Measurement of Symptoms, Lung Hyperinflation,
and Endurance during Exercise in
Chronic Obstructive Pulmonary Disease
DENIS E. O’DONNELL, MIU LAM, and KATHERINE A. WEBB
Respiratory Investigation Unit, Departments of Medicine, and Community Health and Epidemiology, Queen’s University,
Kingston, Ontario, Canada
Changes in lung hyperinflation, dyspnea, and exercise endurance are important outcomes in assessing therapeutic responses in chronic obstructive pulmonary disease (COPD). Therefore, we studied
the reproducibility of Borg dyspnea ratings, inspiratory capacity (IC; to monitor lung hyperinflation),
and endurance time during constant-load symptom-limited cycle exercise in 29 patients with COPD
(FEV1 5 40 6 2% predicted; mean 6 SEM). Responsiveness was also studied by determining the
acute effects of nebulized 500 mg ipratropium bromide (IB) or saline placebo (P) on these measurements. During each of four visits conducted over an 8-wk period, spirometry and exercise testing
were performed before and 1 h after receiving IB or P (randomized, double-blinded). Highly reproducible measurements included: endurance time (intraclass correlation R 5 0.77, p , 0.0001); Borg
ratings and IC at rest, at a standardized exercise time (STD), and at peak exercise (R . 0.6, p ,
.
0.0001); and slopes of Borg ratings over time, oxygen consumption ( VO2), and ventilation (R . 0.6,
p , 0.0001). Responsiveness was confirmed by finding a significant drug effect for: change (D) in
endurance time (p 5 0.0001); DBorgSTD and DBorg-time slopes (p , 0.05); and DIC at rest, at STD,
and at peak exercise (p 5 0.0001). With all completed visits, DBorgSTD correlated better with DICSTD
than any other resting or exercise parameter (n 5 115, r 5 20.35, p , 0.001). We concluded that
Borg dyspnea ratings, and measurements of IC and endurance time during submaximal cycle exercise
testing are highly reproducible and responsive to change in severe COPD. O’Donnell DE, Lam M,
Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during exercise
in chronic obstructive pulmonary disease.
AM J RESPIR CRIT CARE MED 1998;158:1557–1565.
For patients with advanced chronic obstructive pulmonary
disease (COPD), alleviation of symptoms such as dyspnea and
leg discomfort, and improvement in activity level, become important therapeutic goals. It follows that, in clinical studies designed to evaluate the efficacy of therapeutic interventions in
this population, reliable measurements of symptom intensity
and of relevant physiological parameters should ideally be
employed. The Borg category scale is being used increasingly
to measure the intensity of dyspnea and leg discomfort during
cardiopulmonary exercise testing in patients with pulmonary
disease. However, the reliability (reproducibility) and responsiveness (ability to detect change) of this scale remain to be
determined with precision in patients with advanced COPD.
No definitive conclusions can be made from the existing literature because of the very small sample sizes in previous studies
and because of interstudy differences in the sensations being
(Received in original form April 2, 1998 and in revised form June 5, 1998)
Supported by Boehringer Ingelheim (Canada) Limited.
Dr. O’Donnell holds a career scientist award from the Ontario Ministry of Health.
Correspondence and requests for reprints should be addressed to Denis O’Donnell, Kingston General Hospital, Richardson House, 102 Stuart Street, Kingston,
ON, K7L 2V7 Canada. E-mail: <[email protected]>
Am J Respir Crit Care Med Vol 158. pp 1557–1565, 1998
Internet address: www.atsjournals.org
rated (i.e., respiratory effort versus dyspnea), in the mode of
exercise employed (i.e., treadmill versus cycle), and in the
testing protocol (i.e., incremental versus submaximal constant-load) (1–4). There is also considerable variation in the
time intervals over which reproducibility of this measurement
has been assessed (1–4). Finally, we could find no specific information in the literature about the reproducibility of Borg
ratings of exertional leg discomfort. Leg discomfort is the primary symptom that limits exercise in many patients with
COPD (5) and is, therefore, an important outcome measure to
examine when assessing the effects of interventions such as
exercise training.
Both incremental testing and constant-load endurance testing have been used to assess therapeutic responses in patients
with COPD. Both approaches have the potential to produce
different, but complementary, information about changes in
exercise performance following interventions. Increasingly,
investigators are using endurance testing at a standardized
submaximal work load to evaluate the impact of interventions
such as exercise training, oxygen therapy, bronchodilator medication, or volume reduction surgery. The question arises, therefore, whether endurance times using symptom-limited constantload exercise protocols are sufficiently reliable and sensitive to
detect clinically important changes in COPD.
A variety of cardiopulmonary responses are traditionally
measured during exercise testing for the assessment of the
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
dyspneic COPD patient. With many therapeutic interventions, dyspnea relief is multifactorial and includes alterations
in ventilatory demand (6–8), in ventilatory mechanics (9–11),
or in both. Repeated measurements of inspiratory capacity
(IC) during exercise have been used by several investigators
(12, 13), including ourselves (14), to track the behavior of dynamic end-expiratory lung volume (EELV) during exercise in
COPD. There is increasing evidence that the IC during exercise, and the rate of change in IC during exercise (i.e., dynamic
hyperinflation), are strong predictors of exertional dyspnea intensity and exercise intolerance (14). Thus, the availability of
this simple method of tracking EELV during exercise could
have wide clinical application, provided it is proved reliable.
