Exercise and Chronic Obstructive Pulmonary Disease

Obstructive Lung Disease

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Exercise and Chronic Obstructive Pulmonary Disease Charles G. Gallagher, MD*

A comprehensive discussion of all aspects of exercise in chronic obstructive pulmonary disease (COPD) is beyond the scope of this brief review. Therefore, the following selected aspects of dynamic exercise will be discussed: 1. Exercise pathophysiology in COPD 2. Clinical exercise testing

Other important topics, such as the effects of limb muscle training, respiratory muscle training, and oxygen and drug therapy on exercise performance, will not be reviewed here except as they relate to the above topics. Exercise in patients with bronchial asthma will not be discussed here. EXERCISE PATHOPHYSIOLOGY IN COPD It is well known that maximal exercise performance and endurance time at submaximal exercise are reduced in patients with COPD compared to healthy persons matched in age and gender. The index of maximal exercise performance used here will be maximal O 2 uptake (Vo2MAX).

*Associate

Professor of Medicine and Director, Respiratory Training Program, Division of Respiratory Medicine, University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Abbreviations used in this paper-V02' oxygen uptake; VC02 ' carbon dioxide output; R, respiratory exchange ratio; VozMAX, maximal oxygen uptake; OT' cardiac output; HR, heart rate; SV, stroke volume; (Ca02 -Cv 02 ), O 2 content difference between arterial and mixed venous blood; YE, minute ventilation; VA , alveolar ventilation; VEMAX, minute ventilation at maximal exercise; VT, tidal volume; F, respiratory frequency; Pam and P:lc02, arterial partial pressure of 0, and CO 2 respectively; VDsIVT , ratio of physiologic dead space to tidal volume; MVC, maximum ventilatory capacity; MVV = maximal voluntary ventilation; AT = "anaerobic threshold."

Medical Clinics of North America-Vo!' 74, No. 3, May 1990

619

620

CHARLES G. GALLAGHER

Before discussing the response to exercise of patients with COPD, exercise physiology in healthy persons will be summarized briefly. Normal Exercise Physiology. Physical exercise is a state of heightened metabolic rate; oxygen (0 2) consumption and carbon dioxide (C0 2) production by working muscles (including myocardium and respiratory muscles) both rise which, in turn, necessitates an increase in O 2 delivery to and CO 2 removal from these muscles. Accordingly, the body's O 2 uptake C(02 ) from and CO 2 output CVC02) to the environment increases. The normal physiologic response to exercise involves essentially all body systems, but this discussion will deal mainly with the respiratory and cardiovascular responses because they are very abnormal in patients with COPD. The normal response to exercise depends on many factors including intensity, duration, and type of exercise and the age, sex, lean body mass, and physical fitness of the person exercising. The cardiovascular responses may be represented by the following equations:

V02 V02

(Ca02

QT

=

(HR.SV) (Ca02

-

Equation 1

CV 02)

=

-

CVQ2)

Equation 2

where (h is cardiac output, the product of stroke volume (SV) and heart rate (HR) and (Ca02 - CV02) is the O 2 content difference between systemic arterial and mixed venous blood. When inspired CO 2 concentration is zero or negligible, the respiratory response to exercise is best represented by: •

v

=

A

v E

=

863

Ve02

863 Ve02 Paco2 (1 - VDslVT )

Equation 3 Equation 4

where VE is minute ventilation, the sum of alveolar ventilation (VA) and dead space ventilation. Pac02 is arterial P C02 and VDS/VT is the ratio of physiologic dead space to tidal volume. Equations 3 and 4 are used because normally VE and VA are related more to VCO2 than to V02. Increasing VDS/VT is a potent ventilatory stimulant; the possible mechanisms responsible for ventilatory stimulation with altered VDS/VT are discussed elsewhere. 53 The ratio of VC02 to V02 is defined as the respiratory exchange ratio

(R):

R

Ve02 = -.V 02

Equation 5

The major cardiorespiratory adaptations to incremental exercise are shown graphically in Figure 1. QT increases as an approximately linear function of V02. VE increases initially in a linear fashion but rises disproportionately at high work rates. While there is some controversy regarding the underlying mechanisms, this appears to be largely related to the development of significant metabolic acidosis at high exercise intensities.

621

EXERCISE AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

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30 (a) AnaerobIC Threshold

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Figure 1. Changes in cardiac output, arterial blood hydrogen ion concentration, minute ventilation, arterial CO, partial pressure, systolic and diastolic blood pressures, and heart rate as work rate is gradually increased from rest to maximum exercise in normal humans. (From Johnson RL: Exercise testing in lung disease. In Sackner MA (ed): Diagnostic Techniques in Pulmonary Disease. New York, Marcel Dekker, 1980, pp 473-501; with permission.)

