Ventilatory limitations in chronic obstructive
pulmonary disease
DENIS E. O’DONNELL
Departments of Medicine and Physiology, Division of Respiratory and Critical Care Medicine, Queen’s University,
Kingston, Ontario, CANADA
ABSTRACT
O’DONNELL, E. D. Ventilatory limitations in chronic obstructive pulmonary disease. Med. Sci. Sports Exerc., Vol. 33, No. 7, Suppl.,
pp. S647–S655, 2001. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by dysfunction of the
small and large airways, as well as by destruction of the lung parenchyma and vasculature, in highly variable combinations.
Breathlessness and exercise intolerance are the most common symptoms in COPD and progress relentlessly as the disease advances.
Exercise intolerance is multifactorial, but in more severe disease, ventilatory limitation is often the proximate exercise-limiting event.
Multiple factors determine ventilatory limitation and include integrated abnormalities in ventilatory mechanics and ventilatory muscle
function as well as increased ventilatory demands (as a result of gas exchange abnormalities) and alterations in the neuroregulatory
control of breathing. Despite its heterogeneity, the pathophysiological hallmark of COPD is expiratory flow limitation. When
ventilation increases in flow-limited patients during exercise, air trapping is inevitable and causes further dynamic lung hyperinflation
(DH) above the already increased resting volumes. DH causes elastic and inspiratory threshold loading of inspiratory muscles already
burdened with increased resistive work. It seriously constrains tidal volume expansion during exercise. DH compromises the ability
of the inspiratory muscles to generate pressure, and the positive intrathoracic pressures likely contribute to cardiac impairment during
exercise. Progressive DH hastens the development of critical ventilatory constraints that limit exercise and, by causing serious
neuromechanical uncoupling, contributes importantly to the quality and intensity of breathlessness. The corollary of this is that
therapeutic interventions that reduce operational lung volumes during exercise, by improving lung emptying or by reducing ventilatory
demand (which delays the rate of DH), result in clinically meaningful improvement of exercise endurance and symptoms in disabled
COPD patients. Key Words: DYSPNEA, DYNAMIC HYPERINFLATION, MECHANICS, FLOW–VOLUME LOOPS
V
entilatory limitation and the associated respiratory
discomfort contribute importantly to exercise curtailment in chronic obstructive pulmonary disease
(COPD). Our knowledge of the complex interface between
ventilatory impairment and exercise intolerance has increased considerably in recent years and is the primary focus
of this review. Advances in our ability to evaluate the
prevailing ventilatory constraints during exercise, together
with the development of reliable methods to assess symptom intensity, have increased our understanding of this
impairment– disability interface. These new insights into the
nature of ventilatory limitation to exercise will be reviewed,
and their implications for the management of the disabled
COPD patient will be discussed.
abnormalities, 3) peripheral muscle dysfunction, 4) cardiac
impairment, 5) exertional symptoms, and 6) any combination of these interdependent factors. The predominant contributory factors to exercise limitation vary among patients
with COPD, or indeed, in a given patient over time. The
more advanced the disease, the more of these factors come
into play in a complex integrative manner. In patients with
severe COPD, ventilatory limitation is often the predominant contributor to exercise limitation—that is, exercise is
terminated because of the inability to further increase ventilation in the face of increasing metabolic demands. The
patient is deemed to have ventilatory limitation if, at the
breakpoint of exercise, he or she has reached estimated
maximal ventilatory capacity (MVC), while at the same
time cardiac and other physiological functions are operating
below maximal capacity.
In practice, it is difficult to precisely determine if ventilatory limitation is the proximate boundary to exercise performance in a given individual. Attendant respiratory discomfort
may limit exercise before “physiological limitation” occurs,
and the relative importance of other nonventilatory factors is
impossible to quantify with precision. Our assessment of
MVC, as estimated from resting spirometry or from brief bursts
of voluntary hyperventilation, is inaccurate (1). Prediction of
the peak ventilation actually achieved during exercise from
maximal voluntary ventilation at rest is problematic because
the pattern of ventilatory muscle recruitment, the changes in
intrathoracic pressures and respired flows and volumes, and the
DETECTION OF VENTILATORY LIMITATION
IN COPD
Exercise limitation is multifactorial in COPD. Recognized contributory factors include 1) ventilatory limitation
because of impaired respiratory system mechanics and ventilatory muscle dysfunction, 2) metabolic and gas exchange
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Copyright © 2001 by the American College of Sports Medicine
Received for publication October 2000.