To address these questions, we set the following study objectives. First, we wished to determine the reproducibility of
Borg measurements of dyspnea and leg discomfort during
constant-load cycle exercise tests performed over an 8-wk
period in patients with stable advanced COPD. Second, we
wished to evaluate the responsiveness of Borg dyspnea ratings
by comparing the acute effects of a bronchodilator (nebulized
ipratropium bromide [IB]) using a randomized, placebo-controlled, double-blind crossover design. Third, we wished to
test the reproducibility and responsiveness of IC measurements during exercise, and to determine whether changes in
IC following bronchodilator therapy can accurately predict
symptomatic responses.
METHODS
Subjects
Subjects included patients with stable COPD who satisfied the following criteria: (1) moderate to severe COPD (FEV1 , 60% predicted)
with a clinical course consistent with chronic bronchitis and/or emphy-
VOL 158
1998
sema and a long history of cigarette smoking; (2) moderate to severe
chronic breathlessness (modified Baseline Dyspnea Index [BDI] < 6)
(15); (3) age 55 yr or older; and (4) clinically stable as defined by no
changes in medication dosage or frequency of administration with no
exacerbations or hospital admissions in the preceding 6 wk. Exclusions included: a history of asthma, atopy, or nasal polyps; other active
lung disease or other significant disease that could contribute to dyspnea or exercise limitation; or oxygen desaturation to less than 80%
during exercise on room air.
Study Design
Reliability (or reproducibility) was established by analyzing baseline
measurements taken at repeated visits, i.e., a replication reliability
study. Responsiveness to treatment was assessed by comparing the
acute effects of two treatments (single-dose IB versus placebo [P]) using a randomized, double-blind, two-period crossover design (Figure
1). The crossover design ensures equality in numbers of patients assigned each treatment, and allows each subject to serve as his or her
own control.
After hospital/university research ethics approval was obtained,
subjects gave informed consent and entered the study on a staggered
basis. During an initial screening visit, subjects underwent thorough
familiarization with all procedures and symptom rating scales, medical
history, pulmonary function testing with reversibility to b2-agonists,
dyspnea evaluation, and symptom-limited incremental cycle exercise
testing. Thirty-six patients were then randomized to receive either
nebulized IB (500 mg) or P three times a day in unit dose vials for a
3-wk period. Each subject was crossed over to the alternate treatment
for an additional 3-wk period, after a 2- to 7-d washout period. Four experimental visits per subject were conducted at the beginning and
end of each 3-wk period (Figure 1). In these visits, pulmonary function testing, dyspnea evaluation, and constant-load cycle exercise testing were performed immediately before and 1 h after the treatment
corresponding to that being given during the coinciding 3-wk period.
Concomitant respiratory medications permitted for the duration
of the study included regularly taken inhaled steroids and bronchodi-
Figure 1. The study design illustrates the sequence and timing of visits. The timing of events and measurements is also shown for experimental visits.
O’Donnell, Lam, and Webb: Symptoms and Hyperinflation during Exercise in COPD
lators other than anticholinergic medications. Use of medications remained stable throughout the study treatment periods. Patients requiring additional medication or changes in medication for greater
than 2 d were withdrawn from the study. Before each visit, patients
were asked to withdraw from inhaled b2-agonists, anticholinergics,
and theophyllines for at least 4 h, 12 h, and 24 h prior to testing, respectively. Subjects avoided caffeine and heavy meals at least 4 h prior
to testing, and avoided alcohol and major physical exertion entirely on
the day of each visit. All visits were conducted at the same time of day
for each subject.
Treatment
Treatments to be compared in this trial were administered by inhalation via face mask from a Hudson Up-Draft Nebulizer Unit (Model
No. 1712; Hudson Respiratory Care Inc., Temecula, CA) at a flow of
8 L/min over a period of approximately 15 min. The total volume of
nebulized solution was 5 ml for all patients: IB 500 mg was compared
with a placebo which consisted of sterile 0.9% sodium chloride solution. All test materials were obtained from clinical supplies manufactured by Boehringer Ingelheim Limited, United Kingdom.
Pulmonary Function Testing
Routine spirometry (Spirolite 201; Medical Systems Corp., Greenvale,
NY) was performed prior to exercise testing in accordance with recommended techniques (16). The predicted normal values for spirometry were those of Morris and associates (17). Maximal inspiratory
mouth pressures (MIP) from FRC and residual volume (RV), and
maximal expiratory mouth pressures (MEP) from TLC were measured with a standard mouthpiece and a direct-reading dial pressure
gauge (Magnehelic; Dwyer Instruments, Inc., Michigan City, IN). MIP
at RV and MEP at TLC were compared with the predicted normal
values of Black and Hyatt (18); values for MIP at FRC were compared with the predicted normal values of Hamilton and coworkers
(19).
