Mechanisms of Dyspnea during Cycle Exercise in
Symptomatic Patients with GOLD Stage I Chronic
Obstructive Pulmonary Disease
Dror Ofir1, Pierantonio Laveneziana1, Katherine A. Webb1, Yuk-Miu Lam2, and Denis E. O’Donnell1
1
Respiratory Investigation Unit, Department of Medicine, and 2Department of Community Health and Epidemiology, Queen’s University,
Kingston, Ontario, Canada
Rationale: Smokers with a relatively preserved FEV1 may experience
dyspnea and activity limitation but little is known about underlying
mechanisms.
Objectives: To examine ventilatory constraints during exercise in
symptomatic smokers with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage I chronic obstructive lung disease (COPD)
so as to uncover potential mechanisms of dyspnea and exercise curtailment.
Methods: We compared resting pulmonary function and ventilatory
responses (breathing pattern, operating lung volumes, pulmonary gas
exchange) with incremental cycle exercise as well as Borg scale ratings
of dyspnea intensity in 21 patients (post-bronchodilator FEV1, 91 6 7%
predicted, and FEV1/FVC, 60 6 6%; mean 6 SD) with significant
breathlessness and 21 healthy age- and sex-matched control subjects
with normal spirometry.
Measurements and Main Results: In patients with COPD compared with
control subjects, peak oxygen consumption and power output were
significantly reduced by more than 20% and dyspnea ratings were
higher for a given work rate and ventilation (P , 0.05). Compared with
the control group, the COPD group had evidence of extensive small
airway dysfunction with increased ventilatory requirements during
exercise, likely on the basis of greater ventilation/perfusion abnormalities. Changes in end-expiratory lung volume during exercise were
greater in COPD than in health (0.54 6 0.34 vs. 0.06 6 0.32 L,
respectively; P , 0.05) and breathing pattern was correspondingly
more shallow and rapid. Across groups, dyspnea intensity increased as
ventilation expressed as a percentage of capacity increased (P ,
0.0005) and as inspiratory reserve volume decreased (P , 0.0005).
Conclusions: Exertional dyspnea in symptomatic patients with mild
COPD is associated with the combined deleterious effects of higher
ventilatory demand and abnormal dynamic ventilatory mechanics,
both of which are potentially amenable to treatment.
Keywords: mild chronic obstructive pulmonary disease; respiratory
mechanics; ventilation; dynamic hyperinflation
Recent studies have confirmed that patients with mild airflow
obstruction as defined by traditional spirometric criteria have
evidence of airway inflammation (1). Moreover, patients with
relatively preserved FEV1 may have extensive small airway dysfunction as measured by closing volume and tests of abnormal
distribution of ventilation (2–4). In such patients, significant
_ inequalities may exist as a result of
_ Q)
ventilation/perfusion (V/
inflammation of the lung parenchyma and its vasculature (5).
(Received in original form July 19, 2007; accepted in final form November 15, 2007)
Supported by the William Spear Endowment Fund, Queen’s University.
Correspondence and requests for reprints should be addressed to Dr. Denis
O’Donnell, M.D., F.R.C.P.C., 102 Stuart Street, Kingston, ON, K7L 2V6 Canada.
E-mail: [email protected]
This article has an online supplement, which is accessible from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 177. pp 622–629, 2008
Originally Published in Press as DOI: 10.1164/rccm.200707-1064OC on November 15, 2007
Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Patients with mild chronic obstructive pulmonary disease
(COPD) and a relatively preserved FEV1 may report poor
perceived health status. The link between ventilatory impairment, symptom development, and activity limitation
has never been systematically explored in mild GOLD
stage I COPD.
What This Study Adds to the Field
Symptomatic patients with GOLD I COPD can have significant pathophysiologic abnormalities that lead to clinically important dyspnea and exercise intolerance. Dyspnea
correlated with increased ventilation and dynamic lung hyperinflation during exercise.
This, in turn, may contribute to a higher ventilatory requirement than normal during exercise. It is known that patients with
apparently mild airflow obstruction may report poor perceived
health status, chronic activity-related dyspnea (6), and reduced
activity levels. Such patients may seek medical attention for
relief of dyspnea but the underlying mechanisms and the impact
of therapeutic interventions other than successful smoking
cessation remains unknown (7, 8).
The Global Initiative for Chronic Obstructive Lung Disease
(GOLD) definition of mild chronic obstructive pulmonary
disease (COPD) based on a fixed FEV1/FVC ratio (,0.7) has
recently been criticized because of the risk of false-positive
diagnosis, particularly in the elderly. The added concern is that
overdiagnosis could lead to inappropriate treatment with expensive inhaled bronchodilator and corticosteroid treatment.
This view is further justified by the absence of proof of the longterm safety and efficacy of these medications in patients with
milder disease (FEV1 . 60% predicted). However, this must be
balanced by the clinical experience that some symptomatic
smokers who fit the mild GOLD criteria may indeed have extensive physiologic impairment that is obscured by a relatively
preserved FEV1. It is reasonable to assume that, in older smokers,
widespread small airway bronchiolitis, in conjunction with the
natural pulmonary impairment associated with aging, will give
rise to perceived greater breathing difficulty during exercise
than in healthy nonsmoking control subjects. The main purpose
of this study was, therefore, to increase our understanding of the
mechanisms of exertional dyspnea and activity limitation in this
population.
