Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston, Ont., Canada
Summary
Exercise intolerance in patients with chronic obstructive pulmonary disease (COPD) is the result of a complex interac-tion of factors that include ventilatory constraints, skeletal muscle dysfunction, and the distressing exertional symptoms of dyspnea and leg discomfort. Cardiopulmonary exercise testing can be used to uncover the various pathophysiological contri-butions to exercise intolerance, on an individual basis. Recent advances in the assessment of ventilatory constraints by quanti-tative flow-volume loop analysis during excercise and the mea-surement of exertional symptoms using validated scales, now permit a more rigorous evaluation of physiological impairment and disability. In severe COPD, ventilatory factors are often predominant. Thus, interventions that increase ventilatory ca-pacity (i.e., bronchodilators) or that reduce ventilatory demand (i.e., exercise training and oxygen therapy) have been shown to improve exercise endurance. Additionally, pharmacological and surgical interventions that reduce dynamic lung overdis-tention during exercise effectively alleviate exertional dyspnea.
Skeletal muscle weakness and deconditioning have been shown to respond favorably to targeted training. Comprehensive management strategies that incorporate pharmacological ther-apies and supervised exercise training can minimize exercise capabilities, and thus the health status of patients with advanced symptomatic disease.
Introduction
The inability to engage in the usual activities of daily living is one of the most distressing experiences of people afflicted with COPD. Exercise intolerance progresses rel-entlessly as the disease advances and can lead to virtual immobility and social isolation. Our understanding of the complex interface between physiological impairment and disability in COPD has increased considerably in recent years and is the main focus of this review. It has become clear that in COPD, exercise intolerance ultimately re-flects integrated abnormalities of the ventilatory, cardio-vascular, peripheral muscle, and neurosensory systems.
Ventilatory limitation is the dominant contributor to exercise curtailment in more advanced disease and will be considered in detail. Important advances have been made in our ability to ‘noninvasively’ assess dynamic ventilato-ry mechanics in COPD during exercise and will be high-lighted in this review. The derangements of ventilatory mechanics peculiar to this disease will be reviewed so as to better understand how these can be therapeutically manipulated to improve exercise performance. Recent important research into the role of peripheral muscle dys-function in exercise limitation will be reviewed, as well as emerging concepts on the pathophysiology of cardiopul-monary-locomotor muscle interactions in COPD.
Exercise in COPD 139
Exercise Limitation in COPD
Exercise limitation is multifactorial in COPD. Recog-nized contributing factors include: (1) ventilatory limita-tion due to impaired respiratory system mechanics and ventilatory muscle dysfunction; (2) metabolic and gas exchange abnormalities; (3) peripheral muscle dysfunc-tion; (4) cardiac impairment; (5) intolerable exertional symptoms, and (6) any combination of these interdepen-dent factors. The predominant contributing 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.
Cardiopulmonary Exercise Testing (CPET) in COPD CPET, using an incremental cycle ergometry protocol, has traditionally been used to evaluate exercise perfor-mance in COPD. Standard CPET measures the following physiological responses: metabolic load [oxygen uptake (VO2) and carbon dioxide output (VCO2)], power output, ventilation (VE), breathing pattern, arterial oxygen satura-tion, heart rate, electrocardiogram, oxygen pulse, and blood pressure. Increasingly, exertional symptom assess-ment using validated scales (i.e. Borg and visual analogue scales) is being used during CPET and this constitutes an important advance [1, 2]. Common physiological re-sponses to incremental cycle exercise in COPD are now well established (table 1). These patterns, however, are not specific for COPD: for example, similar patterns are observed in interstitial lung disease and pulmonary vascu-lar disease. Thus, traditional CPET protocols do not allow diagnostic discrimination between various pulmonary conditions. However, conventional CPET has the poten-tial to yield important clinical information on an individ-ual basis: (1) it provides an accurate assessment of the patient’s exercise capacity that cannot be predicted from resting physiological measurements; (2) it measures the perceptual responses to quantifiable physiological stimuli (i.e. VO2, ventilation and power output); (3) it can pro-vide insight into the pathophysiological mechanisms of exercise intolerance and dyspnea in a given patient (e.g.