Dyspnea Evaluation
At study entry and at the beginning of each study period, the modified
BDI was used to assess chronic activity-related breathlessness (15). At
the end of each study period, the Transition Dyspnea Index (TDI)
was used to detect changes in chronic activity-related breathlessness
over time (20). The same unbiased observer, blinded to the treatment
received by each patient, was used throughout the study period to assess BDI and TDI.
Exertional dyspnea was defined as “the sensation of labored or
difficult breathing” and leg discomfort as “the level of difficulty/discomfort experienced during exercise.” Before exercise testing, subjects were familiarized with the Borg scale (21) and its endpoints were
anchored such that zero represented “no breathlessness (leg discomfort)” and 10 was “the most severe breathlessness (leg discomfort) that
they had ever experienced or could imagine experiencing.” By pointing to the Borg scale, subjects rated the magnitude of their perceived
breathlessness and leg discomfort at rest and every minute throughout exercise. Upon exercise cessation, subjects were also asked to verbalize their main reason for stopping exercise and this reason was documented.
Exercise Testing
During initial screening, an incremental cycle exercise test was performed to a symptom-limited maximum as described in a previous
publication (14). In experimental visits, symptom-limited endurance
cycle exercise tests were performed in a similar manner at the same
constant work rate equal to approximately 50 to 60% of the maximum
work rate achieved during screening. Exercise responses were compared
with the predicted normal values of Jones (22), and ventilation
·
(VE) was compared with the predicted maximal ventilatory capacity
(MVC) of Dillard and associates (23).
Changes in operational lung volumes were evaluated from measurements of IC at rest, every 3 min during exercise, and at peak exercise. Assuming that TLC remains constant during exercise in COPD
(24), changes in IC reflect changes in end-expiratory lung volume
(EELV 5 TLC 2 IC). Changes in end-inspiratory lung volume
(EILV) were reflected by changes in inspiratory reserve volume (IRV),
1559
which was derived by subtracting tidal volume (VT) from the coinciding IC. Techniques for performing and accepting IC measurements
have been previously described (14). After a full explanation to each
subject, satisfactory technique and reproducibility of IC maneuvers
was established during an initial practice session at rest. Subjects were
given a few breaths warning before a maneuver, a prompt for the maneuver (i.e., “at the end of the next normal breath out, take a deep
breath all the way in”), and then verbal encouragement to make a
maximal effort before relaxing. If efforts appeared submaximal or if
anticipatory changes in breathing pattern occurred immediately preceding a maneuver, then the IC was not accepted.
Statistical Analysis
The study was originally designed to look at both acute and chronic
responses to bronchodilator therapy in severe COPD. It was estimated that a sample size of at least 28 subjects was required for each
treatment arm of the study: calculations were based on the change in
chronic dyspnea (TDI) as the primary endpoint, our own laboratory
values for a similar COPD population, a 5 0.05, b 5 0.20, and a twotailed test of statistical significance. The focus of this part of the study,
however, was to look at the acute responses to IB or placebo; specifically, Borg symptom ratings, IC measurements, and exercise endurance time.
Results are reported as means 6 SEM. The conventional level of
statistical significance of 0.05 was used for all analyses. Baseline demographics, lung function, and exercise capacity measurements were
compared between the two treatment sequence groups using unpaired
t tests. Exercise responses were studied using linear regression analysis of data sets from each individual, with slopes and intercepts expressed as means of these regression lines. Standardized exercise time
(STD) was equal to the time of the highest equivalent amount of work
or time completed in all experimental exercise tests for each subject,
i.e., the time of the shortest exercise test rounded down to the nearest
minute.
The intraclass correlation coefficient of reliability (R) (25) was
employed to evaluate the reliability of using: (1) the Borg scale for the
quantification of exertional dyspnea intensity; (2) the Borg scale for
the quantification of exertional leg discomfort; (3) IC measurements
for the evaluation of operational lung volumes at rest and during exercise; and (4) symptom-limited peak time for the assessment of submaximal exercise endurance. Various forms of measuring exertional
symptom intensity and IC were considered in the study, i.e., slopes
and intercepts, values at STD, and peak values. As R increases toward
unity, error constitutes a smaller portion of the observed measurement: R , 0.4 indicates poor reliability, 0.4 < R < 0.75 fair to good reliability, and R . 0.75 excellent reliability (25). The coefficient of variation (CV), which describes the variance involved in a measurement
relative to the mean of the measurement, was also calculated withinsubjects for the above measurements.
Analysis of variance models incorporating the repeated measures
crossover design of the study (26) were applied to assess the responsiveness of exercise endurance, dyspnea, and IC measurements to
bronchodilator treatment. Possible carryover and period effects were
first considered and assessed in the models.
To examine the strength of the relationship between acute changes
in exertional dyspnea and lung hyperinflation in response to therapy,
Pearson’s correlations were performed with data from all completed
tests. In this analysis, change (D) in BorgSTD was the dependent variable and independent variables included changes in concurrent exer·
V
cise
· measurements of lung hyperinflation (IC, IRV), ventilation ( · E,
VE/MVC, ratio of minute ventilation to oxygen consumption [VE/
·
·
VO2], ratio of minute ventilation to carbon dioxide production [VE/
·
·
·
VCO2]), breathing pattern (F, VT, VT/IC), gas exchange (VCO2/VO2,
SaO2), cardiovascular function (heart rate, blood pressure), as well as
changes in resting pulmonary function (FEV1, FVC, IC, MIP). Changes
in endurance time were similarly analyzed.