Previous studies have demonstrated that exercise capacity is
abnormally diminished in subjects with a mildly reduced postbronchodilator FEV1 (,80% predicted) (9, 10). In this study,
we extend these observations by examining ventilatory constraints during exercise in symptomatic patients with GOLD
Ofir, Laveneziana, Webb, et al.: Exercise in GOLD Stage I COPD
stage I COPD (post-bronchodilator FEV1 > 80% predicted and
FEV1/FVC , 0.7) so as to uncover potential mechanisms of
dyspnea and exercise curtailment. We reasoned that, in mild
COPD, a higher intensity of exertional dyspnea compared with
age-matched healthy participants would be associated with the
following: (1) greater ventilatory demand, (2) increased mechanical loading of the ventilatory muscles during exercise, or (3)
a combination of both. We therefore compared ventilatory responses (breathing pattern, operating lung volumes, and gas exchange parameters) to incremental cycle exercise in 21 patients
and 21 healthy age- and sex-matched control subjects. We then
conducted a correlative analysis to examine possible contributors to exertional dyspnea intensity.
Some of the results of this study have been previously
reported in the form of an abstract (11).
METHODS
Subjects
We studied 21 symptomatic patients with GOLD stage I COPD (postbronchodilator FEV1 > 80% predicted and FEV1/FVC , 0.7) (12)
who were referred to the COPD Centre at our institution. Patients
were excluded if they had (1) other unstable medical conditions that
could cause or contribute to breathlessness (i.e., metabolic, cardiovascular, or other respiratory diseases) or (2) other disorders that could
interfere with exercise testing, such as neuromuscular diseases or
musculoskeletal problems. In addition, 21 healthy age-and sex-matched
subjects were included with normal baseline spirometry (FEV1 > 80%
predicted, FEV1/FVC > 0.7) and absence of any health problems,
including cardiovascular, neuromuscular, musculoskeletal, or respiratory diseases that could contribute to breathlessness or exercise limitation. Healthy subjects were recruited from the local community using
word-of-mouth, notices posted in community health care facilities, and
newspaper advertisements.
Study Design
This was a controlled, cross-sectional study in which informed consent
was obtained from all subjects, and ethical approval was received from
the Queen’s University and Hospital Health Sciences Human Research
Ethics Board. Subjects were tested on two occasions. On the first visit,
after informed consent and appropriate screening of medical history, all
subjects completed pulmonary function testing pre- and post-bronchodilator (400 mg salbutamol) and a variety of questionnaires: chronic
activity-related dyspnea questionnaires included the Baseline Dyspnea
Index (13) and the Medical Research Council scale (14), and a selfreported habitual physical activity questionnaire (Community Healthy
Activities Model Program for Seniors [CHAMPS]), which was used to
evaluate each subject’s weekly caloric expenditure in physical activities
(15). On the second visit, subjects completed pulmonary function testing
and cardiopulmonary exercise testing.
Subjects with COPD were asked to withdraw from any respiratoryrelated medications for between 8 and 72 hours, based on the medication used (short- or long-acting), before any of the visits to eliminate
any effect on exercise or pulmonary function. All subjects were required to eat a normal mixed diet before laboratory visits to provide
valid experimental/metabolic results during exercise. Subjects were also
asked to avoid the ingestion of alcohol, caffeine-containing products, and
heavy meals for at least 4 hours, and to refrain from strenuous activity
(e.g., cycling, running) for at least 12 hours before testing. Experimental
visits were conducted at the same time of day for each subject.
Procedures
Routine spirometry, constant-volume body plethysmography, singlebreath diffusing capacity (DLCO), and maximum inspiratory and expiratory mouth pressures (PImax and PEmax, measured at FRC and TLC,
respectively) were performed in accordance with recommended techniques (16–20) using an automated pulmonary function testing system
(6200 Autobox DL and Vmax229d; SensorMedics, Yorba Linda, CA).
Closing volumes were measured using the single-breath nitrogen test as
623
modified by Anthonisen and colleagues (21). Measurements were repeated 30 minutes post-bronchodilator (400 mg salbutamol) in all
patients with mild COPD and in 10 healthy subjects. Measurements
were standardized as percentages of predicted normal values (22–28);
predicted normal values for inspiratory capacity (IC) were calculated as
predicted TLC minus predicted FRC.
Symptom-limited incremental exercise testing was conducted on an
electronically braked cycle ergometer (Ergometrics 800S; SensorMedics) using the Vmax229d Cardiopulmonary Exercise Testing System
(SensorMedics) according to recommended guidelines (29) as previously described (30). Exercise tests consisted of a steady-state resting
period and a 1-minute warm-up of unloaded pedalling followed by
a stepwise protocol in which the work rate was increased in 2-minute
intervals by increments of 20 W. All exercise tests were terminated at
the point of symptom limitation (peak exercise). Upon exercise cessation, subjects were asked to verbalize their main reason for stopping
exercise: for example, breathing discomfort, leg discomfort, both breathing and leg discomfort, or some other reason to be documented.
