The percentage increase in area under the curve above baseline with tiotropium was 16% for IC.

Tiotropium significantly increased spirometric measures (FEV1, FVC, and SVC) at all time points on all test days compared to placebo (p < 0.01). These increases were observed within 30 min after a single dose of tiotropium. The time course of improvement for FEV1 and FVC is illustrated in Figures 2, 3 . On day 28, the differences in AUC0–3 and trough FEV1 between the tiotropium and placebo groups were 0.22 and 0.16 L (p < 0.0001), respectively. The difference between the two treatment groups in AUC0–3 and trough FVC were 0.45 and 0.33 L (p < 0.0001), respectively. The difference in AUC0–3 and trough SVC was 0.37 and 0.29 L, (p < 0.0003), respectively, between the tiotropium and placebo groups. Peak FEV1, FVC, and SVC were also higher on all test days in the tiotropium group. A summary of the differences in displayed in Table 2 . The percentage improvement in area under the curve above baseline with tiotropium was as follows: FEV1, 18%; FVC, 20%; and SVC, 16%.

Body Plethysmography

The time course over 3 h of TGV on day 28 is illustrated in Figures 4, 5 . Tiotropium also significantly increased peak IC on all test days (p < 0.001). When compared to placebo, tiotropium significantly decreased the mean TGV AUC0–3 at all time points (p < 0.01). By day 28, the absolute differences between the two treatment groups were 0.7 and 0.54 L for AUC0–3 and trough TGV, respectively (p < 0.03). The maximum response (ie, reduction) in TGV between tiotropium and placebo was also significantly different on all test days (p < 0.01). The percent reduction in TGV AUC0–3 from baseline with tiotropium was 14%.

The mean AUC0–3, trough, and peak Raw in the tiotropium group were significantly less than those seen in the placebo group on all test days (p < 0.005). The mean absolute differences between treatment groups for AUC0–3 and trough Raw were 1.33 and 1.0 cm H2O/L/s, respectively, on day 28 (p < 0.001). The maximum response in Raw for tiotropium-treated patients was also significantly larger than that observed in placebo patients (p < 0.001) on all test days.

COPD is a disease characterized by the presence of incompletely reversible airflow limitation.15 In moderate-to-severe COPD, this airflow limitation is usually associated with gas trapping and hyperinflation as assessed objectively through an increase in TGV. This hyperinflation is also reflected by a reduction in IC. These physiologic abnormalities translate to symptoms of dyspnea, exercise intolerance, and patient disability.5,16 To this end, it is now accepted that while spirometric evaluations are important for evaluating the severity of the airflow obstruction and monitoring the progression of disease, these assessments do not adequately profile the full impact of COPD on the patient’s health status.

The present study was designed to evaluate changes in resting IC in addition to other lung volumes following 4 weeks of treatment with tiotropium in patients with COPD. Significant improvements in the primary end points for trough and average (AUC0–3) IC were observed in patients treated with tiotropium on the last day of treatment (day 28). In addition, there was a decrease in TGV and an increase in SVC in patients treated with tiotropium, indicating that tiotropium reduced lung hyperinflation associated with gas trapping. Although not evaluated in this study, the resulting pharmacologic lung volume reduction could have beneficial consequences on respiratory muscle function, similar to those observed after surgical lung volume reduction.17 Indeed, the decrease in TGV is of a similar magnitude to that reported 3 to 6 months after lung volume reduction surgery.18

Airway resistance also declined with tiotropium. Furthermore, treatment with tiotropium improved the spirometric measures of airflow limitation including trough, average, and peak FEV1 and FVC. This finding is consistent with all other studies, which have demonstrated significant improvements for lung function with tiotropium compared to placebo, ipratropium, or salmeterol treatment in patients with COPD.1011,19

A potential limitation of the results comes from several between-group differences in baseline demographics. However, these differences have been taken into account in the analysis by adjusting for baseline differences. In addition, while the FEV1 and FVC were lower in the placebo group, the TGV percentage of predicted was similar between the groups. There were more men in the tiotropium group but a gender difference in volume responses to an inhaled bronchodilator would not be expected.

As COPD progresses, destruction of the supporting tissues and elastin fibers within the lung results in increased tissue compliance and reduced elastic recoil on expiration. As a result, residual volume and TGV increase and result in lung hyperinflation and gas trapping. Ultimately, as hyperinflation increases, the obstructive disease leads to a restrictive defect with a diminished IC and an inability to expand tidal volume to meet increased metabolic demands.20 Furthermore, lung hyperinflation results in disruption of neuroventilatory coupling, increased work of breathing, and the perception of dyspnea, which can be altered with bronchodilator administration.21 Hence, strategies that decrease hyperinflation should improve the aforementioned parameters and result in clinically meaningful improvements in patient breathlessness and quality of life.