RESULTS
Subjects
Of the 36 randomized patients, there were 29 evaluable patients (Table 1). Seven patients were prematurely withdrawn
1560
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
TABLE 1
SUBJECT CHARACTERISTICS*
Male:Female
Age, yr
Height, cm
Weight, kg
Body mass index, kg/m2
Smoking history, pack-yr
Modified Baseline Dyspnea Index
Reversibility to b2-agonists, DFEV1 in L (%)
Pulmonary function, % predicted
FEV1, L
FVC, L
FEV1/FVC, %
MIP at FRC, cm H2O
MIP at RV, cm H2O
MEP, cm H2O
Symptom-limited maximal exercise, % predicted
Work rate, watts
Heart rate, beats/min
·
V O2, L/min
·
V E, L/min
SaO2,%
22:7
67 6 1
169 6 2
75.9 6 2.9
26.5 6 0.9
54 6 7
5.3 6 0.2
0.11 6 0.02
“severe”
(11 6 2)
1.05 6 0.07
2.24 6 0.14
47 6 2
53 6 7
60 6 9
91 6 6
(40 6 2)
(59 6 3)
(69 6 3)
(66 6 11)
(65 6 9)
(50 6 3)
54 6 4
107 6 3
1.09 6 0.08
34.9 6 2.5
93 6 1
(39 6 3)
(64 6 2)
(61 6 4)
(72 6 4)
* Values are means 6 SEM.
from the study because of hospital admission with respiratory
tract infection (n 5 2), hospital admission with congestive
heart failure (n 5 1), repeated attacks of respiratory panic (n 5
1), increased breathlessness requiring a change in treatment
for greater than 2 d (n 5 1), facial skin irritation from the nebulizer (n 5 1), and noncompliance due to lack of time (n 5 1).
One of the 29 evaluable patients experienced an acute exacerbation of COPD requiring additional medication 7 d before the
last visit and did not complete the exercise testing in this visit.
Statistical Considerations
The two treatment sequence groups were comparable at study
entry for demographics, lung function, and exercise capacity:
Measurements of Exercise Performance
Exercise performance for constant-load testing was assessed
·
by looking· at symptom-limited peak endurance time, peak VO2
and peak VE; each of these measurements showed excellent reproducibility with an R . 0.75 (Table 2). The responsiveness of
a measurement was confirmed by the occurrence of a significant drug effect in response to therapy (Table 4); of the above
measurements, the only one showing a drug effect in response
to treatment was the endurance time (p 5 0.0001). Therefore,
the outcome measure looking at exercise performance that was
both reliable and responsive to change was the exercise endurance time.
Measurements of Symptom Intensity
Repeated measurements of dyspnea at rest, at STD, and at
peak exercise were shown to be highly reproducible (Figure 2,
Table 2), as were Borg
dyspnea
ratings expressed as slopes
·
·
over exercise time, VO2, and VE (Table 3) and their respective
y-intercepts. However, significant drug effects were only
TABLE 2
* Values are means 6 SEM.
1998
n 5 13 were in the treatment sequence that received IB in the
first two experimental visits and placebo in the last two visits,
n 5 16 received treatments in the reverse order. Stability of
baseline spirometry was verified before making inferences
from significance tests on treatment effects: predose measurements of FEV1 and FVC were highly repeatable (Table 2), ensuring that the level of airflow limitation was constant for the
duration of the study. Before establishing the significance of
direct treatment effects, various carryover and period effects
were also ruled out.
With the change in the slope of Borg dyspnea ratings over
time as the primary endpoint, a significant drug effect was observed in this study (Table 3). The power for detecting this response was 92%: calculated with values obtained in response
to IB for the 29 subjects, a 5 0.05, and a two-tailed test of significance.
