Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
doi:10.1378/chest.06-1662
(Chest. 2007; 131:690-695)
© 2007 American College of Chest Physicians
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gelb, A. F.
Right arrow Articles by Zamel, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gelb, A. F.
Right arrow Articles by Zamel, N.

Tiotropium and Simplified Detection of Dynamic Hyperinflation*

Arthur F. Gelb, MD, FCCP; Colleen Flynn Taylor, MA; Patricia A. McClean, MSc; Chris M. Shinar, PharmD; Marcelo T. Rodrigues, MD, PhD; Carlos A. Gutierrez, MD, MSc; Kenneth R. Chapman, MD, MSc, FCCP and Noe Zamel, MD, FCCP

* From the Department of Pharmacy Services (Dr. Shinar), Lakewood Regional Medical Center, Lakewood, CA; and Geffen School of Medicine at UCLA (Dr. Gelb), Los Angeles, CA; and Faculty of Medicine (Drs. Gutierrez, Rodrigues, Chapman, and Zamel, and Ms. McClean), University of Toronto, Toronto, ON. Canada.

Correspondence to: Arthur F. Gelb, MD, FCCP, 3650 E South St, Suite 308, Lakewood, CA 90712; e-mail: afgelb{at}msn.com

Abstract

Study objective: To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium.

Methods: IC and FEV1 were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 ± 10 years [± SD]) before and after 30 days of treatment with tiotropium bromide, 18 µg. Patients were encouraged to maintain a constant tidal volume during MPH.

Results: At baseline, mean FEV1 was 1.5 ± 0.1 L (± SE) [57 ± 1.6% of predicted], mean FVC was 2.6 ± 0.1L (77 ± 1.8% of predicted), and mean FEV1/FVC was 56 ± 1%. After 180 µg of aerosolized albuterol sulfate, mean FEV1 was 1.7 ± 0.1 L (63 ± 1.5% of predicted) [p < 0.001] and mean FEV1/FVC was 58 ± 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 ± 0.04L (p < 0.0001); FEV1 of 0.13 ± 0.03 L (5.6 ± 0.8% of predicted; p = 0.0002); FVC of 0.22 ± 0.05 L (6.5 ± 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of – 3.1 ± 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of – 2.9 ± 1.3% (p = 0.03); and no change in TLC (– 0.06 ± 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (– 0.35 ± 0.03 L; p < 0.001); FEV1 (– 0.05 ± 0.04 L; p = 0.2); and FVC (– 0.22 ± 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 ± 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 ± 1.3% of predicted, p < 0.003).

Conclusion: In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.

Key Words: COPD • dynamic hyperinflation • lung function • metronome-paced hyperventilation • tiotropium

As previously noted, since FEV1 may be a poor predictor of clinical symptoms, exercise tolerance, and response to bronchodilators in COPD, additional measures have been sought.1 Alternatively, exercise testing using constant or incremental cycle ergometry with repeated measurements of inspiratory capacity (IC) has been used to detect dynamic hyperinflation (DH) and evaluate the response to bronchodilators.1 O’Donnell et al2 provided confirmatory evidence that "Borg dyspneic ratings and measurements of inspiratory capacity (IC) and endurance time during submaximal cycle exercise testing are highly reproducible and responsive to changes in severe COPD."

We have emphasized1 that previous studies have demonstrated the utility of repeated measurements of IC during exercise to reflect changes in end-expiratory lung volume (EELV)345 since total lung capacity (TLC) remains constant after acute bronchodilation and during exercise.67 Progressive reduction in IC during exercise reflects DH and is a good predictor of decreased exercise ability as well as increased exertional dyspnea.5 Additionally, peak values of inspiratory esophageal pressures used as a surrogate to estimate effort are relatively constant and correlated with breathing frequency at a given tidal volume during multiple measurements of exercise IC.89

Changes in IC reflect DH and are correlated with breathing frequency in COPD patients.5 We have suspected increasing breathing frequency would produce changes in IC similar to change in IC observed during exercise. We recently compared metronome-paced hyperventilation (MPH), a relatively simple procedure, with incremental symptom-limited cycle ergometry to provoke respiratory rate-induced DH and reduction of IC in patients with moderate-to-severe COPD and reported similar changes in IC.1 We also reported 54 µg of inhaled ipratropium bromide failed to blunt the decrease in IC.1 O’Donnell et al2 showed greater bronchodilation with much larger doses of nebulized ipratropium bromide (500 µg) when compared to usual doses of inhaled albuterol sulfate in patients with COPD. In a subsequent study, using constant cycle ergometry, O’Donnell et al10 reported that 18 µg of tiotropium in patients with moderate-to-severe COPD improved IC, exercise endurance, and exertional dyspnea.

