(Chest. 2000;117:42S-47S.)
© 2000
American College of Chest Physicians
Assessment of Bronchodilator Efficacy in Symptomatic COPD*
Is Spirometry Useful?
Denis E. O’Donnell, MD, FCCP
*
From the Respiratory Investigation Unit, Department of Medicine, Queen’s University, Kingston, Ontario, Canada.
Correspondence to: Denis E. O’Donnell MD, FCCP, Richardson House, 102 Stuart St, Kingston, Ontario, Canada K7L 2V6; e-mail: odonnell{at}post.queensu.ca
 |
Abstract
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Bronchodilator therapy in COPD is deemed successful if it improves
ventilatory mechanics to a degree where effective symptom alleviation
and increased exercise capacity are achieved. A greater understanding
of the pathophysiologic mechanisms of dyspnea and exercise intolerance
in COPD has prompted a reevaluation of the manner in which we currently
assess therapeutic efficacy. The traditional reliance on an improved
postbronchodilator FEV1 as indicative of a positive
clinical response has recognized limitations. To the extent that
pharmacologic volume reduction is a desirable therapeutic goal with
favorable implications for dyspnea relief and increased exercise
tolerance, the potential value of bronchodilator-induced changes in
lung volume measurements is currently being studied. It is unlikely,
however, given the multifactorial nature of dyspnea and exercise
limitation in COPD, that resting spirometric measurements of maximal
flows and volumes alone will be sufficiently sensitive to adequately
predict a positive clinical response to bronchodilator therapy. Thus,
additional direct measurements of exercise dynamic hyperinflation and
exercise endurance together with reliable subjective measurements of
dyspnea and quality of life are recommended in the setting of a
suitable placebo-controlled design.
Key Words: bronchodilators • COPD • dyspnea • exercise • inspiratory capacity • lung hyperinflation • spirometry
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Introduction
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In
patients with symptomatic COPD, desirable therapeutic goals include
improvement of ventilatory mechanics, alleviation of dyspnea, increased
activity levels, and improved quality of life. Studies designed to
evaluate the efficacy of interventions, such as bronchodilator therapy,
increasingly incorporate these important clinical outcomes.
Traditionally, the primary outcome measure for clinical trials has been
the measurement of FEV1. The recognition that
meaningful improvements in symptoms, exercise capacity, and quality of
life can occur in the presence of minimal changes in
FEV1 has prompted the search for better
evaluative methods.
Recent studies have provided greater appreciation that symptomatic
benefit in COPD patients with lung hyperinflation is clearly linked to
effective pharmacologic volume reduction. In this review, we will
briefly discuss the mechanical abnormalities of advanced COPD, the
mechanisms of dyspnea and exercise intolerance, and the means by which
bronchodilator therapy can favorably affect each of these variables.
Specifically, we will review the role of spirometry in evaluating
therapeutic responses in advanced COPD, and consider the potential
value of broadening existing bronchodilator "responsiveness"
criteria to include spirometric lung volumes.
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Nature of the Mechanical Abnormalities in COPD
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In COPD, the most obvious pathophysiologic abnormality is
expiratory flow limitation; however, the main consequence of this is a
restrictive mechanical deficit as a result of lung hyperinflation
because of air trapping (Fig 1)
.1
Although breathing at a high lung volume optimizes
tidal expiratory flow generation, it results in serious negative
mechanical and sensory consequences. The deleterious effects of resting
hyperinflation are amplified during exercise when increased ventilatory
demands (and reduced expiratory timing) result in further air trapping,
dynamic hyperinflation (DH), and increased mechanical
restriction.1
Thus, the inspiratory capacity (IC) that
indirectly reflects the end-expiratory lung volume (EELV), and which is
already diminished at rest in COPD, progressively decreases further
during exercise as dynamic EELV increases (Fig 1)
.2
3
4
The
inability to expand tidal volume (VT) appropriately in
response to increasing respiratory drive results in greater reliance on
increasing breathing frequency to increase ventilation; the resultant
tachypnea, however, further increases DH in a vicious
cycle.1
As IC diminishes during exercise (Fig 2)
,
VT and end-inspiratory lung volume become positioned
closer to total lung capacity (TLC) and the upper alinear extreme of
the respiratory systems pressure-volume relationship, where there is
increased elastic loading. The greater the dynamic EELV is relative to
passive functional residual capacity, the greater the inspiratory
threshold load on the inspiratory muscles. This hidden load
(ie, auto-positive end-expiratory pressure,
intrinsic-positive end-expiratory pressure) can be substantial,
particularly in the setting of severe DH during exercise. DH also
compromises the ability of the inspiratory muscles to generate pressure
and results in dynamic functional muscle weakness and altered patterns
of ventilatory muscle recruitment. It follows that during exercise,
tidal inspiratory pressure excursions represent a much higher fraction
of their maximal force-generating capacity in COPD than in health (Fig 2)
.5
The net mechanical effect of DH is that there is a
marked disparity between the level of inspiratory effort (which
approaches maximum) and the actual mechanical response of the
respiratory system (which is greatly diminished; ie, reduced
VT response and diminished thoracic displacement;
Fig 2
).5
The coexistence of higher ventilatory demands
during exercise in COPD (as a result of high physiologic dead space,
metabolic acidosis, or hypoxemia) results in worsening expiratory flow
limitation with consequent mechanical restriction, (ie,
end-inspiratory lung volume/TLC ratio > 90%), earlier attainment of
ventilatory limitation, and intolerable dyspnea at relatively low
exercise work rates (Fig 1)
.5
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Figure 1. Comparison of maximal and tidal flow-volume loops
in a healthy subject and a patient with COPD, at rest and at a
standardized exercise level (oxygen consumption 30% predicted max).
Volume compartments of the VC are also depicted at rest and at a
standardized exercise level. In normal subjects, minimal expiratory
flow limitation is evident during exercise, there is no ventilatory
limitation, and IC increases during exercise. By contrast, expiratory
flow limitation is evident at rest in COPD, with dynamic lung
hyperinflation as evidenced by the reduced IC during exercise. IC =
inspiratory capacity; RV=residual volume.
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Figure 2. Comparison of (top left, A)
operational lung volumes; (top right, B) inspiratory
effort relative to maximum; (bottom left, C) the ratio
of effort (Pes/maximal inspiratory pressure) to VT (%
predicted VC), ie, an index of neuromechanical
dissociation; and (bottom right, D) exertional dyspnea,
each expressed as a function of ventilation during exercise in normal
subjects and COPD patients. Note that in COPD, despite increased
inspiratory effort, the VT response is seriously
constrained, in part because of dynamic hyperinflation, with severe
encroachment on the IRV at low ventilation levels (top left,
A, and top right, B). The relationship between
effort and VT is constant throughout exercise in health but
increased markedly in COPD, partly as a result of dynamic
hyperinflation and mechanical restriction. The increased dyspnea at any
given ventilation in COPD (bottom right, D) is explained
in part by this high ratio, which is an index of neuromechanical
dissociation of the respiratory system. Reprinted with permission from
O’Donnell et al.5
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Lung Hyperventilation and Dyspnea
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The intensity of exertional dyspnea in COPD has been shown to
correlate well with the level of acute DH during exercise and also with
the increased disparity between effort and volume displacement
(ie, Pes/maximal inspiratory pressure:
VT/% predicted vital capacity [VC]; Fig 2
).4
5
This disparity is a consequence of DH and
ultimately reflects neuromechanical dissociation of the ventilatory
pump. It follows that interventions that successfully reduce
hyperinflation should enhance neuromechanical coupling, and improve
dyspnea and exercise tolerance (see below).
Chrystyn et al6
demonstrated an association between
improved exercise endurance following increasing
theophylline therapy (in a dose-response manner), and
reduced plethysmographic thoracic gas volume. Belman et
al,7
in an elegant mechanical study, have shown that
exertional dyspnea relief following salbutamol therapy in COPD
correlated well with a reduction in operational lung volumes during
exercise, which, in turn, was related to enhanced neuroventilatory
coupling (ie, improved effort-displacement ratio).
O’Donnell et al8
have recently reported similar findings
in response to acute high-dose anticholinergic therapy in advanced
COPD. In this study of 29 patients
(FEV1 = 40 ± 2% predicted), dyspnea relief
correlated best with reduced dynamic EELV (ie, increased IC)
at submaximal levels of exercise. Moreover, improved exercise endurance
after anticholinergic therapy was explained by the reduced
dyspnea and reduced operational lung volumes. Recently, dyspnea relief
following surgical volume reduction in COPD has also been shown to
correlate well with reduced dynamic EELV (ie, increased IC),
and enhanced neuromechanical coupling of the
diaphragm.9
10
11
These studies collectively point to the
importance of DH in dyspnea causation and exercise intolerance in COPD.
It follows that systematic assessment of the therapeutic efficacy of
bronchodilator therapy should ideally include measurements of DH
(ie, IC at a standardized work rate), endurance time (for
example, at a constant load of 75% of the predetermined maximal work
rate), and dyspnea (measured by Borg or visual analog scales).
Measurements of these three variables during constant load submaximal
cycle exercise in advanced COPD have recently been shown to be
reliable, being both reproducible and responsive.8
However, this comprehensive therapeutic assessment of bronchodilator
efficacy may be unrealistic for many clinicians managing COPD. The
question arises, therefore, whether spirometry alone, which includes
resting lung volumes, provides sufficient information to predict a
positive clinical response.
The Role of Spirometry in Therapeutic Evaluation
Bronchodilator reversibility criteria have traditionally been
based on changes in the FEV1. Thus, acceptable
minimum spirometric improvements by American Thoracic Society
criteria,12
(increase in FEV1 by
12%, and at least 0.2 L), or by European Respiratory Society
criteria13
(increase by 10% predicted) are more likely to
indicate actual reversible airway obstruction than random variation of
the measurement. The FEV1 is a simple, reliable
measurement that is of unquestionable diagnostic utility and allows an
accurate assessment of disease progression. However, the
FEV1 correlates only weakly with exercise
capacity and dyspnea,14
15
16
17
and the change in
FEV1 following bronchodilator therapy is poorly
predictive of improved symptoms and exercise endurance in advanced
COPD.18
19
20
In COPD of moderate severity, change in
FEV1 is possibly a better predictor of exercise
performance after bronchodilators than in severe disease, but
considerable intersubject variability remains.21
The
FEV1 gives no information about the extent of
expiratory flow limitation, the shape of the maximal expiratory flow
curve over the operating VT range, or the extent of resting
hyperinflation required to maximize tidal expiratory flow rates. All of
these parameters are relevant with respect to dyspnea causation and
exercise limitation in COPD. Each can vary greatly for a given
FEV1.16
Furthermore, resting maximal
spirometric tests, which are prone to measurement artifact (volume
history and gas compression effects) give little information about
dynamic airway function and the attendant mechanical abnormalities
during exercise.
The pattern of spirometric response to bronchodilators varies greatly
between patients with COPD and may depend in some instances on the dose
and type of bronchodilator agent used. Some patients show increases in
both FEV1 and FVC, others show changes in each of
FEV1 or FVC alone, and a minority do not show
changes in either.20
In many patients, changes in
FEV1 after bronchodilators simply reflect lung
volume recruitment (ie, FEV1/FVC ratio
does not change).20
22
As with the FEV1, improvement in FVC after
bronchodilator therapy, which generally reflects a reduction in
residual volume, is poorly predictive of improved dyspnea and exercise
tolerance.20
This, in part, reflects the variability of
this measurement, especially if the time of exhalation is not
standardized. Slow VC or timed VC may be more reproducible and
responsive than the FVC and may correlate better with improved clinical
outcomes,22
but this requires further study. Similarly, it
is not known whether direct plethysmographic measurements of thoracic
gas volume or trapped gas volume (body box–helium-derived lung
volumes) are stronger predictors of improved activity levels and
symptoms than spirometric volume measurements.
Spirometric IC and derived measurements (ie,
VT/IC ratios and inspiratory reserve volume
[IRV]) provide indirect measures of resting lung hyperinflation and
the extent of mechanical restriction and may provide complementary
information to the FEV1 in therapeutic
evaluation.20
Resting and dynamic spirometric IC
measurements have recently been shown to be both reproducible and
responsive.8
In a recent study, the change in IC after
high-dose anticholinergic therapy emerged as the only spirometric
correlate (p < 0.02) with improved exercise endurance and reduced
exertional dyspnea.20
Resting IC, and not the VC,
represents the true operational limits for VT
expansion during exercise. Thus, as a result of improved airway
function, resting IC and IRV were significantly increased after
ipratropium bromide inhalation, and this meant that patients could
maintain the same exercise ventilation for a longer duration with a
more efficient breathing pattern (ie, slower and deeper), at
lower dynamic operational lung volumes (Fig 3)
.
Thus, improved resting IC delayed ventilatory limitation during
exercise: IRV was significantly greater after ipratropium than after
placebo at end of exercise.20
In that study, a mean
improvement in resting IC by 14% predicted was associated with an
improvement in exercise endurance time of 32%.20
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Figure 3. Resting spirometry, operational lung volumes
during exercise, and exertional dyspnea ratings in COPD patients before
(pre-IB) and after (post-IB) the administration of nebulized
ipratropium bromide (IB), 500 µg. Note improved volume-matched
expiratory flows over the VT range with increased resting
IC. There is consequent reduction in operational lung volumes and an
increased IRV at the peak of symptom-limited exercise, with less
mechanical restriction. These mechanical improvements translated into
improved dyspnea and exercise capacity. FVC-pre = FVC before
treatment; FVC-post = FVC after treatment; see Figure 1
for
abbreviation. Reprinted with permission from O’Donnell et
al.8
|
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Two recent studies23
24
have shown that a lack of increase
in resting IC after ß2-agonist bronchodilator
therapy in a subset of patients with COPD may indicate the absence of
true expiratory flow limitation and resting dynamically determined lung
hyperinflation. It is also possible that an unchanged IC after
bronchodilator therapy may occasionally obscure a true clinical benefit
if TLC reduction is relatively greater than EELV reduction. In general,
however, an increase in IC, regardless of the behavior of TLC, is
likely to be clinically beneficial to patients.
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Summary
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In conclusion, exclusive reliance on the change in
FEV1 as the primary outcome measure in assessing
therapeutic efficacy can lead to underestimation of a true clinical
benefit in some patients with advanced COPD. Additional consideration
of bronchodilator- induced changes in spirometric lung volumes (or
capacities) can provide clinically useful information. In this respect,
the spirometric resting IC, which is a simple reproducible measurement,
is an acceptable surrogate for direct measurements of resting lung
hyperinflation. Improved resting IC following anticholinergic therapy
has been shown to correlate significantly, albeit weakly, with improved
exercise performance and dyspnea alleviation, and provides a reasonable
mechanistic rationale for these benefits. Clearly, further studies are
required to determine the ultimate clinical utility of IC and other
lung volume measurements. For a comprehensive therapeutic evaluation of
bronchodilator therapy, detailed resting spirometric assessments,
however, are unlikely to obviate the need for direct measurements of
dynamic lung hyperinflation, symptom intensity, exercise endurance, and
quality of life. The future development of a composite index that
collectively incorporates these outcome measures may increase our
ability to critically evaluate the clinical benefit of combination
bronchodilator therapy in symptomatic COPD patients.
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Footnotes
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Abbreviations:
DH = dynamic hyperinflation; EELV = end-expiratory lung volume;
IC = inspiratory capacity; IRV = inspiratory reserve volume;
Pes = tidal esophageal pressure swing; TLC = total lung
capacity; VC = vital capacity; VT = tidal volume
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TOP
Abstract
Introduction
