Ventilatory Assistance Improves Exercise Endurance

in Stable Congestive Heart Failure

DENIS E. O’DONNELL, CHRISTINE D’ARSIGNY, SATISH RAJ, HOSHIAR ABDOLLAH,
and KATHERINE A. WEBB
Respiratory Investigation Unit, Department of Medicine, Queen’s University, Kingston, Ontario, Canada

We postulated that ventilatory assistance during exercise would improve cardiopulmonary function,
relieve exertional symptoms, and increase exercise endurance (Tlim) in patients with chronic conges-
tive heart failure (CHF). After baseline pulmonary function tests, 12 stable patients with advanced
CHF (ejection fraction, 24 6 3% [mean 6 SEM]) performed constant-load exercise tests at approxi-
.
mately 60% of their predicted maximal oxygen consumption (VO2max) while breathing each of con-
trol (1 cm H2O), continuous positive airway pressure optimized to the maximal tolerable level (CPAP 5
4.8 6 0.2 cm H2O) or inspiratory pressure support (PS 5 4.8 6 0.2 cm H2O), in randomized order.
Measurements during exercise included cardioventilatory responses, esophageal pressure (Pes), and
Borg ratings of dyspnea and leg discomfort (LD). At a standardized time near end-exercise, PS and
CPAP reduced the work of breathing per minute by 39 6 8 and 25 6 4%, respectively (p , 0.01). In
.
response to PS: Tlim increased by 2.8 6 0.8 min or 43 6 14% (p , 0.01); slopes of LD–time, VO2–time,
.
VCO2–time, and tidal Pes–time decreased by 24 6 10, 20 6 11, 28 6 8, and 44 6 9%, respectively (p ,
0.05); dyspnea and other cardioventilatory parameters did not change. CPAP did not significantly al-
ter measured exercise responses. The increase in Tlim was explained primarily by the decrease in LD–
.
time slopes (r 5 20.71, p , 0.001) which, in turn, correlated with the reductions in VO2–time (r 5
0.61, p , 0.01) and tidal Pes–time (r 5 0.52, p , 0.01). in conclusion, ventilatory muscle unloading
with PS reduced exertional leg discomfort and increased exercise endurance in patients with stable
advanced CHF. O’Donnell DE, D’Arsigny C, Raj S, Abdollah H, Webb KA. Ventilatory assistance
improves exercise endurance in stable congestive heart failure.
AM J RESPIR CRIT CARE MED 1999;160:1804–1811.