The present study evaluates the role of tiotropium in MPH-induced DH in patients with moderate-to-severe COPD. At baseline, all COPD patients were tiotropium naïve (80% of patients) or had a 30-day washout time (20% of patients).

Materials and Methods

We selected 60 patients with a smoking history > 20 pack-years and documented moderate-to-severe COPD11 who were clinically stable for at least 6 weeks prior to the present study and were not receiving oxygen. History of wheezing and/or responsiveness to aerosolized albuterol were not specific inclusion or exclusion criteria. Patients were instructed to continue all their usual medications but to withhold short-acting ß2-agonists and/or aerosolized ipratropium bromide for 6 h and long-acting ß2-agonists for 48 h prior to testing.

After obtaining informed patient consent and approval from the Institutional Review Board from each participating site, patients underwent lung function studies before and after 180 µg of aerosolized albuterol sulfate using techniques and predictive values previously described in detail.112 We used a spirometer (Vmax29; SensorMedics; Yorba Linda, CA) and pressure-compensated flow plethysmograph (model 6200; SensorMedics).

Subsequently, on separate days, MPH was performed (Vmax29 spirometer) outside the plethysmograph using previously described methods1 in 60 COPD patients. The goal was to achieve a respiratory rate twice the baseline rate for 20 s, which was immediately followed by sequential measurement of IC, expiratory spirometry, and within 30 s plethysmographic measured functional residual capacity. While no attempt was made to control end-tidal carbon dioxide, patients were coached to maintain a respiratory rate synchronous with the metronome. Near-constant dynamic tidal volume during MPH was achieved by having patients observe a graphic display of their breathing pattern; however, no attempt was made to blunt any increase in ventilation synchronous with the metronome. Patients were studied before (baseline) and after 30 days of 18 µg of tiotropium. Technicians who performed these studies were blinded as to patient medication(s). The technique for measuring IC has been previously described.124

Statistical Analysis
Repeated-measures analysis of variance was used for lung function results obtained before and after tiotropium intervention. For the 60 patients with MPH, models with time (day 0 and day 30) [baseline and after hyperventilation] were tested. Pairwise tests were performed using the Tukey adjustment method for post hoc multiple comparisons for intervention. Results are presented as mean ± SE. Analysis was done using a statistical software package (SAS 8.02 for Windows; SAS Institute; Cary, NC). Statistical significance was p < 0.05.

Results

Baseline Studies
We studied 60 COPD patients (28 men; mean age, 66 ± 10 years [± SD]) with a smoking history of 53 ± 37 pack-years. Thirty patients were studied in Lakewood and 30 patients were studied in Toronto, and there were no significant site differences in age, gender, and smoking history. At baseline, routine lung function findings were similar in patients from the two sites (combined data are described in Table 1 ) and are consistent with moderate-to-severe COPD.11 Following 180 µg of aerosolized albuterol sulfate, FEV1 increased 14 ± 12%.


View this table:
[in this window]
[in a new window]

  		Table 1. Baseline Results of Lung Function Studies in 60 Patients With Moderate-to-Severe COPD Aged 66 ± 10 Years Prior To Starting Tiotropium*

 
Bronchodilator Response After 30 Days of Tiotropium
After 18 µg/d of inhaled tiotropium for 30 days, the changes in lung function results at 1 h predose (trough) and 1.5 h after tiotropium appear in Table 2 and Figure 1 . There was significant persistent bronchodilation at trough compared to baseline but significantly less magnitude than at 1.5 h after tiotropium (Table 2). Compared to the baseline IC of 2.15 ± 0.09 L, IC increased 0.09 ± 0.03 L (p = 0.0001) at trough, and 0.18 ± 0.04 L (p < 0.0001) at 1.5 h after dose. Compared to the baseline FEV1 of 1.5 ± 0.06 L, FEV1 increased 0.08 ± 0.03 L (p = 0.004) at trough and 0.13 ± 0.03 L (p = 0.0002) at 1.5 h after dose (Table 2; Fig 1). No significant changes were noted in TLC.


View this table:
[in this window]
[in a new window]

  		Table 2. Changes in Lung Function at Trough and Peak Value After 30 Days of Tiotropium Compared to Baseline*

 

Figure 1
View larger version (22K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Increase in IC from baseline compared to day 30 plus 1.5 h (hr) after tiotropium.