REPEATABILITY OF PREDOSE VARIABLES DURING FOUR EXPERIMENTAL VISITS
CONDUCTED OVER AN 8-wk PERIOD* (n 5 29)
Rest
FEV1, L
FVC, L
IC, L
IRV, L
Dyspnea, Borg
Isotime exercise
Dyspnea, Borg
Leg discomfort, Borg
IC, L
IRV, L
DH (-DIC), L
·
V O2, L/min
·
V E, L/min
Peak exercise
Exercise time, min
Dyspnea, Borg
Leg discomfort, Borg
IC, L
IRV, L
DH (-DIC), L
·
V O2, L/min
·
V E, L/min
VOL 158
Visit 1
Visit 2
Visit 3
Visit 4
Within-Subject
CV (%)
Intraclass
R
0.95 6 0.07
2.04 6 0.12
1.83 6 0.13
1.18 6 0.10
0.9 6 0.2
0.94 6 0.07
2.06 6 0.12
1.90 6 0.12
1.19 6 0.09
1.2 6 0.2
0.93 6 0.07
2.08 6 0.13
1.95 6 0.14
1.23 6 0.12
1.3 6 0.2
1.00 6 0.07
2.21 6 0.13
1.94 6 0.12
1.27 6 0.10
1.0 6 0.2
12.0
12.8
17.1
24.4
69.9
0.904
0.831
0.767
0.699
0.605
3.5 6 0.4
3.2 6 0.4
1.63 6 0.12
0.65 6 0.08
0.21 6 0.08
0.78 6 0.06
25.2 6 1.9
3.6 6 0.3
3.2 6 0.3
1.73 6 0.13
0.66 6 0.08
0.17 6 0.07
0.87 6 0.07
28.0 6 2.1
3.4 6 0.2
3.4 6 0.4
1.80 6 0.13
0.74 6 0.11
0.15 6 0.08
0.88 6 0.06
28.1 6 1.9
3.1 6 0.3
2.8 6 0.3
1.80 6 0.12
0.75 6 0.09
0.14 6 0.05
0.83 6 0.06
26.5 6 2.0
30.7
35.2
19.9
43.7
150.1
16.8
16.2
0.583
0.657
0.720
0.593
0.567
0.814
0.822
7.6 6 1.0
5.2 6 0.3
4.8 6 0.4
1.51 6 0.11
0.49 6 0.07
0.32 6 0.08
0.91 6 0.07
29.0 6 2.0
7.7 6 1.1
4.7 6 0.3
4.2 6 0.4
1.59 6 0.11
0.46 6 0.06
0.31 6 0.06
0.96 6 0.07
31.1 6 2.2
7.4 6 1.0
4.5 6 0.3
4.3 6 0.4
1.64 6 0.13
0.53 6 0.09
0.32 6 0.09
0.97 6 0.06
30.7 6 1.9
9.6 6 1.3
4.4 6 0.3
4.1 6 0.4
1.58 6 0.10
0.46 6 0.06
0.36 6 0.06
0.97 6 0.06
30.8 6 2.0
33.6
20.1
26.2
19.7
52.8
88.3
14.5
14.7
0.767
0.645
0.726
0.735
0.552
0.494
0.835
0.826
1561
O’Donnell, Lam, and Webb: Symptoms and Hyperinflation during Exercise in COPD
TABLE 3
REPEATABILITY AND RESPONSIVENESS OF VARIOUS SLOPE* MEASUREMENTS
Dyspnea-time, Borg ? min21
·
Dyspnea-V O2, Borg ? (L/min)21
·
Dyspnea-V E, Borg ? (L/min)21
Leg-time, Borg ? min21
·
Leg-V O2, Borg ? (L/min)21
·
V E-time, L/min ? min21
·
V O2-time, L/min ? min21
· ·
V E-V O2, L/min ? (L/min)21
Group
Mean
Within-Subject
SD
Within-Subject
CV (%)
Intraclass
R
Drug Effect
p Value
0.66
6.62
0.24
0.78
7.88
2.71
0.10
28.0
0.24
3.69
0.15
0.41
4.01
1.10
0.04
4.66
36.9
55.7
60.3
52.7
50.9
40.3
41.2
16.7
0.832
0.713
0.615
0.641
0.731
0.463
0.394
0.471
0.019
0.109 NS
0.158 NS
0.001
0.108 NS
0.828 NS
0.346 NS
0.224 NS
* Note: all y-intercepts were highly reproducible and did not change with treatment.
found for changes in Borg at STD (p , 0.01) (Table 3) and
Borg-time slopes (p , 0.05) (Figure 3, Table 4). As with Borg
dyspnea ratings, Borg-derived measurements of exertional leg
discomfort were also highly reproducible (Figure 2, Tables 2
and 3).
FEV1 and FVC, and for changes in measurements of both IC
and IRV evaluated at rest, at STD, and at peak
exercise
(Ta·
·
ble 4). Slopes of IC relative to time (Figure 3), VO2 or VE were
not responsive to drug therapy in this study.
Measurements of Operational Lung Volumes
For all completed tests (n 5 115), the change in exertional
dyspnea intensity at a standardized time correlated better with
the concurrent change in IC, expressed in absolute terms (r 5
20.34, p , 0.0005) or as a percentage of predicted normal (r 5
20.35, p , 0.0005), than with any other resting or exercise parameter. Other significant correlates of DBorgSTD included
resting changes in FEV1 (r 5 20.26, p 5 0.006) and IC (r 5
20.25, p 5 0.007), and concurrent changes in exercise breathing pattern: DF (r 5 0.31, p 5 0.001) and DVT/IC (r 5 0.34,
p , 0.0005).
Improvement in exercise endurance time correlated best
with resting spirometric changes (p , 0.0005): DFVC (r 5
0.43), DFEV1 (r 5 0.40), change in peak expiratory flow rate
Measurements of IC at rest showed excellent reproducibility
(R . 0.75), as did resting spirometric measurements of FEV1
and FVC (Table 2). Measurements of IC at STD and at peak
exercise were also highly reproducible (Figure 2, Table 2).