622

CHARLES C. CALLAGHER

The relative importance of the different respiratory and cardiovascular adjustments is depicted in Table 1, which shows the average results of five normal men who were studied in the author's laboratory. The approximately ten-fold increase in V02 at maximum exercise was accompanied by a 3.7 and 2.8 fold increase in QT and (Ca 02-Cv02 ) respectiveJy. VC02 increased 14-fold while Pa C02 and the VDslVT ratio both fell, and VE showed a 13.5fold increase. These data are presented, not to provide "normal predicted values," but rather to emphasize the relative demands placed on cardiorespiratory function. When related to resting values, ma:cimal exercise imposes a greater relative stress on the respiratory system (V E increased 13.5-fold) than on the heart (QT increased 3.7-fold). Oxygen Consumption During Exerci~e in COPD. There is a linear relation between external work rate and V02 in normal persons. This also holds true for COPD patients. In their classic paper, Jones et aP4 found a greater V02 for a given external work rate in 50 patients with COPD than in normal persons. The difference was not statistically significant. Levison and Cherniack42 and Shuey et al 69 found that the V02-work rate relation was not significantly different from normal in their COPD patients. The major intersubject variability in the V02 -work rate relation, even in normal persons, makes detection of significant differences. between subject groups difficult. Accordingly, the extent to which the V02-work rate relation is altered in COPD remains unclear. If it is altered, the likely mechanisms include poor exercise technique or increased O 2 cost of breathing or both. Ventilation and Pulmonary Mechanics. The increased dead space ventilation (see later section on Blood Gases) of patients with COPD necessitates a greater minute ventilation (V E) than normal persons with the same alveolar ventilation (Equations 3 and 4). As a group, patients with predominant emphysema have an increased VE response to exercise so that PaC02 remains normal or near normal. 34.48 Some patients with COPD with little or no emphysema (previously referred to as having "bronchitis") may have a normal or near normal VE response to exercise so that their exercise PaC02 is high. The reasons for the differing ventilatory responses are beyond the scope of this review. Those who maintain PaC02 constant during exercise may still have an inadequate ventilatory response as shown by the absence of a hyperventilatory response to metabolic acidosis in some patients62 (see later section on Metabolic Acidosis). However it must be emphasized that many patients do not fall neatly into the "emphysema" or '.'bronchitis" categories and, as a group, COPD patients have an elevated VE response to exercise. Patients with COPD have reduced maximum expiratory flow rates at all lung volumes with lesser reductions in maximum inspiratory flow rates. The shape of the expiratory curve is distorted, but the shape of the inspiratory curve is essentially normal (Fig. 2). Some patients with severe COPD demonstrate expiratory flow limitation at rest. They also have reduced inspiratory muscle strength partly because of the mechanical disadvantage at which their inspiratory muscles operate and partly because some of them have generalized respiratory muscle weakness. 64 For these reasons, their maximal voluntary ventilation (MVV) and their ability to maintain elevated levels of VE for prolonged periods are both reduced. Therefore, the ventilatory demands of exercise involve a much greater

~

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5.8 21.6 3.7

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HR (beats/min) 0.83 1.12 1.35

R

0.24 3.36 14

Ve02 (Llmin) 40 33 0.83

Pac02

(mmHg)

5.2 88 17

VA

(Llmin)

0.34 0.18 0.53

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7.9 107 13.5

VE

(Llmin)

*Mean data of .5 normal men aged 36-43 years. MAX EXERCISE/REST is the ratio of each variable at maximal exercise to its value at rest. Abbreviations as in the footnote (p 619).

Rest Max Exercise Max Exercise/ Hest

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(Llmin)

V02

(Llmin)

Table 1. Normal Exercise Responses*

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VOLUME Figure 2. Spontaneous flow-volume curves at rest (dashed lines) and maximum exercise (dotted lines) as well as maximum flow-volume curves at rest (outer solid lines) in a normal subject and a patient with COPD. Total lung capacity is at the extreme right and residual volume at the extreme left in each curve. (From Leaver DC, Pride NB: Flow-volume curves and expiratory pressures during exercise in patients with cardiorespiratory disease. Scand J Resp Dis 52:23-27, 1971; with permission.)

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EXERCISE AND CHRONIC OBSTRUCTIVE PUL:\IONARY DISEASE

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fraction of MVV than in normal persons. Minute ventilation at end exercise CV EMAX) approaches or reaches their MVV. 12,47,50 In some patients VEMAX exceeds MVV measured over 12 or 15 seconds. 47 , 50 In contrast, normal persons usually have a VEMAXlMVV ratio less than 0.75 though higher values are seen in very fit athletes. The validity of MVV as a measure of ventilatory capacity is discussed later under Exercise Limitation. Normal persons demonstrate expiratory flow limitation only at very high work rates and then usually only during part of expiration. In contrast, expiratory flow limitation occurs even at rest in some patients with severe COPD. In others, flow limitation develops when VE increases at low exercise intensities and it occurs during most or all of expiration (Fig. 2).29, 40, 61 Accordingly, their ability to further increase VE is impaired. They increase end-expiratory lung volume during exercise, 19, 71 which is beneficial in allowing greater expiratory flow rates (Fig. 2), but it increases the load on the already weakened inspiratory muscles (see section on Respiratory Muscles). In contrast, end-expiratory lung volume decreases during exercise in normal persons. The importance of respiratory timing in allowing further increases in VEin COPD patients is discussed under Breathing Pattern. Some COPD patients have expiratory flow rates during exercise that exceed the maximum expiratory flow volume (MEFV) curve measured at rest;29, 61 some patients with severe COPD even exceed the MEFV curve during resting breathing. The possible reasons for this are listed in Table 2 and discussed below: 1. Thoracic gas compression: The development of positive intrathoracic pressure during expiration will compress alveolar gas and therefore expired volume measured at the mouth will underestimate the reduction of lung gas volume. 30 Accordingly, flow volume curves with volume measured at the mouth generally underestimate expiratory flow at a particular lung volume. This will be especially marked in COPD patients because of their high lung volumes. Because of the greater intrathoracic pressure during MEFV maneuvers, this effect should be much greater with MEFV curves than during spontaneous breathing at rest or during exercise. 2. Errors in absolute lung volume during exercise so that the exercise flow-volume curve is placed incorrectly in relation to the MEFV curve. 3. Bronchoconstriction during the MEFV maneuvers caused by inspiring to total lung capacity;21 the MEFV would therefore underestimate expiratory flow available for spontaneous breathing at rest or during exercise. This is the opposite of the airway hysteresis observed in normal humans. 4. Inhomogeneous lung emptying: In the presence of nonuniformity,

Table 2. Reasons (Mechanisms) Why Expiratory Flow May Exceed Maximum Expiratory Flow Volume Curve in COPD Thoracic gas compression Errors in absolute lung volume Bronchoconstriction after deep inspiration in MEFV maneuvers Nonuniform lung emptying Bronchodilation during exercise

626

CHARLES C. CALLAGHER

maximal expiratory flow at a particular lung volume will vary with the time required to reach that volume. 54 Thus maximal flow should be less during MEFV maneuvers than during spontaneous expirations commencing below total lung capacity. 5. Bronchodilation during exercise. There is evidence that this may occur in COPD patients. 16, 63 This might be due to altered airway mechanics or to increase in respiratory recoil. Stubbing and associates 71 found that the MEFV curve was not exceeded during submaximal exercise when lung volume was measured directly in a body plethysmograph. This indicates that mechanisms (1) and possibly (2) above are important. However analysis of the study of Crimby and Stiksa29 suggests that the other mechanisms may also be important. They measured MEFV curves in a body plethysmograph (dashed lines of Figure 3) and exercise flow-volume curves at the mouth. The exercise curves clearly exceeded the MEFV curves measured by body plethysmography in their patients CL, HL, AA, and NA (Fig. 3) with lesser increases in several other patients. This cannot be due to gas compression during exercise, because this should cause underestimation of expiratory flow at a given lung volume, that is, the opposite of the effect seen. These changes are unlikely to be caused by errors of lung volume placement (mechanism 2) because there was no change in total lung capacity as measured by magnetometers. 29 Stubbing et aF1 also found no change in total lung capacity during exercise in COPD patients when volume was measured by body plethysmography. The reason for different findings in the studies of Crimby and Stiksa29 and Stubbing et aF1 is unclear but it may be because the former involved maximal and the latter submaximal exercise. In conclusion, the fact that the MEFV curve is exceeded during exercise in some COPD patients may be partly due to gas compression effects, but bronchodilation during exercise, airway narrowing during MEFV maneuvers, and nonuniform lung emptying are probably important in some patients. Respiratory Muscles. Respiratory muscle function in COPD patients is discussed by Coldberg and Roussos elsewhere in this issue. Respiratory muscle function during exercise will be briefy reviewed here. The increase in VE with exercise in COPD patients and normal persons is associated with a relatively greater increase in tidal abdominal expansion than rib cage expansion. 19, 28 The increased abdominal contribution is due to a fall in end expiratory abdominal volume. However, unlike normal persons, exercising COPD patients increase end-expiratory rib cage volume, resulting in a net increase of end-expiratory lung volume. 19, 28 This pattern of reduced abdominal volume with increased rib cage volume implies that abdominal muscles are contracting during expiration. The increased end inspiratory lung volume with exercise is almost completely due to increased rib cage volume with abdominal volume at end inspiration showing essentially no change. Because diaphragm length and configuration are related to abdominal wall expansion, the pattern of abdominal movements with exercise serves to optimize diaphragm function despite the increase in endexpiratory lung volume. However, the marked chest wall distortion that occurs significantly increases the elastic work of breathing.

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Figure 3. Maximum expiratory and inspiratory flow-volume curves with volume measured at the mouth (continuous lines) and in a body plethysmograph (dashed lines) for 12 patients with COPD. Each patient's spontaneous flow-volume curves at rest and maximum exercise are also shown. Total lung capacity is at the extreme left and residual volume at the extreme right in each case. See text for discussion. (From Grimby G, Stiksa J: Flow-volume curves and breathing patterns during exercise in patients with obstructive lung disease. Scand J Clin Lab Invest 25:303-313, 1970; with permission.)

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CHARLES C. CALLAGHER

The increase of net inspiratory muscle pressure with exercise in patients with severe COPD exceeds the increase in transdiaphragmatic pressure while abdominal pressure falls. 7. 19 Therefore intercostal or "accessory" inspiratory muscles or both make a major contribution to the increased VE of exercise in these patients. This becomes very important when these muscles are also required for locomotor tasks during arm exercise-especially unsupported arm exercise. This results in greater limitation of arm than of leg exercise in many patients with severe COPD. IO Using abdominal pressure-chest wall volume plots, Dodd et aP9 have clearly documented abdominal and expiratory rib-cage muscle recruitment during expiration in exercising COPD patients. The rapid relaxation of these muscles at the start of inspiration has a net inspiratory effect. Patients with COPD have inspiratory muscle weakness. 64 Because of altered respiratory mechanics, they have to generate much greater inspiratory pressures than do normal persons for the same level of ventilation. The rise in end-expiratory lung volume with exercise increases the elastic load against which the inspiratory muscles operate as well as reducing their pressure generating capacity. The fall in Pa 02 and rise in PaC02 , which many develop during exercise, may further impair inspiratory muscle function. It has therefore been suggested that inspiratory muscle fatigue may develop during exercise in patients with COPD. 59 Several studies using esophageal or surface electrodes have shown changes in the electromyographic frequency spectrum that are consistent with diaphragmatic fatigue. 27 • 59 However, recent evidence indicates that such changes are not specific to fatigue. 2 Similarly, the development of abdominal paradox7 during exercise in patients with COPD does not confirm fatigue because such changes are not specific to fatigue. 73 Because inspiratory muscle fatigue causes rapid shallow breathing,23 it seems reasonable that patients with COPD should have relative tachypnea (compared to exercise breathing pattern) during recovery from maximal exercise if fatigue really limits their maximal exercise performance. In studying seven patients with severe COPD no difference was found between exercise and recovery breathing patterns,24 which provides evidence against the development of fatigue with exercise. This study is also not conclusive because fatigue is only one of many factors that may alter breathing pattern (that is, it is possible that the tachypneic influence of fatigue was offset by another influence that tends to increase tidal volume). Other evidence regarding the importance of inspiratory muscle dysfunction in exercise performance comes from attempts to unload them or to improve their strength and endurance. Pardy and associates 59 showed improved exercise performance after inspiratory muscle training in those patients who initially developed electromyographic evidence (see above) of diaphragmatic fatigue during exercise. While others:l also found improved exercise performance in COPD patients after ventilatory muscle training, other studies did not or found similar changes in control groups. 11. 22 Because of differences in patient selection, training protocols, and study end points as well as the fact that some but not all studies had control groups, no definite conclusions regarding the benefits of training are possible at this time. This topic is reviewed elsewhere. 58 Raimondi et al 63

EXERCISE AND CHRONIC OBSTRUCTIVE PUL~IONARY DISEASE

629

examined exercise tolerance in patients with COPD breathing air and when airflow resistance was reduced by breathing 21 per cent oxygen in helium. There was no change in exercise performance during maximal incremental exercise or during constant work exercise at 70 per cent of maximum work rate. Because pleural pressure was not measured, it is not clear how much the inspiratory muscles were unloaded in their study. Using the unloading device developed by Younes,80 O'Donnell and co-workers applied continuous positive airway pressure (CPAP) to COPD patients and found an improvement of endurance time at submaximal exercise. 56 This is the most direct evidence to date that inspiratory muscle function contributes to exercise limitation in COPD patients. It is not clear whether it also contributes to limitation of maximal exercise performance. Petrof et al 60 have shown that CPAP does unload inspiratory muscles in such patients. It is not clear to what extent improved exercise endurance is due directly to inspiratory muscle function (for example, delaying inspiratory muscle fatigue or reducing the O 2 cost of breathing so that O 2 delivery to limb muscles improves) or to reduced respiratory discomfort due to unloading. The application of CP AP shows promise as a possible means of improving exercise performance in COPD patients and further studies are warranted. Breathing Pattern. The increase in ventilation with exercise in normal persons initially occurs through increases in both tidal volume (VT) and respiratory frequency (F). However at high work rates VT stabilizes at ~pproximately 50 to 60 per cent of vital capacity and further increases in VE are due to increasing F alone. There may even be a progressive fall in Vr as VE increases further at high work rates. 24 The same general pattern occurs in COPD patients,24, 5.5 but VT is less and F is greater than in normal persons at similar levels of VE' However, this is not surprising in view of their altered respiratory mechanics. The ratio of peak exercise tidal volume to vital capacity is usually similar to that of normal persons,25, 70 although some patients with very severe COPD may have a slightly smaller ratio. 25 The ratio of inspiratory duration to total breath duration (inspiratory duty cycle) in normal persons increases from approximately 0.35 to 0.40 at rest to as high as 0.50 to 0.55 at maximal exercise. In contrast, patients with moderate or severe COPD show little or no increase in inspiratory duty cycle with exercise. 19, 66 This is beneficial in allowing greater time for expiration, thus facilitating further increases in VE; however, it increases the load on the inspiratory muscles. Patients with less severe COPD do increase the inspiratory duty cycle to some extent with exercise. 67 Blood Gases. Patients with COPD often have a reduced Pa02 at rest and some patients develop even greater hypoxemia with exercise. 33, 62, 78 Not surprisingly, oxygen de saturation during exercise is generally most marked with increasing disease severity. 62, 70 Jones·33 found that patients with predominant emphysema showed a fall of Pa02 with exercise while it usually increased in patients with little or no evidence of emphysema. Studies using the multiple inert gas technique have shown that the increased hypoxemia with exercise is due to (1) the effects of fall in mixed venous P 02 on low ventilation-perfusion lung units and shunt (2) hypoventilation in some patients. 15, 74 There was no significant change in the ventilationperfusion distribution with exercise in these studies and no evidence of

630

CHARLES C. CALLACIIER

diflusion limitation. However, ventilation-perfusion distribution must change in those who improve or do not change Pa02 with exercise. Arterial O 2 desaturation during exercise is a ventilatory stimulant, so that VE for a given V02 or VC02 will be increased. Exercise de saturation is unlikely in patients with a normal or near normal diffusing capacity (>55 per cent predicted),57 but it is difficult to predict which patient will desaturate from resting measurements. The severity of de saturation with bicycle exercise may underestimate that with walking in some patients.]3 The ratio of physiologic dead space to tidal volume (V DSIVT) is increased in COPD patients and, though it falls slightly during exercise in some, it remains much higher than in normal persons. 3:l , 55, 70 Therefore, if alveolar ventilation is to remain normal, total ventilation must exceed that of normal persons (Equation 4); the increased VDSIVT is the major reason for the increased ventilatory response to exercise of these patients. However the compensation of increased VE for increased VDslVT is rarely completepatients with moderate or severe COPD frequently increase PaC02 with exercise. 33, 43, 70 Cardiovascular Function. The pulmonary vasculature in COPD is discussed by Matthay elsewhere in this issue. The cardiovascular adjustments to exercise will be briefly reviewed here. COPD patients usually ~ave a normal cardiac output (QT)-V02 relation during exercis~,44, 48, 70, 78 but QT at end exercise is reduced in proportion to the reduced V02MAX. This fact has often been cited as evidence of a normal cardiac response to exercise in COPD, but this is invalid because the V02-QT relation is a poor index of cardiac dysfunction. For example, many patients with congestive heart failure have a normal V02-QT relation up to their (reduced) maximal

QT'77

The normal QT response implies that the O 2 content difference between arterial and mixed venous blood is normal or near normal in exercising COPD patients. Up to 70 per cent of arterial O 2 content is extracted by the tissues at end exercise,62, 78 which is similar to that of normal untrained persons. However, fractional O 2 extraction may be less than normal in some COPD patients. 62 The significance of this is unclear. While the QT response to exercise is normal, stroke volume is less and heart rate (HR) is greater than in normal persons at the same V02. 44, 48, 55, 70 However, the slope of the HR-V02 relation is usually normal in COPD patients 55, 70 and HR at end exercise is usually less than normal24, 34, 55, 70 though it may be near normal or even normal in some patients with relatively mild or moderate disease. 50 Because the fractional reduction in maximal HR is less than that of V02MAX, oxygen pulse (that is, V02 divided by HR) at end exercise is low in COPD patients. . Because of their increased pulmonary vascular resistance and normal QT response, patients with COPD have much higher pulmonary artery pressures during exercise than normal persons. 44, 46, 62 This is the major reason for their impaired right ventricular function. Right ventricular dysfunction during exercise occurs in the majority of patients with moderate or severe COPD 6 , 46, 49 and in as many as 50 per cent of those with mild disease (defined as FEV] ;::: 65 per cent predicted).49 Left ventricular

EXERCISE AND CHHONIC OBSTHUCTIVE PULMONARY DISEASE

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dysfunction during exercise is seen in some COPD patients who have no evidence of primary cardiac disease. 6 , 49 Metabolic Acidosis. It is well recognized that normal persons and patients with cardiovascular disease develop Significant metabolic acidosis during exercise. It has often been assumed that COPD patients develop exercise limitation at work rates lower than those associated with metabolic acidosis. However, it is clear that many COPD patients develop metabolic acidosis during exercise. 34, 36, 62, 68, 69, 72 The "anaerobic threshold" has been detected nonirlVasively by conventional or modified gas exchange measurements in a number of studies. IS, ,36, 55, 72 COPD patients may have quite marked metabolic acidosis at end exercise. Servera and co-workers 68 found an average arterial lactate at end exercise of 7.6 mmol per L in 26 patients. Sue et aF2 found an average decrease in arterial standard bicarbonate with exercise of 4.7 mEq per L in 14 COPD patients, which was only slightly smaller than that of normal persons (6.6 mEq per L). Eight other patients in their study had no significant metabolic acidosis. Other authors also have reported significant metabolic acidosis at end exercise. 62, 69 Metabolic acidosis is a respiratory stimulant and may therefore further increase the ventilatory demands of exercise in patients with COPD. This could contribute to exercise limitation because of impaired ventilatory capacity. However, many COPD patients do not show a disproportionate increase in VEin response to metabolic acidosis 36, 62, 70 because of their ventilatory impairment, but some may do so. Examination of the study of Marcus et al (Figure 8 of reference 48) indicates that the Vc V02 slope increased in several COPD patients after they reached the anaerobic threshold. Even in those who do not increase VE as expected, metabolic acidosis may contribute to exercise impairment because of increased CO 2 production due to buffering of acid and, if severe, because of the effects of acidosis on cellular function. If VE does not increase appropriately, the former will cause PaC02 to rise. As might be expected, metabolic acidosis at maximal exercise generally is greatest in patients with the least impairment of exercise performance. 68, 70 This suggests that lactic acidosis in exercising COPD patients is derived largely from working limb muscles, not respiratory muscles. However, acidosis may occur at lower work rates than normal in some patients with severe COPD. 48 This is supported by the finding of greater blood lactates than in normal persons at similar submaximal work rates. 34, 6[) The possible mechanisms include unfitness, cardiovascular dysfunction, and lactate production by respiratory muscles. However, N ery et al 55 found a normal "anaerobic threshold" in their patients who had a threshold. The prevalence of a low "anaerobic threshold" in COPD patients remains to be determined. Exercise (limb) training reduces metabolic acidosis at submaximal work rates. 9 It is possible that limb muscle training, by reducing the ventilatory stimulation of metabolic acidosis, may improve exercise performance in some COPD patients. Preliminary data indicate that this is SO.8 Symptoms. It is well known that patients with COPD have exertional dyspnea, but the importance of other symptoms has received too little attention. Limb tiredness and fatigue are dominant symptoms at end

632

CHARLES G. GALLACHER

exercise in many COPD patients and there is evidence that, in general, this may be more common with less severe exercise impairment. Jones et aP5 recently reported that exercise capacity averaged 54.7 per cent of predicted normal in COPD patients, with breathing discomfort as the limiting symptom at end exercise. Exercise capacity averaged 65.1 per cent in those with predominant leg discomfort. All 26 patients (mean FEV! 1. 8 L) studied by Servera et al 68 had aching legs at end exercise and only 8 complained of dyspnea. The main symptom given for stopping incremental exercise in the study of Mahler and Harver47 was leg fatigue in 18 patients, breathlessness in 14, both leg fatigue and breathlessness in 7, and back pain in 1. Those who stopped due to breathlessness had greater impairment of exercise performance (Vo2 MAX 14.4 versus 25.4 ml per kg per min), pulmonary function tests, and inspiratory muscle strength than those who stopped because of leg fatigue. In patients with severe COPD, dyspnea is usually the dominant symptom at end exercise. 55, 70 However, viewing these symptoms as "all or nothing" phenomena is an oversimplification. The intensity and other characteristics of these symptoms can-and shouldbe assessed quantitatively. 4 The mechanisms underlying the symptom of breathlessness remain incompletely understood. Killian and Campbell have suggested that breathlessness may be due to the perception of respiratory muscle effort.38 This is supported by studies showing a strong correlation between indices of inspiratory motor output and exertional dyspnea in normal persons and patients with chronic lung disease. 20. 4!. 52 This topic is reviewed elsewhere. 38 The high prevalence oflimb fatigue at end exercise must focus attention on limb muscle function in COPD. There is evidence that limb muscle strength may be reduced in patients with COPD.! The most likely causes are malnutrition and inactivitv. Studies are needed to determine whether the mechanisms underlying e;ercise limitation vary with different exertional symptoms in COPD patients. The possible role of limb muscle function in exercise limitation in COPD merits study. Exercise Limitation. Knowledge of the physiologic factors that directly contribute to exercise limitation in COPD patients is important in its own right and may have major therapeutic implications. A detailed discussion of this important topic is not possible in this brief review. The main factors limiting exercise tolerance are likely to vary among COPD patients. However most of the available evidence supports the view that ventilatory factors usually contribute to exercise limitation in COPD patients. But other factors may also be contributory. There has been little discussion regarding the criteria that should be used to determine factors that limit exercise tolerance in these patients. The following are suggested as appropriate criteria; they may equally well be applied to other patient groups and to end points other than exercise capacity: 1. Reducing the stress (demand/capacity) on that physiologic function without changing the stress on other physiologic functions improves exercise capacity. The converse, that is, increasing stress on that function alone reduces exercise capacity, may also be a valid criterion but only if it involves a relatively small increase in stress; any physiologic function that is not

EXEHCISE AND CHHONIC OBSTHUCTIVE PULI\IONAHY DISEASE

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normally limiting to exercise may eventually become limiting when subjected to a very high stress. 2. The maximum capacity of that physiologic function is used at end exercise while all other physiologic functions are operating below maximal capacity. It must be emphasized that a physiologic function that limits one form of exercise may not limit another (for example, incremental versus constant load exercise). The term physiologic function is used here in a broad sense also to include the sensations associated with exercise. The capacity of a physiologic function refers to its capacity at that time during exercise; this may be very different from the capacity at rest. Many studies have used the general approach of criterion 2 above to examine exercise limitation in COPD patients. They have usually expressed VE at maximal exercise (V EMAX) as a fraction of maximal voluntary ventilation (MVV), an index of maximum ventilatory capacity. In some studies, MVV has been measured directly over 12 seconds, 15 seconds, or 4 minutes. For example VEMAX averaged approximately 91 per cent and 88 per cent of 15-second MVV in two studies l2 , 50 and 91 per cent of 12-second MVV in another. 47 Clark et aP2 found that average VEMAX (30.9 L per min) was closer to 4-minute MVV (32.6 L per min) than to 15-second MVV (36.4 L per min) in seven patients with COPD. These studies show that VEMAX obviously represents a much greater fraction of resting MVV in COPD patients than in normal people and they provide evidence that these patients are probably breathing near to their MVV at maximal exercise. However, they must be interpreted with caution because measured MVV may not represent maximal ventilatory capacity (M VC) at end exercise for several reasons. First, MVV varies significantly with tidal volume and endexpiratory lung volume and these may be quite different between the MVV maneuver and exercise (Gallagher et aI, unpublished observations). Second, the pattern of respiratory muscle activation during exercise is very different from-and more efficient than-that during MVV maneuvers in normal humans 39 and this is probably also true for COPD patients. Finally, if bronchodilation occurs in exercising COPD patients (see section on Ventilation and Pulmonary Mechanics), resting MVV may underestimate MVV at end exercise. In short, MVV (12 seconds, 15 seconds, 4 minutes, and so forth) as currently measured is probably a poor index of ventilatory capacity at end exercise. This is supported by the finding of VEMAX greater than MVV in some patients;47, 50 obviously MVV underestimated true MVC in these patients. Therefore, studies measuring the VEMAXlMVV ratio do not provide definitive evidence regarding ventilatory limitation to maximal exercise in COPD patients. Studies in which MVV is predicted from resting pulmonary function test results are even less useful in this regard because such predictions are not precise at present. While many studies have attempted to predict VEMAX in COPD, it must be emphasized that such equations do not necessarily predict MVC. More direct evidence regarding the role of ventilatory factors in exercise limitation comes from studies that use the general approach of criterion 1 above. Brown et a!5 increased the ventilatory demands of exercise

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by adding external dead space and found that VozMAX and peak work rate fell while minute ventilation at end exercise increased slightly. While this shows the importance of ventilatory limitation of exercise, the question remains whether this is primarily related to expiratory flow limitation, inspiratory muscle dysfunction, or both. At least with constant work-rate exercise, inspiratory muscle dysfunction appears to be the major cause of ventilatory limitation. This is because of the demonstrated improvement in endurance time with inspiratory muscle unloading56 (see section on Respiratory Muscles). Although ventilatory factors contribute to exercise limitation in COPD patients, it is unclear whether this is due to ventilatory limitation per se or to respiratory discomfort. In other words, do they stop exercise because of respiratory discomfort before all their ventilatory capacity is utilized (which could be a protective mechanism) or because they truly have reached their physiological limit? This question is unanswered at present. The above discussion relates to factors that may directly contribute to exercise limitation. However, many factors may also contribute indirectly. Any factor that increases ventilation (Equation 4) for a given work rate (for example, higher V DSIVT' higher alveolar ventilation due to hypoxia, and so forth) will cause ventilatory factors to limit exercise at a lower work rate. Because there is great intersubject variability in the variables to the right of Equation 4, it is not surprising that there is not a close correlation between ventilatory capacity and VozMAX in COPD patients. While ventilatory factors directly contribute to exercise limitation in COPD patients, the importance of other factors (for example, limb muscle weakness) also merits investigation.

CLINICAL EXERCISE TESTING The use of exercise testing as a tool in patient assessment has increased markedly in recent years. Clinical exercise testing is useful because it documents the physiologic and subjective responses to exercise. Patients' symptoms usually develop or become most marked during exercise. It is not surprising that testing patients when their symptoms are most marked would aid in clinical assessment. Some important clinical uses of exercise testing are listed in Table 3. Exercise testing in the individual patient frequently addresses several of these goals. For example, exercise testing in a patient with COPD might: Table 3. Uses of Clinical Exercise Testing Assessment of exercise capacity Aid to diagnosis of cause for exercise limitation/symptoms Assessment of factors contributing to exercise limitation Prescription of exercise training program Assessment of need for specific therapy that may improve exercise performance, e.g., oxygen therapy during exercise Assess response to therapy

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1. Detect incrcased Vm-work rate relation due to poor exercise tech-

niquc.

2. Assess impairment of maximal exercise capacity, that is, reduction of Vo2MAX. Despite numerous studies, it is not possible to predict accurately V02MAX in an individual patient from measurements at rest or submaximal exercise or even from maximum work rate. When assessment of cxercise capacity is desired, Vo2MAX should be measured. 3. Determine factors that contribute to increased VE during exercise (for example, increased V DS/VT' hypoxia, metabolic acidosis). 4. Detect nonventilatory factors that contribute to exercise limitation. 5. Allow prescription of an exercise program.

The potential uses of exercise testing vary from patient to patient and those listed above are only examples. Methods. Clinical exercise tests vary in complexity from those measuring only one or two variables to those in which multiple measurements including intracardiac and intravascular pressures are made. The type of measurements made during an exercise test must depend on: 1. Complexity of information desired, which depends on the goal(s) of

the test it

2. Equipment available 3. Accuracy of equipment available and familiarity of personnel with

4. Safety

There is obviously no point in measuring intravascular pressures or sampling blood gases if the test is simply to assess degree of exercise limitation. All equipment, including the cycle ergometer or treadmill, must be accurate under the operating conditions of the exercise test and should be calibrated regularly under conditions that closely simulate those of the test. For example, devices that measure respired flow and volume must be accurate ovcr the flow range expected during exercise; they should have a flat frequency response up to 12 cycles per second. It is very important that pneumotachographs be calibrated with the same gas mixture as that measured during the test; errors of approximately 12 per cent occur when they are calibrated with room air and used with 100 per cent oxygen. The commercial availability of computerized exercise systems has been a significant advance but has wrongly led to complacency regarding the need for calibration. Such systems may have significant errors,51 that may markedly impair the usefulness of a clinical exercise test. All such systems-like all methods of measurement-should be calibrated in the laboratory where they will be used. There are several different types of exercise tests. 32 When objective assessment is required, the most useful is generally incremental symptomlimited (maximum) exercise on a cyc~e ergometer or treadmill. Th~ measurements made most commonly are V 02 ' V C02' external work rate, V E' and breathing pattern, heart rate, blood pressure, electrocardiogram, arterial O 2 saturation (oximetry), and symptoms. End tidal PC0 2 may be measured as an indirect index of PaC02 ' but it differs significantly from Pa C02 during

636

CHARLES G. GALLAGHER

exercise. Exercise testing protocols and equipment are discussed elsewhere ..32. 76. 77 Diagnostic Value of Exercise Testing. Clinical exercise testing is frequently used to help confirm that a particular disease accounts for a patient's exercise limitation or to determine the major cause(s) for exercise limitation when more than one disease is present. It is also diagnostically useful in patients with unexplained symptoms who have little or no evidence of disease at rest. The clinical utility is maximized when the interrelationships between different exercise variables are examined at a number of work rates. 79 Some common patterns of exercise responses in six cardiorespiratory disorders are shown in Table 4. These should be regarded as typical responses; no pattern is invariable in any disease state. The responses shown are in comparison to the average response of normal people of the same sex, age, and body size (for example, height). Normal predicted values are provided elsewhere. 32. 76 Patients with cardiac disease frequently have altered respiratory responses to exercise and patients with COPD or other respiratory diseases usually have abnormal cardiovascular responses to exercise. For example, both heart rate and VE at submaximal work rates are increased in most patients with cardiac or respiratory disease. The former is usually associated with an impaired stroke volume response to exercise. The latter is related to increased VDSIVT in most and to hypoxia or excessive metabolic acidosis, or both in some. Relatively few studies have specifically examined the diagnostic value of measurements made during exercise testing. For example, the increased VE at submaximal work in COPD patients is very important in understanding their physiologic response to exercise, and is it clinically useful in determining whether a particular patient's exercise limitation is primarily due to COPD or mitral valve disease? However conclusions can be made regarding the utility of some common exercise variables in the differential diagnosis of the disorders listed in Table 4. The finding of an elevated HR at submaximal exercise is of little diagnostic value because it frequently occurs in all of these disorders. However, examination of the HR-Vo2 slope may be useful because it is Table 4. Common Patterns of Exercise Response COPD

Maximal V02 HR at submaximal work Maximal HR VE at submaximal work Peak VE/MVV Peak VTIVC Arterial O2 de saturation

t

t t

rarely N or N

t

t t

N or t + or -

t

RLD

CHF

'VlVD

PVD

UNF

t

t t

t t

t t t t

t t

or N

t t t

N

+

t

or N

N

N N

N N

t

t

N ?N

+

t

N above AT Nit N

Abbreviations: COPD = chronic obstructive pulmonary disease; RLD = restrictive lung disease; CHF = congestive heart failure; MVD = mitral valve disease; PVD = pulmonary vascular disease; UNF = unfitness. VD' = 0, uptake; HR = heart rate; VE = minute ventilation; MVV = maximal voluntary ventilation; VT = tidal volume; VC = vital capacity; t , N or t refer to an increase, no change or decrease compared to normal response; + or - refers respectively to the presence or absence of arterial 0, desaturation with exercise.

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usually elevated in mitral valve disease and normal or near normal in COPD. 55 Maximal HR has limited diagnostic value because it is frequently reduced in patients with congestive heart failure or pulmonary vascular disease as well as patients with primary lung disease, that is, a reduced maximal HR does not exclude cardiac limitation. Elevated VEat submaximal exercise is found in most patients with cardiorespiratory disease and therefore this is of little diagnostic value. Despite the previously discussed reservations regarding the validity of maximal voluntary ventilation (MVV) as a measure of ventilatory capacity, the VEMAXlMVV ratio is diagnostically useful. It is elevated in patients with COPD and less so in patients with restrictive lung disease; it is usually normal or near normal in patients with cardiovascular disease. Patients with cardiorespiratory disease usually have a smaller tidal volume (VT) during submaximal exercise and a smaller peak exercise VT (VTMAX) than do normal persons. However, the reductions in VTMAX are largely related to their reduced vital capacity (VC), that is, to their altered respiratory mechanics. 26 It was recently shown that the VTMAXlVC ratio is similar in patients with COPD, restrictive lung disease, bronchial asthma, and cardiac disease (left ventricular dysfunction or mitral valve disease).26 Therefore, measurement of the VTMAXlVC ratio is of little or no help in the differential diagnosis of cardiopulmonary disease at present. 26 Gallagher and Younes 24 reported the development of relative rapid shallow breathing (possibly due to the development of mild pulmonary edema with exercise) during recovery from maximal exercise in patients with cardiac disease, but not in patients with pulmonary disease. They suggested that this may be diagnostically useful, but further studies are needed to examine this. The development of arterial oxygen de saturation during exercise is diagnostically useful because it occurs frequently in patients with COPD, interstitial lung disease,37 and pulmonary vascular disease,14 including right to left shunts. Exercise de saturation does not occur in patients with congestive heart failure,65 mitral valve disease, or unfitness. It does occur with very heavy exercise in some super-fit athletes,17 but this does not pose a diagnostic problem. The anaerobic threshold is typically low in patients with cardiac disease, pulmonary vascular disease, peripheral vascular disease, or anemia. 75 It is also low in some very sedentary subjects. As discussed above, the anaerobic threshold appears to be normal in some, but probably not all, COPD patients. Other aspects of the usefulness of exercise testing as a diagnostic tool are discussed elsewhere. 45, 79 There are insufficient data regarding the utility of many exercise variables in the assessment of cardiorespiratory and other diseases. Accordingly, while exercise testing is a very useful clinical tool, it is less useful than it should be. Further studies that examine the clinical value of different exercise variables are needed. ACKNOWLEDGMENTS I am grateful to Dr. Magdy Younes for having initially stimulated my interest in exercise physiology and to Mrs. Theresa Dufault for her careful preparation of this manuscript.

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CHARLES G. GALLAGHER

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Address reprint requests to Charles G. Gallagher, MD Division of Respiratory Medicine University Hospital University of Saskatchewan Saskatoon, Saskatchewan S7N OXO Canada