 
MPH-Induced DH at Baseline and After Tiotropium
Following MPH, there was a significant decrease in FEV1 and IC at baseline as reported in Table 3 and Figure 2 . Resting respiratory rate was 15 ± 0.6 breaths/min (mean ± SE); after 20 s of MPH, respiratory rate was 31 ± 0.2 breaths/min (p < 0.0001). Resting tidal volume was 0.92 ± 0.03 L; after 20 s of MPH, tidal volume was 0.76 ± 0.03 L (p = 0.001). Resting IC was 2.15 ± 0.09 L; after 20 s of MPH, IC was 1.78 ± 0.07 L (p < 0.0001). Resting FEV1 was 1.37 ± 0.07 L; after 20 s of MPH, FEV1 was 1.30 ± 0.06 L (p = 0.005). There was no change in TLC. The magnitude of the decrease in IC correlated modestly with decrease in tidal volume during MPH (Spearman {rho} = 0.453, p = 0.0003).


View this table:
[in this window]
[in a new window]

  		Table 3. Change in Lung Function Following MPH at Baseline Before and After 30 Days Plus 1.5 h of 18 µg of Tiotropium*

 

Figure 2
View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Decrease in IC from baseline and on day 30 following MPH. See Figure 2 legend for expansion of abbreviation.

 
After 30 days and 1.5 h after 18 µg of tiotropium, following MPH, the magnitude of the changes in FVC, IC, respiratory rate, and tidal volume were similar to baseline MPH-induced DH results prior to initiation of tiotropium. However, the decrease in FEV1 was not significant (Table 3; Fig 2).

Discussion

The present study in 60 COPD patients with moderate-to-severe expiratory airflow limitation demonstrated the provocative ability of MPH at twice the resting respiratory rate for 20 s to induce DH with a significant decrease in IC. There was a similar decrease in IC following MPH-induced DH at baseline when compared to 30 days of inhaled tiotropium, 18 µg. However, tiotropium was a potent bronchodilator, and the resultant increase in IC and decrease in operational EELV and end-inspiratory lung volume (EILV) from baseline helped blunt the subsequent challenge of MPH-induced DH. The noninvasive simplicity of hyperventilation at a respiratory rate of 30 breaths/min for 20 s provided a clinically useful screening surrogate to incremental or constant cycle ergometry to monitor changes in IC following exercise and to study the effect of tiotropium on DH.

The present results are consistent with our previous observations. We reported close agreement using Bland and Altman method, indicating MPH was more sensitive than incremental cycle ergometry to detect a decrease in IC both before and after aerosolized inhaled ipratropium bromide, 54 µg.1

In normal subjects during exercise, minute ventilation increases primarily as a result of increased tidal volume rather than increased respiratory rate.13 In contrast, when COPD patients with at least moderately severe expiratory airflow limitation and increased EELV undergo symptom-limited exercise, we1 and others5814 have noted the increase in respiratory rate to approximately double the baseline value was primarily responsible for increased minute ventilation. Not surprisingly, O’ Donnell and Webb5 reported respiratory frequency strongly correlated with Borg dyspnea scores and DH strongly correlated with breathlessness during exercise in COPD.

It has been previously reported2315 in COPD patients following acute bronchodilation, even after exercise, that a decrease in EELV is associated with an improvement in breathlessness symptom score. During exercise and MPH, EELV increases at the same rate; but since the starting point for EELV is lower after acute bronchodilation, the peak is also lower when the same load is reached. A similar phenomenon occurs with EILV. However, no interaction has been shown for the effect of bronchodilators on either EELV or EILV.2315 The rationale to measure IC during exercise is that among all variables studied, changes in IC (baseline and peak exercise) not only showed good reproducibility but correlated best with changes in Borg dyspnea scale.2315

In our previous study,1 the failure to achieve reduction in EELV and EILV or equivalent increase in IC after administration of 54 µg of ipratropium bromide at all levels (baseline and peak exercise and after hyperventilation) is in contrast to results previously reported.215 However, 500 ug of nebulized ipratropium bromide was used by O’Donnell et al,215 which is approximately 10 times the dose used in our initial study. In contrast to our initial study1 using 54 µg of ipratropium bromide, the results in the present study following 18 µg of tiotropium demonstrated significant increases in IC, FVC, and FEV1, and decreases in EELV and EILV at 30-day trough and peak response time when compared to baseline values.