IRV measurements were also reproducible at rest, at STD,
and at peak exercise (Table 2). For the assessment of the extent of dynamic· hyperinflation
(DH) during exercise, slopes of
·
IC over time, VO2, or VE showed very poor reliability (R ,
0.4). However, when DH was measured more simply as the
change in IC from rest, fair to good reliability was found for
changes occurring at STD and at peak exercise (Table 2).
Significant drug effects were found for changes in resting
Correlates of Improvement
TABLE 4
POSTDOSE CHANGES IN RESPONSE TO IB AND PLACEBO AT THE BEGINNING AND
END OF EACH 3-wk EXPERIMENTAL PERIOD* (n 5 29)
Ipratropium Bromide (500 mg)
Postperiod
Preperiod
Postperiod
Drug Effect
(p Value)
0.24 6 0.04†
0.47 6 0.07†
0.45 6 0.07†
0.43 6 0.08†
20.3 6 0.1‡
0.17 6 0.04†
0.32 6 0.07†
0.33 6 0.10†
0.33 6 0.09†
20.3 6 0.1‡
20.01 6 0.02
0.01 6 0.06
0.03 6 0.07
0.04 6 0.06
20.2 6 0.2
20.03 6 0.02
20.11 6 0.07
20.09 6 0.06
20.08 6 0.04
0.0 6 0.1
0.0001
0.0001
0.0001
0.0001
0.060
20.6 6 0.2‡
20.3 6 0.2
0.39 6 0.07†
0.32 6 0.06†
20.02 6 0.02
20.3 6 0.7
0.07 6 0.02†
22.2 6 0.6†
20.3 6 0.2
0.1 6 0.2
0.29 6 0.11
0.23 6 0.10
20.01 6 0.02
0.6 6 0.7
0.06 6 0.02‡
20.7 6 0.5
0.2 6 0.3
0.3 6 0.3
0.05 6 0.09
0.04 6 0.07
0.03 6 0.03
0.7 6 1.0
0.01 6 0.03
0.2 6 0.5
0.0 6 0.2
0.0 6 0.1
20.04 6 0.05
0.00 6 0.04
20.03 6 0.02
21.2 6 0.6
20.04 6 0.02
0.0 6 0.5
0.003
NS
0.0001
0.0005
NS
NS
0.004
0.001
2.8 6 0.9†
20.4 6 0.3
0.1 6 0.2
0.41 6 0.08†
0.28 6 0.07†
0.01 6 0.02
1.7 6 0.4†
1.1 6 0.4‡
20.1 6 0.2
0.4 6 0.2‡
0.30 6 0.11†
0.24 6 0.11
0.00 6 0.02
0.9 6 0.7
20.3 6 0.4
0.1 6 0.2
0.2 6 0.2
20.08 6 0.07
20.08 6 0.05
0.04 6 0.03
1.2 6 1.0
20.1 6 0.4
0.2 6 0.1
0.3 6 0.3
20.02 6 0.06
0.03 6 0.05
20.03 6 0.03
21.2 6 0.7
0.0001
0.073
NS
0.0001
0.0002
NS
NS
Preperiod
Rest
FEV1, L
FVC, L
IC, L
IRV, L
Dyspnea, Borg
Isotime exercise
Dyspnea, Borg
Leg discomfort, Borg
IC, L
IRV, L
·
V O2, L/min
·
V E, L/min
VT, L
F, breaths/min
Peak exercise
Exercise time, min
Dyspnea, Borg
Leg discomfort, Borg
IC, L
IRV, L
·
V O2, L/min
·
V E, L/min
Placebo
* Values are means 6 SEM.
†
p , 0.01, significant change from baseline.
‡
p , 0.05.
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1998
Figure 2. Repeatability of measurements at rest, at a standardized time during exercise (STD), and at the
end of symptom-limited exercise (PEAK) are shown for Borg ratings of dyspnea and leg discomfort, inspiratory capacity, and ventilation. STD 5 the highest equivalent time each subject completed in all exercise tests.
(DPEFR; r 5 0.37), and DIC (r 5 0.33). The increase in exercise endurance also correlated significantly with the reduction
in the slope of exertional Borg dyspnea ratings over time (r 5
20.25, p 5 0.007) and in standardized Borg dyspnea ratings
(r 5 20.32, p , 0.0005).
DISCUSSION
The novel findings of our study are as follows. Borg ratings of
dyspnea and leg discomfort were highly reproducible when
measured during constant-load cycle exercise in patients with
stable advanced COPD, at least over an 8-wk time period. The
Borg dyspnea ratings measured with this protocol were also
highly responsive. Exercise time was a reliable measure of exercise endurance in COPD, being both reproducible and responsive to change. Serial IC measurements during exercise
were reproducible and responsive, and changes in IC after
bronchodilator therapy correlated well with changes in exertional dyspnea.