Accepted for publication April 2001.
S647
extent of dynamic lung hyperinflation are often vastly different
under the two conditions (21). Although an increased ratio
(0.9) of peak ventilation (VE) to the estimated MVC strongly
suggests serious ventilatory constraints, a lower peak VE/MVC
ratio (i.e., ⬍0.75) by no means excludes the possibility of
significant ventilatory impairment during exercise. Thus, simultaneous analysis of exercise flow–volume loops at the
symptom-limited peak of exercise may show marked constraints on flow and volume generation in the presence of an
apparent adequate ventilatory reserve, as estimated from the
peak VE/MVC ratio (17,21).
An alternative approach to the evaluation of the role of
ventilatory factors in exercise limitation is to determine the
effects of interventions that selectively increase or decrease
ventilatory demand or capacity on exercise performance.
For example, the addition of hypercapnic stimulation or
external dead space to the breathing circuit will increase
ventilatory demand (3,18). In this regard, the inability to
increase ventilation with earlier attainment of peak VE and
premature termination of exercise when an external dead
space is added indicates that ventilatory factors likely contributed importantly to poor exercise capacity in the unloaded condition (3). Similarly, we can conclude that ventilatory limitation contributed importantly to exercise
intolerance in chronic pulmonary disease; by using an intervention that decreases ventilatory demand and delays
peak ventilation (i.e., such as oxygen therapy), we can
improve exercise tolerance (36). Studies of how exercise
capacity can be increased in patients with COPD that have
used therapeutic manipulation of the ventilatory demand–
capacity relationship allow us to explore, in a novel manner,
the nature of the existing ventilatory constraints to exercise
(see below).
VENTILATORY MECHANICS IN COPD
COPD is a heterogeneous disorder characterized by dysfunction of the small and large airways and by parenchymal
and vascular destruction, in highly variable combinations.
Although the most obvious physiological defect in COPD is
expiratory flow limitation caused by combined reduced lung
recoil and airway tethering, as well as intrinsic airway
narrowing, the most important mechanical consequence of
this is a “restrictive” ventilatory deficit attributable to lung
hyperinflation (54,61) (Fig. 1). When expiratory flow limitation reaches a critical level, lung emptying becomes incomplete during resting tidal breathing, and lung volume
fails to decline to its natural equilibrium point (i.e., passive
functional residual capacity [FRC]). End-expiratory lung
volume (EELV), therefore, becomes dynamically and not
statically determined and represents a higher resting lung
volume than in health (54). In COPD, EELV is a continuous
variable that fluctuates widely with rest and activity. When
VE increases in flow-limited patients (e.g., during exercise),
dynamic EELV (EELVdyn) increases even further above
resting values: this is termed dynamic lung hyperinflation
(DH) (Fig. 1). By contrast, in healthy, non–flow-limited
subjects, EELVdyn may actually decline during the inS648
Official Journal of the American College of Sports Medicine
FIGURE 1—In a normal healthy subject and a typical patient with
COPD, tidal flow–volume loops at rest and during exercise (peak
exercise in COPD compared with exercise at a comparable metabolic
load in the age-matched healthy person) are shown in relation to their
respective maximal flow–volume loops.
creased VE of exercise, particularly in younger individuals
(14,19,29) (Fig. 1). This allows tidal volume (VT) expansion
within the linear portion of the respiratory system’s pressure–volume relationship where “high end” elastic loading
is avoided. Expiratory muscle recruitment and reduced EELVdyn also favorably affect diaphragmatic function in health
(14,19,29). Many of these important advantages are lost in
COPD patients because of DH. The extent and pattern of
DH development in COPD patients is highly variable: the
average range of increase in EELVdyn in published series is
0.3 to 0.6 L (53,11,37). However, some patients do not
increase EELVdyn during exercise, whereas others show
dramatic increases (i.e., ⬎1 L). Patients with a predominant
“chronic bronchitis” clinical profile show comparable levels
of dynamic hyperinflation during exercise to those with a
more “emphysematous” profile. Important determinants of
DH include 1) the level of baseline lung hyperinflation, 2)
the extent of expiratory flow limitation, 3) ventilatory demand, and 4) breathing pattern for a given ventilation.