Subjects rated the magnitude of their perceived breathing and leg
discomfort at rest, every minute during exercise, and at peak exercise
by pointing to the 10-point Borg scale. Oxygen saturation (SpO2) by
pulse oximetry, electrocardiographic monitoring of heart rate (HR),
rhythm and ST-segment changes, and blood pressure by indirect sphygmomanometry were performed at rest and throughout exercise testing.
Breath-by-breath data were collected at baseline and throughout exercise while subjects breathed through a mouthpiece with nasal passages
occluded by a nose-clip: computer software calculated minute ventila_
_ 2 ), carbon dioxide production (Vco
_ 2 ), endtion (Ve),
oxygen uptake (Vo
tidal carbon dioxide partial pressure (PETCO2), VT, breathing frequency
(f), inspiratory and expiratory time (TI and TE, respectively), duty cycle
(TI/Ttot), and mean inspiratory and expiratory flow (VT/TI and VT/TE,
respectively). Exercise variables were measured and averaged over the
last 30 seconds of each minute and at peak exercise. Exercise parameters
were compared with the predicted normal values of Blackie and colleagues (31) and Jones and coworkers (32). Changes in end-expiratory
lung volume (EELV) were estimated from IC measurements at rest, at
the end of each 2-minute increment of exercise, and at peak exercise
(33). Ventilation was also compared with the maximal ventilatory capacity (MVC), which was estimated by multiplying the measured FEV1 by
35 (34). The ventilatory threshold (VTh) was detected individually using
the V-slope method (35). Breathing pattern was evaluated by examining
individual Hey plots (36).
Additional detail on the methods for performing pulmonary
function and exercise test measurements is provided in the online
supplement.
Statistical Analysis
A sample size of 16 was used to provide the power (80%) to detect
a significant difference in dyspnea intensity (Borg scale) measured at a
standardized work rate during incremental cycle exercise based on
a relevant difference in Borg ratings of 61, an SD of 1 for Borg ratings
changes found at our laboratory, a 5 0.05. Results were expressed as
means 6 SD. A P , 0.05 level of statistical significance was used for all
analyses.
Group responses at different time points and/or intensities during
exercise were compared using t tests with appropriate Bonferroni adjustments for multiple comparisons. Dyspnea descriptors were analyzed as frequency statistics and compared using the Fisher’s exact test.
Physiologic contributors to exertional dyspnea intensity in subjects with
COPD were determined by multiple regression analysis. In this analysis,
Borg dyspnea ratings at a standardized exercise work rate (dependent
variable) were analyzed against concurrent relevant independent variables (i.e., exercise measurements of ventilation, breathing pattern, operating lung volumes, cardiovascular and metabolic parameters, and
baseline pulmonary function measurements).
RESULTS
Subject characteristics are summarized in Table 1. Compared
with the healthy control group, the COPD group showed significant expiratory airflow limitation and lung hyperinflation,
a reduced DLCO, a greater closing capacity and N2 slope, and
624
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 177
TABLE 1. SUBJECT CHARACTERISTICS AND PULMONARY
FUNCTION IN PATIENTS WITH GOLD STAGE I CHRONIC
OBSTRUCTIVE PULMONARY DISEASE AND IN HEALTHY
CONTROL SUBJECTS
Control
Male, %
Age, yr
Body mass index, kg/m2
BDI focal score (0–12)
MRC dyspnea scale (1–5)
CHAMPS, kcal/wk consumed
at moderate activities*
FEV1, L
(% predicted)
FEV1 post–b2-agonist, L
(% predicted)
FEV1/FVC post–b2-agonist, %
FVC, L
(% predicted)
PEFR, % predicted
FEF25–75%, % predicted
IC, % predicted
FRC, % predicted
TLC, % predicted
RV, % predicted
RV/TLC, %
sRaw, % predicted
PImax at FRC, % predicted
PImax at TLC, % predicted
DLCO, % predicted
CV/VC, % predicted*
CC/TLC, % predicted*
Estimated MVC, L/min
57
63
26.2
11.5
1.1
1744
6
6
6
6
6
9
3.4
0.7
0.1
880
2.77 6 0.48
(117 6 9)
2.88 6 0.52
(124 6 12)
82 6 4
3.79 6 0.67
(106 6 13)
120 6 15
99 6 27
109 6 13
102 6 21
105 6 13
97 6 20
33 6 4
132 6 42
132 6 46
94 6 25
118 6 20
103 6 21
97 6 12
102.0 6 16.4
COPD
64
64
27.7
8.3
1.9
2820
all four ex-smokers had less than a 10 pack-year smoking history
and had stopped smoking for more than 10 years.