Exertional Symptom Intensity
Despite increasing evidence to the contrary, there is prevailing
skepticism about the reliability of simple category scaling to
quantify symptom intensity and response to therapy. Lack of
reproducibility of such subjective measurements could arise
for a variety of reasons including: (1) random error; (2) inherent lability of the measured characteristic; (3) deficiencies of
the measuring instrument; and (4) misunderstanding on the
part of subjects or interviewers with respect to the precise
question being asked. To evaluate reproducibility of Borg
measurements of exertional symptoms, we calculated R (25)
in a large study sample of patients with stable COPD. This
correlation expresses the relative magnitude of the main components of the variance of a measurement (i.e., variability
among the steady-state values and variability of random errors) such that most of the untoward effects of unreliability
are expressible as functions of it (25). We found good to excellent reliability (R . 0.6) for Borg ratings of dyspnea and leg
discomfort, indicating that error constituted only a small portion of the observed measurement on repeated testing.
A prerequisite for the determination of reproducibility of
symptom measurement is clinical stability. In our study, stability was evident from the high level of reproducibility of FEV1
and other spirometric measurements over the 8-wk observation period. Borg ratings at the symptom-limited peak of exercise were highly reproducible in our patients, as others have
found for peak Borg ratings following incremental cycle or
treadmill exercise in COPD (1, 2, 27). However, peak Borg
ratings were poorly responsive and, therefore, not appropriate
in evaluating symptom responses to therapy, because such ratings before and after therapeutic interventions are often similar despite improvements in exercise endurance.
For this reason, comparison of submaximal Borg ratings at
a standardized time, work rate, or metabolic load, or comparison of the slopes and
intercepts of Borg ratings expressed as a
·
function of time, VO2, work rate, or ventilation, may be preferable in evaluating responses to therapy. However, in previous
studies, submaximal dyspnea ratings during both constantload treadmill testing and incremental cycle ergometry showed
poor reproducibility in COPD (27). Belman and coworkers
(3) demonstrated a reduction in Borg ratings on sequential
testing during submaximal treadmill exercise and postulated
O’Donnell, Lam, and Webb: Symptoms and Hyperinflation during Exercise in COPD
desensitization to dyspnea as an explanation. However, we
found that submaximal Borg values showed good reproducibility (R 5 0.58) when tested repeatedly at a constant work
load of approximately 50 to 60% of their predetermined maximum (Figure 2). The measurement of a continuum of subjective ratings
as a function of independent physiologic stimulus
·
·
(i.e., VO2, VE) provides added information in assessing dyspneic
patients. Mador and associates (27), however, showed large intrasubject variation
in the slopes of Borg-time, Borg-work rate,
·
and Borg- VO2, while employing an incremental cycle exercise
protocol in COPD. With the
constant-load protocol, we found
·
and their intercepts showed
that Borg-time and Borg- VO2 slopes
·
excellent reproducibility; Borg- VE slopes were somewhat less
reproducible (Table 3). Borg-time slopes also demonstrated
greater responsiveness to acute bronchodilator
therapy than
·
·
Borg expressed as a function of VO2 or VE (Table 3). Our results, therefore, support the finding of Mahler and coworkers
(28) who also found Borg-time
slopes to ·be more reproducible
·
and responsive than Borg- VO2 or Borg- VE slopes in asthmatic
patients during incremental cycle exercise testing. We conclude
that the measurement of Borg-time slopes is the most reliable
method of evaluating symptomatic responses in patients with
stable COPD during endurance exercise testing.
Several recent studies have shown that perceived leg discomfort, either exclusively or partially, limits exercise performance in COPD. Whereas dyspnea is more likely to be the
primary limiting symptom in more advanced COPD (5, 8, 29),
leg discomfort has been shown to be the predominant limiting
1563
symptom in mild to moderate disease (5). An assessment of
the intensity of exertional leg discomfort and its contribution
to exercise limitation is, therefore, an integral component of
the evaluation of disabled COPD patients who are, for example, entering pulmonary rehabilitation programs. Our study
showed that
the slopes of Borg ratings of leg discomfort over
·
time and VO2 are both highly reproducible (R . 0.6). Moreover, in two previous controlled studies in patients with severe
COPD, we have shown that Borg-time slopes for exertional
leg discomfort were also responsive to change when using constant-load protocols similar to the one used here (6, 8). Thus,
Borg-time slopes of leg discomfort fell significantly after exercise training, but not after a control period, in COPD (8). Similarly, slopes of exertional leg discomfort over time fell significantly while breathing added oxygen (60%), but not room air,
in patients with advanced COPD (6).
Exercise Performance
There is no consensus with respect to which measurement of
exercise performance should be used in the clinical evaluation
of symptomatic patients with advanced COPD. Endurance
tests, such as the 6-min walk or constant-load treadmill or cycle testing, have widespread use, and there is anecdotal information that such tests may be more responsive than incremental tests. Our study shows that endurance times on sequential
cycle tests over a moderate time interval are highly reproducible (R 5 0.78) and sufficiently sensitive to detect a clinically
relevant increase (i.e., 32 6 9% improvement, p , 0.001) after
Figure 3. Measurements of dyspnea intensity, intensity of leg discomfort, inspiratory capacity, and ventilation are shown over time during constant-load exercise before (dashed lines) and after (solid lines) either
nebulized 500 mg ipratropium bromide (IB) or saline placebo (P). Borg-time slopes fell significantly after IB
(*p , 0.05) with no change in y-intercepts; inspiratory capacity was increased at any given time after IB
(*p , 0.001), although slopes over time were unchanged. Values shown were calculated at the first visit of
each 3-wk period (mean 6 SEM; n 5 29).
