Effects of Hyperoxia on Ventilatory Limitation
During Exercise in Advanced Chronic Obstructive
Pulmonary Disease
DENIS E. ODONNELL, CHRISTINE DARSIGNY, and KATHERINE A. WEBB
Respiratory Investigation Unit, Department of Medicine, Queens University, Kingston, Ontario, Canada
We studied interrelationships between exercise endurance, ventila-
tory demand, operational lung volumes, and dyspnea during acute
hyperoxia in ventilatory-limited patients with advanced chronic
obstructive pulmonary disease (COPD). Eleven patients with COPD
(FEV1.0 31 3% predicted, mean SEM) and chronic respira-
tory failure (PaO2 52 2 mm Hg, PaCO2 48 2 mm Hg) breathed
room air (RA) or 60% O2 during two cycle exercise tests at 50% of
their maximal exercise capacity, in randomized order. Endurance
time (Tlim), dyspnea intensity (Borg Scale), ventilation (VE), breath-
ing pattern, dynamic inspiratory capacity (ICdyn), and gas exchange
were compared. PaO2 at end-exercise was 46 3 and 245 10
mm Hg during RA and O2, respectively. During O2, Tlim increased
4.7 1.4 min (p 0.001); slopes of Borg, VE, VCO2, and lactate
TLC (11).
over time fell (p 0.05); slopes of BorgVE, VEVCO2, VElactate
were unchanged. At a standardized time near end-exercise, O2 re-
duced dyspnea 2.0 0.5 Borg units, VCO2 0.06 0.03 L/min, VE 2.8
1.0 L/min, and breathing frequency 4.4 1.1 breaths/min (p
0.05 each). ICdyn and inspiratory reserve volume (IRV) increased
throughout exercise with O2 (p 0.05). Increased ICdyn was ex-
plained by the combination of increased resting IRV and decreased
exercise breathing frequency (r2 0.83, p 0.0005). In conclusion,
improved exercise endurance during hyperoxia was explained, in
part, by a combination of reduced ventilatory demand, improved
operational lung volumes, and dyspnea alleviation.
Ambulatory oxygen therapy has been shown in several con-
trolled studies to improve exercise performance and to relieve
exertional dyspnea in patients with chronic obstructive pulmo-
nary disease (COPD) (15). However, responses to this inter-
vention are highly variable and are unpredictable in any given
individual (69). The mechanisms of improvement when
breathing oxygen are complex and poorly understood. Ulti-
mately, the success of ambulatory oxygen therapy in COPD
likely depends on its net effect on integrated cardiopulmonary
function and symptom generation. Previous studies have iden-
tified several potential contributing factors that include (1) al-
tered central perception of dyspnea, independent of the drop
in ventilation; (2) reduced ventilatory demand; (3) improved
respiratory and peripheral muscle function; and (4) possible
cardiovascular effects (19).
It is a common clinical observation that some patients with
COPD and unequivocal ventilatory limitation to exercise
show marked improvements in exercise performance with am-
bulatory oxygen. To gain new insights into the mechanisms of
this improvement, we examined the effects of supplemental
(Received in original form July 7, 2000 and in revised form November 27, 2000)
Presented, in part, at the ALA/ATS International Conference, Toronto, May 510,
2000.
Supported by the Ontario Thoracic Society. Denis ODonnell holds a career sci-
entist award from the Ontario Ministry of Health.
Correspondence and requests for reprints should be addressed to Denis ODon-
nell, M.D., Richardson House, 102 Stuart Street, c/o Kingston General Hospital,
Kingston, ON, K7L 2V7 Canada. E-mail: odonnell@post.queensu.ca
Am J Respir Crit Care Med Vol 163. pp 892898, 2001
Internet address: www.atsjournals.org
oxygen in a group of patients with COPD whose exercise was
limited primarily by ventilatory insufficiency, that is, patients
with severe lung hyperinflation and a limited ability to in-
crease respired volume or flow with exercise. Our hypothesis
was that oxygen therapy would reduce ventilatory demand, re-
duce the rate of dynamic hyperinflation and, therefore, reduce
the stress on the ventilatory system during exercise, thus im-
proving exercise endurance. On the basis of previous work
(10), we further postulated that relatively small changes in op-
erational lung volumes, as a result of reduced ventilation and
altered breathing pattern, would convey important clinical
benefit in this group who breathe at lung volumes close to their
Using a randomized, double-blind, cross-over design, we
compared the acute effects of room air and 60% oxygen on
ventilation, operational lung volumes, breathing pattern, dys-
pnea intensity, and metabolic parameters in hypoxemic patients
with stable, advanced COPD during constant-load exercise.
We explored potential mechanisms of improvement in exercise
endurance by studying interrelationships between the above-
listed dynamic physiological and psychological variables.
METHODS
Subjects
We studied 11 clinically stable patients with advanced COPD (FEV1
50% predicted) who met medical criteria for ambulatory O2 in On-
tario (Ministry of Healths Home Oxygen Program): (1) PaO2 55
mm Hg or oxygen saturation 88% at rest or (2) PaO2 between 56
and 60 mm Hg at rest with desaturation to 88% for 2 min during
exercise. Patients also had severe activity-related dyspnea with a score
of 6 on the modified Baseline Dyspnea Index (12). Patients with
other significant disorders that could contribute to dyspnea or exer-
cise limitation were excluded.
Study Design
This study was a randomized, double-blind, placebo-controlled, cross-
over trial with local university/hospital research ethics approval. After
giving written informed consent, patients were familiarized with all
testing procedures and completed a symptom-limited incremental ex-
ercise test. In a subsequent visit, subjects performed two constant-
load exercise tests at approximately 50% of their previously deter-
mined maximal work rate while breathing either 60% O2 or room air
(RA, 21% O2), in randomized order, with a 60- to 90-min washout or
recovery period between tests. Subjects were blinded to the oxygen
concentration being breathed, as was the investigator evaluating sub-
jective responses and performing data analysis.
Procedures
Subjects performed pulmonary function and cycle exercise tests as
previously described (7). In addition, subjects described their breath-
ing discomfort at the end of exercise by selecting descriptor phrases
from a questionnaire modified from that of Simon and coworkers (13).
Operational lung volumes. Assuming that TLC did not change dur-
ing exercise (14), measurements of dynamic inspiratory capacity (ICdyn)
were used to derive end-expiratory lung volume (EELVdyn TLC
ICdyn) and inspiratory reserve volume (IRV ICdyn tidal volume
[VT]). Tidal flowvolume loops were also placed relative to each sub-
ODonnell, DArsigny, and Webb: Lung Hyperinflation in Hypoxic COPD 893

TABLE 1. SUBJECT CHARACTERISTICS* tions for multiple comparisons. Before treatment comparisons were
made, the possibility of sequence effects was evaluated (17). Treat-
Parameter Value
ment comparisons were made using paired t tests. Exercise endurance
Male:female 4:7 was evaluated as total cumulative work performed [ work rate [%
Age, yr 68 2 predicted maximum] minutes); exercise slopes were expressed as
Height, cm 163 2 means of individual regression lines; isotime exercise was defined as
Weight, kg 68 6 the highest equivalent minute of exercise completed during both tests.
Body mass index, kg/m2 25.5 1.9 Pearson correlations were used to establish associations between
Modified baseline dyspnea index 4.5 0.3 (severe) change in endurance (Work) with hyperoxia and concurrent changes

Peak V O2, L/min (% predictededicted maximum) 0.47 0.09 (38) in relevant independent variables (i.e., dyspnea, leg discomfort, minute

Peak V O2, ml/kg/min 7.2 1.1 ventilation [VE], respiratory frequency [fR], VT, inspiratory capacity

Pulmonary function and gas exchange (% of predicted normal) [IC], IRV, oxygen consumption [VO2], carbon dioxide production [VCO2],
FEV1, L 0.65 0.06 (31) lactate, PaO2, PaCO2). Stepwise multiple regression analysis was carried
FVC, L 1.59 0.11 (53) out with these variables and possible covariates (baseline lung func-
FEV1/FVC, % 41 3 (59) tion and gas exchange) to establish the best equation for improvement
TLC, L 6.86 0.51 (127) in exercise endurance. Similar analyses were carried out to examine
RV, L 5.07 0.50 (237) interrelationships between changes in dyspnea intensity, ventilation,
FRC, L 5.64 0.50 (190) operational lung volumes, breathing pattern, and other relevant car-
IC, L 1.23 0.12 (50)
dioventilatory parameters.
PImax, cm H2O 42 4 (59)
SRaw, cm H2O s 26.7 2.5 (666)
DLCO, ml/min/mm Hg 6.9 0.8 (36) RESULTS
PaO2 (room air), mm Hg 52.4 2.2
Subject characteristics are summarized in Table 1 (1822). No
PaCO2 (room air), mm Hg 48.5 2.1
pH (room air) 7.41 0.02
significant sequence effects were found in this study with re-
HCO3 (room air), mM 28.1 1.7 spect to exercise responses (i.e., measurements of exercise en-
durance, symptom intensity, ventilation and metabolic re-
*n 11. Values represent means SEM. Pulmonary function variables in parenthe-
ses represent the percentage of predicted normal values. Predicted normal values for
sponses), thereby allowing a valid analysis of treatment effects
spirometry, lung volumes, DLCO, and PImax were those of Morris and associates (18), in response to supplemental O2.
Goldman and Becklake (19), Gaensler and Wright (20), and Hamilton and associates

(21), respectively. Peak VO2 was compared with predicted normal values of Jones (22). Symptom-limited Exercise Endurance
Symptom-limited endurance exercise at 23 3 W (26 5% of
the predicted maximum work rate) on RA was severely cur-
jects TLC, using concurrent IC measurements. IC maneuvers were car-
tailed at 38 7% predicted maximum VO2 after 4.1 0.9 min
ried out at the end of each 10-min resting baseline until three reproduc-
ible efforts were achieved (within 5%), every 23 min during exercise, (Table 2). Although endurance time increased significantly by
and at peak exercise. This has been found to be a reliable and respon- 4.7 1.4 min (p 0.001) during 60% O2, peak
values for VO2
sive method of tracking acute changes in lung volume (10, 15, 16). (n 7, where technically satisfactory) and VCO2 did not change
significantly with added O2 (Table 2). Breathing 60% O2 during
Statistical Analysis exercise did not result in any significant change in peak Borg
Results are presented as means SEM. A statistical significance of ratings (23) of dyspnea or leg discomfort; however, slopes of
0.05 was used for all analyses, with appropriate Bonferroni correc- Borg ratings of both dyspnea and leg discomfort over time fell
significantly during hyperoxia (p 0.01) (Figure 1).
All patients reported breathing discomfort as a primary
reason for stopping exercise while breathing RA: eight sub-
TABLE 2. SYMPTOM-LIMITED PEAK EXERCISE jects stopped exercise because of breathlessness alone, whereas
Room Air 60% O2 the remaining three stopped because of a combination of both
breathing and leg discomfort. At the end of RA exercise, the
Endurance time, min 4.1 0.9 8.8 1.3*
Dyspnea intensity, Borg rating 5.2 0.7 5.0 0.8
main descriptors used to describe dyspnea were I feel a need
Leg discomfort, Borg rating 4.1 0.8 4.5 0.8
Reason for stopping exercise, number of subjects:
Breathlessness 8 5
Leg discomfort 0 3
Both 3 1
Other 0 2
HR, beats/min 112 5 110 4
SaO2, % 82 2 99 0.1*
PaO2, mm Hg 45.9 2.8 244.7 10.4*
PaCO2, mm Hg 53.3 3.0 58.0 5.0*
Lactate, mM 2.9 0.4 2.8 0.4

V CO2, L/min 0.54 0.09 0.53 0.09

V E, L/min 23.0 3.5 22.4 2.9

V E/ V CO2 45.0 2.2 45.4 4.2
fR, breaths/min 30.0 2.0 28.6 2.2
VT, L 0.77 0.11 0.80 0.10
ICdyn, L 1.07 0.13 1.25 0.16
IRV, L 0.30 0.04 0.45 0.08
Dynamic lung hyperinflation (DH), L 0.26 0.07 0.21 0.08 Figure 1. Slopes of Borg ratings of perceived breathlessness and leg ef-
EILV, %TLC 95 1 93 1 fort were significantly reduced over time during exercise on 60% O2
* p 0.01, significant difference between room air and 60% O 2. compared with room air (RA, 21% O2) (p 0.01). Exercise endurance

Other reasons for stopping exercise included general tiredness (n 1) and dis- time also increased significantly on O2 (p 0.01). Values represent
comfort on the bicycle seat (n 1). means SEM. *p 0.05, **p 0.01, difference between values at

p 0.05, significant difference between room air and 60% O 2. isotime.
894 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 163 2001

TABLE 3. STEADY STATE BREATHING DURING REST

Room Air 60% O2

Dyspnea intensity, Borg rating 0.8 0.2 0.9 0.3

HR, beats/min 94 3 87 2*
BP systolic, mm Hg 123 6 125 5
BP diastolic, mm Hg 74 3 73 4
SaO2, % 88.5 1.9 98.8 0.1
PaO2, mm Hg 56 3 244 9
PaCO2, mm Hg 44 3 51 4*
pH 7.41 0.01 7.39 0.01

V CO2, L/min 0.21 0.03 0.16 0.02

V E, L/min 11.0 1.1 10.0 1.1
fR, breaths/min 19.3 1.5 18.3 2.3
TE, s 2.28 0.26 2.42 0.28
VT, L 0.60 0.07 0.56 0.06
ICdyn, L 1.33 0.13 1.46 0.18
IRV, L 0.73 0.13 0.91 0.18
EILV, %TLC 88 2 86 3

Figure 2. Ventilatory responses to exercise over time in 11 patients * p 0.05, significant difference between room air and 60% O 2.
with severe, hypoxic COPD while breathing RA and 60% O2. Values

p 0.01, significant difference between room air and 60% O 2.
represent means SEM. *p 0.05, difference at isotime exercise.

below (increased EELVdyn) (Figure 2). In all subjects at rest

for more air (82% of subjects), I cannot get enough air in
(64%), and breathing in requires effort (64%). Breathing
discomfort was still a primary reason for stopping exercise
during O2 in six patients (five because of breathlessness alone,
and one because of the combination of breathing and leg dis-
comfort); however, three subjects then stopped because of leg
discomfort and two for other reasons (one because of general
tiredness, one because of discomfort from sitting on the bi-
cycle seat).
Of the patients who stopped exercise because of dyspnea
during both RA and O2 tests (n 6), there were no changes in
peak measurements of ventilation, operational lung volumes,
or breathing pattern. Interestingly, in the subgroup (n 5)
that continued exercise and stopped because of a new reason
during O2 (i.e., leg discomfort, other), there was a significant
improvement in IRV (p 0.05) and IC (p 0.05) throughout
exercise and at peak exercise.
Ventilatory Responses to Exercise
While breathing room air, mean peak VE was low at only 23.0
3.5 L/min; the small increase in VE during exercise was accom-
plished almost exclusively through an increase in fR, because
VT was severely constrained from above (minimal IRV) and
and throughout exercise, tidal expiratory flows met or ex-
ceeded isovolume maximal flows throughout VT (Figure 3A).
Gas exchange and various other parameters measured at
rest on RA and 60% O2 are presented in Table 3. Gas ex-
change responses to 60% O2 during exercise are shown in Fig-
ure 4 and are reported in Tables 2 and 4. Exercise response
slopes that fell significantly
when expressed over time in-
cluded
(Figures 2 and 3) VE (p 0.015), lactate (p 0.14),
VCO2 (p 0.021), breathing frequency (p 0.002), IRV/pre-
dicted TLC (p 0.011), and IC% predicted (p 0.031) (Ta-
ble 5). To highlight these reductions that became more appar-
ent in the latter part of exercise with O2, variables were
compared at a time near exercise cessation on RA with those
at isotime during exercise on O2 (Table 4). VO2 responses to
hyperoxia at isotime were variable, and thus, we could not
evaluate the possibility
of a shift in substrate utilization during
exercise (n 7): VO2 was similar or tended to go down in five
of seven subjects, but increased in the other two subjects, with
no significant change on average. At isotime, the fall in VE
correlated strongly
with the fall
in VCO2 (r 0.86, p 0.0005).
2
The fact that VE/VCO2 and VE/lactate slopes were not altered

Figure 3. Tidal and maximal flowvolume loops while breathing room Figure 4. Gas exchange responses to exercise over time in 11 patients
air (A) and 60% O2 (B). At isotime during exercise, note reduced dy- with severe, hypoxic COPD while breathing RA and 60% O2. Values
namic lung hyperinflation and increased IRV during O2. represent means SEM. *p 0.05, difference at isotime exercise.
ODonnell, DArsigny, and Webb: Lung Hyperinflation in Hypoxic COPD 895

TABLE 4. RESPONSES AT ISOTIME DURING EXERCISE*

Room Air 60% O2 Mean Difference

Dyspnea intensity, Borg rating 4.9 0.5 2.9 0.6 2.0

Leg discomfort, Borg rating 3.9 0.7 2.7 0.8 1.2
HR, beats/min 114 4 103 4 11

V CO2, L/min 0.50 0.08 0.45 0.06 0.06

V E, L/min 21.5 2.8 18.7 1.9 2.8

V E/ V CO2 45.3 2.2 45.3 3.1 0.04
fR, breaths/min 28.4 1.6 23.9 1.8 4.4
TI, s 0.72 0.05 0.85 0.07 0.13
TE, s 1.46 0.09 1.81 0.17 0.35
TI/Ttot 0.33 0.01 0.33 0.02 0.00
Midtidal expiratory flow, L/s 0.72 0.13 0.54 0.10 0.18
Midtidal inspiratory flow, L/s 1.51 0.17 1.42 0.14 0.09
VT, L 0.76 0.10 0.80 0.09 0.04
VT/IC, % 73 3 63 4 10
ICdyn, L 1.05 013 1.34 0.17 0.29
DH from rest, L 0.28 0.06 0.13 0.04 0.16
IRV, L 0.29 0.05 0.53 0.11 0.25
EILV/TLC, % 95 1 92 2 3
VD/VT, % 37 4 41 4 4
Lactate, mM 2.7 0.4 2.3 0.3 0.5
PaO2, mm Hg 45.3 2.6 245.9 9.3 200.6
PaCO2, mm Hg 53.3 3.0 57.6 3.4 4.4
PETCO2 43.1 2.0 47.2 1.9 4.1

* 3.6 0.9 min.

p 0.1, significant difference between room air and 60% O 2.

p 0.05, significant difference between room air and 60% O 2.

p 0.065, significant difference between room air and 60% O 2.

with hyperoxia also supports the notion that these variables tion in the extent of dynamic hyperinflation (ICdyn): ICdyn
changed in proportion to each other (Figure 5). was decreased by 0.28 0.06 and 0.13 0.04 L from rest at
isotime exercise on RA and O2, respectively (p 0.05). IC
Operational Lung Volumes (and IRV) were also increased for any given ventilation dur-
Along with the decrease in ventilation during O2, there was a ing exercise with O2 due, in part, to alterations in breathing
corresponding decrease in midtidal expiratory flow rates that pattern. By stepwise multiple regression analysis, the fall in IC
allowed tidal flowvolume loops to shift rightward within the at isotime was best predicted by the combination of an in-
maximal loop (Figure 3); that is, there was an increase in IC crease in resting IRV and a decrease in isotime breathing fre-
and IRV at rest (see above) and throughout exercise. At iso- quency (r2 0.83, p 0.0005). Of note, the increase in IRV at
time during exercise with O2, there was also a significant reduc- rest occurred,

in part, as a result of associated small reductions
in resting VCO2
(IRV versus V CO2, r 0.81, p 0.003)
and, in turn, VE (IRV versus VE, r 0.75, p 0.008).
TABLE 5. EXERCISE RESPONSE SLOPES
Mechanisms of Improved Exercise Endurance
Room Air* 60% O2* p Value and Relief of Breathlessness
Symptom intensity Improvements in exercise endurance

(Work) correlated best
Dyspneatime, Borg/min

1.47 0.29 0.53 0.13 0.004 with changes in the slopes of VE/time (r 0.626, p 0.039)
Dyspnea V E, Borg/L/min 0.79 0.34 0.32 0.08 NS
Leg discomforttime, Borg/min 1.20 0.25 0.70 0.15 0.006

Leg discomfortV CO2 10.2 7.0 10.5 3.5 NS
Slopes over time

V Etime, L/min/min 3.13 0.66 1.54 0.31 0.015

V CO2time 0.09 0.02 0.04 0.01 0.021
Lactatetime 0.5 0.1 0.3 0.1 0.014
fRtime 3.2 0.7 1.4 0.4 0.002
VTtime 0.03 0.03 0.02 0.01 NS
ICtime 0.10 0.04 0.02 0.01 0.055
IC% predictedtime 3.9 1.4 0.0 0.0 0.031
IRVtime 0.14 0.04 0.03 0.02 0.013
IRV% predicted TLCtime 2.5 0.7 0.7 0.3 0.011
HR% predicted maxtime 3.3 0.7 1.9 0.5 0.002
Slopes expressed against ventilation

F V E 1.41 0.57 0.63 0.19 NS

VT V E 0.00 002 0.03 0.01 NS

IC V E 0.08 0.05 0.00 0.01 NS

IRV V E 0.08 0.04 0.03 0.01 NS

V Elactate 9.9 3.3 11.3 4.2 NS

V E V CO2 33.0 2.9 33.3 6.9 NS
Figure 5. VE/ VCO2 and VE/lactate relationships
did not change during
* Values represent means SEM. exercise with added O2. Changes in VE at isotime correlated signifi-

NS no significant difference between room air and 60% O 2. cantly with concurrent changes in VCO2 (r 0.93, p 0.0005).
896 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
and lactate/time (r 0.625, p 0.040), and with baseline
resting maximal midexpiratory flow (MMEF)% predicted (r
0.656, p 0.028) and resting IC% predicted (r 0.603, p
0.049); that is, the subjects who improved exercise endurance
the most were those with the least baseline constraints on tidal
volume or flow expansion, and with greater reductions in
exercise ventilation or lactate. By stepwise multiple regression
analysis, the combination of the baseline MMEF% predicted
and lactate/time accounted for 71% of the variance in
Work (r 0.841, p 0.0005). In a subgroup of five subjects
who improved exercise endurance by less than 2 min with O2,
there was no significant change in operational lung volumes at
rest (IRV 0.00 0.07 L, IC 0.02 0.04 L) or at iso-
time during exercise on O2 (IRV 0.08 0.11 L, IC
0.19 0.11 L). This was in contrast to the remaining six sub-
jects who had significantly larger increases in endurance with
O2 (by 7.4 4.7 min), as well as significant improvements in
operational lung volumes at rest (IRV 0.32 0.17 L, IC
0.23 0.11 L; p 0.05 each) and at isotime during exercise
(IRV 0.39 0.16 L, IC 0.37 0.15 L; p 0.05 each). Ventilatory limitation and the attendant severe breathing dis-
Dyspneaventilation relationships fit a single-exponential
model that did not change significantly with the addition of
supplemental O2 (Figure 6): equations for this model were
Borg 0.16e0.16(Ve) (r2 0.98) and 0.24e0.13(Ve) (r2 0.99) on
RA and O2, respectively. Therefore, Borg ratings of dyspnea
intensity and ventilation were reduced proportionally within
this relationship during hyperoxia.
The slopes of dyspnea over exercise time fell inversely to
the slopes on RA; that is, the greater the intensity of exer-
tional dyspnea on RA, the greater the reduction with O2 (r
0.895, p 0.0005). Improvement in respiratory sensation
did not correlate with baseline pulmonary function, gas ex-
change, PaO2, PaCO2, or ventilatory mechanics. Although per-
ceived leg discomfort during exercise fell significantly during
hyperoxia, it was not the primary symptom limiting exercise
on RA. Thus, reductions in leg discomfort were not as impor-
tant with respect to improvements in exercise endurance.
Figure 6. The exponential relationship between Borg dyspnea ratings
and ventilation is not different during RA (dashed line) and O2 (solid
line). Within this relationship, exertional dyspnea intensity decreased
significantly (p 0.05) in proportion to the fall in VE at isotime during
hyperoxia. In a previously studied group of COPD patients with less
mechanical constraints and without significant hypoxia (dashed line)
(data taken from Reference 7), the slope of this relationship is reduced,
and there are smaller reductions in dyspnea intensity for a given reduc-
tion in ventilation.
VOL 163 2001
DISCUSSION
The novel aspects of this study are as follows. First, hyperoxia
had profound effects on dyspnea and exercise endurance in
this group of patients with chronic ventilatory insufficiency.
Second, improved exercise performance was primarily related
to reduced ventilatory demand, which, in turn, led to improved
operational lung volumes and a delay in the attainment of lim-
iting ventilatory constraints on exercise and the onset of intol-
erable dyspnea. Third, modest changes in submaximal ventila-
tion and dynamic ventilatory mechanics resulted in relatively
large improvements in symptom intensity and exercise capac-
ity. Fourth, reduced submaximal ventilation was likely linked,
in part, to altered metabolic requirements under hyperoxic
conditions. Finally, hyperoxia resulted in additional, and po-
tentially important, effects on cardiovascular function and
perceived leg discomfort.
Effects on Ventilatory Responses
comfort were the primary factors curtailing exercise in these
severely hyperinflated patients with chronic respiratory fail-
ure. Perusal of the tidal and maximal flowvolume loops on
room air confirmed their limited ability to increase ventilation
further when challenged with the increasing metabolic de-
mands of exercise (Figure 3). Significant ventilatory con-
straints were evident at peak exercise on RA: end-inspiratory
lung volume (EILV)/TLC was 95%, and dynamic IRV was
only 0.3 L on average.
Oxygen therapy resulted in modest, but consistent, reduc-
tions in submaximal ventilation, by an average of 11% at
isotime, with a significant time delay in reaching the peak ven-
tilation attained under RA conditions. Reduced submaximal
ventilation was achieved primarily by a reduction in breathing
frequency (by 16% at isotime), because VT in these severely
hyperinflated patients was relatively fixed.
The mechanism by which hyperoxia results in a reduction
in submaximal ventilation throughout exercise is debated.
Many previous studies have suggested that the primary mech-
anism is direct reduction of peripheral chemoreceptor activa-
tion with consequent reduced central medullary motor
drive
(i.e., loss of the hypoxic stimulus to breathe) (14). VE/VCO2
slopes were
identical on RA and oxygen; therefore, the reduc-
tion
of VE at isotime correlated strongly with
simultaneous
VCO2 reduction (Figure 5). Thus, reduced VCO2 at rest and
during low levels of exercise could have been reflective of re-
duced ventilatory drive and the attendant reduced work
of
breathing, which is high in such patients. Reduction in VCO2,
particularly toward the end of exercise, may additionally re-
flect reduced acid buffering effects because of reduced meta-
bolic acidemia (7). With hyperoxia, oxygen delivery to the ac-
tive peripheral muscles is increased for a given blood flow
with less reliance on anaerobic glycolysis. In our subjects, hy-
peroxia delayed metabolic acidemia, of which blood lactate is
a marker. Lactate levels at the breakpoint of exercise during
RA and oxygen were identical; therefore, oxygen delayed fur-
ther accumulation of lactate despite the large increases in cu-
mulative work performed. However, the relative contribution
of reduced hypoxic drive
and altered metabolic loading to re-
duced submaximal VE during hyperoxia could not be deter-
mined in this study, but both mechanisms are likely to be in-
strumental.
Effects on Operational Lung Volumes
In conjunction with reduced ventilationtime slopes, oxygen
also resulted in a delay in dynamic hyperinflation during exer-
ODonnell, DArsigny, and Webb: Lung Hyperinflation in Hypoxic COPD
cise: at isotime, the change in EELVdyn from rest was 0.13 L,
on average, which was half the magnitude of the change in
EELVdyn on room air at this point of comparison. Thus, while
the changes in EELVdyn at peak exercise on RA and oxygen
were similar, the time to reach this level of hyperinflation was
greatly increased (i.e., by greater than 2-fold) when breathing
oxygen. The reduced dynamic lung hyperinflation (DH) was as-
sociated with less restrictive mechanical constraints: IRV was
significantly increased at isotime, thus delaying the onset of
ventilatory limitation. There was a spectrum of responses to hy-
peroxia among study subjects; those individuals who had only
minimal changes in endurance time were the ones whose mea-
sured ICdyn did not change on oxygen compared with RA. Pa-
tients with the greatest response to oxygen were those with the
largest reserves for tidal volume and flow
generation at baseline,
and who had the greatest reductions in VEtime and lactatetime
slopes during oxygen.
The extent of DH in these patients with advanced disease is
less than that reported previously in patients with less severe
COPD, who had average increases of 0.3 to 0.6 L, but with
considerable variation in the range (10, 14). The relatively re-
duced rate of DH in our patients likely reflects the marked
resting hyperinflation. The extent of DH in COPD depends
on the resting level of hyperinflation, the extent of expiratory
flow limitation (EFL), the ventilation during exercise, and the
breathing pattern for a given ventilation (24, 25). It follows
that possible mechanisms of delay in dynamic hyperinflation
during oxygen are (1) reduced ventilation for a given level of
EFL; (2) altered breathing pattern (i.e., increased TE) at a
given ventilation with unchanged EFL; (3) increased maximal
and tidal volume-matched expiratory flows with enhanced
lung emptying (i.e., bronchodilator effect); or (4) any combi-
nation of the above.
Comparison of tidal flowvolume loops at isotime during
exercise showed that midtidal expiratory flow rates were di-
minished on oxygen compared with RA, suggesting a persis-
tence of expiratory flow limitation during oxygen, but at lower
operational lung volumes, as dictated by the reduced ventila-
tory demands. Previous studies have suggested a direct, but
mild, bronchodilator effect of hyperoxia in COPD (11). How-
ever, the lack of a significant increase in tidal expiratory flow
rates during hyperoxia makes this mechanism less likely. Thus,
there was no evidence to suggest that improved dynamic air-
way function during exercise was responsible for the reduced
operational lung volumes during hyperoxia.
It is interesting to note that ICdyn was also reduced at a
given ventilation on RA and oxygen: in the absence of a bron-
chodilator effect, this could be explained by alterations in re-
spiratory timing (i.e., prolonged TE) for a given ventilation dur-
ing oxygen. Using multiple regression analysis, the increased
ICdyn at isotime was explained primarily by reductions in
breathing freqency and improved resting inspiratory reserve
volume (r2 0.83, p 0.0005).
Effects of Hyperoxia on Exertional Symptoms
Patients with the greatest intensity of exertional dyspnea (i.e.,
Borgtime slopes) on RA were those who had the greatest
alleviation of dyspnea during hyperoxia. Moreover, the re-
sponses to 60% oxygen in our current study patients were
much more dramatic than those achieved previously, when
60% oxygen was delivered to a group of patients with less se-
vere COPD (FEV1.0 37% predicted) but with only mild ex-
ercise hypoxemia (7). Indeed, it is remarkable that relatively
modest reductions in submaximal VE (by approximately 3 L/
min) and operational lung volumes (by approximately 0.3 L)
have such clinically important effects on symptom intensity
897
and exercise performance. Perusal of the BorgVE slopes in
the previously studied group of patients with less severe dis-
ease (7) and our present study subjects helped to explain the
differences in the
magnitude of response to 60% oxygen (Fig-
ure 6). BorgVE slopes become steeper as baseline mechani-
cal and gas exchange abnormalities increase. It follows that
small reductions in submaximal ventilation, on the order of 3
L/min, result in relatively greater reductions in dyspnea in pa-
tients with more severe mechanical impairment and hypox-
emia.
It is interesting to note that in the setting of less restrictive
ventilatory mechanics at peak exercise on oxygen, dyspnea
was displaced by leg discomfort (or some other complaint) as
the primary exerciselimiting symptom in several patients. In
a subgroup of five patients whose more prolonged exercise
was limited by a new symptom on hyperoxia, there were sig-
nificant improvements in IRV and IC throughout exercise and
at peak exercise. Reductions in operational lung volumes in
this severely mechanically compromised group translate into
reduced elastic and threshold loading of functionally weak-
ened inspiratory muscles, reduced muscular effort of breath-
ing, and enhanced neuromechanical coupling of the respira-
tory system (10). Collectively, these mechanical changes would
be expected to reduce perceived respiratory discomfort at any
given work rate.
The relative importance of reduced chemoreceptor activa-
tion in contributing to dyspnea relief in this study was impossi-
ble to quantify. The extent to which hypoxia directly contrib-
uted to unpleasant respiratory sensations during exercise,
independent of ventilatory muscle activity, is debated (58).
While there is strong evidence that hypercapnia can cause un-
pleasant sensations of air hunger independent of muscle ac-
tivation in healthy subjects paralyzed by neuromuscular
blockade, and in ventilated quadriplegics with high cervical
spine transection, direct effects of hypoxia on respiratory sen-
sation appear to be inconsistent (26, 27). It is noteworthy that
while breathing 60% oxygen, PaCO2 rose at peak exercise by an
average of 7 mm Hg above an already increased resting value,
reflecting a combination of respiratory depression, increased
ventilationperfusion mismatching (note increased physiolog-
ical deadspace in the setting of a preserved VT), and the
Haldane effect (28). However, this was not associated with an
increase in perceived dyspnea intensity at a similar ventilation,
perhaps reflecting effective compensatory buffering in these
patients with chronic respiratory failure. Moreover, air hun-
ger was not selected as a representative qualitative descriptor
of dyspnea by any of the study subjects, either under RA or
hyperoxic conditions despite acute on chronic hypercapnia
during exercise.
It must be emphasized that the effects of hyperoxia are
multifactorial and involve many integrated mechanisms. In
addition to reducing the stress on the ventilatory system, hy-
peroxia may (1) improve oxygen delivery to the peripheral
muscles and possibly the ventilatory muscles, and thus delay
fatigue; (2) improve cardiovascular function; (3) improve cen-
tral nervous system function; (4) modify afferent inputs from
peripheral chemoreceptors; and (5) alter the perception of
symptom intensity. During 60% oxygen in this study, exercise
tachycardia was consistently reduced despite patients achiev-
ing higher levels of cumulative work. In addition, 60% oxygen
significantly reduced perceived leg discomfort throughout ex-
ercise. However, the relative contributions of these various
physiological effects of hyperoxia to improved exercise endur-
ance were impossible to quantify using this study design.
In summary, hyperoxia resulted in relatively large improve-
ments in exercise endurance in patients who were severely dis-
898 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
abled by advanced COPD. Improvement was multifactorial
and ultimately reflected the integrated effects of hyperoxia on
ventilatory drive, the metabolic load, and improved dynamic
ventilatory mechanics, which together resulted in a delay in the
attainment of critical ventilatory constraints and the attendant
intolerable respiratory discomfort. The important clinical im-
plication of our study is that in advanced COPD, modest re-
ductions in ventilation and in operational lung volumes trans-
late into clinically important dyspnea alleviation and enhanced
exercise capabilities.
Acknowledgment : The authors acknowledge Dr. Emma Hollingworth for
valuable assistance in patient recruitment and testing in this study.
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