Although DH serves to maximize tidal expiratory flow rates
during exercise, it has serious consequences with respect to
dynamic ventilatory mechanics, inspiratory muscle function, respiratory sensation, and probably cardiac function
(37) (Table 1).
An important mechanical consequence of DH is severe
mechanical constraints on VT expansion during exercise: VT
is truncated from below by the increasing EELVdyn and
constrained from above by the relatively reduced inspiratory
reserve volume (IRV) and the total lung capacity (TLC)
envelope (61) (Figs. 1 and 2). Thus, at comparable low work
rates in COPD patients, dynamic end-inspiratory lung
TABLE 1. Negative effects of dynamic hyperinflation during exercise.
Restricted tidal volume response to exercise, with tachypnea
Increased elastic/threshold loading of the inspiratory muscles
Functional inspiratory muscle weakness
“Neuromechanical uncoupling” of the respiratory system
Increased exertional dyspnea
Cardiac impairment
Early exercise termination
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FIGURE 2—Behavior of (A) operational lung volumes, (B) respiratory
effort (Pes/PImax), and (D) exertional dyspnea as ventilation increases
throughout exercise in normals and COPD. In COPD, tidal volume
(VT) takes up a larger proportion of the reduced inspiratory capacity
(IC), and the inspiratory reserve volume (IRV) is decreased at any
given ventilation—these mechanical constraints on tidal volume expansion are further compounded because of dynamic hyperinflation
during exercise. (C) Because of a truncated VT response to exercise,
patients with COPD must rely more on increasing breathing frequency
(F) to generate increases in ventilation. Adapted from O’Donnell et al.
(38) with permission.
volume (EILVdyn) and VT/inspiratory capacity (IC) ratios
are greatly increased, and the IRV is diminished compared
with healthy subjects (Figs. 1 and 2). To increase VE during
exercise, such patients must rely on increasing breathing
frequency; but this tachypnea, in turn, causes further DH in
a vicious cycle (Fig. 2).
The behavior of EELV during exercise is usually tracked
by serial IC maneuvers (11,37,53). This is a reasonable
approach since, to our knowledge, TLC does not change
appreciably during exercise in COPD (59). Repeated IC
measurements during constant load exercise have recently
been shown to be both reproducible and responsive (39). In
contrast to health, where IC remains unchanged or actually
increases (14,19,29), IC progressively diminishes with increasing levels of exercise in COPD patients (Figs. 1 and 2).
The smaller the IC during exercise, the closer VT is positioned to TLC and the upper alinear extreme of the respiratory system’s (combined chest wall and lung) pressure–
volume relationships, where there is increased elastic
loading of muscles already burdened by increased resistive
work. The combined elastic and resistive loads on the ventilatory muscles substantially increase the mechanical work
VENTILATORY LIMITATIONS
and the oxygen cost of breathing at a given ventilation in
COPD compared with health. At a peak exercise VE of
approximately 20 L·min⫺1, ventilatory work may approach
over 200 J·min⫺1 and respiratory muscle V̇O2 exceeds 300
mL·min⫺1 in COPD (27).
Another more recently recognized mechanical consequence of DH is inspiratory threshold loading (ITL) (54).
Since in flow-limited patients, inspiration begins before
tidal lung emptying is complete, the inspiratory muscles
must first counterbalance the combined inward (expiratory)
recoil of the lung and chest wall before inspiratory flow is
initiated. This phenomenon (i.e., reduced lung emptying) is
associated with positive intrapulmonary pressures at the end
of quiet expiration (autoPEEP or intrinsic PEEP). The ITL,
which may be present at rest in some flow-limited patients
with COPD, further increases with exercise and can be
substantial (e.g., ⫺6 to ⫺14 cm H2O) and may have important implications for dyspnea causation (30,38).