excessive ventilatory demand, arterial oxygen desatura-tion), and (4) it can identify other co-existent conditions that contribute to exercise limitation (i.e. cardiac disor-ders, intermittent claudication, musculoskeletal prob-lems, etc.). The results of CPET can also assist in deve-loping individualized exercise training protocols and sequential CPET can be used to evaluate the impact of therapeutic interventions in patients with COPD. One
Table 1. Typical abnormalities during exercise in COPD
Significant dyspnea and leg discomfort Reduced peak VO2 and work rate Low maximal heart rate
Elevated submaximal ventilation Low peak ventilation
High ratio of ventilation to maximal ventilatory capacity (VE/MVC)
Blunted VT response to exercise, with increased breathing frequency High deadspace (VD/VT)
Variable arterial oxygen desaturation PaCO2 usually normal but may increase
Reduced dynamic IC with exercise (i.e., dynamic hyperinflation) Reduced IRV at low work rates
High VT/IC ratios at low work rates
shortcoming of traditional CPET is that it gives little or no information about the prevailing dynamic ventilatory mechanics during exercise. This information is arguably important in the assessment of mechanisms of exercise intolerance in a given patient. In this regard, exercise flow-volume loops can provide a noninvasive assessment of dynamic mechanics, and allow greater refinement in the evaluation of the ventilatory constraints to exercise (see below) [3, 4] (fig. 1).
Serial IC measurements have been used to track end-expiratory lung volume (EELV) during exercise for more than 30 years [4–8] (fig. 1, 2). This approach is based on the reasonable assumption that TLC does not change appreciably during exercise in COPD, and that reductions in dynamic IC must, therefore, reflect increases in EELV or dynamic hyperinflation (DH) [6]. However, regardless of any possible changes in TLC with exercise, progressive reduction of an already diminished resting IC means that VT becomes positioned closer to the actual TLC and the upper alinear extreme of the respiratory system’s pres-sure-volume relationship, where there is increased elastic loading of the respiratory muscles (fig. 3). Reduction of IC as exercise progresses in COPD is likely a true reflection of shifts in EELV rather than simply the inability to gener-ate maximal effort because of dyspnea or functional mus-cle weakness. In fact, several studies have established that dyspneic patients, even at the end of exhaustive exercise, are capable of generating maximal inspiratory efforts as assessed by peak inspiratory esophageal pressures [6, 8].
Moreover, we have recently shown that IC measurements during constant load cycle exercise are both highly repro-ducible and responsive in patients with severe COPD,
140 O’Donnell
Fig. 1. In a normal healthy subject and in a typical patient with COPD, tidal flow-vol-ume loops at rest and during exercise (peak exercise in COPD compared with exercise at a comparable metabolic load in the age-matched person) are shown in relation to their respective maximal flow-volume loops.
In the COPD example, note expiratory flow limitation (tidal flows overlap the maximal curve) and an increase in end expiratory lung volume (EELV), as reflected by a decrease in IC during exercise. ‘Minimal IRV’ is the upper volume boundary that could be achieved during exercise.
Fig. 2. Changes in operational lung volumes are shown as ventilation increases with exercise in COPD (n = 105) and in normal subjects (n = 25). ‘Restrictive’ constraints on tidal volume (VT, solid area) expansion during exercise are significantly greater in the COPD group from both below (reduced IC) and above (minimal IRV, open area). Rrs = Relaxation volume of the respiratory system. From O’Donnell et al. [4] with permission.
Exercise in COPD 141 Fig. 3. Pressure-volume (P-V) relationships of the lung, chest wall, and total respiratory system in health and in COPD. Tidal pressure-volume curves during rest (filled area) and exercise (open area) are provided. Note that in COPD, because of resting and dynamic hyperinflation, VT encroaches on the upper alinear extreme of the respiratory system’s P-V curve where there is increased elastic loading.
provided due attention is taken with their measurement [12].
Changes in the dynamic volume components during exercise can be measured by a combination of serial IC and tidal volume measurements, and inspiratory lung vol-ume (EILV) can be calculated by adding EELV to VT (fig. 2). The operating lung volumes during exercise dic-tate the length-tension and the force-velocity characteris-tics of the ventilatory muscles, and influences breathing pattern and the quality and intensity of dyspnea (see below). Moreover, dynamic volume measurements give clear information about the extent of mechanical restric-tion during exercise in COPD (fig. 1, 2). Inspiratory re-serve volume (IRV) during exercise, in particular, pro-vides an indication of the existing constraints on VT
expansion. Similarly, the reserves of inspiratory flow can be evaluated by measuring the difference between tidal inspiratory flow rates and those generated at the same vol-ume during a simultaneous maximal IC maneuver (fig. 1).
In COPD, the pressure generating capacity of the inspira-tory muscles and, thus, the ability to generate inspirainspira-tory flow, may be compromised when breathing at a high
dynamic EELV compared with when a breath is initiated from RV at rest during the forced vital capacity (FVC) maneuver. Hence, maximal inspiratory flow rates during exercise IC maneuvers may be the more appropriate com-parator to use when calculating inspiratory flow reserves than the FVC plot.