Patients with advanced, stable congestive heart failure (CHF)
often have limited ability to participate in activities of daily
living. Exercise limitation in CHF is multifactorial, but recog-
nized contributing factors include impaired cardiac perfor-
mance (1), abnormal ventilatory responses (2–4), peripheral
muscle dysfunction (5, 6), or any combination thereof. Phar-
macological interventions such as vasodilators or inotropes
that improve central hemodynamics in patients with stable
CHF have inconsistent acute effects on exercise performance
(7, 8). These findings support the notion that exercise curtail-
ment in CHF is not determined by cardiac factors alone, but
likely depends on complex, integrated cardiopulmonary and
locomotor muscle interactions.
(Received in original form August 26, 1998 and in revised form February 23, 1999)
Presented in part at the ALA/ATS International Conference, Chicago, Illinois, April
1998.
Supported by the Physicians’ Services Incorporated (PSI) Foundation, and by the
Ontario Ministry of Health.
Denis O’Donnell holds a career scientist award from the Ontario Ministry of Health.
Correspondence and requests for reprints should be addressed to Dr. Denis O’Don-
nell, Richardson House, 102 Stuart Street, Kingston General Hospital, Kingston,
ON, K7L 2V7 Canada. E-mail: odonnell@post.queensu.ca
Am J Respir Crit Care Med Vol 160. pp 1804–1811, 1999
Internet address: www.atsjournals.org
It has become clear that patients with CHF may stop exer-
cise because of intolerable exertional symptoms of leg fatigue,
discomfort, and/or dyspnea at a point where there is apparent
cardiopulmonary reserve (9). The mechanisms of exertional
leg discomfort in stable CHF are unknown but are thought ul-
timately to reflect the net effect of a combination of peripheral
muscle weakness and metabolic alterations in the active lo-
comotor muscle. With respect to the latter, poor peripheral
blood perfusion, reduced oxygen delivery, reduced capacity
for oxidative metabolism, and reduced clearance of CO2 and
active metabolites are all likely to be instrumental (6). The
presence of peripheral muscle weakness would dictate that in-
creased neural activation or motor drive would be required to
perform a given muscular task (10, 11). It is postulated that in
the sensory domain, increased locomotor drive may be directly
perceived (via central corollary discharge) as an increased sense
of contractile muscle effort (10–13). In addition, local alterations
in the metabolic milieu may activate muscle mechanorecep-
tors (12) whose afferent inputs may directly or indirectly give
rise to unpleasant sensations perceived as leg discomfort (12).
The mechanisms of exertional dyspnea in CHF are also
poorly understood, but likely contributing factors include ex-
cessive ventilatory requirements (9), restrictive ventilatory
mechanics (14), inspiratory muscle weakness (15), or any com-
bination of these factors. All of these conditions necessitate
increased central motor command output to respiratory mus-
O’Donnell, D’Arsigny, Raj, et al.: Exercise in Congestive Heart Failure
cles, which may be perceived as increased sense of effort (10),
as in the case of peripheral skeletal muscles.
It is reasonable to assume that any intervention that will fa-
vorably alter integrated cardiopulmonary function, so as to re-
duce leg discomfort and dyspnea, should improve exercise en-
durance. Therefore, this study was designed to determine the
effects of ventilatory assistance on exertional symptoms and
cardiopulmonary exercise responses in patients with stable
CHF. Studies by Naughton and coworkers (16) have shown
that the administration of continuous positive airway pressure
(CPAP) to patients with stable CHF at rest acutely improved
cardiac performance and also reduced the work of breathing.
We reasoned that in patients with CHF who are exercising, ven-
tilatory assistance, by similarly unloading the ventilatory mus-
cles and improving cardiac performance, and possibly also by
improving peripheral muscle blood flow, could have salutary
effects on dyspnea and leg discomfort with consequent im-
provement in exercise endurance.
Therefore, we compared the effects of CPAP and inspira-
tory pressure support (PS) on exertional leg discomfort and
dyspnea, exercise endurance time, dynamic ventilatory me-
chanics, breathing pattern, and cardiac responses in symptom-
limited patients with stable CHF. A comparison of the effect
of PS and CPAP of equal magnitude allowed us to examine
the effects of the positive end-expiratory pressure (PEEP) com-
ponent in isolation in these patients.
METHODS
Study Design
This study was a randomized, blinded, controlled trial in which 12 pa-
tients with stable CHF participated. After providing informed con-
sent, patients completed a screening visit that included a medical his-
tory and clinical assessment, chronic dyspnea evaluation, pulmonary
function testing, symptom-limited maximal incremental exercise test-
ing, and optimization of CPAP levels during exercise (see below).
During the subsequent experimental visit, patients performed three
constant-load exercise tests at approximately 75% of the previously
determined maximum work rate, each separated by recovery periods
of at least 1 h. In random order, these exercise tests were conducted
while breathing under each of the following conditions: (1) optimized
CPAP, (2) inspiratory pressure support (PS) of the same magnitude
as CPAP, and (3) a control consisting of a minimal assist of 1 cm H2O
CPAP. Exertional symptoms of dyspnea and leg discomfort, and car-
dioventilatory responses to exercise, were compared during each
mode of ventilatory assistance. Mechanisms for improvement in exer-
cise endurance, if any, were also studied.
Subjects
Patients with CHF satisfied the following inclusion criteria: (1) CHF
documented for at least 6 mo, (2) echocardiography showing left ven-
tricular ejection fraction (LVEF) < 35% within the previous 6 mo, (3)
New York Heart Association class II–IV disease of either ischemic or
idiopathic etiology, (4) stable disease with no hospitalizations in the
previous month. Patients were excluded from the study if they had sig-
nificant obstructive lung disease (FEV1/FVC , 80% predicted), un-
stable angina or significant cardiac arrhythmias, myocardial infarction
within the previous 3 mo, primary valvular heart disease, inability to
exercise owing to neuromuscular or musculoskeletal disease, or other
potential causes of dyspnea or fatigue.
Pulmonary Function
Routine spirometry was performed at rest in the sitting position, in ac-
cordance with recognized standards (17), using an automated pulmo-
nary function testing center (6200 Autobox DL; SensorMedics, Yorba
Linda, CA). Baseline lung volumes (i.e., functional residual capacity
[FRC]) and specific airway resistance (SRaw) were determined by con-
stant-volume body plethysmography (6200 Autobox DL). Total lung
capacity (TLC) was calculated as the sum of the FRC and spirometric
inspiratory capacity (IC). Single-breath diffusing capacity for carbon
1805
monoxide (DLCO-SB) was also measured (6200 Autobox DL). Maxi-
mum inspiratory and expiratory mouth pressures (MIP and MEP, re-
spectively) measured at FRC and TLC, respectively, were assessed by
the use of a standard mouthpiece and a direct-reading pressure manom-
eter (Magnehelic; Dwyer Instruments, Michigan City, IN). Predicted
normal values for spirometry, lung volumes, DLCO-SB, and SRaw were
those of Morris and associates (18), Goldman and Becklake (19), Gaen-
sler and Wright (20), and Briscoe and Dubois (21), respectively.
Evaluation of Exertional Symptoms
Dyspnea, or breathlessness, was defined as an “unpleasant sensation
of labored or difficult breathing.” Chronic activity-related dyspnea
was evaluated using the modified Baseline Dyspnea Index (22). Exer-
tional dyspnea and leg discomfort were evaluated using the Borg
Scale (23) during exercise. Before exercise testing, the Borg Scale was
explained and its end points anchored such that “0” indicated no dys-
pnea or leg discomfort and “10” represented the maximal dyspnea or
leg discomfort that the patient could imagine or had ever experienced.
Immediately after exercise cessation and the completion of mechani-
cal measurements, subjects were asked the reason(s) for exercise ter-
mination (i.e., dyspnea, leg discomfort/fatigue, both, or other).
Application of CPAP and PS
CPAP and PS were applied using a Respironics ventilator (Respiron-
ics, Murrysville, PA). To determine whether IC could be reliably used
to track end-expiratory lung volume (EELV) during the application
of ventilator support, we tested the effects of breathing with 5, 10, and
15 cm H2O of CPAP on the TLC (FRC 1 IC) derived from body
plethysmography performed while sitting at rest.
During the screening visit, CPAP was carefully adjusted upward in
increments of 1 cm H2O while cycling at the selected level of constant-
load exercise to the point of maximum symptom benefit. The applied
level of PS was identical to that of the selected CPAP. These “opti-
mized” levels of CPAP and PS were applied during separate constant-
load exercise tests on the day of the experimental visit.
Exercise Testing
Exercise tests were conducted on an electronically braked cycle ergo-
meter (Ergometrics 800S; SensorMedics) to a symptom-limited end
point. Steady-state resting measurements were taken over a 1-min in-
terval after at least 3 min of quiet breathing through the breathing cir-
cuit. For the initial progressive exercise tests, subjects began cycling at
a work rate of 10 W for 2 min and thereafter the load was increased in
2-min intervals by increments of 10 to 20 W until a maximum work
rate was reached. Subsequent constant-load exercise tests were con-
ducted at a work rate of approximately 75% of the predetermined
maximal work rate. Pedalling rates were maintained between 50 and
70 revolutions per minute (rpm) for all tests.
The breathing circuit for experimental exercise tests was designed
to minimize pressure fluctuations during the application of CPAP, to
avoid the occurrence of leaks during ventilatory assistance, and to
minimize the possibility of rebreathing. With nasal passages occluded
by a nose clip, all subjects breathed through a mouthpiece attached to
a low-resistance two-way nonrebreathing valve (2700 series; Hans Ru-
dolph, Kansas City, MO). The valve setup was adjusted and fixed at a
comfortable height for each subject. Inspiratory and expiratory flow
rates were measured by pneumotachographs (No. 3; Fleisch, Lausanne,
Switzerland) and differential pressure transducers (MP45, 6 2 cm
H2O; Validyne, Northbridge, CA) and tidal volume (VT) was inte-
grated from inspiratory flow. Expiratory air was circulated through a
2.5-L mixing chamber and analyzed for oxygen (FEO2) (S-3A oxygen
analyzer; Applied Electrochemistry, Pasadena, CA) and carbon diox-
ide content (FECO2) (LB-2 gas analyzer; SensorMedics). End-tidal
CO2 (FETCO2) was analyzed continuously by the LB-2 gas analyzer.
Oxygen saturation (SaO2) by pulse oximetry (503 pulse oximeter;
Criticare Systems, Wakesha, WI) and electrocardiographic monitor-
ing (Cardiovit CS-6/12Z; Schiller, Baar, Switzerland of heart rate
(HR) were carried out continuously throughout testing.
All equipment was calibrated immediately before and after each
test. Signals were collected using an eight-channel recorder (RS3800;
Gould Instruments, Cleveland, OH). Flow, volume, mouth pressure
1806 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 160 1999