DH alters the length–tension relationship of the inspiratory muscles, particularly the diaphragm, and compromises
their ability to generate pressure (20,55–57). Attendant
tachypnea and increased velocity of muscle shortening during exercise results in further functional inspiratory muscle
weakness (20). Because of weakened inspiratory muscles
and the intrinsic mechanical loads already described, tidal
inspiratory pressures represent a much higher fraction of
their maximal force-generating capacity than in health at a
similar work rate or ventilation (20,55–57) (Fig. 2). DH may
alter the pattern of ventilatory muscle recruitment to a more
inefficient pattern with negative implications for muscle
energetics (34). The net effect of DH in COPD is, therefore,
that the VT response to increasing exercise is progressively
constrained despite inspiratory efforts that approach the
maximum: the ratio of effort (i.e., tidal esophageal pressures
relative to maximum [Pes/PImax]) to tidal volume response
(VT/VC) are thus significantly higher at any given work rate
or ventilation in COPD compared with health (38) (Fig. 2).
Accelerated dynamic hyperinflation during exercise hastens the onset of critical ventilatory limitation, which in turn
leads to premature termination of exercise (Figs. 1 and 2). In
flow-limited patients, the degree of resting lung hyperinflation, as reflected by reduced inspiratory capacity, is a powerful predictor of exercise capacity (9,33). In a recent study,
the resting IC in conjunction with the FEV1.0/FVC ratio
together accounted for 72% of the variance in exercise
capacity in a group (n ⫽ 52) of patients with COPD (9).
Moreover, it has recently been shown that improvement in
resting IC after bronchodilator therapy was the strongest
correlate of improved exercise endurance in patients with
severe COPD (43).
DYNAMIC HYPERINFLATION AND DYSPNEA
Dyspnea intensity during exercise has been shown to
correlate strongly with measures of dynamic lung hyperinflation (37) (Fig. 3). In a multiple regression analysis with
Borg ratings of dyspnea intensity as the dependent variable
versus a number of relevant independent physiological
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FIGURE 3—The relationship between respiratory effort (Pes/PImax)
and the tidal volume response (VT standardized as a % of predicted
VC) increases during exercise in patients with COPD (i.e., neuromechanical dissociation). Increasing ventilation and the mechanical load
on the respiratory muscles (i.e., dynamic hyperinflation) results in
increased elastic recoil and an inspiratory threshold load (ITL). (left
panel). Significant interrelationships have been found between dyspnea
intensity, neuromechanical dissociation (Pes/VT ratio), and the extent
of dynamic lung hyperinflation (EELV) at a standardized level of
exercise in COPD (right panel). Adapted from O’Donnell et al. (38)
with permission.
variables, the change in EILVdyn (expressed as % TLC)
during exercise emerged as the strongest independent correlate (r ⫽ 0.63, P ⬍ 0.001) in 23 patients with advanced
COPD (average FEV1.0 ⫽ 36% predicted) (37). Change in
EELVdyn and change in VT (the components of EILVdyn)
emerged as significant contributors to exertional breathlessness and, together with increased breathing frequency, accounted for 61% of the variance in change in exercise
dyspnea by Borg ratings (37). A second study showed
equally strong correlations between intensity of inspiratory
difficulty during exercise and EILVdyn/TLC (r ⫽ 0.69, P ⬍
0.001) (38). DH gives rise to restrictive ventilatory mechanics and an increased ratio of inspiratory effort to VT response (Figs. 2 and 3). It is not surprising, therefore, that
Borg ratings of dyspnea intensity also correlate strongly
with this increased effort/displacement ratio (38) (Fig. 3).
This increased ratio ultimately reflects increased neuromechanical uncoupling of the respiratory system and may
provide a neurophysiological basis for perceived respiratory
distress.
These studies collectively attest to the importance of DH
and its adverse mechanical consequences on dyspnea causation during exercise in COPD patients. Further evidence
of the importance of DH in contributing to exertional dyspnea in COPD has come from a number of studies that have
shown that dyspnea was effectively ameliorated by interventions that reduced operational lung volumes, either pharmacologically (2,7,39) or surgically (13,32), or that counterbalanced
the negative effects of DH on the respiratory muscle (i.e.,
continuous positive airway pressure (CPAP)) (40,51).