The crucial abnormality in COPD is expiratory flow limitation (EFL), and its presence during exercise can be evaluated by measuring the overlap of the tidal expiratory volume curves with the maximal expiratory flow-volume curve [3, 13] (fig. 1). However, this assessment provides at best imprecise quantitative information about EFL. This ‘overlap’ method may become inaccurate be-cause of errors in placement of the VT curve on the abso-lute volume axis due to erroneous IC measurements.
Additionally, in many incidences, tidal expiratory flow rates exceed those generated during the FVC maneuver.
This occurs because of gas compression and airway com-pression effects, differences in volume history and in the uniformity of lung emptying during the maximal breath initiated from TLC compared with tidal breathing. De-spite these reservations, it is clear that patients with more
142 O’Donnell
advanced COPD often have markedly reduced maximal expiratory flow rates at lower lung (operating) volumes and, therefore, show substantial overlap of the tidal and maximal curves. Expiratory flow limitation can reason-ably be assumed to exist in this setting, particularly when there is attendant DH. In patients who demonstrate DH during exercise, tidal expiratory flow rates represent the maximal possible flows that can be generated at that vol-ume.
The negative expiratory pressure test (NEP) has been developed by Milic-Emili and colleagues [14] in order to provide a more accurate determination of EFL. Under conditions of EFL, tidal expiratory flow rates are deter-mined by the transpulmonary pressure and the resistance of the airways upstream from the flow-limiting segment, and are independent of downstream mouth pressure [13].
Therefore, negative pressure or suction (e.g. –5 to –12 cm H2O) applied at the mouth does not increase expiratory flow rates apart from a brief transient increase at the onset of expiration, representing gas discharged from the upper airways (anatomical deadspace) [14–16]. By contrast in non-flow-limited patients, NEP results in consistent and substantial increases in tidal expiratory flow rates [14, 15]. The NEP test does not provide any quantitative information about the extent of EFL, merely whether or not it is present at rest. The absence of EFL at rest, as determined by the NEP test, certainly does not preclude the development of significant EFL and consequent DH at low exercise levels, particularly if ventilation is exces-sive.
Ventilatory Constraints on Exercise Performance in COPD
In patients with severe COPD, ventilatory limitation is often the predominant contributor to exercise intoler-ance. The patient is deemed to have ventilatory limitation if, at the breakpoint of exercise, he or she has reached esti-mated maximum 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 ven-tilatory limitation is the proximate boundary to exercise performance in a given individual. Attendant respiratory discomfort may limit exercise before actual physiological limitation occurs, and the relative importance of other nonventilatory factors is impossible to quantify with pre-cision. Our assessment of the MVC, as estimated from resting spirometry (i.e. FEV1.0 ! 35 or 40) [17, 18] or from brief bursts of voluntary hyperventilation is inaccu-rate [3]. Prediction of the peak ventilation actually
achieved during exercise from maximal voluntary venti-lation at rest is problematic because the pattern of ventila-tory muscle recruitment, the changes in intrathoracic pressures and in respired flows and volumes, and the extent of DH are often vastly different under the two con-ditions. While an increased ratio (i.e. 190%) of peak exer-cise ventilation (VE) to the estimated MVC strongly sug-gests limiting ventilatory constraints, a preserved peak VE/MVC ratio (i.e. !75% predicted) by no means ex-cludes the possibility of significant ventilatory impair-ment during exercise [4]. Thus, simultaneous analysis of exercise flow-volume loops at the symptom-limited peak of exercise may show marked constraints on flow and vol-ume generation in the presence of an apparently adequate ventilatory reserve as estimated from the peak VE/MVC ratios [4]. In a recent study, 14% of a population sample of clinically stable patients with COPD (n = 105), with apparent ventilatory reserve at peak exercise (i.e. VE/ MVC !75% predicted) had coexisting limiting restrictive ventilatory constraints as indicated by an EILV 195% of the TLC (i.e. significantly reduced peak IRV) at the same time point [4].
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 per-formance. For example, the addition of hypercapnic stim-ulation, or external dead space, to the breathing circuit will increase ventilatory demand. 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 contribute importantly to poor exercise capacity in the unloaded condition. Similarly, we can con-clude that ventilatory limitation contributes 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 [19]. If exercise perfor-mance is enhanced by unloading the ventilatory pump, either by mechanical ventilation or by breathing helium-oxygen mixtures, we can conclude that the load on the inspiratory muscles (or its perception by the patient) con-tributes to exercise limitation during nonassisted exercise [20, 21]. Studies of how exercise capacity can be increased in patients with COPD that have used therapeutic manip-ulation 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).