(Pm), esophageal pressure (Pes), FETCO2, FECO2 and FEO2 were sam- parisons were made between measurements taken during each pres-
pled by a computer at a rate of 100 Hz using computer data acquisi- sure application (CPAP, PS) and control using statistical methods for
tion software (CODAS; Dataq Instruments, Akron, OH) and stored repeated measures and longitudinal data. Analyses were designed to
for later analysis. For each breath, computer software calculated tim- answer the following questions:
ing (TI, TE, TI/Ttot), flow· (VT/TI, VT/TE), and volume· (VT) parame- Does ventilatory support improve exercise endurance in CHF? By
ters. Minute ventilation ( VE), oxygen consumption (VO2), and carbon unloading the respiratory muscles, was dyspnea (perceived leg discom-
·
dioxide output (VCO2) were calculated using standard formulas (24). fort/fatigue) relieved? Symptom-limited exercise times were compared
Anaerobic thresholds were assessed using the v-slope method (25). during control, CPAP, and PS exercise using an ANOVA for re-
Exercise parameters were compared with the predicted normal values peated measures. Comparisons were made between measurements of
according to Jones (24). Borg–time slopes and standardized Borg ratings during control, CPAP,
Operational lung volumes. With the assumption that TLC did not and PS tests using ANOVA for repeated measures.
change with exercise, measurements of end-expiratory lung volume Were improvements in exercise endurance, if any, related to reduc-
(EELV) were derived from IC maneuvers performed at rest, every 2– tions in exertional symptom intensity? To establish an association be-
3 min during exercise, and at peak exercise; thus, changes in IC re- tween the change in exercise endurance with ventilatory assistance
flected changes in EELV during exercise. Confirmation of satisfac- and the concurrent change in exertional symptom intensity, simple re-
tory technique and reproducibility of IC measurements for each gression analysis using Pearson correlations was performed with the
subject was first established during an initial practice session at rest. change in symptom-limited exercise endurance time (DTlim) as the de-
This method has been previously tested and found to be both repeat- pendent variable and the change in the Borg–time slope as the inde-
able and responsive to change (26). pendent variable. This was carried out for Borg–time slopes of both
Breathing pattern analysis. Tidal flow–volume curves at rest, at a dyspnea and leg discomfort.
standardized time near end-exercise, and at peak exercise were con- What were the possible mechanisms of improvement in response to
structed for each patient and placed within their respective maximal ventilatory assistance? To establish associations between the change in
flow–volume envelopes according to coinciding IC measurements. exercise endurance during ventilatory assistance and possible contrib-
Maximal flow–volume loops were performed at rest and immediately uting factors, simple regression analysis was performed using DTlim as
after exercise for this analysis. The presence or absence of flow limita- the dependent variable and changes in operational lung volumes (IC,
tion was then determined by comparing tidal expiratory flows with inspiratory reserve volume [IRV], EELV, end-inspiratory lung vol-
those of the maximal envelope at isovolume: we looked at the shape ume [EILV], ·VT/IC), breathing pattern (VT, f, VT/TI, VT/TE, TI/Ttot),
and limits of the maximal flow–volume curve in the tidal operating ventilation (VE), ventilatory mechanics (Pes/PImax, other Pes-derived
range (FEF75, FEF50, FEF25, PEFR), as well as the extent of expira- measurements such as WOB, TTI), an index of neuromechanical cou-
tory flow limitation (percentage of VT that encroached on the maximal pling (Pes/PImax:VT/IC ratio), lactate concentrations, indices of expira-
flow envelope, the extent of encroachment of flow at the midrange of tory flow limitation (extent of VT overlap), and cardiovascular param-
VT on the maximal envelope at isovolume). eters (HR, oxygen pulse, blood pressure, SaO2) as independent
Measurement and analysis of lung mechanics. Esophageal pressure
(Pes) was recorded continuously using a balloon-tipped catheter sys-
tem during exercise testing. A 10-cm latex balloon, containing 0.5 ml
of air and connected by a polyethylene catheter to a Validyne differ- TABLE 1
ential pressure transducer, was positioned according to an accepted
technique (27). At rest and immediately after exercise (i.e., peak), SUBJECT CHARACTERISTICS
maximum inspiratory maneuvers against an occluded airway at Percentage of
EELV were performed to obtain maximum values for Pes (PImax). Parameter Value Predicted Value
The work of breathing (WOB) was calculated using Campbell dia-
grams constructed from tidal Pes–volume loops (28). The tension– Male:Female 11:1
time index of the inspiratory muscles (TTI) was calculated as the Age, yr 61 6 4
product of mean inspiratory Pes/PImax and TI/Ttot (29). Finally, an in- Height, cm 172 6 2
Weight, kg 86.8 6 4.0
dex of neuromechanical coupling was calculated as the ratio of in-
Body mass index, kg/m2 29.3 6 1.1
spiratory Pes/PImax to standardized tidal volume (VT/IC) (30).
Left ventricular ejection fraction (LVEF), % 24 6 3
Blood lactate. A venous catheter was inserted into the forearm of
each patient and a standard set-up was implemented to maintain pa- Pulmonary function
tency of the line. Lactate samples were obtained after at least 5 min of FEV1, L 2.22 6 0.15 74
steady-state rest, every 2–3 min of exercise, at peak exercise, and 3 FVC, L 2.99 6 0.16 71
min after exercise cessation. Samples were drawn into dry sterile FEV1/FVC, % 74 6 2 104
tubes containing 6.0 mg of potassium oxalate and 7.5 mg of sodium PEFR, L/s 7.00 6 0.59 88
FEF50, L/s 2.15 6 0.30 53
fluoride for glycolytic inhibition, were stored on ice during testing,
FEF75, L/s 0.66 6 0.08 45
and taken to the hospital chemistry laboratory for analysis immedi-
TLC, L 6.04 6 0.21 94
ately after the completion of each exercise session. The plasma was FRC, L 3.28 6 0.15 92
separated by centrifugation and analyzed for lactate using a colori- RV, L 2.76 6 0.11 123
metric analysis involving the reduction of NAD1 to NADH and the ERV, L 0.53 6 0.08 41
oxidation of lactate to pyruvate. MIP, cm H2O 74 6 9 80
DLCO, ml/min/mm Hg 20.3 6 1.4 90
Statistical Analysis Peak incremental exercise
Results are expressed as means 6 SEM and a p , 0.05 level of signifi- Work rate,† W 73 6 10 41‡
Heart rate, beats/min 127 6 8 75‡
cance was used for all analyses. Relevant exercise response slopes and ·
VO2, L/min 1.52 6 0.17 66‡
their intercepts were determined using linear regression analysis of in- ·
VE, L/min (%MVC) 52.9 6 5.6 69‡
dividual data sets. Although summarizing a curve into one data point · ·
VE/ VCO2 39 6 2
(such as a slope) usually means that the curvature of the relationship SaO2, % 97.2 6 0.2
is missed, this method is a simple and reliable way to represent
changes in measurements during exercise and is generally appropriate Definition of abbreviation: MVC 5 maximal ventilatory capacity.
when not trying to “fit” data. We have previously shown that slopes * Values presented are means 6 SEM.
†
Predicted maximum work rate (males) 5 2,169(height) 2 9.63(age) 1 4.00(weight) 2
derived by linear regression are reproducible and responsive to
2,413; predicted maximum work rate (females) 5 950(height) 2 9.21(age) 1
change (26). Measurements were also compared at standardized times 6.1(weight) 2 765, divided by 6.12 for watts; work rate in kpm/min, height in m,
during constant-load exercise, specifically at the highest equivalent weight in kg (see Reference 18).
‡
time achieved in all exercise tests by each subject (i.e., isotime). Com- Percentage of predicted maximum value.
O’Donnell, D’Arsigny, Raj, et al.: Exercise in Congestive Heart Failure 1807