Symptom-limited Incremental Cycle Exercise
P Value
7
4.1
2.0
0.1
2103
NS
NS
NS
,0.0005
,0.0005
NS
2.28 6 0.56
(85 6 11)
2.47 6 0.54
(91 6 7)
60 6 6
3.93 6 0.98
(102 6 11)
89 6 16
34 6 12
105 6 19
121 6 20
114 6 9
129 6 21
41 6 6
290 6 97
109 6 35
81 6 23
98 6 21
128 6 47
118 6 18
79.6 6 19.3
,0.05
,0.0005
NS
,0.0005
,0.0005
NS
NS
,0.0005
,0.0005
NS
,0.005
0.01
,0.0005
,0.0005
,0.0005
NS
NS
,0.005
NS
,0.005
,0.0005
6
6
6
6
6
2008
Definition of abbreviations: BDI 5 modified Baseline Dyspnea Index; CHAMPS 5
Community Healthy Activities Model Program for Seniors; CC 5 closing capacity;
COPD 5 chronic obstructive pulmonary disease; CV 5 closing volume; DLCO 5
diffusing capacity of the lung for carbon monoxide; FEF25–75% 5 force expiratory
flow between 25 and 75% of FVC; IC 5 inspiratory capacity; MRC 5 Medical
Research Council; MVC 5 maximal ventilatory capacity estimated as 35 3 FEV1;
NS 5 not significant; PEFR 5 peak expiratory flow rate; PEmax 5 maximal
expiratory pressure; PImax 5 maximal inspiratory pressure; RV 5 residual volume;
sRaw 5 specific airways resistance; TLC 5 total lung capacity.
Values are means 6 SD.
* Data only collected in 10 of the 21 healthy control subjects.
significantly greater chronic activity-related dyspnea. The healthy
control subjects had normal spirometry and were well matched
for age, sex, body mass index, and habitual physical activities,
when compared with the subjects with COPD.
All subjects with COPD were symptomatic and had a diagnosis of COPD; the majority (15 of 21) had a diagnosis made
within the previous 5 years. Eleven subjects with COPD were prescribed respiratory medication: nine subjects used their inhalers
on a regular basis (n 5 9 long- and/or short-acting b2-agonist
bronchodilators, n 5 5 long- and/or short-acting anticholinergic
bronchodilators, n 5 7 inhaled corticosteroid/long-acting b2-agonist
combination) and two subjects used a short-acting b2-agonist
bronchodilator on an ‘‘as needed’’ basis only. Comorbidities in
the COPD group included the following: stable coronary artery
disease (n 5 2), diabetes mellitus type 2 (n 5 1), well-controlled
hypertension (n 5 2), and varying degrees of osteoarthritis (n 5 4).
Comorbidities in the control group included mild osteoarthritis
(n 5 4) and diabetes mellitus type 2 (n 5 1). See the online supplement for more details on subjects.
All of the patients with COPD had a significant (>15 packyears) smoking history (46.4 6 19.8 pack-years; range, 15–100
pack-years). Five patients were current smokers and 16 were exsmokers who had stopped smoking at least 2 years before the
study. In the control group, there were no current smokers and
The majority of patients with COPD (60%) stopped exercise
due to severe breathing discomfort, either alone or in combination with leg discomfort (Figure 1). In contrast, the majority
of healthy control subjects (81%) stopped exercise primarily
because of leg discomfort. Dyspnea intensity was higher in the
COPD group during exercise at a given work rate (Figure 2):
group mean differences were greater than 1 Borg unit at 60 W
_ 2 and
and thereafter during exercise (P , 0.05). Dyspnea/Vo
_ slopes were also greater in COPD than control
dyspnea/Ve
groups by 49 and 51%, respectively (P , 0.05). At the end of
exercise, dyspnea intensity was rated 1.5 Borg units higher in
subjects with COPD compared with control subjects (P 5 0.08),
and a significantly greater number of patients with COPD
described their breathing as rapid compared with control subjects (45 vs. 5%, respectively; P , 0.05).
Measurements at the VTh and at peak exercise are shown in
Table 2. Patients with COPD stopped exercise at a lower peak
_ 2 ; work rate, and HR than healthy control subjects: Vo
_ 2 /work
Vo
rate (Figure 3) and HR/work rate relationships were not different
between the two groups throughout the exercise. Compared with
_ in the COPD group was significantly higher
the control group, Ve
_
at any submaximal exercise intensity: mean differences in Ve
ranged from approximately 5 L/minute at 20 W (P , 0.0005) and
became greater with increasing work rate (Figure 3). At the VTh,
_ was similar in both groups; however, patients with COPD
Ve
_ 2 as well as a lower work rate.
reached their VTh at a lower Vo
More subjects with COPD (n 5 10) than control subjects (n 5 5)
had a VTh below 50% of the predicted maximum work rate,
whereas more subjects with COPD also had a VTh in the lower
_ 2 range (n 5 5 between 40 and 49%, n 5 8 between 50 and 59%
Vo
_ 2 ) than control subjects (n 5 3 between 40
of predicted peak Vo
_ 2 ).
and 49%, n 5 3 between 50 and 59% of predicted peak Vo
PETCO2 was lower in the COPD group compared with the control
group at rest (36.0 6 4.3 vs. 39.5 6 4.5 mm Hg, respectively), at
any given work rate during exercise (see Figure E1 of the online
supplement) and at VTh (Table 2).
During exercise in COPD, IC decreased significantly by
0.54 6 0.34 L (P , 0.0001), with changes in IC ranging between
10.26 L (9% predicted) and 21.11 L (241% predicted). In
contrast to COPD, there was no significant change in IC from
Figure 1. Selection frequency of the reason for stopping cycle exercise
in the GOLD stage I chronic obstructive pulmonary disease (COPD)
group and healthy control group. *P , 0.05, COPD versus control.