GAS EXCHANGE ABNORMALITIES IN COPD
Arterial hypoxemia during exercise commonly occurs in
patients with severe COPD as a result of the effects of a fall
in mixed venous oxygen tension (PvO2) on low ventilation–
perfusion lung units and shunting (1). In severe COPD, both
the ability to increase lung perfusion and to distribute inS650
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FIGURE 4 —(A) Tidal flow–volume loops at rest (solid lines) and at
isotime during a given load of exercise (dotted lines) are shown while
breathing room air and oxygen. The maximal flow–volume envelope
measured on room air is also shown (solid line on left, dashed line on
right). In response to a drop in ventilation (VE) of approximately 3
L·minⴚ1, inspiratory capacity (IC) is improved and dynamic hyperinflation (DH) is reduced. (B) Exertional dyspnea fell significantly (*P <
0.05) in response to oxygen therapy.
spired ventilation during exercise is compromised (1,8).
Resting physiological dead space is often increased, reflecting ventilation–perfusion abnormalities, and may fail to
decline further during exercise, as is the case in health (1,8).
To maintain appropriate alveolar ventilation and blood gas
homeostasis in the face of an increased physiological dead
space, minute ventilation must increase. High physiological
dead space in the setting of a blunted VT response to
exercise in hyperinflated COPD patients will compromise
CO2 elimination. Thus, exercise-induced hypercapnia, as a
result of alveolar hypoventilation, can occur in severely
mechanically compromised patients with COPD. Derangements of blood gases beyond a critical level will excessively
stimulate ventilation, aggravate dynamic hyperinflation, and
cause early ventilatory limitation to exercise (Fig. 4). It must
be emphasized that the effects of hypoxemia are multifactorial and involve many integrated mechanisms that culminate in reduced exercise performance in COPD. In addition
to the stress on the ventilatory system caused by hypoxia,
reduced oxygen delivery to the active peripheral muscles
may increase reliance on anaerobic glycolysis and also
contribute to muscle fatigue. Other deleterious effects of
acute exercise hypoxemia include 1) impaired cardiovascular function, 2) impaired central nervous system function,
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3) alteration of afferent inputs from peripheral chemoreceptors, and 4) altered perception of dyspnea and leg discomfort. The relative importance of these factors likely varies
between individuals. Although gas exchange abnormalities,
such as severe hypoxemia, are inextricably linked to ventilatory limitation in COPD, the effects of correction of arterial hypoxemia on exercise performance are quite variable
and unpredictable in a given subject (6,24,60). However, in
general, patients with the most severe mechanical and gas
exchange abnormalities benefit most in terms of improved
dyspnea and exercise endurance (36,45).
INCREASED VENTILATORY DEMAND
The effects of the above-outlined mechanical derangements in COPD are often compounded by concomitantly
increased ventilatory demand. Many studies have shown
that VE at a given submaximal work rate is significantly
increased compared with normal (10,16,41). Factors contributing to increased ventilation include high physiological
dead space, earlier lactate acidosis, hypoxemia, high metabolic demands, low arterial CO2 set point, and other nonmetabolic sources of ventilatory stimulation (e.g., anxiety,
hyperventilation). For a given level of expiratory flow limitation, the extent of dynamic hyperinflation and its consequent negative sensory consequences will vary with ventilatory demand. Those with the highest ventilation will
develop limiting ventilatory constraints on flow and volume
generation, and greater dyspnea early in exercise (41). There
is abundant evidence that increased ventilatory demand contributes to dyspnea causation in COPD, and dyspnea intensity during exercise has been shown in several studies to
correlate strongly with the change in VE or with VE expressed as a fraction of maximal breathing capacity
(26,41,42). For a given FEV1.0, patients who have greater
ventilatory demands will have more severe chronic activityrelated dyspnea (41). Moreover, exertional dyspnea relief
after interventions such as exercise training (42), oxygen
therapy (45), and opiates (28) has been shown to result, in
part, from the reduced submaximal ventilation (see below).
DELAYING VENTILATORY LIMITATION
Quantitative flow–volume loop analysis during constantload exercise testing (at approximately 75% of the achievable peak work rate or V̇O2), allows a noninvasive assessment of ventilatory mechanics in COPD: changes in
dynamic IC correlate strongly with the elastic load (2,38).
Furthermore, comparison of exercise flow–volume loops
before and after therapeutic interventions at a standardized
time using this protocol provide valuable insights into the
mechanisms of improved exercise performance and symptoms, vis-à-vis their effects on ventilatory limitation (39).