variables. Baseline symptomatology, lung function, pulmonary me-
chanics, breathing pattern, and other relevant factors were analyzed
as possible covariates. Stepwise multiple regression analysis was car-
ried out to establish the best predictive equation for DTlim, and the
resultant model was reestimated with significant predictors only. Mech-
anisms of improvement in exertional symptom intensity were evalu-
ated in a similar manner.
RESULTS
Subjects
Subject characteristics are shown in Table 1. The mean left
ventricular ejection fraction (LVEF) was significantly re-
duced, ranging from 10 to 35%. Medications being taken in-
cluded angiotensin-converting enzyme inhibitors (n 5 10),
diuretics (n 5 10), digoxin (n 5 5), nitrates (n 5 3), and
b-blockers (n 5 3). Although all but one subject had a smok-
ing history, only one had smoked within the previous 5 yr, and
seven had quit smoking at least 10 yr before the study. Base-
line pulmonary function parameters were within normal limits
except for a mild reduction in lung volume (FVC), and a re-
duced expiratory reserve volume (ERV). In addition, maxi-
mal flow–volume curves showed progressive scooping of expi-
ratory flows (i.e., reduced FEF50, FEF75).
Subjects had a Baseline Dyspnea Index focal score of 6.8 6
0.6, indicating a moderate level of chronic activity-related dys-
pnea. Incremental maximal exercise tests were stopped owing
to severe leg discomfort/fatigue (n 5 4), dyspnea (n 5 2), or a
combination of both (n 5 6). Exercise capacity was severely
curtailed with significantly reduced maximum oxygen con-
· whereas only 5 of 12 subjects improved in response to CPAP.
sumptions ( VO2max) and peak work rates, and modestly in-
· ·
creased VE/ VCO2 ratios (Table 1). Anaerobic thresholds were
· both dyspnea and leg discomfort did not change in response to
in the low to normal range in all subjects at a mean VO2 of 39 6
· PS or CPAP (Table 2). Slopes of Borg ratings of perceived leg
2% of the predicted VO2max, where normal is between 40 and
60%. All subjects showed expiratory flow limitation at rest,
i.e., tidal expiratory flows overlapped the maximum expira-
tory envelope at isovolume over the majority of VT (see exam-
ple in Figure 1A). At end-exercise, EELV increased by a
mean of 0.26 6 0.06 L from rest, and EILV reached 92 6 2%
of TLC.
Optimization of CPAP and PS
CPAP was optimized during cycle exercise at 54 6 8 W, i.e.,
75% of the maximum work rate achieved in incremental test-
ing. A mean “optimal” CPAP of 4.8 6 0.2 cm H2O (range, 4–6
cm H2O) was selected as the level providing the maximum
symptom benefit. For each patient, PS of this same level was
used during experimental testing.
CPAP between 5 and 15 cm H2O did not alter measured
lung volumes at rest (i.e., TLC, RV, FRC, IC). Therefore, with
the assumption that TLC at rest did not change during exer-
cise, we justified using the change in IC to derive the change in
EELV as an indicator of dynamic hyperinflation during exer-
cise with ventilator assistance.
Exercise Responses during Ventilatory Assistance
There were no significant carryover effects resulting from per-
forming three constant-load tests in 1 d with respect to (1) ex-
· · ·
ercise slopes of dyspnea, leg discomfort, VO2, VCO2, VE, IC,
tidal Pes, and lactate expressed over time, or (2) isotime mea-
· · ·
surements of VO2, VCO2, VE, IC, tidal Pes, and lactate, there-
fore allowing intertest comparisons to be made.
Endurance during cycle exercise using the constant-load pro-
tocol was limited primarily by leg discomfort (n 5 7), a combi-
nation of leg discomfort and dyspnea (n 5 4), or by dyspnea
(n 5 1). Total exercise time increased significantly during ex-
ercise with PS (2.8 6 0.8 min or 43 6 14%; p 5 0.004), but
only modestly with CPAP (1.4 6 0.7 min or 28 6 15%; p 5
0.079) compared with control (Table 2). The majority (n 5 8)
of subjects increased their exercise endurance in response to PS,
Despite differences in exercise time, peak Borg ratings of
discomfort over time were significantly reduced in response to
TABLE 2
MEASUREMENTS AT THE END OF
CONSTANT-LOAD EXERCISE*