Ofir, Laveneziana, Webb, et al.: Exercise in GOLD Stage I COPD
625
Figure 2. Exertional dyspnea intensity was greater during cycle
exercise in subjects with mild
chronic obstructive pulmonary disease (COPD) than in healthy control subjects. Dyspnea/work rate
and dyspnea/ventilation slopes
were significantly (P , 0.05)
steeper in patients with COPD than
in healthy subjects. Graphs represent mean 6 SE values at rest; at
20, 40, 60, and 80 W during exercise; and at peak exercise. *P ,
0.05, COPD versus control at
a standardized work rate in watts.
rest to peak exercise in the normal group (0.06 6 0.32 L or 1 6
9% predicted). Although 19 of 21 (90%) patients with COPD
decreased their IC during exercise by more than 0.2 L, only
24% of the control subjects decreased IC, 29% increased IC,
and 47% did not change IC.
_
Upon evaluation of individual Hey plots (36), the average Ve
at the VT inflection point was similar at 44 and 45 L/minute in the
control and COPD group, respectively (Figure 4); however, this
_ 2 and
inflection occurred at a significantly (P , 0.05) lower Vo
work rate in COPD. Between-group differences in breathing
_ in COPD, there was a plateau
pattern were found beyond this Ve:
_ were achieved
in VT at this point so that further increases in Ve
by increasing f alone; in the control group, further increases in
_ were achieved by increasing both VT and f. In COPD, VT after
Ve
the inflection point was constrained by further reductions in IC
of 0.23 L (P , 0.0005). Interestingly, the inspiratory reserve
_ inflection point was similar across
volume (IRV) at the VT/Ve
groups.
TABLE 2. MEASUREMENTS AT THE VENTILATORY THRESHOLD AND AT THE PEAK OF
SYMPTOM-LIMITED INCREMENTAL CYCLE EXERCISE
Ventilatory Threshold
Control
Dyspnea, Borg scale
Leg discomfort, Borg scale
Work rate, W
(%predicted maximum)
_ 2 , L/min
Vo
(%predicted maximum)
_ 2 ; ml/kg/min
Vo
HR, beats/min
(%predicted maximum)
O2 pulse, ml O2/beat
SpO2, %
_ L/min
Ve,
(% estimated MVC)
_ Vco
_ 2
Ve/
_ 2
VE/Vo
PETCO2, mm Hg
f, breaths/min
VT , L
(%predicted VC)
IC, L
(%predicted)
DIC from rest, L
(%predicted)
IRV, L
(%predicted TLC)
EFL, % of VT overlapping
maximal flow–volume curve
1.8
2.4
91
(62
1.34
(65
18.7
121
(72
11.2
97
36.2
(36
28.9
27.7
45.6
24
1.55
(44
2.84
(105
0.02
(1
1.29
(22
25
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
1.5
1.5
32
18)
0.29
12)
4.9
17
9)
2.9
1
7.8
6)
4.2
3.6
4.2
4
0.35
7)
0.51
9)
0.28
11)
0.48
8)
27
Peak Exercise
COPD
3.0
3.6
79
(49
1.25
(56
15.6
118
(70
10.8
96
39.8
(51
34.3
32.0
41.0
25
1.64
(42
2.82
(95
20.28
(210
1.18
(19
63
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
1.9
1.9
13
13*)
0.33
9*)
3.8*
19
11)
2.9
2
10.6
13*)
6.0*
5.2*
5.7*
5
0.48
8)
0.72
16*)
0.27*
9*)
0.47
7)
25*
Control
5.4
6.8
144
(97
2.11
(101
29.1
156
(93
13.5
96
78.0
(75
34.2
37.7
37.4
38.5
2.06
(54
2.76
(96
20.06
(22
0.70
(12
40
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
2.8
2.5
43
23)
0.59
16)
7.1
15
9)
3.3
2
23.9
19)
6.7
8.1
5.6
9.1
0.47
9)
0.53
14)
0.32
12)
0.37
6)
23
COPD
6.9
7.2
116
(72
1.75
(78
21.7
142
(85
12.4
96
67.7
(85
36.8
38.7
37.3
36.6
1.87
(45
2.56
(82
20.54
(218
0.69
(11
80
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
2.8
2.2
38*
14*)
0.55*
12*)
5.7*
21*
12*)
3.4
2
23.6
20)
6.3
6.3
5.6
8.1
0.55
9*)
0.68
15*)
0.34*
11*)
0.31
4)
19*
Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease; EFL 5 expiratory flow-limitation; FEF25–75% 5 force
expiratory flow between 25 and 75% of FVC; HR 5 heart rate; IC 5 inspiratory capacity; IRV 5 inspiratory reserve volume; MVC 5
maximal ventilatory capacity estimated as 35 3 FEV1; PETCO2 5 partial pressure of end-tidal CO2; TLC 5 total lung capacity.
Values are means 6 SD.
* P , 0.05, COPD versus control within the given stage of exercise.
626
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 177
2008
Figure 3.
Minute ventilation
_
(Ve),
oxygen consumption (VO2),
ventilatory equivalent for carbon
_ Vco
_ 2 ), and oxygen
dioxide (Ve/
saturation by pulse oximetry
(SpO2) are shown in response to
symptom-limited incremental cycle exercise in patients with mild
chronic obstructive pulmonary disease (COPD) and in healthy control subjects. Graphs represent
mean 6 SE values at rest; at 20,
40, 60, and 80 W during exercise;
and at peak exercise. *P , 0.05,
COPD versus control at a standardized work rate in watts.
Mechanisms of Exertional Dyspnea
The relationships between Borg ratings of dyspnea intensity and
_ (% estimated MVC) or IRV (% predicted TLC) during
Ve
exercise were both superimposed in COPD and control groups,
indicating that dyspnea intensity increased as a function of each of
these independent variables. This concept is supported by the
strong correlation across groups between ratings of exertional
dyspnea at the highest common work rate (80 W) and the
_ expressed as % estimated MVC (r 5 0.61, P ,
concurrent Ve
0.0005) and IRV standardized as % predicted TLC (r 5 20.62,
P , 0.0005); the best physiologic correlate of dyspnea intensity at
this work rate was the concurrent IC expressed as % predicted
_ (% estimated MVC) and
(r 5 20.63, P , 0.0005). Although Ve
IRV (% predicted TLC) were moderately interrelated (r 5
20.58, P , 0.005), each variable explained an additional 10%
to the variance in dyspnea ratings after accounting first for the
_ at this work
other. Dyspnea intensity and absolute values of Ve
rate were not as strongly correlated (r 5 0.39, P 5 0.013);
_ explained an additional 8% of the variance in
however, Ve
dyspnea intensity after accounting for the concurrent IC %pre-
Figure 4. VT, breathing frequency
(F ), inspiratory capacity (IC), and
inspiratory reserve volume (IRV)
are shown in response to increasing
minute ventilation or work rate during incremental cycle exercise in
patients with mild chronic obstructive pulmonary disease (COPD) and
in healthy control subjects. Graphs
represent mean 6 SE values at rest;
at 20, 40, 60, and 80 W during
exercise; and at peak exercise. *P ,
0.05, COPD versus control at a standardized work rate or at peak exercise.
Ofir, Laveneziana, Webb, et al.: Exercise in GOLD Stage I COPD
dicted. By stepwise multiple regression analysis, dyspnea intensity at 80 W was best described by the combination of concurrent measurements of IC % predicted and peak tidal expiratory flow (r25 0.56, P , 0.0001). Within the COPD group, the
strongest correlates of exertional dyspnea intensity at a given
work rate (80 W) were the simultaneous measurements of IC
% predicted (r 5 20.57, P 5 0.011), IRV expressed as % predicted TLC (r 5 20.51, P 5 0.025), and the VT/IC ratio (r 5 0.47,
P 5 0.042).
DISCUSSION
The main findings of this study are as follows: (1) exercise capacity was significantly reduced and exertional dyspnea ratings
were higher at a given work rate in symptomatic patients with
GOLD stage I COPD, compared with healthy control subjects;
(2) resting pulmonary function tests confirmed that patients had
significant small airway dysfunction; (3) ventilatory abnormalities during exercise in patients with mild COPD included
higher ventilatory demand, significant dynamic lung hyperinflation (DH), and a relatively rapid and shallow breathing pattern.
Our patients with COPD with a relatively preserved FEV1 had
mild to moderate chronic activity-related dyspnea as measured by
validated questionnaires. In fact, 11 of 21 patients had previously
sought medical attention for dyspnea and were receiving regular
or as-needed inhaled bronchodilator therapy. Peak symptom_ 2 was reduced by 22% of the predicted normal value
limited Vo
(Table 2), and patients were more likely to report dyspnea (and
less likely to report leg discomfort) as an exercise-limiting
symptom compared with age- and sex-matched healthy participants (Figure 1). We are satisfied that the reduced exercise
performance in our patients with COPD was not the result of
reduced motivational effort: patients reported intolerable exertional symptoms at the peak of exercise and generally demonstrated significant encroachment on their cardiopulmonary and
metabolic reserves. Although exercise limitation was multifactorial and the proximate cause likely varied among individuals,
significant ventilatory constraints and attendant respiratory difficulty were evident in the majority of patients.
During exercise, dyspnea intensity ratings were higher at
a given power output (e.g., by 2 Borg units at 80 W) (Figure 2),
_ 2 and dyspnea/Ve
_ slopes were approxwhereas both dyspnea/Vo
imately 50% steeper in the COPD than in the healthy control
group. We considered the following potential contributors to
exertional dyspnea in patients with mild COPD: (1) higher
ventilatory demand as a result of pulmonary gas exchange or
metabolic abnormalities, (2) greater abnormalities of dynamic
ventilatory mechanics and muscle function that would cause
dyspnea to increase for any given ventilation compared with
health, or (3) a combination of both of these.