Exercise in COPD 143
Ventilatory Mechanics in COPD
COPD is a heterogeneous disorder characterized by dysfunction of the small and large airways and by paren-chymal and vascular destruction, in highly variable com-binations. Although the most obvious physiological defect in COPD is expiratory flow limitation, due to combined reduced lung recoil (and airway tethering effects) as well as intrinsic airway narrowing, the most important me-chanical consequence of this is a ‘restrictive’ ventilatory deficit due to DH [4, 22, 23] (fig. 2, 3). 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. the relaxation volume of the respiratory sys-tem). EELV, therefore, becomes dynamically and not sta-tically determined, and represents a higher resting lung volume than in health [22] (fig. 2, 3). In flow-limited patients, EELV is therefore, a continuous variable which fluctuates widely with rest and activity. When VE in-creases in flow-limited patients, as for example during exercise, increases in EELV (or DH) is inevitable (fig. 1–
3). DH (and its negative mechanical consequences) can occur in the healthy elderly, but at much higher VE and VO2 levels than in COPD [3, 24, 25]. For practical pur-poses, the extent of DH during exercise depends on the extent of expiratory flow limitation, the level of baseline lung hyperinflation, the prevailing ventilatory demand, and the breathing pattern for a given ventilation [4].
The extent and pattern of DH development in COPD patients during exercise is highly variable. Clearly, some patients do not increase EELV during exercise, whereas others show dramatic increases (i.e. 11 l) [4, 8, 12]. We recently studied the pattern and magnitude of DH during incremental cycle exercise in 105 patients with COPD (FEV1.0 = 37 B 13% predicted; mean BSD) [4] (fig. 1, 2).
In contrast to age-matched healthy control subjects, the majority of this sample (80%) demonstrated significant increases in EELV above resting values: dynamic IC decreased significantly by 0.37 B 0.39 l (or 14 B 15%
predicted) from rest [4]. Similar levels of DH have recent-ly been reported in COPD patients after completing a 6-min walking test while breathing without an imposed mouthpiece [26]. For the same FEV1.0, patients with low-er diffusion capacity (DLCO !50% predicted), and pre-sumably more emphysema, had faster rates of DH at low-er exlow-ercise levels, earlilow-er attainment of critical volume constraints (peak VT), greater exertional dyspnea, and lower peak VE and VO2 when compared with patients with a relatively preserved DLCO [4]. In the latter group, the magnitude of rest to peak change in EELV was similar
to that of the low DLCO group, but air trapping occurred predominantly at a higher VO2 and VE at the end of exer-cise. Patients with predominant emphysema likely had faster rates of DH because of reduced elastic lung recoil (and airway tethering), and an increased propensity to expiratory flow limitation. In this group, DH is often fur-ther compounded by a greater ventilatory demand as a result of higher physiological dead space, reflecting great-er ventilation-pgreat-erfusion abnormalities [27]. The extent of DH during exercise is inversely correlated with the level of resting lung hyperinflation: patients who were severely hyperinflated at rest showed minimal further DH during exercise [4].
Tidal Volume Restriction and Exercise Intolerance An important mechanical consequence of DH is severe mechanical constraints on tidal volume expansion during exercise: VT is truncated from below by the increasing EELV and constrained from above by the TLC envelope and the relatively reduced IRV (fig. 2). Thus, compared with age-matched healthy individuals, COPD patients at comparable low work rates and VE showed substantially greater increases in dynamic EILV, a greater ratio of VT to IC, and marked reduction in the IRV (fig. 2). In 105 COPD patients, the EILV was found to be 94 B 5%
of TLC at a peak symptom-limited VO2 of only 12.6 B 5.0 ml/kg/min – this indicates that the diaphragm is maxi-mally shortened at this volume and greatly compromised in its ability to generate greater inspiratory pressures [4].
The resting IC and, in particular, the dynamic IC dur-ing exercise (and not the restdur-ing VC) represent the true operating limits for VT expansion in any given patient.
Therefore, when VT approximates the peak dynamic IC during exercise or the dynamic EILV encroaches on the TLC envelope, further volume expansion is impossible, even in the face of increased central drive and electrical activation of the diaphragm [28]. (fig. 2)
In our study, using multiple regression analysis with symptom-limited peak VO2 as the dependent variable, and several relevant physiological measurements as
In our study, using multiple regression analysis with symptom-limited peak VO2 as the dependent variable, and several relevant physiological measurements as