Control CPAP PS

Time, min† 7.2 6 1.0 8.7 6 1.1‡ 10.1 6 1.5§

Leg discomfort, Borg 6.0 6 0.3 6.7 6 0.6 6.3 6 0.5
Dyspnea, Borg 5.2 6 0.5 5.1 6 0.5 5.5 6 0.5
Heart rate, beats/min 121 6 7 122 6 8 119 6 7
Lactate, mmol/L 3.8 6 0.4 3.8 6 0.4 4.2 6 0.4
SaO2, % 97.6 6 0.3 97.5 6 0.2 97.6 6 0.3
·
VCO2, L/min 1.45 6 0.15 1.46 6 0.15 1.47 6 0.15
·
VO2, L/min 1.50 6 0.14 1.46 6 0.14 1.47 6 0.14
·
VE, L/min 54.4 6 5.7 57.1 6 5.1 56.5 6 5.0
VT, L 1.88 6 0.15 1.89 6 0.14 1.84 6 0.14
VT/IC, % 83 6 4 80 6 4 74 6 4
f, breaths/min 28.7 6 2.1 30.4 6 2.2 31.1 6 2.3i
TI/Ttot 0.41 6 0.01 0.42 6 0.01 0.41 6 0.01
VT/TI, L/s 2.16 6 0.20 2.23 6 0.18 2.27 6 0.17
VT/TE, L/s 1.57 6 0.18 1.68 6 0.16 1.63 6 0.16
IC, L 2.27 6 0.13 2.42 6 0.18 2.50 6 0.15
Peak inspiratory Pes, cm H2O† 210.5 6 1.3 29.3 6 1.2# 28.6 6 1.0i
Inspiratory Pes, %PImax† 24 6 4 20 6 3# 17 6 3i
Peak expiratory Pes, cm H2O 6.7 6 1.1 6.4 6 1.2 6.5 6 1.0
Tidal Pes, cm H2O† 17.2 6 2.1 15.7 6 2.1i 15.1 6 1.8i
Tidal Pes/VT, cm H2O/L 9.7 6 1.4 8.8 6 1.3 9.0 6 1.4
Figure 1. Typical example of a CHF patient (A) Tidal flow–volume
TTIdyn† 0.19 6 0.02 0.19 6 0.03 0.15 6 0.02i
loops at rest and at the peak of symptom-limited exercise are
shown relative to the maximal envelope. These indicate resting ex- * Values presented are means 6 SEM.
piratory flow limitation, and dynamic hyperinflation with persist-
†
p , 0.05 difference between tests by ANOVA for repeated measures.
‡
p 5 0.08, relative to control.
ing flow limitation during exercise. (B) Flow–volume loops at iso- §
p , 0.01, relative to control.
time during control, CPAP, and PS exercise tests show no differences i
p , 0.05, relative to control.
in EELV or in the extent of expiratory flow limitation. #
p 5 0.09, relative to control.
1808 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 160 1999