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
bronchodilator therapy
compared
with placebo. It is notewor·
·
thy that, while VO2 and VE at the breakpoint of symptom-limited submaximal exercise were also highly reproducible, each
of these measurements were insensitive to the effects of bronchodilator therapy.
Evaluation of Respiratory Mechanics
During cardiopulmonary exercise testing, measurement of the
ventilatory response is deemed to be particularly relevant with
respect to the evaluation of dyspneic patients and the assessment of therapeutic responses. We have previously shown, for
example, that after exercise training (8) or oxygen therapy (6)
in patients with severe COPD, relief of exertional dyspnea
was explained primarily by reduction in the slopes of ventilation over time. Dyspnea relief or improved exercise tolerance
in response to other interventions such as bronchodilator therapy (12) or volume reduction surgery (9, 30), however, may
occur in the absence of a change in ventilation. In these circumstances, improvements in ventilatory mechanics, specifically
reduced dynamic lung hyperinflation, are likely to be important contributing factors. Serial IC measurements throughout
exercise allow noninvasive assessment of ventilatory mechanics (without the need for esophageal balloon placement) and
permit us to track the behavior of operational lung volumes.
To the extent that TLC does not change appreciably during
exercise (24), changes in IC accurately reflect changes in dynamic EELV. In similar patients with COPD, we and others
(31, 32) have previously confirmed that peak values of inspiratory esophageal pressure (an estimate of effort) did not change
during repeated IC measurements, thereby validating the use
of IC measurements throughout exercise.
Inspiratory capacity is determined by the degree of hyperinflation, inspiratory muscle strength, and the extent of intrinsic mechanical loading of these muscles. The IC also provides
information about the position of tidal volume on the respiratory system’s pressure–volume (P–V) curve: the smaller the
IC, the closer VT is to TLC and the upper alinear extreme of
the P–V relation. IC also represents the operating limits for
volume expansion during exercise: the greater the VT/IC ratio,
the greater the mechanic constraints on volume expansion and
the greater the intensity of dyspnea (14, 31).
Another reason for rigorous evaluation of IC measurements
is the recent emergence of commercial software packages for
clinical cardiopulmonary exercise testing that measure tidal
flow–volume loops throughout exercise. Such programs use
IC measurements to place tidal flow–volume loops on the volume axis within their maximal envelopes. However, there is
little or no information about the reproducibility and responsiveness of repeated IC measurements during exercise. Our
results showed that IC measurements at rest, at a standardized
level of submaximal exercise, and at peak exercise were all
highly reproducible (Figure 2) and responsive to change (Figure 3); as were other IC-derived measurements such as IRV or
EILV. Although changes in IC from rest to a standardized
level of exercise were acceptably reproducible, they were not
responsive to change, and exercise slopes of IC were neither
reproducible nor responsive. This is not surprising, because
changes in IC throughout exercise are variable and often alinear. Moreover, in response to bronchodilator therapy, the slope
of IC over time may remain unaltered and merely be shifted
downward in parallel (Figure 3). Therefore, independent measurements of IC, rather than slope determinations, should be
used preferentially to assess the effects of an intervention on
dynamic hyperinflation. It is noteworthy that changes in IC measured during exercise correlated more strongly with changes in
VOL 158
1998
instantaneous Borg dyspnea ratings than any other physiologic
parameter measured at rest or during exercise.
After acute bronchodilator therapy, change in dyspnea occurred in the absence of any change in ventilation, indicating
the importance of changes in ventilatory mechanics. Bronchodilators acutely reduced the level of expiratory flow limitation, and thus hyperinflation, for any given ventilation. For
these patients with advanced COPD and minimal demonstrable reversibility to b2-agonists, the reduction in dyspnea intensity after high-dose anticholinergic therapy also correlated
with the change in resting IC and FEV1 measurements. However, in 17% of the sample, IC changed in the presence of
minimal or no change in resting FEV1. Similarly, a study by
Belman and associates (12) has shown that dyspnea relief following albuterol therapy in COPD was explained by significant changes in operational lung volumes and not by changes
in the resting FEV1. In our studies, an increase in IC (or reduction in dynamic hyperinflation) of approximately 0.3 to
0.4 L during exercise translated into a clinically significant improvement in exercise endurance and reduction in exertional
dyspnea. It should be emphasized that while the dose of nebulized IB (i.e., 500 mg) used in this study represented a standardized single dosage for patients with advanced COPD, it
likely exceeds the dosage of this drug that is generally prescribed using a metered dose inhaler (MDI) and spacer device. In the absence of dose–response data for anticholinergics
comparing the two modes of delivery, it is not possible to determine whether similar therapeutic responses could have
been achieved in this population using lower doses of ipratropium delivered by MDI.
In conclusion, our study confirms the availability of reliable
evaluative instruments to quantify symptom intensity, exercise
endurance, and the level of dynamic hyperinflation in patients
with advanced COPD. Accurate assessment of these important clinical outcomes is integral to the effective management
of symptomatic patients with advanced pulmonary disease.
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