It is important to compare our results before and after tiotropium intervention on MPH-induced DH with those previously reported by O‘Donnell et al10 and Maltais et al16 using constant-load cycle ergometry. In the present study, baseline (mean ± SD) FEV1 was 1.5 ± 0.1 L (55 ± 11% of predicted), compared to 1.3 ± 0.5 L (41 ± 12% of predicted)10 and 1.2 ± 0.4 L (43 ± 13% of predicted).16 The mean increase in FEV1 after 30 days plus 1.5 h of tiotropium in the present study was 130 mL, compared to 220 mL after 42 days plus 1.3 h10 and 260 mL after 42 days plus 1.3 h of tiotropium.16 At similar time thresholds as above, in the current study, the mean increase in IC was 180 mL, compared to 250 mL10 and 220 mL.16 The decreased magnitude of these responses compared to previous studies1016 may be related to initial less expiratory airflow limitation at baseline and incomplete washout of long-acting ß2-agonists at 48 h. In the current study, the mean decrease in IC immediately following MPH was – 370 mL at baseline and – 350 mL following 1.5 h of tiotropium for 30 days. This compares to a mean decrease in IC following constant-load ergometry of – 450 mL at both baseline and following tiotropium10 and – 410 mL vs – 490 mL.16 In the above studies, the magnitude of decrease in IC following MPH-induced DH and constant-load ergometry was similar before and after tiotropium. However, because of tiotropium induced bronchodilation and reduction in resting operational lung volumes both at rest and during exercise (increased IC), patients noted improvement in exertional dyspnea and exercise endurance.1016 These and other physiologic results171819 support the observation of improved clinical outcomes in similar COPD patients receiving long-term tiotropium.2021

Attempts have been made to find simpler and less expensive tests to objectively assess exercise limitation and response to bronchodilator therapy.2223 Marin et al22 showed that IC decreased, using a standard 6-min walk test, as with standard exercise testing among COPD patients. MPH at two times the resting breathing frequency is a simple maneuver that can be performed by almost any patient and can be done in any respiratory laboratory. If the decrease in IC following MPH is as reproducible as that following exercise,11424 it may be used as a screening surrogate for exercise-induced DH and to assess response to bronchodilators in COPD patients as in our present and previous study.1 Normal age-matched control subjects in our previous study1 did not decrease IC with exercise as do patients with COPD.117 Furthermore, since the extent of DH and decrease in IC with exercise is related to resting IC,24 hyperventilation testing should be provocative in COPD patients with moderate-to-severe expiratory airflow limitation.

The response to 180 µg of aerosolized albuterol sulfate by metered-dose inhaler was not considered an inclusion or exclusion criteria in the present study, and the mean (SD) increase in FEV1 in liters was 14 ± 12%, and only 17 of 60 COPD patients were responders according to American Thoracic Society criteria.25 In a previous study,14 16 of 29 COPD patients (55%) met the American Thoracic Society criteria25 for responders following 500 µg of aerosolized ipratropium bromide, yet there was poor correlation with exercise endurance time. Lack of response or poor reproducibility of FEV1 are among the reasons that prompted the search for other objective markers of abnormal lung function that correlate with symptoms and are responsive and reproducible in COPD patients.1214212627

If confirmed by other investigators, we suspect the decrease in IC obtained during MPH at twice the resting respiratory rate for 20 s may be used as a screening surrogate for exercise testing in the evaluation and response to DH before and after aerosolized or systemic bronchodilator in COPD patients with mild-to-severe expiratory airflow limitation. The goal of the present study was not to displace standardized cardiopulmonary testing with its inherent merits including quantification of exercise work performance, endurance time, and exertional dyspnea, but rather to simplify the detection of DH using MPH as a screening surrogate.

Acknowledgements

We thank Michelle Curry and Christy Kirkendall for providing patient coordination, and Norm Spier (Boehringer-Ingelheim Pharmaceuticals; Ridgefield, CT) for additional statistical assistance.

Footnotes

Abbreviations: DH = dynamic hyperinflation; EELV = end-expiratory lung volume; EILV = end-inspiratory lung volume; IC = inspiratory capacity; MPH = metronome-paced hyperventilation; TLC = total lung capacity

Ms. Taylor is an independent contractor.

Dr. Shinar is presently at Pharmacy Services, Orange Coast Memorial Medical Center, Fountain Valley, CA.

Continuing support was provided by Cara Cassino, MD, and Steven Kesten, MD, of Boehringer-Ingelheim Pharmaceuticals throughout this study. This study and article were conceived, developed, and completed without any input from Boehringer-Ingelheim Pharmaceuticals and Pfizer Pharmaceuticals.

This research was supported by an investigator initiated grant to Dr. Gelb and Dr. Zamel funded by Boehringer-Ingelheim Pharmaceuticals Inc, Ridgefield, CT, and Pfizer Pharmaceuticals Inc, New York, NY. The other authors have no financial conflicts of interest to declare.

Received for publication July 3, 2006. Accepted for publication November 7, 2006.