TABLE 3
MEASUREMENTS AT ISOTIME*
DURING CONSTANT-LOAD EXERCISE†

Control‡ CPAP‡ PS‡

Leg discomfort, Borg§ 5.4 6 0.4 5.9 6 0.7 4.8 6 0.4

Dyspnea, Borg 4.5 6 0.4 4.5 6 0.4 4.2 6 0.4
Heart rate, beats/min 118 6 8 120 6 8 116 6 7
Systolic BP, mm Hg 139 6 7 140 6 5 129 6 13
Diastolic BP, mm Hg 81 6 4 82 6 4 80 6 3
Lactate, mmol/L 3.6 6 0.4 3.5 6 0.4 3.4 6 0.4
SaO2, % 97.5 6 0.2 97.4 6 0.2 97.5 6 0.2
·
VCO2, L/min 1.38 6 0.16 1.37 6 0.15 1.33 6 0.15
·
VO2, L/min§ 1.44 6 0.14 1.38 6 0.13 1.33 6 0.13i
·
VE, L/min 51.6 6 5.6 54.6 6 5.1 53.1 6 5.1
VT, L 1.91 6 0.14 1.85 6 0.14 1.81 6 0.14
VT/IC, % 83 6 4 77 6 5 73 6 3
f, breaths/min§ 26.6 6 1.8 29.7 6 2.3 29.5 6 2.0#
TI/Ttot 0.42 6 0.01 0.43 6 0.01 0.41 6 0.01#
VT/TI, L/s 2.02 6 0.21 2.07 6 0.18 2.08 6 0.16
VT/TE, L/s§ 1.51 6 0.17 1.64 6 0.17i 1.56 6 0.18
IC, L 2.31 6 0.13 2.45 6 0.17 2.46 6 0.14
Peak inspiratory Pes, cm H2O§ 210.7 6 1.3 28.8 6 1.0# 27.9 6 1.0i
Inspiratory Pes, %PImax§ 25 6 4 18 6 2# 17 6 3#
Peak expiratory Pes, cm H2O 6.4 6 1.1 6.7 6 0.9 5.8 6 1.0
Tidal Pes, cm H2O§ 17.1 6 1.9 15.5 6 1.8# 13.7 6 1.9i
Tidal Pes/VT, cm H2O/L 9.5 6 1.3 8.8 6 1.1 8.3 6 1.4
WOB, J§ 1.3 6 0.2 0.9 6 0.2i 0.8 6 0.2i
TTIdyn§ 0.20 6 0.02 0.16 6 0.02** 0.14 6 0.01i

* 6.4 6 1.0 min.

†
54 6 8 W.
‡
Values presented are means 6 SEM.
§
Significant difference between tests by ANOVA for repeated measures.
i
p , 0.01, relative to control.
#
p , 0.05, relative to control.
** p 5 0.09, relative to control.

Figure 2. Borg ratings of leg discomfort and dyspnea are shown

relative to time during constant-load exercise (values are means 6 ·
SEM). *p , 0.05, significant difference in slope compared with lated primarily with the reduction in VO2, both expressed as
control. slopes over time (r 5 0.61, p , 0.01); while the decrease in
·
VO2/time correlated with the decrease in Pes/time (r 5 0.55,
·
p,
0.01). In other words, the reduction in total body VO2 was
PS compared with control (p , 0.05), but did not change sig-
likely related to the fall in the oxygen cost of breathing.
nificantly with CPAP compared with control (Figure 1). Slopes
Changes in exercise endurance during ventilator assistance
of Borg dyspnea ratings over time were not different between
were not related to changes in ventilation, breathing pattern,
control, PS, or CPAP tests (Figure 2).
operational lung volumes, the level of respiratory muscle un-
Cardiopulmonary measurements obtained at peak or end-
loading, expiratory pleural pressures, or the extent of expira-
exercise did not change significantly, other than a reduction in
tory flow limitation.
Pes-derived measurements during PS and CPAP indicative of
respiratory muscle unloading (Table 2). Comparisons made at
isotime for each exercise test are shown in Table 3. At isotime,
·
significant differences were found for VO2 and various Pes-
derived measurements: tidal Pes, peak inspiratory Pes, Pes/
PImax, TTIdyn, and WOB. At this standardized time, WOB per
minute was decreased from control by 39 6 8 and 25 6 4%
during PS and CPAP, respectively. There were no differences
between tests with respect to cardiovascular parameters, ven-
tilation, peak expiratory Pes, operational lung volumes, gas
exchanges, or venous lactate concentrations. Finally, the ex-
tent of expiratory flow limitation was not different between
tests at isotime: tidal flow–volume loops overlapped the maxi-
mal expiratory envelope over a mean of 20 6 8, 31 6 8, and 37 6
10% of VT during control, PS and CPAP, respectively; with no
differences in EELV (see example in Figure 1B).

Correlates of Improvement in Endurance

Increased endurance (DTlim) with both modes of ventilator as- Figure 3. Changes in exercise endurance ( DTlim) with CPAP
sistance correlated best with the reduction in the slope of ex- (squares) and PS (circles) correlated inversely with changes in exer-
ertional leg discomfort over time (r 5 20.71, p , 0.01) (Figure tional leg discomfort expressed as DBorg–time slopes (r 5 20.71,
3). In turn, the reduction in exertional leg discomfort corre- p , 0.01).
O’Donnell, D’Arsigny, Raj, et al.: Exercise in Congestive Heart Failure 1809