To improve exercise capacity in symptomatic COPD patients, therapeutic interventions must either increase ventilatory capacity (i.e., the maximal flow–volume envelope),
delay the rate of DH (i.e., the shift of exercise tidal flow–
VENTILATORY LIMITATIONS
volume loops toward TLC during exercise), or a combination of both.
Bronchodilator therapy. Combination bronchodilator
therapy with inhaled anticholinergic and ␤2 sympathomimetic agents represents the first step in the management of
symptomatic COPD. These agents have each been shown to
successfully alleviate dyspnea and improve exercise performance, even in advanced COPD (2,39). Bronchodilator
therapy has been shown to increase maximal (and tidal)
expiratory flow rates over the operating volume range, consequently providing more effective lung emptying with a
reduction in dynamic lung volumes throughout exercise
(2,39) (Fig. 5). Bronchodilators, therefore, delay the attainment of critical ventilatory limitation and significantly improve exercise endurance and reduce dyspnea (43). For
example, after high-dose anticholinergic therapy in advanced COPD, we have shown that the inspiratory reserve
volume was significantly increased at any given work rate or
ventilation compared with placebo, in conjunction with an
increase in exercise endurance time by 32% of the control
value (43) (Fig. 5). Because of this delay in ventilatory
limitation, dyspnea was displaced by leg discomfort in many
patients as the primary exercise-limiting symptom (43). It is
noteworthy that important improvements in exercise operational lung volumes and endurance times often occur after
bronchodilators in the presence of minimal or no change in
the resting postbronchodilator FEV1.0 (2,7,39). This likely
reflects the fact that the FEV1.0 provides only a crude
estimation of dynamic small airway dysfunction and the
extent of prevailing expiratory flow limitation. The change
in resting IC, which indicates greater capacity for VT expansion during exercise, correlates better with improved
exercise endurance than the FEV1.0 (43).
Lung volume reduction surgery. Surgical reduction
of lung volume by resection of targeted areas of emphysematous lung destruction has also been shown to delay ventilatory limitation. This is achieved by increasing the maximal and tidal flow–volume loops chiefly by increasing
static lung recoil and airway tethering effects (12,32). Improved airway conductance in turn promotes more effective
lung emptying and reduces resting and exercise operational
lung volumes (12,32). Reduced operational lung volumes
after lung volume reduction surgery (LVRS) correlated
closely with the extent of symptom relief (32). Additional
improvements in dynamic ventilatory mechanics occur after
LVRS as a result of reduced ventilatory demand. Reduced
submaximal VE after surgery may reflect improved oxygenation in some cases, but more importantly, often reflects the
response to ancillary perioperative exercise training (43).
Oxygen therapy. Since the extent of DH during exercise in flow-limited COPD patients depends on the ventilation and the breathing pattern for a given ventilation, it
follows that therapeutic interventions that reduce submaximal ventilation during exercise, such as supplemental oxygen therapy, exercise training, and opiates, should delay the
rate of DH and the onset of critical ventilatory constraints
that limit exercise (45) (Fig. 4). These interventions do not
typically affect the maximal flow–volume loop envelope (as
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FIGURE 5—Responses to bronchodilator therapy (nebulized ipratropium bromide, 500 ␮g) are shown. As maximal expiratory flow–
volume relationships improved after dose, tidal flow–volume curves at
rest can shift to the right, i.e., lung hyperinflation is reduced as
reflected by an increased IC (top panel). Exertional dyspnea decreases
significantly (*P < 0.05) in response to bronchodilator therapy (middle
panel). Operational lung volumes improve in response to bronchodilator therapy, i.e., mechanical constraints on VT expansion are reduced
as IC and IRV are increased significantly (*P < 0.05) (lower panel).
Adapted from O’Donnell et al. (38) with permission.
in the case of bronchodilators), but merely alter the time
course for the development of restrictive ventilatory mechanics (45) (Fig. 4). In a placebo-controlled, crossover
study, where patients with advanced COPD received either
60% oxygen or room air, we have recently shown that
hyperoxia more than doubled the time to reach ventilatory
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limitation (45) (Fig. 4). In this study, the improvements in
dyspnea and exercise endurance during hyperoxia were explained, in large measure, by the effects of reduced ventilatory demand (i.e., by reducing hypoxic drive and the
metabolic load) on operational lung volumes (45). At a
standardized submaximal work rate, VE was decreased by
approximately 3 L·min⫺1 and the inspiratory reserve volume increased by 0.3 L during 60% oxygen compared with
room air (45) (Fig. 5).
The effects of oxygen therapy on exercise performance
are complex: in addition to delaying ventilatory limitation,
oxygen also improves the metabolic load, peripheral muscle
function, and cardiac function. The relative importance of
these various factors in contributing to improved exercise
endurance in a given individual is difficult to evaluate, but
in patients with unequivocal ventilatory limitation on room
air, O2-induced changes in operational lung volumes and
dyspnea appear to be most important (30,45).
Exercise training. Exercise training, which has been
shown repeatedly to reduce submaximal ventilation in advanced COPD (by improving efficiency and/or reducing the
metabolic acidemia) should also, theoretically, alter ventilatory limitation in a manner similar to hyperoxia (5,44).
Clearly, improved exercise endurance after exercise training is multifactorial, but improved dyspnea and/or leg discomfort are important contributory factors. Improved dyspnea is likely related to improved ventilatory muscle
strength and endurance and reduced ventilatory demand.
Reduced submaximal ventilation after training mainly reflects reduced breathing frequency responses to exercise. In
some patients, this is accompanied by increased VT expansion. This more efficient breathing pattern is associated with
more effective CO2 elimination, and both factors may combine to ameliorate respiratory discomfort. Dyspnea relief
after exercise training is also undoubtedly linked to “nonphysiological” factors such as reduced fear and anxiety,
increased tolerance, or systemic desensitization to respiratory discomfort as a result of participation in a comprehensive pulmonary rehabilitation program. These subjective
changes alone may improve exercise endurance in some
patients in the absence of measurable physiological training
effects.
Evidence is accumulating that small reductions in ventilation and operational lung volumes have clinically important effects in people with hyperinflated COPD who are
ventilatory limited during exercise (31,45). Moreover, a
comprehensive multimodality approach to management
with combined bronchodilator therapy, oxygen, and exercise training generally results in additive or synergistic
effects on exercise performance (Fig. 6).
VENTILATORY MUSCLE DYSFUNCTION
IN COPD
Inspiratory muscle function. The degree to which
ventilatory pump failure contributes to ventilatory limitation
in COPD is uncertain and has been the subject of intense
study (4,13,22,23,52). Theoretically, reduced ventilatory
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FIGURE 6 —(A) Exercise endurance increases significantly (*P <
0.05, **P < 0.01) in response to various interventions in COPD:
nebulized ipratropium bromide (IB) 500 ␮g, 60% O2 (shown for both
hypoxic (open bar) and nonhypoxic (solid bar) patients), exercise training (EXT), inhaled morphine (opiates), optimized low-level continuous
positive airway pressure (CPAP), and volume reduction surgery
(VRS). From references 39, 36, 45, 44, 40, and 49, respectively. (B)
Exertional dyspnea improves cumulatively with a stepwise approach to
therapy. Adapted from O’Donnell (48) with permission.
capacity caused by reduced ventilatory muscle strength or
fatigue in the setting of increased ventilatory muscle loading
should contribute to ventilatory limitation in many patients
with advanced COPD (4,13,22,52). However, the evidence
that a weakened ventilatory pump contributes to exercise
intolerance is not conclusive (22,23,35,38). The prevalence
of inspiratory muscle weakness in the COPD population has
not been established and may not be as pervasive as previously thought. In fact, there is evidence that functional
muscle strength is remarkably preserved in some patients
with advanced chronic ventilatory insufficiency (57). Patients with acute-on-chronic hypercapnia during exercise
have been shown to have no acute deterioration in maximal
force-generating capacity, and do not exhibit alteration in
the pattern of ventilatory muscle recruitment compared with
nonhypercapnic individuals matched for FEV1.0 (35). The
results of studies on the effects of specific inspiratory muscle training on exercise performance in COPD have been
inconsistent (58). Similarly, the effects of long-term, noninvasive ventilatory assistance (designed to reduce chronic
fatigue) on dyspnea and exercise performance in a large
COPD population have been negative.
Role of assisted ventilation. Indirect evidence that
acute inspiratory muscle weakness contributes to ventilatory
VENTILATORY LIMITATIONS
limitation in some individuals with COPD comes from
studies of acute ventilatory assistance during exercise in
COPD using CPAP or pressure support, alone or in combination (50 –52). Such studies have shown an improvement
in exercise endurance by 30 – 40%, on average, with impressive relief of dyspnea in individual COPD patients
(40,51). Optimized CPAP counterbalances the negative effects of the inspiratory threshold load on the inspiratory
muscles, and pressure support provides variable resistive
and elastic unloading of these muscles. In general, the
effects of ventilatory assistance on exercise capacity have
been quite variable and the magnitude of the response is
either comparable to, or less than, the effects of ambulatory
oxygen (36,45). Ventilatory assistance often does not affect
ventilatory limitation per se but, by assisting the weakened,
overburdened muscles, may delay the point of intolerable
dyspnea and the breakpoint of exercise.
Expiratory muscle recruitment. In the presence of
expiratory flow limitation, tidal expiratory flow rates are
independent of expiratory transpulmonary pressures beyond
a critical level (15). In fact, increasing expiratory effort
beyond this level not only fails to increase expiratory flow,
but results in dynamic airway compression of the airways
downstream from the flow-limiting segment (15). Expiratory muscle recruitment appears to be highly variable in
COPD during exercise (11,34,53). During constant-load exercise, some patients allow expiratory transpulmonary pressures to reach, but not exceed, the critical flow-limiting
pressure, thus attenuating dynamic airway compression
(25). Expiratory muscle recruitment may assist the inspiratory muscles by favorably altering diaphragmatic configuration or by the release of stored elastic energy at the onset
of inspiration. Several studies have shown marked expiratory muscle activity at high work rates in COPD (11,34,53).
This possibly maladaptive behavior will not improve alveolar ventilation and will aggravate dynamic airway compression, which in turn likely contributes to increased exertional dyspnea (46,47). Excessive expiratory intrathoracic
and abdominal pressures, with reduced velocity of shortening of the expiratory muscles, may also significantly impair
cardiac function in exercising COPD patients (53). The net
effect of intense expiratory muscle recruitment on exercise
performance will vary among COPD patients. In many
patients, the deleterious effects of vigorous expiratory muscle contraction on symptoms and cardiac performance may
outweigh potential beneficial effects on inspiratory muscle
function.
SUMMARY
On the basis of extensive studies in COPD patients, we
can conclude that ventilatory limitation contributes importantly, and often predominantly, to exercise limitation. Expiratory flow limitation is the hallmark of this heterogeneous condition, and its most important consequence during
exercise is dynamic lung hyperinflation, which accelerates
ventilatory limitation and exercise termination. The recognition that dynamic hyperinflation is one factor contributing
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to reduced ventilatory capacity is potentially clinically important, since lung hyperinflation is at least partially reversible and can, therefore, be manipulated for the patient’s
benefit. Interventions that improve airway function and lung
emptying will reduce operational lung volumes during exercise, and delay the occurrence of critical ventilatory constraints, thus improving exercise endurance and symptoms.
An integrative approach that maximizes lung emptying
(combined bronchodilators) and further reduces the rate of
gas accumulation by reducing ventilatory demand during
exercise (i.e., oxygen therapy and exercise training) can
result in clinically meaningful benefits for the patient with
advanced symptomatic COPD.
Although much of the scientific evidence currently available refers to COPD patients, certain of the principles of
exercise limitation described above also apply to patients
with other types of chronic pulmonary disease. The reduced
ventilatory capacity in chronic restrictive pulmonary disease
would imply that measures to reduce exercise ventilation,
such as supplemental oxygen and exercise training, would
have similar applicability as in COPD. Furthermore, patients with neuromuscular diseases have important mechanical abnormalities, including respiratory muscle dysfunction
and altered respiratory system compliance, that likely impact exercise ability. Investigation of the ventilatory limitation needs to be extended to these other forms of chronic
pulmonary disease. In the future, better understanding of the
pathophysiology of all types of chronic pulmonary disease
will, perhaps, lead to more specific treatment strategies
depending on the type of patient.
Address for correspondence: Dr. Denis E. O’Donnell, 102 Stuart
Street, Kingston, Ontario K7L 2V6, Canada; E-mail: odonnell@post.
queensu.ca.
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