References

  1. Gelb, AF, Gutierez, AC, Weisman, AM, et al (2004) Simplified detection of dynamic hyperinflation. Chest 126,1855-1860[Abstract/Free Full Text]
  2. 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 Med 1998;158,1557-1565[Abstract/Free Full Text]
  3. Belman, MJ, Botnick, WC, Shin, JC Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153,967-975[Abstract]
  4. Dodd, DS, Brancatisano, T, Engel, LA Chest wall mechanics during exercise in patients with severe chronic airflow obstruction. Am Rev Respir Dis 1984;12,33-38
  5. O’Donnell, DE, Webb, KA Exertional breathlessness in patients with chronic airflow limitation: the role of lung hyperinflation. Am Rev Respir Dis 1993;148,1351-1357[ISI][Medline]
  6. Stubbing, DG, Pengelly, LD, Morse, JLC, et al Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. J Appl Physiol 1980;49,511-515[Abstract/Free Full Text]
  7. Duranti, R, Filipelli, M, Bianchi, R, et al Inspiratory capacity and decrease in lung hyperinflation with albuterol in COPD. Chest 2002;122,2009-2014[Abstract/Free Full Text]
  8. O’Donnell, DE, Chau, LKL, Bertley, JC, et al Qualitative aspects of exertional breathlessness in chronic airflow limitation: pathophysiologic mechanisms. Am J Respir Crit Care Med 1997;155,109-115[Abstract]
  9. Yan, S, Kaminski, D, Sliwinski, P Reliability of inspiratory capacity for estimating end-expiratory lung volume changes during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997;156,55-59[Abstract/Free Full Text]
  10. O’Donnell, DE, Fluge, T, Gerken, F, et al Effects of tiotropium on lung hyperinflation, dyspnoea, and exercise tolerance in COPD. Eur Respir J 2004;23,832-840[Abstract/Free Full Text]
  11. Fabbri, LM, Hurd, SS, for the GOLD Scientific Committee.. Global strategy for the diagnosis, management and prevention of COPD: 2003 update. Eur Respir J 2003;22,1-2[Free Full Text]
  12. Gelb, AF, Zamel, N Pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med 2000;162,1778-1782[Abstract/Free Full Text]
  13. Henke, KG, Sharratt, M, Pegelow, D, et al Regulation of end-expiratory lung volume during exercise. J Appl Physiol 1988;64,135-146[Abstract/Free Full Text]
  14. Hamilton, AL, Killian, KJ, Summers, E, et al Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 1995;152,2021-2031[Abstract]
  15. 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 Med 1999;160,542-549[Abstract/Free Full Text]
  16. Maltais, F, Hamilton, A, Marciniuk, D, et al Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Chest 2005;128,1168-1178[Abstract/Free Full Text]
  17. Casaburi, R, Conoscenti, CS Lung function improvement with once-daily tiotropium. Am J Med 2004;117(Suppl 12A),33s-40s
  18. Van Noord, JA, Aumann, JL, Janssens, E, et al Effect of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with chronic obstructive pulmonary disease. Chest 2006;129,509-517[Abstract/Free Full Text]
  19. Celli, B, ZuWallack, R, Wang, S, et al Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased lung volumes. Chest 2003;124,1743-1748[Abstract/Free Full Text]
  20. Niewoehner, DE, Rice, K, Cote, C, et al Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med 2005;143,317-326[Abstract/Free Full Text]
  21. Calverly, PM Reducing the frequency and severity of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2004;1,121-124[Abstract/Free Full Text]
  22. Marin, JM, Carrizo, SJ, Gascon, M, et al Inspiratory capacity, dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute walk test with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163,1395-1399[Abstract/Free Full Text]
  23. 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 Med 2000;162,216-220[Abstract/Free Full Text]
  24. O’Donnell, DE, Revill, SM, Webb, KA Dynamic hyperventilation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;154,770-774
  25. American Thoracic Society.. Lung function testing: selection of reference values and interpretative strategies. Am J Respir Crit Care Med 1991;144,1202-1218
  26. Guyatt, GH, Townsend, M, Nogradi, S, et al Acute response to bronchodilator: an imperfect guide for bronchodilator therapy in chronic airflow limitation. Arch Intern Med 1988;148,1949-1952[Abstract]
  27. Hatipoglu, U, Laghi, F, Tobin, MJ Does inhaled albuterol improve diaphragmatic contractility in patients with chronic obstructive pulmonary disease? Am J Respir Crit Care Med 1999;160,1916-1921[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gelb, A. F.
Right arrow Articles by Zamel, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gelb, A. F.
Right arrow Articles by Zamel, N.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS