Exercise Capacity and Ventilatory, Circulatory, and Symptom Limitation in Patients with Chronic Airflow Limitation 1- 3

KIERAN J. KILLIAN, PIERRE LEBLANC, DAVID H. MARTIN, EDITH SUMMERS, NORMAN L. JONES, and E. J. MORAN CAMPBELL

Introduction

The symptoms most frequently cited as limiting exercise are referred to the peripheral muscles and to the act of breathing. There is uncertainty about the neurophysiologic mechanism through which symptoms are generated and the exact nature of the symptoms. The purpose of the present study was to examine the relationship between the symptoms of dyspnea and peripheral muscular effort and the physiologic factors thought to underpin their generation. To examine these relationships we formally identified the self-reported intensity of dyspnea and leg effort at maximal exerciseand compared it with the ventilation and heart rate expressed as percentage of capacity in individual patients with chronic airflow limitation (CAL) and in normal control subjects. The rationale was as follows. The existence of a ventilatory boundary is an intuitively reasonable explanation for exercise intolerance in chronic airflow limitation and is supported by several studies (1-4). Dyspnea has been traditionally thought to reflect the ventilation in relationship to capacity. In a similar manner, the sense of peripheral muscle effort reflects power output in relationship to capacity to perform work. Cardiovascular factors, reflected in heart rate relative to capacity, have been traditionally thought to limit the muscular performance of large muscle groups. Patients with CAL and matched normal control subjects underwent an incremental exerciseprotocol to maximum tolerance. They rated the perceptual magnitude of discomfort in the act of breathing (dyspnea) and the effort associated with the leg muscles, and maximum heart rate relative to heart rate capacity. (HRmax/HRcap) and maximum minute ventilation as a percentage of maximum achievable minute ventilation (VEmax/ VEcap ) were measured at maximal exercise. The symptom rated at the higher in-

SUMMARY Dyspnea, leg effort (Borg 0 to 10 scale), ventilation, and heart rate (VEm811NEcap; HRm811IHRcap expressed as a percentage of capacity) were measured at maximal exercise (cycle ergometer) In 97 patients with chronic airflow limitation (CAL) (FEV, 46.6 ± 14.23% of predicted) and compared with 320 matched control subjects. Patients with CAL achieved a maximum power output of 86 ± 39.5 W (60 ± 23.2% of predicted) compared with 140 ± 37.5 W (98 ± 14.5% of predicted) In controls (p < 0.0001), VEm811NEcap was 72 ± 19.3% compared with 53 ± 18.6% (p < 0.0001), and HRm811/HRcap was 76 ± 13.5% compared with 82 ± 13% (p < 0.001). These findings were expected. The median Intensity of dyspnea was 6 (severe to very severe) and leg effort was 7 (very severe) In both groups, and these findings were unexpected. The patients with CAL were handicapped by an Increase In both dyspnea and peripheral muscular effort relative to the actual power output. The rating of dyspnea exceeded leg effort In 25 (26%) of CAL veraus 69 (22%) control subjects: the rating of leg effort exceeded dyspnea In 42 (43%) CAL and 117(36%) control subjects; both were rated equally In 30 (31%) CAL and 134 (42%) control SUbjects, respectively (NS). VEm811NEcap and HRm811/HRcap were not significantly different In those limited by dyspnea, leg fa· tigue, or a combination of both. All values are expressed ± SO. AM REV RESPIR DIS 1992: 148:935-940

tensity was taken to be limiting, and if rated equally they were considered colimiting. In this manner we were able to look at the physiologic factors traditionally considered limiting in relationship to symptom limitation. Methods

Subjects A group of 97 patients (75 males and 22 females) and 320 normal control subjects (218 males and 102 females) were selected over a period of 12 months from referrals to the exercise laboratory (table 1). Patients had a clinical diagnosis of chronic airflow limitation, FEV, less than 80070 of predicted (5), FEVlVC (vital capacity) ratio less than 60%; no history of congestive cardiac failure; no chest pain or exercise electrocardiographic changes suggesting myocardial ischemia; and no nonrespiratory medical disorders that might influence exercise performance. Patients limited by nonspecific discomfort with the equipment (mouthpiece and bicycle), arthritic symptoms, or claudication wereexcluded. All patients meeting these admission criteria were included. The control group selected over the same time period had normal exercise capacity; normal spirometry,with FEV, and VC above 80% of predicted and FEV,/VC above 75% (6); no chest pain and/or electrocardiographic evidence of isch-

emia; and no known disease. All subjects meeting these criteria within the age and height range of the patients with CAL were included. In the control subjects exercisetesting was performed for a variety of nonclinical reasons: (1) spouses of patients entering a cardiac rehabilitation program; (2) experimental studies on the effect of aging and exerciseon osteoporosis; (3)experimental studies on muscle strength and endurance training with aging; (4) volunteers for normal standards for incremental exercise; (5) screening before entering exercise training programs; and (6) a variety of other miscellaneous reasons.

Procedure On arrival in the exerciselaboratory the procedure and attendant risks were explained, and written informed consent was obtained. Height, weight, spirometry (pVC and FEV,), (Receivedin originalform September 21,1989and in revisedform March 9, 1992) , From the Department of Medicine, McMaster University Medical Centre, Hamilton, Ontario. Canada. 2 Correspondence and requests for reprints should be addressed to Kieran J. Killian, Ambrose Cardiorespiratory Unit, McMaster UniversityMedical Centre, 1200Main Street West, Hamilton. Ontario, Canada.

935

936

KILLIAN, LEBLANC, MARTIN, SUMMERS, JONES, AND CAMPBELL

TABLE 1 CHRONIC AIRFLOW LIMITATION: PATIENT AND NORMAL CONTROL CHARACTERISTICS'

CAL male, n

= 75

CAL female, n Normal male, n

= 22 = 218

Normal female, n

• CAL, n

= 102

Age (yr)

Height (em)

64 (9.5) 62 (12.6) 63 (4.1) 63 (3.9)

171 (5.5) 160 (5.8) 173 (6.8) 160 (7.0)

Weight (kg)

FEV, (L)

VC (L)

FEVNC (%)

VE••

VI••

(LIs)

(LIs)

MIP (em H2O)

MEP (em H2O)

rr

1.5 (0.52) 1.2 (0.39) 3.4 (0.49) 2.5 (0.42)

3.0 (0.82) 2.3 (0.58) 4.2 (0.60) 3.0 (0.51)

50 (9.1) 52 (7.1) 82 (4.3) 83 (4.7)

1.3 (1.15) 1.3 (1.39) 4.7 (1.31) 3.6 (1.02)

4.3 (1.74) 3.0 (1.59) 6.0 (1.67) 4.1 (1.21)

66 (27) 50 (24) 89 (23) 59 (20)

97 (27) 73 (24) 112 (22) 80 (25)

(13.6)

63 (12.6) 82 (10.8) 69 (11.2)

= 97; normal control, n = 320. Mean (SO).

maximum inspiratory and expiratory flowvolume curve, maximum inspiratory pressure at functional residual capacity, and expiratory pressure at total lung capacity were measured. The exercise tests were performed on an electrically braked cycle ergometer with electrocardiographic monitoring under the supervision of a physician and with defined criteria for stopping, such as serious cardiac arrhythmias, hypotension, and electrocardiographic changes; termination of exercise by the supervising physician was not required by any patient. Before exercise,while seated comfortably on the cycle ergometer (Elema illl 370; Elema-Schonander, Stockholm, Sweden) patients breathed for 1 min through a unidirectional valve (Hans Rudolph) with the expired air going to a universal exercise testing system (Sensorjdedics'" Horizon System; SensorMedics Corp., Anaheim, CA). After 1 min of loadless pedaling, subjects cycledat 60 rpm at an initial power output of 16.3 W. Patients wereencouraged to continue exerciseuntil exhaustion (6). At the end of each minute the work load wasincreased by 16.3 W. Heart rate, blood pressure, ventilation, respiratory rate, and tidal volume weremeasured. Immediately following the completion of the test they were asked whythey stopped and werethen requested to estimate the intensity of discomfort with breathing and the intensity of leg effort at their maximum using the Borg scale (7, 8). Symptoms referred to the legs and breathing were considered limiting by all subjects. The perceived intensities of discomfort with breathing and of leg effort were estimated separately by matching the subjective estimates of intensity to a number from 0 to 10; the numbers were tagged to simple descriptive terms, such as slight, moderate, and severe, as shown in figure 1. Maximum exercisecapacity (W cap) was expressed relative to that predicted using the equations of Jones and coworkers (9); maximum heart rate was expressed relative to the predicted heart rate capacity (210 - 0.66 x age). Maximum ventilation was expressed as a percentage of the maximum achievable ventilation. VEcap was calculated from the maximum tidal volume achieved during exercise (VTmax) and the maximum rate at which this volume could be inspired and expired. VTmax and inspiratory flow recorded at midinspira-

tion in the flow-volume curve (Vrso) wereused to derive minimum inspiratory duration (1l:); VTmax and expiratory flow were used to determine minimum expiratory duration (Th). 1l: plus Th yielded the minimum duration for the total breath (Ttot), from which maximum breathing frequency (fb) was derived (6O/Ttot); fbVT yielded maximum achievable ventilation (VEcap). The flow rates adopted for the calculation of VEcap were chosen because lung volume has a dominant effecton expired flow that is reflected in the FEV,. VIso is well maintained over a wide range of inspired volume, and both are reproducible and easy to measure. This approach to ventilatory capacity was adopted instead of maximum voluntary ventilation (MVV), because this measurement is dependent on patient cooperation, varies with the adopted tidal volume and frequency, and in practice is highly variable. The commonly used indirect estimation of ventilatory capacity, FEV, x 35, or other related estimates (10) proved unreliable because ventilation at W cap exceeded FEV, x 35 in 33010 of the patients and similar results have been found in previous studies (1).

A nalysis oj Results Wcap%, VEmax/VEcap, HRmax/HRcap, and the perceived intensity of dyspnea and leg effort were compared using an unpaired t test between the CAL and normal control groups. Subjects weredivided into subgroups: (1)dyspnea, perceptual magnitude of dyspnea exceeded leg effort; (2) leg fatigue, perceptual magnitude of legeffort exceeded dyspnea; and (3) combined, perceptual magnitude rated equal. 1\vo-wayanalysis of variance was used to determine if HRmax/HRcap or VEmaxl VEcap was significantly different between the symptom subgroups and between patients with CAL and normal subjects. Frequency analysis (chi-square) was used to ascertain if the symptoms limiting exercise were significantly different between CAL patients and the normal control subjects. Subgroup analysis was performed to see if dyspnea as a limiting symptom increased with the severity of airflow limitation. For this purpose the study population divided into normal (FEV, > 80%), mild (FEV, 60 to 80%), moderate (FEV, 40 to 60%), and severe (FEV, < 40%) airflow limitation. Symptom tolerance was

taken from the rated intensity of the limiting symptom. Confidence limits were calculated from the frequency distribution curve of the limiting tolerance ratings. The Borg scale was used in the present study for a number ofreasons: ease of administration; widespread use in several clinical contexts; verbal descriptors convey metric properties related to absolute intensities; and it is purported to incorporate ratio properties (7, 8, 11, 12). Because of the nonlinear relationship between physical stimuli and their perceptual magnitude, the geometric mean is the preferred index of central tendency. The median is the preferred alternative when zero is included in the scale and calculation of geometric means is impossible. Hence, median values were used throughout the study.

Repeatability ojsymptom intensityduring exercise. The intraindividual reproducibility of responses was examined in 90 patients with cardiorespiratory disorders exercised to a symptom-limited maximum capacity on more than one occasion. The 90 patients underwent 122 repeated exercise tests in which exercise capacity (120 ± 5.00 versus 120 ± 5.23 W), % pulmonary function FEV, (70 ± 2.62 versus 71 ± 2.66%), and FEVlVC ratio (66.4 ± 1.72versus 66.8 ± l.72%)wereunchanged. The intensity of dyspnea (6.3 ± 0.20 versus 6.8 ± 0.23) and of leg effort(6.2 ± 0.23 versus 6.0 ± 0.21)(± standard error of the mean, SEM) were not significantly different in repeated tests (paired t test). The limiting symptom remained the same in 115 of 122 tests, and in only sevenof 122did the limiting symptom change from dyspnea to leg fatigue or the reverse. Formal validation requirements customary in studies of sensory scales (13, 14) have not been satisfactorily established for this or other scales of its type. Results

Work Capacity CAL patients achieved a Wcap of 86 ± 39.4 W (59.8 ± 23.21% of predicted) compared with 140 ± 37.5 W (98.0 ± 14.53070 of predicted) in the normal control group (p < 0.0001).

Ventilation ± 17.1 L/min in CAL

VE max was 43.4

937

SYMPTOMS IN CHRONIC AIRFLOW LIMITATION

Normals

CAL N=97

SYMPTOM INTENSITY

N=320

Maximal 10 Very, very savere 9

DL

~ ~1 11.1

75th%

50th%

7

6 5

, , :l-l

Severe somewhat .evere 4 Moderate 3

I' ., " W

II ' I, 25th%

I I

'"

120

D

L

80

Symptom Intensity

60

40 100

I·.•·• m~ I

90 HRmax/HRcap % 80

70 60 100 80 VEmax/VEcap %

60

40 N

Limited by:

25

42

30

97 97

97

D Dy.pnea!illl

89

117 134

320 320 320

L Leg Effort ~

B

Both.

Fig. 1. Symptoms and phySiologic variables at maximum exercise in 'd1 CAL patients (left pane~ and 320 control subjects (right p8ne~. Patients were grouped according to the limiting symptoms (dyspnea. 0; leg effort. l; and both equally. B). For each variable the bars indicate median and 25th and 75th percentiles. Symptom intensity was rated with the Borg scale; for patients limited by dyspnea. ratings for leg effort are shown as cross hatched bar.and similarly for dyspnea rating in patients limited by leg effort. Peak exercise power is expressed as a percentage of predicted power (Wcap%). and heart rate is expressed as a percentage of predicted maximum exercise heart rate (HRmaxlHRcap). Ventilation at peak exercise is expressed as a percentage of maximum ventilatory capacity (VEmaxNEcap).

patients compared with 60.5 ± 21.8 L/min in normal control subjects (p < 0.0001). Ventilatory capacity was 63 ± 22.5 L/min in the CAL group compared with 117 ± 26.6 L/min in the normal control group (p < 0.0001). VEmax/VEcap was significantly higher in the CAL group, 72 ± 19.4070 CAL compared with 53 ± 18.6% in normal control subjects (p < 0.0001). VEmax/VEcap was not significantly different in those limited by dyspnea

(not significant, NS), but HRmax/HRcap was significantly lower in CAL, 76 ± 13.5%, compared with 82 ± 13.0% in the normal control group. HRmax/HRcap was not significantly different in those limited by dyspnea than in those limited by leg fatigue or both in the normal control subjects or patients with CAL (figure 1).

B

_~I

100 Wcep %

l

D

8 Very .evere

beats/min in normal control subjects

(p < 0.001). Heart rate capacity was similar, 168 ± 6.8 in the CAL compared with 168 ± 7.0 in the normal control group

than in those limited by leg fatigue or a combination of both symptoms in the normal control subjects or patients with CAL (figure 1). There was a significant linear relationship between VEmax and VEcap in CAL patients (r == 0.742, P < 0.0001).

Circulation HRmax was 128 ± 23.4 beats/min in CAL compared with 138 ± 21.9

The intensity of dyspnea (median rating 6, severe to very severe) and leg effort (median rating 7, very severe) were the same in CAL and normal control subjects. Discomfort with breathing exceeded leg effort in 25 of 97 (26%) CAL and 69 of 320 (22%) control subjects; leg effort exceeded dyspnea in 42 of 97 (43%) CAL compared with 117 of 320 (37%) control subjects, and both symptoms were equal in intensity in 30 of 97 (31%) CAL compared with 134 of 320 (42%) control subjects. These differences were not significantly different (figure 1; chisquare 3.74, p == 0.15). The intensity of the limiting symptom (dyspnea, leg effort, or both) was 7.2 ± 2.18 CAL and 6.9 ± 2.33 normal control (mean ± standard deviation, SD) and was not significant. The intensity of the limiting symptom varied in both groups (figure 2); 20% of CAL patients and 17% of normal control subjects continued to exercise until intensity reached 10 (maximum), and 89% of CAL patients and 80% of normal control subjects stopped at a symptom intensity of 5 (severe) or greater. The major difference between the groups was that patients with CAL experienced limiting tolerance at 60 ± 23.2% of predicted normal work capacity compared with 98 ± 14.5070 of predicted capacity in the normal control subjects. Thus the patients with CAL were handicapped by both more intense dyspnea and leg effort for the absolute work performed (table 2).

Symptoms and Airflow Limitation In subjects grouped according to reductions in FEV It dyspnea was more frequently limiting in the group with lowest FEV1 (0 to 40% of predicted) (chi-square 13.8, p ~ 0.05); symptom limitation was not significantly different in those with mild and moderate airflow limitation (FEV1 40% of predicted) than in normal control subjects) (table 2).

938

KILLIAN, LEBLANC, MARTIN, SUMMERS, JONES, AND CAMPBELL

TABLE 2 NUMBER OF PATIENTS LIMITED BY EACH SYMPTOM' Symptom Limitation

Breathlessness

FEV, Q-40oJb. n =31 Perceived intensity Work capacity. % VEmaxNEeap• % HRmax/HReap• %

n = 12 7.5 :t 0.67 38 :t 4.9 81 :t 6.4 76:t 4.1

n = 6.8 :t 41 :t 75 :t 66 ±

11 0.60 6.2 4.9 3.1

n =8 8.0:t 0.80 50 :t 3.9 73 :t 5.9 75 ± 2.5

FEV, 40-60%. n = 48 Perceived intensity Wor" capacity. 0Jb VEmaxNEcap• % HRmax/HRcap• %

n =7 7.0:t 1.15 61 :t 8.1 72 ± 8.1 68 ± 5.3

n = 7.9 ± 73 ± 74 ± 84 ±

22 0.43 4.2 4.7 2.5

n = 19 6.5 ± 0.50 58 :t 5.0 73 ± 4.7 74 ± 3.2

FEV, 60-80%. n = 48 Perceived intensity Work capacity. % VEmaxNEcap. 0Jb HRmax/HRcap. %

n 6.3 75 62 80

= 6 ± 0.88 :t 4.4 ± 5.8 ± 8.0

n = 7.2 ± 75 ± 56 ± 81 ±

10 0.65 8.0 4.6 3.6

n = 2 6.5 :t (5-8) 76 :t (66-89) 55 ± (40-70) 78 ± (76-80)

FEV, 80-too%. n = 48 Perceived intensity Work capacity. % VEmaxNEcap• % HRmax/H Reap. %

n 6.9 98 55 82

= ± ± ± ±

n = 7.0 ± 97 ± 51 ± 80 ±

117 0.21 1.4 1.2 1.4

n = 134 6.8 ± 0.21 99 ± 1.25 52 :t 1.3 83 ± 1.0

69 0.28 1.6 2.1 1.5

Leg Fatigue

Both

, Limiting symptom intensity, work capacity, maximum ventilation expressed as percentage of capacity, and maximum heart rate expressed as percentage of age-predicted maximum as severity of airflow limitation increases. (Mean ± SEM; n = 417.)

Ventilatory, Circulatory, and Symptom Limitation All subjects were subdivided into subcategories based on VEmax/VEeap, 0 to 60070, 60 to 80070, and > 80070, and HRmax/HReap, 0 to 70070, 70 to 85070, and> 85070. No consistent relationships were found between symptom intensity or the limiting symptom and these physiologic factors (table 3). Arterial Oxygen Saturation (Sa02) Although not a formal part of the study, 76 ofthe CAL patients underwent 98 exercise tests in which Sa02 was measured by ear oximetry. Mean Sao, at rest was 96.5 ± 4.12070 SO; there was a significant fall at maximal exercise to 94.9 ± 2.41070 (p < 0.0001, paired t test). From rest to maximal exercise arterial saturation increased by 1070 or more in 6 of the 98 studies; it was unchanged (± 1070) in 24, and decreased by more than 1070 in 68 tests. Of the 68 patients with exerciseinduced oxygen desaturation, 30 (44070) were limited by dyspnea, compared with 10 of 24 (42070) of those whose Sao1 remained unchanged and 3 of 6 (50070) of those whose saturation increased (NS).

subjects, ranging from a rating of 4, somewhat severe, to 10, maximal (95070 confidence limits). Dyspnea limited exercise more frequently in patients with severe airflow limitation, but limitation by dyspnea was not universal. The symptoms limiting exercisein the patients with mild or moderate airflow limitation were the same as in age-matched normal control subjects. The patients with chronic airflow obstruction had a reduced exercise capacity similar to previous studies (1)experiencing the same limiting intensity ofleg effort and discomfort at a lower power output. There have been no formal attempts to study the relationship between symp-

10

9

a Severe

8

8

(AI

7

Whether impaired or normal, the average subject stopped exercise when either dyspnea or leg effort reached an intensity of 7 (very severe). The variability was the same in both the normal and impaired

. . .. ...- .

10

• Miid o Moderate

9

...

(B)

6

. C

DVSPNEA

4

c80

o.Jl'o

5 DYSPNEA

4

-- ..... ---.. -..

3

2 1

1

0.5

Discussion

toms limiting exerciseand ventilation and heart rate expressed relative to capacity at maximal. Such studies appear to have been considered impractical because of the unreliability of symptom rating. An alternative explanation is that such studies wereconsidered unnecessary. Dyspnea systematically intensifies as ventilation increasestoward ventilatory capacity. This is acknowledged and accepted. The effort required to drive peripheral muscle systematically intensifies as muscular capacity is approached. This also acknowledged and accepted. Hence, symptoms have been tacitly assumed to reflect limiting physiologic processes. The intensity of the limiting symptom should be maximal when exercise capacity is reached. Hence, measurement is unnecessary. No one would argue that the ability to exerciseis constrained within the limits of tissue respiration. The sequelae of depletion of ATP, irreversible actin and myosin interaction ("rigor mortis"), is never observed in exercising muscle. Whether ventilatory and circulatory capacities are approached during exercise or actually reached is open to question. In this study there was considerable variability in the proximity to HReap and VEeap in both groups, and caution is required before ascribing a "limiting" role to them. VEmax/VEeap was significantly higher (p < 0.0001) and HRmax/HReap was significantly lower (p < 0.001) in the presence of chronic airflow limitation, as expected. This is the kind of information usually used to validate these indices as limiting. However, VEmax/VEeap and HRmax/HRcap were not significantly different for subjects limited by dyspnea, leg fatigue, or a combination of the two in either the control group or the CAL

0.5

CAL n=97

0

Controls n=320

0 i

0 0.5 1

2

I

I

I

I

3

4

5

6

LEG EFFORT

7

8

9

I

j

10

0

0.5 1

2

I

I

i

3

4

5

6

7

8

9

10

LEG EFFORT

Fig. 2. The intensity of dyspnea at maximal exercise as rated on the Borg scale is plolted against the intensity of leg effort rated on the Borg scale in CAL patients (A) and normal control subjects (8). In A. mild implies FEV, 60 to 80%; moderate 40 to 60%; and severe, < 40%.

939

SYMPTOMS IN CHRONIC AIRFLOW LIMITATION

Open-ended questioning regarding limiting symptoms was conducted, but this may have been contaminated by the sensations rated and not reported, although VEmaxNEcap VEmaxN~ap HRmax/HRcap VEmaxN~ap absolute conformity was found. We ac>80% 60-80% 0-60% (%) knowledge that the exact nature of the 0-70 symptoms limiting exercise is not fully 7.2 ± 0.65 7.1 ± 0.65 7.0 ± 0.30 Tolerance threshold understood and the presence of symp6.5 ± 0.67 6.5 ± 0.66 5.7 ± 0.30 Dyspnea 6.5 ± 0.72 6.5 ± 0.71 6.4 ± 0.35 Leg effort toms and the attribution of limitation 50 ± 9.1 55 ± 5.5 93 ± 3.0 FEV, should also be made with caution. 51 ± 5.8 58 ± 4.0 77 ± 1.7 FEVNC, % Many experimental studies have now 55 ± 8.7 66 ± 6.4 85 ± 2.7 Work capacity, % firmly established our ability to recog11; 3/5/3 14; 4/5/5 57; 15/25/17 N; DyslLE/both 70-85 nize, discriminate, and quantify a num7.2 ± 0.50 7.4 ± 0.38 6.4 ± 0.22 Tolerance threshold ber of sensory dimensions related to mus6.8 ± 0.50 6.4 ± 0.42 5.7 ± 0.23 Dyspnea cular activity, including effort, tension, 6.6 ± 0.49 6.8 ± 0.40 6.1 ± 0.24 Leg effort and displacement (15-17). In this con69 ± 6.9 98 ± 1.9 73 ± 4.2 FEV, text, perceived effort appears to reflect 63 ± 3.9 69 ± 4.2 80 ± 0.9 FEVNC. % 80 ± 5.3 78 ± 4.2 Work capacity, % 86 ± 1.8 the intensity of central motor drive, per26; 8/6/12 40; 9/17/14 96; 17/34/45 N; DyslLElboth ceived tension reflects the output of ten> 85 don organs, and perceived displacement ± 0.44 7.35 ± 0.77 6.5 Tolerance threshold 6.9 ± 0.24 reflects the output of muscle spindles, 6.4 ± 0.48 6.2 ± 0.26 6.5 ± 0.36 Dyspnea 7.0 ± 0.47 6.8 ± 0.32 Leg effort 6.5 ± 0.25 joint, and skin receptors. Moreover, the 77 ± 5.5 102 ± 1.7 91 ± 3.0 FEV, linkage between these dimensions yields 70 ± 3.3 76 ± 1.8 81 ± 0.9 FEVNC, % discriminant information related to sev96 ± 4.3 101 ± 2.7 Work capacity, % 102 ± 1.8 eral physiologic functions - impedance 48; 12/22/14 30; 7110113 95; 20/34/41 N; DyslLElboth to movement, through the relationship • Tolerance threshold, the intensity of limiting symptom at maximum (leg effort, dyspnea, and/or between tension and displacement, and both), intensity of dyspnea, leg effort, FEV\, FEVNC ratio, work capacity, the total number of sUbjects, muscle strength, through the relationship and the number limited by dyspnea (Oys), leg effort (LE), or both are also presented for each subcategory. (Mean ± SEM.) between effort and achieved tension or displacement. In addition, behavioral learning leads to an awareness of appropriate interrelationships between these patients. These measurements do not symptoms are rated somewhat severe, dimensions. Inappropriateness is readiclosely reflect the symptoms cited as lim- and others exercise to maximal (well ly recognized and is often the reason for motivated). Overrating and underrating patients seeking medical attention. Sympiting by the subjects. Most subjects in the present study in individual subjects is a confounding toms are physiologicallygenerated via the stopped exercise at submaximal heart issue. However, in this study conducted stimulation of sensory receptors but have rates, submaximal ventilation, and sub- on large numbers of subjects, the effects been generally relegated to a secondary maximal symptom intensities, making it of bias are minimized by balancing posi- role. The explanation of why physiologdifficult to isolate the real limiting fac- tive and negative bias using indices of ic boundaries are approached and not tor. One possibility is that symptoms are central tendency, such as means or me- reached may reside in the reality of symplimiting. Before one can accept that dians. Hence, an alternative explanation tom constraint. symptoms, rather than physiologic fac- for the factor limiting exerciseis that subThe rating of dyspnea is sensitive and tors, are limiting, the submaximal ratings jects stop exercise volitionally when the responsive. Dyspnea increases and berequire explanation. We believe the rea- discomfort associated with continuing comes limiting when breathing is imson lies in the general precepts of human exercise exceeds that they are willing to peded by the addition of loads (18). Furbehavior and is best explained by a sim- tolerate. The results of the present study thermore, the intensity of dyspnea is ple analogy. If asked to maintain a hand reflect this simple behavior. increased in patients with increasing imWe chose the symptoms of dyspnea pairment in lung function. However, the in water as the temperature is progressively increased, some subjects tolerate and leg effort because of the general ex- striking finding in the present study was little discomfort (somewhat severe); the perience that the symptoms limiting in- the high intensity of leg effort, and by average tolerate a greater discomfort cremental exercise on a cycle ergometer inference the prevalence of leg fatigue, (very severe); but few tolerate maximal. are "predominantly" referred to the act as a limiting factor in the presence of "Withdrawal" and "maximal" are not of breathing and leg muscles and our be- CAL. Legfatigue may be expectedto limsynonymous. Hence, it is reasonable to lief that both may be largely related to it performance in patients with mild and expect that the average subject stopped effort. Leg effort and dyspnea are sepa- perhaps even some patients with moderexercise when the symptom intensity of rate sensations, and either one or both ate airflow limitation. However, leg faleg effort and/or dyspnea reached 7, very became limiting during exercise. Symp- tigue remained limiting in 11 of 31 pasevere, and few subjects were willing to toms other than these may also become tients with a percentage FEV 1 less than exercise to maximal. Individual symptom limiting; angina, the pain of claudication, 400/0 of predicted. Several explanations may be considtolerance is a factor. Motivation and arthralgia, or simply the discomfort of symptom tolerance are also related be- the bicycleseat or mouthpiece are exam- ered. Homeostasis in muscleis dependent haviors. Some subjects have low toler- ples. They werenot operative in these sub- on external factors, such as ventilation, ance (poorly motivated) and stop when jects but may be relevant in other cases. circulation, and gas exchange, and any TABLE 3

CONTROL SUBJECTS AND CAL SUBDIVIDED INTO CATEGORIES BASED ON VENTILATORY AND CIRCULATORY INDICES'

940

or all of these factors may indirectly reduce the responsiveness of muscles to motor activation. However,the increased effort is more likely to result simply from muscle weakness secondary to the inactivity that accompanies chronic disorders. Muscle mass, type, and strength are determined by the habitual conditioning stimuli of everyday activity. Inactivity is associated with marked changes in the structure and function of skeletal muscle, as amply demonstrated in studies of bed rest (19), limb immobilization (20-22), and aging (23,24). Contractile protein synthesis and the activity of enzymescontrolling energy metabolism are both dependent on activity. The reality brought out by the present study is that many normal subjects are limited by dyspnea even when the ventilatory index (VEmax/VEcap) is low. In our general experience using the approach described, 12070 of normal subjects claim dyspnea as the limiting symptom during incremental exercise. The higher prevalenceof dyspnea in this study may be due to age, because the subjects were age matched to the patients with CAL. It should also be noted that patients with CAL are frequently limited by leg fatigue even though VEmax/VEcap is high. Factors contributing to both peripheral muscle effort and respiratory muscle effort may account for the wide variability in relationships between reductions in exercisecapacity and physiologic variables found in previous studies (1, 4, 25). The effort required to drive the respiratory muscles has long been recognized as a contributor to the sense of dyspnea. Respiratory effort depends on respiratory muscle force, the strength of respiratory muscles, and the velocity and extent of respiratory muscle contraction. These variables were not addressed in the present study, in which measurements were obtained in a standard noninvasive clinicalexerciseassessment. However, appropriate measurements were made by Leblanc and colleagues (26), who also employed the Borg scale to measure dyspnea during exercise in patients with cardiorespiratory disorders. They were able to show a statistical relationship betweenthe intensity of dyspnea and a complex expression that included the peak negative intrapleura! pressure, the capacity of the respiratory muscles to generate

KILLIAN, LEBLANC, MARTIN, SUMMERS, JONES, AND CAMPBELL

pressure, and the inspiratory flow rate and tidal volume. El-Manshawi and coworkers in a study of normal exercising subjects during loaded breathing (18) confirmed the importance of the same factors. Factors other than the ventilatory index are clearly important and are likely to center on factors influencing endurance performance. In summary, cardiac output and ventilation must increase with muscular exercise, and their capacity limits exercise tolerance. However, the sensory systems of the body are also activated and may provide the proximate limitation. The role of the sensory system and its contribution to exercise limitation may be important in the management of patients with airflow limitation. The exercise capacity of patients with airflow obstruction is limited by the same symptoms as in normal subjects, but the limiting symptom intensity is reached at a lower capacity. Many patients with airflow obstruction are limited by muscular fatigue, and most experience both increased muscular effort and dyspnea relative to work performed. Although ventilation expressed as a proportion of capacity may parallel the intensity of dyspnea in an individual subject, dyspnea may be limiting when VEmax/VEcap is as little as 50% or as high at 90%. The consciously appreciated effort required to drive both the respiratory and peripheral skeletal muscles appears to playa fundamental role in limiting functional muscular activity in healthy subjects and patients with cardiorespiratory disorders. References 1. Jones NL, Jones G, Edwards RHT. Exercise tolerance in chronic airway obstruction. Am Rev Respir Dis 1971; 103:477-91. 2. Bye PTP, Farkas GA, Roussos C. Respiratory factors limiting exercise. Annu Rev Physiol 1983; 45:439-51. 3. Loke J, Mahler DA, Paul Man SF,Wiedemann HP, Matthay RA. Exercise impairment in chronic obstructive lung disease. Clin Chest Med 1984; 5:121-43. 4. Matthay RA, Berger JH. Cardiovascular function in cor pulmonale. Clin Chest Med 1983; 4:269-95. 5. Crapo RO, Morris AH, Gardner RM. Reference spirometricvalues using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981; 123:659-64. 6. Jones NL. Clinical exercise testing. 3rd ed. Philadelphia: W. B. Saunders, 1988. 7. Borg G. A category scale with ratio properties for intermodal and interindividual comparisons.

In: Geissler HS, Petzold P, eds, Psychophysical judgement and the processof perceptions. Proceedings of the 22nd International Congress of Psychology. New York: North Holland Publishing, 1980; 25-34. 8. Borg G. An introduction to Borg RPE-scale. Ithaca, NY: Movement Publications, 1985. 9. Jones NL, Makrides L, Hitchcock C, McCartney N. Normal standards for an incremental progressivecycleergometer test. Am Rev Respir Dis 1985; 131:700-8. 10. Spiro EG. Exercisetesting in clinical medicine. Br J Dis Chest 1977; 71:145-72. Il, Borg G. Psychophysical studies of effort and exertion: some historical, theoretical and empirical aspects. In: The perception of physical exertion in physical work. Proceedings of an international symposium held at the Wenner-Gren Centre, Stockholm. London: Macmillan Press, 1985; 3-12. 12. Killian KJ. Assessment of dyspnea. Eur Respir J 1988; 1:195-7. 13. Stevens SS. On the psychophysical law. Psychol Rev 1957; 64:153-81. 14. Stevens SS. Psychophysics: Introduction to its perceptual, neural and social prospects. Stevens G, ed. New York: John Wiley, 1975. 15. McCloskey DI. Kinesthetic sensibility. Physiol Rev 1978; 58:763-820. 16. Matthews PBC. Where does Sherrington's "muscular sense" originate? Muscles, joints, corol-' lary discharges? Annu Rev Neurosci 1982; 5: 189-218. 17. KillianKJ, Campbell EJM. Dyspnea. In: Roussos C, Macklem PT, eds. The thorax. New York: Marcel Dekker, 1985; 787-827. 18. EI-ManshawiA, KillianKJ, Summers E, Jones NL. Breathlessness during exercise with and without resistive loading. J Appl Physiol 1986; 61: 896-905. 19. Greenleaf SE, Silverstein L, Bliss J, Langenheim V, Rossow H, Chao C. Physiological responses to prolonged bed rest and fluid immersion in man: a compendium of research (1974-1980). NASA technical memorandum 81324.Washington, DC: NASA, 1982. 20. MacDougall JD. Morphological changes in human skeletal muscle following strength training and immobilization. In Jones NL, McCartney N, McComas AJ, eds. Human muscle power. Champaign, IL: Human Kinetics Publishers, 1986; 269-85. 21. White MJ, Davies CTM. The effects of immobilization, after lower leg fracture, on the contractile properties of human triceps surae. Clin Sci 1984; 66:277-82. 22. MacDougall JD, Ward GR, Sale DG, Sutton JR. Biochemicaladaptation of human skeletalmuscles to heavy resistance training and immobilisation. J Appl Physiol 1977; 43:700-3. 23. Grimby S,Saltin B. The ageing muscle. Clin Physiol 1983; 3:209-18. 24. Campbell MJ, McComas AJ, Petito F. Physiological changes in ageing muscles. J Neurol Neurosurg Psychiatry 1973; 36:174-82. 25. Spiro SG, Juniper E, Bowman P, Edwards RHT. An increasing work rate test for assessing the physiologicalstrain of submaxirnal exercise. Clin Sci Mol Med 1974; 46:191-206. 26. Leblanc P, BowieDM, Summers E, Jones NL, Killian KJ. Breathlessness and exercise in patients with cardiorespiratory disease. Am Rev Respir Dis 1986; 133:21-5.

Exercise capacity and ventilatory, circulatory, and symptom limitation in patients with chronic airflow limitation.

Dyspnea, leg effort (Borg 0 to 10 scale), ventilation, and heart rate (VEmax/VEcap; HRmax/HRcap expressed as a percentage of capacity) were measured a...
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