Hyperinflation, Dyspnea, and Exercise Intolerance in
Chronic Obstructive Pulmonary Disease
Denis E. O’Donnell
Department of Medicine, Queen’s University, Kingston, Ontario, Canada
Expiratory flow limitation is the pathophysiologic hallmark of
chronic obstructive pulmonary disease (COPD), but dyspnea
(breathlessness) is its most prominent and distressing symptom.
Acute dynamic lung hyperinflation, which refers to the temporary
increase in operating lung volumes above their resting value, is a
key mechanistic consequence of expiratory flow limitation, and has
serious mechanical and sensory repercussions. It is associated with
excessive loading and functional weakness of inspiratory muscles,
and with restriction of normal VT expansion during exercise. There
is a strong correlation between the intensity of dyspnea at a standardized point during exercise, the end-expiratory lung volume,
and the increased ratio of inspiratory effort to volume displacement
(i.e., esophageal pressure relative to maximum: VT as a % of predicted VC). This increased effort–displacement ratio in COPD
crudely reflects the neuromechanical dissociation of the respiratory
system that arises as a result of hyperinflation. The corollary of this
is that any intervention that reduces end-expiratory lung volume
will improve effort–displacement ratios and alleviate dyspnea. In
flow-limited patients, bronchodilators act by improving dynamic
airway function, thus enhancing lung emptying and reducing lung
hyperinflation. Long-acting bronchodilators have recently been
shown to reduce hyperinflation during both rest and exercise in
moderate to severe COPD. This lung deflation allows greater VT
expansion for a given inspiratory effort during exercise with consequent improvement in dyspnea and exercise endurance.
Keywords: chronic pulmonary obstructive disease; fatigue; respiratory
mechanics; work of breathing
The pathophysiologic hallmark of chronic obstructive pulmonary disease (COPD) is expiratory flow limitation, whereas the
most common symptom is dyspnea (the perception of respiratory
discomfort). Expiratory flow limitation arises because of the
combined effects of reduced elastic lung recoil and increased
airways resistance. Dyspnea is the primary symptom limiting exercise in patients with more advanced disease, and often leads to
avoidance of activity, with consequent skeletal muscle deconditioning. The relationship between the physiologic impairment—as
traditionally measured by FEV1—and the characteristic symptom
of COPD, however, is not straightforward. In this review, the
evidence that lung hyperinflation provides a mechanistic link
between expiratory flow limitation and dyspnea is examined,
with a view to explaining how bronchodilators relieve symptoms.
NEGATIVE CONSEQUENCES OF
DYNAMIC HYPERINFLATION
Lung hyperinflation, defined as an abnormal increase in the
volume of air remaining in the lungs at the end of spontaneous
(Received in original form August 22, 2005; accepted in final form September 19, 2005)
Correspondence and requests for reprints should be addressed to Denis
E. O’Donnell, M.D., F.R.C.P.(I), F.R.C.P.(C), Division of Respiratory and Critical
Care Medicine, Respiratory Investigation Unit, Department of Medicine, Queen’s
University, 102 Stuart Street, Kingston, ON, K7L 2V6 Canada. E-mail: odonnell@
post.queensu.ca
Proc Am Thorac Soc Vol 3. pp 180–184, 2006
DOI: 10.1513/pats.200508-093DO
Internet address: www.atsjournals.org
expiration, is present in COPD because of the effects of increased
lung compliance as a result of the permanently destructive
changes of emphysema and expiratory flow limitation. Although
there are no formal epidemiologic studies, clinical experience
suggests that hyperinflation develops slowly and insidiously over
many years, similar to the decline in FEV1. Consequently, patients may not perceive the negative results of hyperinflation
until the disease is quite advanced, mainly because the respiratory system adapts to the mechanical disadvantages caused by
hyperinflation. For instance, the chest wall reconfigures to accommodate the over-distended lungs, and the diaphragm partially preserves its ability to generate pressure during resting
breathing despite its shortened operating length (1–3). However,
these compensatory mechanisms quickly become overwhelmed
when ventilation rate is acutely increased, for example, during
exercise. A patient with severe COPD, faced with a flight of
stairs, may only be able to climb four or five steps before experiencing intolerable dyspnea and has to stop.
As expected, the relationship between dyspnea intensity
(measured using the modified Borg scale) and V̇o2 (a measure
of oxygen demand) during a symptom-limited incremental cycle
ergometry test is notably different between patients with COPD
and normal subjects (Figure 1) (4). We, and others, have shown
that patients with COPD started to experience dyspnea at a much
lower V̇o2 than healthy subjects. Furthermore, they experienced
severe dyspnea (Borg score, ⭓ 5) and had to stop exercising at a
much lower peak symptom-limited V̇o2 than did healthy subjects,
who, in comparison, had not yet attained noticeable levels of
respiratory difficulty (Borg score, ⬍ 0.5).
This difference in the sensory experience of exertional dyspnea in patients with COPD compared with normal subjects is
accompanied by changes in ventilatory mechanics. Compared
with normal subjects, patients with COPD have a heightened
ventilatory response to exercise (Figure 2), reflecting greater
ventilation–perfusion abnormalities (high fixed physiologic
deadspace). In general, the breathing pattern in COPD is more
rapid and shallow at any given ventilation compared with the
breathing pattern in health (Figure 3) (4).
In healthy subjects, end-expiratory lung volume (EELV) and
inspiratory capacity (IC) are maintained throughout exercise.
During exercise, both the rate and depth (Vt) of respiration are
normally increased to accommodate the increased metabolic
demand. In COPD, the rate of lung emptying, which is dictated
by the product of compliance and resistance (i.e., time constant),
is often substantially delayed. In many patients, the expiratory
time available during spontaneous resting breathing is insufficient to allow EELV to decrease to its relaxation volume, resulting in lung overinflation. This situation is aggravated further
as expiratory time shortens during exercise, resulting in further
increases in EELV. This phenomenon has been termed “air
trapping,” or dynamic hyperinflation, and refers to the temporary and variable increase in EELV above its baseline value.
During exercise, the change in EELV (from rest to peak) in a
large population averaged 0.4 L, with considerable variation in
the range (5). Changes in EELV are reflected by changes in IC,
as total lung capacity (TLC) remains unchanged during exercise.
O’Donnell: Mechanisms of Exercise Intolerance
Figure 1. Relationship between dyspnea intensity (measured using the
modified Borg scale) and V̇O2 during a symptom-limited incremental
cycle ergometry test in patients with chronic airflow limitation (CAL;
closed circles) and in normal subjects (open circles). Patients with CAL
experienced severe dyspnea (Borg score, ⭓ 5) and had to stop exercising
at a much lower V̇O2 than normal subjects, who, in comparison, had not
yet attained noticeable levels of respiratory difficulty (Borg score, ⬍ 0.5).
*p ⫽ 0.001, significantly steeper slope in patients with CAL compared
with normal subjects. Reprinted by permission from Reference 4.
Although Vt is comparable between groups at rest, it comprises a larger proportion of IC in patients with COPD compared
with normal subjects. Because of hyperinflation during the increased demands of exercise, Vt can only increase marginally in
patients with COPD, and reaches a plateau (Figures 3 and 4). At
this point, further increases in ventilation can only be achieved by
increasing breathing frequency, which unfortunately rebounds to
cause greater hyperinflation in a vicious cycle.
In addition, hyperinflation markedly increases the tidal inspiratory pressure or effort (expressed as a percentage of maximal
inspiratory pressure [Pimax]) required to generate an increase in
Vt (expressed as a percentage of the VC) in patients with COPD
compared with normal subjects (Figure 4) (4). This is because the
relationship between pleural pressure and lung volume during a
static maneuver from TLC to residual volume (RV) is sigmoidal
rather than linear (Figure 5). In healthy subjects, breathing at
rest and during exercise takes part in the central linear portion
of the pressure–volume relationship, which means that relatively
Figure 2. Relationship between ventilation and oxygen demand (V̇O2)
during a symptom-limited incremental cycle ergometry test in patients
with CAL (closed circles) and in normal subjects (open circles). Patients with
CAL had a heightened ventilatory response to oxygen demand compared
with normal subjects. MVC ⫽ maximal ventilatory capacity. Reprinted by
permission from Reference 4.
181
Figure 3. Relationship between breathing frequency and VT (expressed
as a percentage of the VC) during a symptom-limited incremental cycle
ergometry test in patients with CAL (closed circles) and in normal subjects
(open circles). Although VT was comparable between groups at rest, it
only increased marginally during exercise in patients with CAL until it
reached a plateau. In contrast, during exercise in normal subjects, both
breathing frequency and VT increased to accommodate the increased
ventilatory demand. Reprinted by permission from Reference 4.
small changes in tidal pressure will produce comparatively large
changes in Vt. In younger individuals, EELV actually declines
(IC increases) as expiratory muscles are recruited during exercise, thus conveying a distinct mechanical advantage (Figure 5).
In COPD, Vt must “cycle” close to the TLC on the steep portion
of the pressure–volume curve, where higher pressures are required for any given volume expansion. At end-expiration in
health, the chest wall recoil is outwardly directed and, therefore,
assists the inspiratory muscles in thoracic displacement. When
Vt is positioned close to TLC in COPD, the inspiratory muscles
must contend with the increased lung elastic recoil pressure at
end-expiration. In addition, at end-expiration, the chest wall, in
contrast to health, is inwardly directed in an expiratory direction,
opposing the action of the inspiratory muscles. Combined inward
recoil of the lung and chest wall at end-expiration essentially
leads to an inspiratory threshold load on the inspiratory muscles,
which must be overcome before respired flow is reversed. This
threshold load can be substantial during exercise in COPD. Consequently, increasingly higher fractional tidal inspiratory pressures
Figure 4. Ratio of VT to inspiratory effort during a symptom-limited
incremental cycle ergometry test in patients with chronic obstructive
pulmonary disease (COPD; closed circles) and in normal subjects (open
circles). The tidal pressure or effort (expressed as a percentage of maximal
inspiratory pressure [PImax]) required to generate an increase in VT (expressed as a percentage of the predicted VC) is markedly increased in
patients with COPD compared with normal subjects. Data adapted from
Reference 4.
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PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY
VOL 3 2006
Figure 6. Correlations between dynamic hyperinflation (end-expiratory
lung volume [EELV]/total lung capacity [TLC]), neuromechanical dissociation (esophageal pressure[Pes]/PImax:VT/VC ratio) and dyspnea (Borg
score), at a standardized time during exercise in patients with COPD.
Borg score at a standardized V̇O2 during a symptom-limited incremental
cycle ergometry test was strongly correlated with the Pes/PImax:VT/VC ratio
(r ⫽ 0.86, p ⬍ 0.001) and EELV/TLC (r ⫽ 0.69, p ⬍ 0.001). The Pes/
PImax:VT/VC ratio was also strongly related to EELV/TLC at a standardized
V̇O2 (r ⫽ 0.78, p ⬍ 0.001).
Figure 5. The static sigmoidal pressure–volume relationship of the respiratory system is shown in healthy subjects (A ) and in patients with
COPD (B ). Superimposed are the tidal pressure–volume loops at rest
(smaller loops) and during exercise (larger loops). In normal subjects,
breathing at rest and during exercise (as inspiratory capacity [IC] increases) takes part in the central linear portion of the pressure–volume
relationship, which means that relatively small changes in tidal pressure
will produce comparatively large changes in VT. In patients with COPD,
however, as IC declines during exercise, VT “cycles” at the upper nonlinear extreme of the pressure–volume relationship. This means that increasingly high tidal pressures must be generated for any given VT
expansion.
(or effort) must be generated for any given Vt expansion.
Breathing at the upper part of the pressure–volume curve weakens the inspiratory muscles, which are not designed to function
near TLC, and undoubtedly contributes to both the intensity
and the quality of dyspnea.
RELATIONSHIP BETWEEN NEUROMECHANICAL
DISSOCIATION AND DYSPNEA
Dyspnea includes a number of qualitatively distinct sensations
that vary in intensity, and differ between patients with COPD
and healthy subjects. In a study designed to compare the qualitative aspects of dyspnea in patients with COPD and age-matched
healthy subjects, study participants were asked to perform a
symptom-limiting exercise test and then describe their sensation
of dyspnea using qualitative descriptors (4). Both healthy subjects and patients with COPD chose descriptors of “increased
work/effort” and “heaviness” of breathing; however, only patients with COPD consistently chose descriptors denoting
“unsatisfied inspiratory effort” (i.e., “can’t get enough air in”),
“inspiratory difficulty,” and “shallow breathing.”
The distinctive qualitative sensations of dyspnea in patients
with COPD suggest that they receive altered peripheral sensory
afferent information from multiple mechanoreceptors in the ventilatory muscles, chest wall, lung, and airways, which indicates
to them that the mechanical response of the ventilatory system
is insufficient or inappropriate for the effort expended. The sense
of heightened effort is believed to be conveyed via corollary
discharge relayed from the motor cortex to the sensory cortex
in the forebrain. In normal subjects, both at rest and during
exercise, there is a harmonious matching of effort to ventilatory
output. This is because Vt is positioned on the linear part of
the pressure–volume curve (Figures 4 and 5).
In health, inspiratory effort increases as ventilation rises during exercise, but the perception of unsatisfied effort is rarely
reported. In contrast, in patients with COPD, there is increasing
disparity between effort and ventilatory output (or neuromechanical dissociation) as exercise progresses, because Vt is positioned in the extreme upper nonlinear part of the pressure–
volume curve due to dynamic hyperinflation. Although patients
with COPD try to meet ventilatory demand by increasing breathing frequency, Vt expansion is constrained by the progressive
encroachment of EELV from below and the finite TLC from
above. Therefore, they experience intolerable dyspnea very
quickly during exercise, as there is “no room to breathe.” This
so-called “intolerable dyspnea threshold” seems to be at the level
at which the inspiratory reserve volume (i.e., the difference between TLC and EELV) approaches less than 500 ml (Figures 4
and 5) (6).
Increased neural drive has previously been linked to the perception of dyspnea, both in asthma and in COPD (7–9). Accumulating evidence suggests that neuromechanical dissociation due
to dynamic hyperinflation is the basis for the inspiratory difficulties experienced by patients with COPD during exercise. For
instance, Borg score at a standardized V̇o2 during a symptomlimited incremental cycle ergometry test is strongly correlated
with pressure/Pimax:Vt/VC ratio (r ⫽ 0.86, p ⬍ 0.001) and EELV/
TLC (r ⫽ 0.69, p ⬍ 0.001; Figure 6) (4). The pressure/Pimax:Vt/
VC ratio is also strongly related to EELV/TLC at a standardized
V̇o2 (r ⫽ 0.78, p ⬍ 0.001). These correlations have been confirmed in further studies (5, 10–12). The corollary of these associations is that an improved ability to expand Vt (due to a reduction in EELV) for a given muscular effort should ameliorate
dyspnea.
RELIEVING DYSPNEA WITH BRONCHODILATORS
A number of strategies have been shown to reduce hyperinflation
in patients with COPD. As mentioned previously, in flow-limited
O’Donnell: Mechanisms of Exercise Intolerance
patients with COPD, the extent of dynamic hyperinflation depends on the prevailing level of ventilation. Therefore, interventions, such as oxygen therapy and exercise rehabilitation, which
reduce ventilatory demand, may also reduce the rate of air trapping and dynamic hyperinflation (see article by Casaburi and
Porszasz in this issue, pp. 185–189) (13–15). Breathing techniques, such as pursed-lip breathing (16), also help to deflate
the lungs. Lung volume reduction surgery is another obvious
approach to reducing hyperinflation (17, 18). In addition, continuous positive airway pressure and noninvasive pressure support
may counteract the negative effects of hyperinflation on the
inspiratory muscles (19, 20). The scope of this review, however,
is limited to the role of bronchodilators in reducing air trapping
and hyperinflation.
Bronchodilators work by improving dynamic airway function,
allowing improved lung emptying with each breath. Therefore,
the time constant for lung emptying is shortened because airways
resistance is diminished. This permits the patient to achieve the
required alveolar ventilation during rest and exercise at a lower
operating lung volume and, thus, at a lower oxygen cost of
breathing. In other words, Vt is positioned at a lower operating
lung volume (i.e., EELV is decreased and IC is increased). By
deflating the lungs, bronchodilators effectively improve ventilatory muscle performance through greater Vt expansion. Exercise
can proceed for a longer duration before the mechanical limitation to ventilation (i.e., critically low inspiratory reserve volume)
is reached.
What effect do these improvements in lung mechanics have
on dyspnea? We conducted a mechanistic crossover study in 23
patients, in which exertional dyspnea was measured using the
modified Borg scale during a constant work-rate cycle ergometry
test at 75% of maximal work capacity after a 2-wk treatment
with the long-acting ␤2-agonist salmeterol (50 ␮g) or placebo
(6). Dyspnea intensity at the point of symptom limitation was not
different between groups (somewhat severe to severe); however,
patients in the salmeterol group exercised for longer before
reaching the same degree of dyspnea as patients in the placebo
group. The reason for this improvement was that, at rest, as well
as throughout exercise, IC was significantly greater and EELV
was significantly reduced in the salmeterol group versus the
placebo group. This reduction in hyperinflation permitted patients taking salmeterol to significantly increase Vt throughout
exercise compared with those on placebo. The increased ability
to expand Vt after bronchodilators correlated closely with improved dyspnea ratings at a standardized time during exercise.
In a recent mechanical study on the effects of the long-acting
anticholinergic tiotropium (21), relief of exertional dyspnea was
closely associated with the improvement in the ratio of expiratory effort to Vt, thus supporting the notion that neuromechanical coupling, as a result of dynamic hyperinflation, forms the
basis (at least in part) for the quality and intensity of dyspnea
during exercise in COPD.
Accumulating evidence suggests that sustained pharmacologic
lung volume reduction with modern-day pharmacotherapy translates into improvements in dyspnea relief and exercise tolerance,
as shown in larger-scale clinical trials. For example, a 4-wk treatment with tiotropium has been shown to significantly reduce trough
(predose) FRC (a measure of lung hyperinflation) by 0.5 L and
peak (postdose) FRC by 0.7 L compared with placebo in 81
patients with severe COPD (22).
Recently, the effects of tiotropium (18 ␮g once daily) versus
placebo on measures of exercise tolerance were compared in
187 patients with severe COPD (23). The results of this 6-wk
study showed that tiotropium provided a significant and sustained reduction in air trapping at rest and during exercise, which
allowed for greater Vt expansion during exercise. The effects of
183
these improvements in lung volume were reflected by significant
increases in exercise tolerance. Furthermore, these improvements in air trapping and exercise tolerance were associated
with reductions in exertional dyspnea. At a standardized time
point during exercise, for example, Borg dyspnea scores were
significantly reduced from baseline in the tiotropium group compared with the placebo group. This allowed patients in the tiotropium group to exercise for longer before their dyspnea became intolerable. These results have been confirmed in a further
study (24). The results from these studies on the effects of longacting bronchodilators support the hypothesis that lung hyperinflation, dyspnea, and exercise intolerance are closely linked in
COPD.
CONCLUSIONS
Although expiratory flow limitation is the pathophysiologic hallmark of COPD, the main consequence of this is lung hyperinflation. During activity, acute-on-chronic hyperinflation has serious
sensory and mechanical consequences. This dynamic hyperinflation likely contributes to both the intensity and the distinct
qualitative sensations of dyspnea, particularly the distressing
feeling of unsatisfied inspiration. Bronchodilator therapy relieves dyspnea by deflating the lungs, which reduces the elastic
load on the inspiratory muscles. This, together with the reduction
of resistive work, improves the functional performance of the
inspiratory muscles. The attendant increased ability to expand
Vt contributes to enhanced neuromechanical coupling of the
respiratory system. Sustained pharmacologic volume deflation
has the potential to impact positively on the important patientcentered outcomes of dyspnea and activity limitation in the long
term.
Conflict of Interest Statement : D.E.O. acted as principal investigator for two multinational trials. Queen’s University received $376,137 between 2001 and 2004
for these. An additional single-site, mechanistic study with Dr. O’Donnell (principal
investigator) was financed to the amount of $83,260, which was received by
Research Services, Queen’s University, Kingston, Ontario, Canada.
References
1. Gorman RB, McKenzie DK, Pride NB, Tolman JF, Gandevia SC. Diaphragm length during tidal breathing in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:1461–
1469.
2. Similowski T, Yan S, Gauthier AP, Macklem PT, Bellemare F. Contractile properties of the human diaphragm during chronic hyperinflation.
N Engl J Med 1991;325:917–923.
3. Cassart M, Pettiaux N, Gevenois PA, Paiva M, Estenne M. Effect of
chronic hyperinflation on diaphragm length and surface area. Am J
Respir Crit Care Med 1997;156:504–508.
4. O’Donnell DE, Bertley JC, Chau LK, Webb KA. Qualitative aspects of
exertional breathlessness in chronic airflow limitation: pathophysiologic mechanisms. Am J Respir Crit Care Med 1997;155:109–115.
5. O’Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in COPD. Am J Respir Crit Care Med 2001;164:770–
777.
6. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol
on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24:86–94.
7. Bellofiore S, Ricciardolo FL, Ciancio N, Sapienza MA, Patane A,
Mistretta A, Di Maria GU. Changes in respiratory drive account for
the magnitude of dyspnoea during bronchoconstriction in asthmatics.
Eur Respir J 1996;9:1155–1159.
8. Burki NK. Breathlessness and mouth occlusion pressure in patients with
chronic obstruction of the airways. Chest 1979;76:527–531.
9. Lahrmann H, Wild M, Wanke T, Tschernko E, Wisser W, Klepetko W,
Zwick N. Neural drive to the diaphragm after lung volume reduction
surgery. Chest 1999;116:1593–1600.
10. Martinez FJ, de Oca MM, Whyte RI, Stetz J, Gay SE, Celli BR. Lungvolume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 1997;155:1984–
1990.
184
11. Di Marco F, Milic-Emili J, Boveri B, Carlucci P, Santus P, Casanova F,
Cazzola M, Centanni S. Effect of inhaled bronchodilators on inspiratory capacity and dyspnoea at rest in COPD. Eur Respir J 2003;21:
86–94.
12. Man WD, Mustfa N, Nikoletou D, Kaul S, Hart N, Rafferty GF,
Donaldson N, Polkey MI, Moxham J. Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD. Thorax
2004;59:471–476.
13. O’Donnell DE, Bain DJ, Webb KA. Factors contributing to relief of
exertional breathlessness during hyperoxia in chronic airflow limitation. Am J Respir Crit Care Med 1997;155:530–535.
14. O’Donnell DE, D’Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:892–898.
15. Somfay A, Porszasz J, Lee SM, Casaburi R. Dose-response effect of
oxygen on hyperinflation and exercise endurance in nonhypoxaemic
COPD patients. Eur Respir J 2001;18:77–84.
16. Bianchi R, Gigliotti F, Romagnoli I, Lanini B, Castellani C, Grazzini M,
Scano G. Chest wall kinematics and breathlessness during pursed-lip
breathing in patients with COPD. Chest 2004;125:459–465.
17. Ciccone AM, Meyers BF, Guthrie TJ, Davis GE, Yusen RD, Lefrak SS,
Patterson GA, Cooper JD. Long-term outcome of bilateral lung volume reduction in 250 consecutive patients with emphysema. J Thorac
Cardiovasc Surg 2003;125:513–525.
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY
VOL 3 2006
18. Ingenito EP, Loring SH, Moy ML, Mentzer SJ, Swanson SJ, Reilly JJ.
Physiological characterization of variability in response to lung volume
reduction surgery. J Appl Physiol 2003;94:20–30.
19. O’Donnell DE, Sanii R, Younes M. Improvement in exercise endurance
in patients with chronic airflow limitation using CPAP. Am Rev Respir
Dis 1988;138:1510–1514.
20. Keilty SE, Ponte J, Fleming TA, Moxham J. Effect of inspiratory pressure
support on exercise tolerance and breathlessness in patients with
severe stable chronic obstructive pulmonary disease. Thorax 1994;
49:990–994.
21. O’Donnell DE, Webb KA. The effects of tiotropium on ventilatory
mechanics during exercise in COPD. Am J Respir Crit Care Med 2005;
2:A494.
22. Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients
with increased static lung volumes. Chest 2003;124:1743–1748.
23. O’Donnell DE, Flüge T, Gerken F, Hamilton A, Webb K, Aguilaniu B,
Make B, Magnussen H. Effects of tiotropium on lung hyperinflation,
dyspnea and exercise tolerance in patients with COPD. Eur Respir J
2004;23:832–840.
24. Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba F, Richter K,
Kesten S, O’Donnell DE. Improvements in symptom-limited exercise
performance over eight hours with once-daily tiotropium in patients
with COPD. Chest 2005;128:1168–1178.