Several studies2,4,2224 have examined the relationship between static lung function to the clinical consequences of dyspnea and exercise intolerance. The correlation of FEV1 with patient dyspnea and exercise tolerance was found to be statistically significant, albeit low.,5 Changes in IC seem to correlate higher than other lung volume measurements to changes in the perception of dyspnea.2,67 The results of the present study demonstrate that tiotropium significantly improves spirometry and lung hyperinflation in patients with COPD and provides physiologic support to earlier findings showing improvements in dyspnea. The present study was not powered to explore the relationship between functional dyspnea and resting hyperinflation. Given that the magnitude of the changes in resting lung volume are similar to those observed after lung volume reduction surgery, such a study might be desirable.

Lung volume improvements with short-acting bronchodilator agents such as albuterol and ipratropium have been observed. These studies have been generally limited to single-dose acute evaluations, which is a reasonable approach given that the physiologic effects have disappeared by the next scheduled dose. In a study reported by Newton et al,25 the authors found that albuterol reduced lung hyperinflation and gas trapping reflected by a decrease in functional residual capacity of 0.44 L and increase in IC of 0.22 L at peak effect in patients with severe COPD. These improvements in lung volumes were not correlated to changes in FEV1 suggesting that meaningful changes in lung function may be missed when evaluating acute therapeutic responses to pharmacotherapy in advanced COPD. In another study, O’Donnell et al,2 reported that treatment with ipratropium, a short-acting anticholinergic bronchodilator, improved IC by 0.39 L while also improving exercise endurance time by 1.9 min and exercise dyspnea (11% reduction in Borg-time slopes [p < 0.05] along with a 0.5% reduction in Borg at standardized exercise time [p < 0.05]) during constant load cycle exercise. Similar to the findings with albuterol, the improvements in lung volume measurements seen with ipratropium were often independent of changes in spirometry (ie, FEV1). The results from the evaluation of these short-acting bronchodilators have demonstrated that improvements in lung volumes provide clinically important information about pharmacologic interventions in COPD. It is notable that the peak effects of the short-acting β-agonists were similar to those observed approximately 23 to 24 h after administration of tiotropium.

Tiotropium is a long-acting inhaled anticholinergic bronchodilator used in the treatment of airflow obstruction in patients with COPD.1011 Previous long-term studies1011 have demonstrated that tiotropium, 18 μg qd, leads to improvements in dyspnea, exacerbations, and health status. In the present study, 4 weeks of treatment with tiotropium resulted in improvements for spirometry and dyspnea in addition to lung volume parameters such as IC, TGV, and SVC. The improvements in IC and TGV with tiotropium support the concept that changes in dyspnea are related to reductions in lung hyperinflation and may help to further our understanding of the impact of bronchodilator therapy on patient-reported health outcomes.

Abbreviations: AUC0–3 = area under the curve over 3 h; IC = inspiratory capacity; Raw = airway resistance; SVC = slow vital capacity; TGV = thoracic gas volume

Drs. Celli and ZuWallack are consultants for Boehringer Ingelheim.

This study was financed by Boehringer Ingelheim, Inc.

Table Graphic Jump Location
Table 1. Baseline Demographics for Tiotropium, Placebo, and Total Population*
* 

Data are presented as mean (SE) unless otherwise indicated.

 

p < 0.05, tiotropium vs placebo.

Figure Jump LinkFigure 1. Changes in IC over 3 h following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location
Figure Jump LinkFigure 2. Changes in FEV1 over 3 h following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location
Figure Jump LinkFigure 3. Changes in FVC over 3 h following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location
Table Graphic Jump Location
Table 2. The Mean Differences (Tiotropium-Placebo) in Predrug (Trough), Peak, and AUC0–3 Values for FEV1 and Lung Volumes Following 4 Weeks of Treatment*
* 

All differences were statistically significant (p < 0.01).

Figure Jump LinkFigure 4. Changes in TGV over 3 h following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location
Figure Jump LinkFigure 5. Changes in lung volumes and spirometry following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location

We thank our co-investigators, Dr. D. Mahler, Dr. E. Diamond, Dr. C. Cote, and Dr. D. Maple.

Rodarte, JR, Noredin, G, Miller, C, et al (1999) Lung elastic recoil during breathing at increased lung volume.J Appl Physiol87,1491-1495. [PubMed]
 
O’Donnell, DE, Lam, M, Webb, KA Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1999;160,542-549. [PubMed]
 
Chrystyn, H, Mulley, BA, Peake, MD Dose response relation to oral theophylline in severe chronic obstructive airways disease.BMJ1988;297,1506-1510. [CrossRef] [PubMed]
 
Waterhouse, JC, Pritchard, SM, Howard, P Hyperinflation, trapped gas and theophylline in chronic obstructive pulmonary disease.Monaldi Arch Chest Dis1993;48,126-129. [PubMed]
 
O’Donnell, DE, Lam, M, Webb, KA Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1998;158,1557-1565. [PubMed]
 
O’Donnell, DE Assessment of bronchodilator efficacy in symptomatic COPD: is spirometry useful?Chest2000;117,42S-47S. [CrossRef] [PubMed]
 
Taube, C, Lehnigk, B, Paasch, K, et al Factor analysis of changes in dyspnea and lung function parameters after bronchodilation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med2000;162,216-220. [PubMed]
 
Barnes, PJ, Belvisi, MG, Mak, JC, et al Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease.Life Sci1995;56,853-859. [CrossRef] [PubMed]
 
Disse, B, Speck, GA, Rominger, KL, et al Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease.Life Sci1999;64,457-464. [CrossRef] [PubMed]
 
Vincken, W, van Noord, JA, Greefhorst, APM, et al Improved health outcomes in patients with COPD during one year treatment with tiotropium.Eur Respir J2002;19,209-216. [CrossRef] [PubMed]
 
Casaburi, R, Mahler, DA, Jones, PA, et al A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.Eur Respir J2002;19,217-224. [CrossRef] [PubMed]
 
Chodosh, S, Flanders, JS, Kesten, S, et al Effective delivery of particles with the HandiHaler dry powder inhalation system over a range of chronic obstructive pulmonary disease severity.J Aerosol Med2001;14,309-315. [CrossRef] [PubMed]
 
American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies.Am Rev Respir Dis1991;144,1202-1218. [CrossRef] [PubMed]
 
Coates, AL, Peslin, R, Rodenstein, D, et al Measurement of lung volumes by plethysmography.Eur Respir J1997;10,1415-1427. [CrossRef] [PubMed]
 
Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society.Am J Respir Crit Care Med1995;152,S77-S121. [PubMed]
 
Diaz, O, Villafranca, C, Ghezzo, H, et al Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest.Eur Respir J2000;16,269-275. [CrossRef] [PubMed]
 
Martinez, FJ, de Oca, MM, Whyte, RI, et al Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function.Am J Respir Crit Care Med1997;155,1984-1990. [PubMed]
 
Benditt, JO, Wood, DE, McCool, FD, et al Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery.Am J Respir Crit Care Med1997;155,279-284. [PubMed]
 
Donohue, JF, van Noord, JA, Bateman, ED, et al A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.Chest2002;122,47-55. [CrossRef] [PubMed]
 
Pellegrino, R, Rodarte, JR, Brusasco, V Assessing the reversibility of airway obstruction.Chest1998;114,1607-1612. [CrossRef] [PubMed]
 
Belman, MJ, Botnick, WC, Shin, JW Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med1996;153,967-975. [PubMed]
 
O’Donnell, DE, Lam, M, Webb, KA Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1999;160,542-549. [PubMed]
 
Leyenson, V, Furukawa, S, Kuzma, AM, et al Correlation of changes in quality of life after lung volume reduction surgery with changes in lung function, exercise, and gas exchange.Chest2000;118,728-735. [CrossRef] [PubMed]
 
Ramirez-Venegas, A, Ward, J, Lentine, T, et al Salmeterol reduces dyspnea and improves lung function in patients with COPD.Chest1997;112,336-340. [CrossRef] [PubMed]
 
Newton, MF, O’Donnell, DE, Forkert, L Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation.Chest2002;121,1042-1050. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Changes in IC over 3 h following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location
Figure Jump LinkFigure 2. Changes in FEV1 over 3 h following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location
Figure Jump LinkFigure 3. Changes in FVC over 3 h following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location
Figure Jump LinkFigure 4. Changes in TGV over 3 h following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location
Figure Jump LinkFigure 5. Changes in lung volumes and spirometry following 4 weeks of treatment with tiotropium or placebo.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Baseline Demographics for Tiotropium, Placebo, and Total Population*
* 

Data are presented as mean (SE) unless otherwise indicated.

 

p < 0.05, tiotropium vs placebo.

Table Graphic Jump Location
Table 2. The Mean Differences (Tiotropium-Placebo) in Predrug (Trough), Peak, and AUC0–3 Values for FEV1 and Lung Volumes Following 4 Weeks of Treatment*
* 

All differences were statistically significant (p < 0.01).

References

Rodarte, JR, Noredin, G, Miller, C, et al (1999) Lung elastic recoil during breathing at increased lung volume.J Appl Physiol87,1491-1495. [PubMed]
 
O’Donnell, DE, Lam, M, Webb, KA Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1999;160,542-549. [PubMed]
 
Chrystyn, H, Mulley, BA, Peake, MD Dose response relation to oral theophylline in severe chronic obstructive airways disease.BMJ1988;297,1506-1510. [CrossRef] [PubMed]
 
Waterhouse, JC, Pritchard, SM, Howard, P Hyperinflation, trapped gas and theophylline in chronic obstructive pulmonary disease.Monaldi Arch Chest Dis1993;48,126-129. [PubMed]
 
O’Donnell, DE, Lam, M, Webb, KA Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1998;158,1557-1565. [PubMed]
 
O’Donnell, DE Assessment of bronchodilator efficacy in symptomatic COPD: is spirometry useful?Chest2000;117,42S-47S. [CrossRef] [PubMed]
 
Taube, C, Lehnigk, B, Paasch, K, et al Factor analysis of changes in dyspnea and lung function parameters after bronchodilation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med2000;162,216-220. [PubMed]
 
Barnes, PJ, Belvisi, MG, Mak, JC, et al Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease.Life Sci1995;56,853-859. [CrossRef] [PubMed]
 
Disse, B, Speck, GA, Rominger, KL, et al Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease.Life Sci1999;64,457-464. [CrossRef] [PubMed]
 
Vincken, W, van Noord, JA, Greefhorst, APM, et al Improved health outcomes in patients with COPD during one year treatment with tiotropium.Eur Respir J2002;19,209-216. [CrossRef] [PubMed]
 
Casaburi, R, Mahler, DA, Jones, PA, et al A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.Eur Respir J2002;19,217-224. [CrossRef] [PubMed]
 
Chodosh, S, Flanders, JS, Kesten, S, et al Effective delivery of particles with the HandiHaler dry powder inhalation system over a range of chronic obstructive pulmonary disease severity.J Aerosol Med2001;14,309-315. [CrossRef] [PubMed]
 
American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies.Am Rev Respir Dis1991;144,1202-1218. [CrossRef] [PubMed]
 
Coates, AL, Peslin, R, Rodenstein, D, et al Measurement of lung volumes by plethysmography.Eur Respir J1997;10,1415-1427. [CrossRef] [PubMed]
 
Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society.Am J Respir Crit Care Med1995;152,S77-S121. [PubMed]
 
Diaz, O, Villafranca, C, Ghezzo, H, et al Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest.Eur Respir J2000;16,269-275. [CrossRef] [PubMed]
 
Martinez, FJ, de Oca, MM, Whyte, RI, et al Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function.Am J Respir Crit Care Med1997;155,1984-1990. [PubMed]
 
Benditt, JO, Wood, DE, McCool, FD, et al Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery.Am J Respir Crit Care Med1997;155,279-284. [PubMed]
 
Donohue, JF, van Noord, JA, Bateman, ED, et al A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.Chest2002;122,47-55. [CrossRef] [PubMed]
 
Pellegrino, R, Rodarte, JR, Brusasco, V Assessing the reversibility of airway obstruction.Chest1998;114,1607-1612. [CrossRef] [PubMed]
 
Belman, MJ, Botnick, WC, Shin, JW Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med1996;153,967-975. [PubMed]
 
O’Donnell, DE, Lam, M, Webb, KA Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1999;160,542-549. [PubMed]
 
Leyenson, V, Furukawa, S, Kuzma, AM, et al Correlation of changes in quality of life after lung volume reduction surgery with changes in lung function, exercise, and gas exchange.Chest2000;118,728-735. [CrossRef] [PubMed]
 
Ramirez-Venegas, A, Ward, J, Lentine, T, et al Salmeterol reduces dyspnea and improves lung function in patients with COPD.Chest1997;112,336-340. [CrossRef] [PubMed]
 
Newton, MF, O’Donnell, DE, Forkert, L Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation.Chest2002;121,1042-1050. [CrossRef] [PubMed]
 
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