Increased Ventilatory Demand
Ventilation was increased significantly by approximately 30% or
more for any given power output throughout exercise in patients
_ 2/
with mild COPD compared with control subjects (Figure 3). Vo
work rate slopes were similar and well within the normal range in
both groups as has previously been described (37) (Figure 3). The
DLCO in the COPD group was slightly but significantly diminished compared with the healthy group but remained within
the predicted normal range. Five patients had a DLCO value that
was lower than 80% predicted, indicating some reduction in
the surface area for gas exchange in these heavy smokers. The
ventilatory equivalents for CO2 and O2 were significantly
elevated throughout exercise compared with in health, sug_ abnormalities. Thus, the higher Ve/
_ Q
_ Vco
_ 2
gesting greater V=
_
_
and Ve/Vo2 in our COPD group likely reflect an impaired ability
627
to reduce a higher physiologic dead space during exercise. The
_ inequality contributed to the accelerated
_ Q
contention that V=
ventilatory response in patients with COPD is supported by the
_ was increased early in exercise before the onset
findings that Ve
_ Vco
_ 2 ratios were also signifiof metabolic acidosis and that Ve/
cantly (P , 0.05) elevated early in exercise (by 10 and 15% at 40
and 60 W, respectively) as well as at the VTh (by 19%) in patients
with COPD compared with those in health. Indeed, Barbera and
_ inequalities
_ Q
colleagues (5) originally described significant V=
during exercise in a group of patients with mild COPD (mean
FEV1/FVC 5 59%) but found that gas exchange in these
individuals was largely preserved through increased alveolar
ventilation. Similarly, ventilatory efficiency was not critically
compromised in COPD, and pulmonary gas exchange abnormalities were not sufficiently pronounced to cause greater
arterial oxygen desaturation during the activity. It is noteworthy
that PETCO2 was decreased at rest and remained similarly decreased throughout all exercise work rates (by z4 mm Hg) in
patients with COPD compared with those in health, suggesting
alveolar hyperventilation and possible alteration in the ventilatory control system.
Earlier metabolic acidosis secondary to the effects of skeletal
muscle deconditioning was considered as a potential explanation
_ and dyspnea in patients with COPD.
for the earlier rise in Ve
_ 2 in
Ventilatory thresholds did occur at a significantly lower Vo
COPD (by 16%) than in health but nevertheless occurred within
the expected normal range (Table 2). However, there was
considerable overlap in the range and more subjects with COPD
than control subjects had a VTh below 50% of the predicted
_ 2 . Perceived
maximum work rate or in the lower range of Vo
exertional leg discomfort was relatively increased in patients with
COPD. However, other indications of the effects of decondition_ 2 slopes, were not discernible in our
ing, such as increased HR/Vo
patients with COPD. Moreover, our estimates of habitual physical activity using the CHAMPS questionnaire (15) were similar
in both groups (Table 1). Significant cardiac impairment was also
unlikely to contribute to the relatively reduced VTh in COPD
because patients with active cardiac comorbidity were carefully
excluded from this group and HR responses and reserve at peak
exercise were normal, as were O2 pulse and blood pressure
measurements. We can conclude, therefore, that pulmonary
_ abnormalities stimulated ventilation during exercise in
_ Q
V=
COPD and that this was likely compounded later in exercise by
the effects of metabolic acidosis.
Regardless of the mechanism, the increased ventilatory demand likely contributed to the greater dyspnea intensity and
exercise curtailment in patients with COPD. Thirteen of 21
_
patients with COPD reached a Ve/MVC
greater than 85% at
a lower peak exercise capacity than in health, suggesting clinically
significant ventilatory constraints to exercise in these individuals
_
(38). A high ventilatory index (Ve/MVC)
has traditionally been
linked to higher levels of exertional dyspnea during exercise (39).
In this study, a correlative analysis confirmed an association be_
tween dyspnea intensity ratings and the Ve/MVC
ratio (r 5 0.61,
P , 0.05). The higher ventilatory demand in patients with COPD
ultimately reflects a relatively increased central neural drive and
contractile muscular effort (relative to the maximal possible
value) for the ventilatory muscles. Neurophysiologically, the perception of increased effort is believed to be conveyed via central
corollary discharge from the motor centers to the somatosensory
cortex, where it is consciously appreciated as unpleasant (39–41).
Abnormal Dynamic Ventilatory Mechanics
_ slopes were consistently elevated during exercise in
Dyspnea/Ve
COPD, suggesting increased intrinsic mechanical loading and/or
functional weakness of the ventilatory muscles. Resting pulmo-
628
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 177
nary function tests confirmed important mechanical abnormalities in the setting of a relatively preserved FEV1, VC, IC, and
maximal static respiratory muscle strength. The presence of clinically significant small airway dysfunction was suggested by the
following: (1) maximal expiratory flow rates were uniformly diminished over the effort-independent portion of the maximal
flow–volume curve, (2) closing capacity was increased, (3) maldistribution of ventilation was suggested by the nitrogen washout
test, and (4) all plethysmographic lung volumes were elevated.
The time course of change in the various lung volume and
capacity components with disease progression is unknown. In
our sample, TLC and FRC were increased in proportion (suggesting increased lung compliance) such that IC was preserved.
Tantucci and colleagues (42) have previously shown that reduction of resting IC (,80% predicted) in patients with moderate
to severe COPD indicated the presence of expiratory flow
limitation at rest (measured by the negative expiratory pressure
technique), with negative implications for exercise performance.
It follows that our patients with COPD were unlikely to manifest
expiratory flow limitation at rest but nevertheless encroached on
their maximal expiratory flow reserve relatively early in exercise.
During the accelerated ventilatory response to exercise in COPD,
EELV increased by an average of 0.54 L from rest to peak
exercise, whereas in healthy participants it increased by an average of 0.06 L. These findings are consistent with the previous
report by Babb and colleagues (9) who demonstrated DH by 0.42
L in a group of patients with GOLD stage 2 COPD. Similar levels
of DH have been reported in patients with moderate to severe
COPD, but at much lower ventilations and work rates than in our
patients with milder disease (33). The presence of this degree of
DH suggests that the respiratory system’s mechanical time constant for lung emptying was delayed even in mild COPD. Thus, in
the setting of exercise tachypnea (and reduction of expiratory
time), progressive air trapping is the inevitable consequence. Our
older control group showed an inability to decrease EELV during
higher exercise intensities, likely reflecting the well-documented
effects of aging on lung compliance, which predisposes these
individuals to expiratory flow limitation (43, 44). It follows that
the superimposition of small airway bronchiolitis and possibly
regional emphysema, as a result of smoking, on the already
impaired physiology of the aging lung may amplify the negative
clinical consequences. Whether the impact of similar smoking
damage on the lungs and airways of younger individuals is less
marked has not been studied but is a reasonable postulation.
DH in our COPD group was associated with a more rapid,
shallow breathing at ventilations beyond 45 L/minute (Figure 4).
Consequently, the VT inflection point on individual Hey plots
_ 2 and work rate (but at a similar dyhappened at an earlier Vo
namic IRV) in COPD than in health. Thus, in patients with
COPD, VT did not increase further from the inflection point to
_ (an increase of 23 L/min), and increases in Ve
_ near endpeak Ve
exercise were achieved mainly by increasing breathing frequency.
In this regard, it is interesting that, at end-exercise, patients with
COPD selected the qualitative dyspnea descriptor ‘‘rapid’’ more
frequently than the healthy group. By contrast, VT expansion in
health continued after the VT inflection point (by a further 0.23 L)
and tachypnea was relatively delayed.
Mechanical abnormalities contributed to perceived exertional
respiratory difficulty in COPD. On the basis of the result of
a previous mechanical study in moderate to severe COPD (45),
we speculate that DH was likely advantageous early in exercise by
attenuating expiratory flow limitation at the relatively higher
absolute lung volume. This may have permitted our patients with
_ to approximately 40 L/minute over the first
COPD to increase Ve
few minutes of exercise with only mild increases in perceived
respiratory discomfort (i.e., Borg, z2 units). Thereafter, further
2008
lung hyperinflation would be expected to cause increased elastic
loading and functional weakness of the inspiratory muscles
(already burdened with increased resistive loading) and to constrain VT expansion in the setting of a progressively increasing
central neural drive (45). Over the final minutes of exercise, it is
clear that, in our patients with COPD, central respiratory drive
was relatively increased, whereas VT expansion was more restricted compared with health. We have previously argued that
this increasing disparity between respiratory effort (or neural
drive) and simultaneous thoracic volume displacement (i.e.,
neuromechanical dissociation) may, in part, form the basis for
the perception of greater respiratory difficulty in patients with
COPD (45). In the current study, dyspnea/IRV relationships
were superimposed in the COPD and control groups. However, it
is noteworthy that, at a standardized power output of 80 W,
dyspnea intensity was significantly higher and dynamic IRV was
proportionately lower in the COPD group than in the control
group, indicating deleterious mechanical effects on respiratory
sensation. The notion that DH contributes to exertional dyspnea
is bolstered by the finding that, within the COPD group, ratings of
dyspnea intensity increased as dynamic IRV diminished during
exercise (r 5 20.51, P , 0.05). Moreover, consistent with a
number of previous studies in patients with moderate to severe
COPD, increased dyspnea intensity ratings at a standardized exercise stimulus correlated well with reduced dynamic IC expressed
as %predicted (46–48). Thus, mechanical factors contributed more
to the variance of exertional dyspnea intensity than the increased
ventilation, although ventilation explained an additional 8% of
the variance in dyspnea ratings after accounting for IC in a stepwise regression analysis.
It is important to emphasize that even among this small group
of patients with COPD, considerable pathophysiologic heterogeneity was evident. For example, three patients had disproportionate reduction of DLCO (,70% predicted) and were subsequently found to have radiographic evidence of localized
emphysema. The extent to which our results can be generalized
to the larger population of less symptomatic patients with GOLD
stage I COPD (e.g., those identified by screening spirometry)
remains to be determined. We can conclude, however, that in
older symptomatic smokers with a largely preserved FEV1,
clinically significant physiologic impairment and exertional symptoms may be present.
In summary, this is the first study to examine mechanisms of
exertional dyspnea in patients with mild COPD as judged by
traditional spirometric criteria. Our study demonstrates that extensive small airway dysfunction may exist in symptomatic
patients with mild COPD with relatively preserved FEV1, FVC,
and resting IC. When abnormal airway function and increased
_ mismatching are superimposed on preexisting age-related
_ Q
V=
pulmonary impairment, greater exercise curtailment and troublesome exertional symptoms are the result. Dyspnea causation is
multifactorial, but our results indicate that the combination of increased ventilatory demand and abnormal dynamic ventilatory
mechanics is likely important. For smokers who experience persistent and apparently disproportionate dyspnea (with reference to
FEV1), cardiopulmonary exercise testing is useful in uncovering the
severity and mechanisms of this symptom, on an individual basis.
Conflict of Interest Statement: None of the authors has a financial relationship
with a commercial entity that has an interest in the subject of this manuscript.
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