DISCUSSION PS could improve peripheral perfusion by improving car-

diac output and/or by altering regional vascular distribution.
The novel findings of this study in patients with stable advanced
Cardiac performance is probably curtailed during exercise in
CHF are as follows: (1) PS significantly improved exercise en-
advanced CHF, even further than at rest, because of greater
durance; (2) increased exercise endurance during PS correlated
inspiratory pleural pressure swings required to maintain venti-
strongly with reduced intensity of exertional leg discomfort;
lation in pace with metabolic demands. Such increases in neg-
(3) changes in Borg ratings of leg discomfort during PS corre-
· ative inspiratory pleural pressure would increase the left ven-
lated with changes in both VO2 and tidal esophageal pressure
tricular (LV) systolic transmural pressure gradient of the
excursions; (4) CPAP of equal magnitude to PS did not consis-
failing heart, and increase LV afterload. The addition of PS (5 cm
tently improve either perceived leg discomfort or exercise en-
H2O) would predictably reduce this transmural pressure gra-
durance; (5) both PS and CPAP had only modest effects on
dient and reduce LV afterload with resultant improvement in
exertional dyspnea intensity during constant-load submaximal
peripheral blood flow to the legs. Improved perfusion would
exercise; and (6) patients showed significant increases in end-
result in improved nutrient supply to the exercising muscle
expiratory lung volumes during exercise.
and enhanced clearance of CO2 and waste metabolites, with
consequent improved acid–base status. There were no signifi-
Mechanisms of Improved Exercise Endurance cant changes in any of the measured cardiac parameters (blood
·
pressure, heart rate, oxygen pulse, VCO2) or in blood lactate
The magnitude of improvement in exercise endurance (i.e.,
measurements during PS. However, these findings alone do
. 40%) during PS substantially exceeded previously reported
not preclude improvements in peripheral blood flow in our
acute effects of pharmacological agents in this population (7,
group, which would require invasive, central, and peripheral
8). Improvement was explained primarily by altered symp-
hemodynamic measurements to confirm. Similarly, lack of re-
toms and did not correlate directly with alterations in any of
duction of nonarterialized venous blood lactate concentra-
the measured cardiopulmonary physiological variables. Se-
tions does not accurately reflect local metabolic alterations in
vere leg discomfort was the primary exercise-limiting symp-
the active muscles.
tom in the majority of study subjects and it was not surprising,
Another possible mechanism of improved leg blood flow
therefore, that alleviation of this symptom during PS contrib-
involves altered vascular distribution during ventilatory mus-
uted to improved exercise endurance. We believe that the sig-
cle unloading. In this respect, Harms and coworkers (31) have
nificant reduction in Borg–time slopes for leg discomfort in
shown that in healthy subjects exercising at supramaximal
our patients was real and not a spurious finding. We have ·
shown that Borg ratings of leg discomfort (and dyspnea) dur- VO2, when their capacity to increase cardiac output was limited
and ventilatory demands were excessive, ventilatory muscle un-
ing constant load exercise are reliable, being both highly re-
loading with proportional assist ventilation (PAV) decreased
producible and responsive to change when tested in a popula-
leg vascular resistance (presumable by altering sympathetic
tion of patients with pulmonary disease (26). ·
tone), increased leg blood flow, and increased leg VO2 (despite
The mechanisms of reduced leg discomfort during PS re- ·
reducing total VO2). The authors postulated that in these sub-
main speculative but it is reasonable to assume that such im-
jects, where the ability to increase cardiac output was already
provements ultimately reflect acute metabolic changes within
maximal and where there are two competing groups of active
the exercising leg muscles. Several studies have shown pro-
working muscles (i.e., leg locomotor muscles and the diaphragm),
found metabolic and structural abnormalities in the peripheral
blood flow to the peripheral muscles may be compromised be-
skeletal muscles of patients with advanced CHF (6, 12). Our
cause of a diaphragmatic vascular “steal” effect (31). Ventila-
patients with dilated cardiomyopathies had significant cardiac
tory muscle unloading may similarly improve peripheral blood
impairment as evidenced by the average ejection fraction of ·
flow and fractional VO2 to the leg muscles of exercising patients
only 24% (range, 10–35%), the significantly reduced maximal
with CHF, whose ability to increase cardiac output is greatly di-
oxygen consumption (66 6 5% of predicted maximum), and
minished at low work rates and whose work of breathing is in-
the reduced anaerobic threshold (39 6 2% of predicted maxi-
· creased compared with unaffected individuals. However, inva-
mum VO2). One would therefore anticipate that, in these sub-
sive thermodilution studies would be required to confirm this
jects, there were significant peripheral muscle metabolic abnor-
hypothesis.
malities due to poor peripheral perfusion and its deleterious
The contention that improvement in leg discomfort ulti-
chronic effects on muscle structure and function.
mately reflects an improved metabolic milieu at the active
The significant correlations between reduced intensity of
· muscle is supported by the findings of a randomized, con-
exertional leg discomfort, reduced VO2–time slopes, and re-
trolled study on the acute effects of hyperoxia (60%) on exer-
duced Pes–time slopes during exercise with ventilator assis-
tional leg discomfort in mildly hypoxemic patients with ad-
tance support the contention that alleviation of leg discomfort
vanced COPD (32). In this study, 60% oxygen, not room air,
is ultimately linked to the extent of inspiratory muscle unload-
· significantly relieved exertional leg discomfort, and oxygen
ing achieved. The small, but significant, reduction in VO2 dur-
therapy resulted in delayed lactate accumulation compared
ing pressure support ventilation could be explained by small
with control (32). From a neurophysiologic perspective, im-
air leaks at the mouth. However, because we did not observe
proving the ionic and acid–base status of the active muscle
any leaks (i.e., puffing out of the cheeks, or escape of air at the
could alter afferent sensory input (12), or reduce requirements
mouth of any of our study subjects) while breathing during the
for neural activation and the attendant sense of contractile
low levels of pressure applications in this study, because the
· muscular effort (10, 11).
reduction in VO2 occurred in conjunction with reduction in
esophageal pressure measurements including the tension time
index (a measurement that reflects the oxygen cost of breath- Comparison of CPAP and PS Effects
·
ing), and because the changes in VO2 were greater with PS The negative effects of CPAP of equal magnitude to PS on leg
than CPAP, we believe that such changes reflect the effect of discomfort and exercise endurance in CHF are possibly due to
inspiratory muscle unloading rather than measurement error the failure to improve cardiac performance to a similar de-
as a result of an undetected air leak. gree, or to less effective ventilatory muscle unloading. While
1810 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
the addition of CPAP (5 to 10 cm H2O) to healthy individuals
at rest is uniformly negative (i.e., reduced venous return and
LV preload, and reduced cardiac output) (16), the effect of
CPAP in patients with acute or chronic CHF are often posi-
tive (16, 33). Naughton and colleagues (16), have shown that
brief administrations of 5 to 10 cm H2O of CPAP to patients
with stable chronic CHF resulted in significant respiratory
muscle unloading, reduced LV systolic transmural pressure
gradients, and reduced LV afterload without compromising
the cardiac index. However, responses to CPAP therapy in
CHF are not easily predicted and depend on such multiple
factors as baseline LV and right ventricular preload and after-
load, ventricular contractility, intravascular volume, and LV
end-diastolic pressure. The factors that predict the acute ef-
fects of CPAP during exercise have not been ascertained.
Some of our study subjects (5 of 12) did improve exercise per-
formance and reduced exertional leg discomfort during
CPAP, whereas the majority did not benefit. Bradley and co-
workers (33), showed that CPAP was beneficial in the acute
setting at rest only in patients with high left ventricular end-di-
astolic pressures. Central hemodynamic variables were proba-
bly quite variable within our patient group; we anticipate that
improvements in cardiac performance would not occur in pa-
tients whose cardiac output was predominantly preload de-
pendent during exercise, or in patients who did not have high
capillary wedge pressures (33).
To the extent that reduced leg discomfort and improved
endurance depend on the degree of inspiratory muscle un-
loading, differences in responses between CPAP and PS could
reflect deleterious effects of the PEEP component of CPAP.
It is noteworthy that the tension–time index (a measure of the
·
oxygen cost of breathing) (34) and the VO2, both measured at
a standardized time during exercise, were both significantly
reduced with PS compared with CPAP. The inferior responses
of CPAP relative to PS could not be explained by differences
in ventilation, breathing pattern, or operational lung volumes.
Effect of Ventilatory Assistance on Dyspnea in CHF
Although leg discomfort was the predominant symptom dur-
ing exercise, our patients also experienced severe dyspnea.
During PS, dyspnea did not increase further despite sustained
high levels of ventilation (. 50 L/min) for a period of approxi-
mately 3 min longer than unassisted control. However, PS did
not appreciably affect dyspnea in the earlier phases of the con-
stant-load exercise test. This lack of response may reflect the
fact that patients were more focused on the salutary effects of
PS on their most prominent exertional symptom of leg dis-
comfort, or alternatively, that the mechanisms of dyspnea in
CHF were not manipulated by PS. The fact that effective in-
spiratory muscle unloading had little effect on dyspnea during
the earlier stage of exercise suggests that factors other than
mechanical loading (i.e., elastic and resistive loads) contrib-
uted predominantly to dyspnea.
In contrast to normal individuals, in whom CPAP (5 cm
H2O) during exercise has been shown to increase perceived
breathing effort (35), CPAP did not worsen exertional dysp-
nea in CHF and likely had a modest effect toward the end of
the endurance run. The response of normal subjects to CPAP
has previously been studied; subjects had the option of allow-
ing EELV to increase or to defend mean expiratory flows and
the EELV by recruiting expiratory muscles (35). Both strate-
gies are disadvantageous and likely give rise to unpleasant re-
spiratory sensations: lung hyperinflation compromises inspira-
tory muscle function and expiratory muscle recruitment may
increase the sense of expiratory effort. In contrast, a CPAP of
5 cm H2O in our patients with CHF had no significant effects
VOL 160 1999
on EELV, EILV, VT/TE, or peak expiratory Pes, therefore
suggesting the presence of significant expiratory limitation. In
this circumstance, expiratory flow rate is independent of down-
stream pressure (36). The contention that our patients with
CHF were flow limited is supported by the finding that tidal
expiratory flow–volume loops met or exceeded the maximal
expiratory flow envelope in all patients at rest and during ex-
ercise. Maximal expiratory flow curves were concave to the
volume axis at low lung volumes, and ERV was uniformly di-
minished. During exercise, EELV increased significantly by a
mean of approximately 0.3 L as a result of expiratory flow lim-
itation. It is possible that the neutral effects of added CPAP
on respiratory sensation, particularly expiratory effort, in CHF
are a consequence of expiratory flow limitation. We have previ-
ously shown that the addition of small increases in positive
pressure on expiration during exercise in patients with chronic
air flow limitation does not effect sensation compared with
healthy normal subjects who experienced increased expiratory
effort (35). The mechanisms of expiratory flow limitation in
CHF were not determined, but may relate to airway dysfunc-
tion as a result of previous smoking history or advanced age,
to the effects of obesity (body mass index was elevated at 29
kg/m2), or to airway dysfunction as a result of CHF (bronchial
edema or increased reactivity).
In summary, added PS resulted in marked improvement in
exercise endurance in CHF. Alleviation of exertional leg dis-
comfort was the main contributor and correlated with the ex-
tent of inspiratory muscle unloading. We postulated that PS
improved cardiac performance or vascular distribution, thus
altering the metabolic milieu of the active muscle. The clinical
implication of our findings is that noninvasive PS could poten-
tially be used as an adjunct to cardiac rehabilitation: patients
could train at higher work loads, and for longer periods of time,
which should translate into enhanced physiological training ef-
fects and enhanced quality of life.
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