Effects of Hyperoxia on Ventilatory Limitation
During Exercise in Advanced Chronic Obstructive
Pulmonary Disease
DENIS E. O’DONNELL, CHRISTINE D’ARSIGNY, and KATHERINE A. WEBB
Respiratory Investigation Unit, Department of Medicine, Queen’s University, Kingston, Ontario, Canada
We studied interrelationships between exercise endurance, ventilatory 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 respiratory 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), breathing 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
· · ·
·
over time fell (p ⬍ 0.05); slopes of Borg–VE, VE–VCO2, VE–lactate
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 explained 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.
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 increase respired volume or flow with exercise. Our hypothesis
was that oxygen therapy would reduce ventilatory demand, reduce the rate of dynamic hyperinflation and, therefore, reduce
the stress on the ventilatory system during exercise, thus improving exercise endurance. On the basis of previous work
(10), we further postulated that relatively small changes in operational 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
TLC (11).
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, dyspnea 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 abovelisted dynamic physiological and psychological variables.
Ambulatory oxygen therapy has been shown in several controlled studies to improve exercise performance and to relieve
exertional dyspnea in patients with chronic obstructive pulmonary disease (COPD) (1–5). However, responses to this intervention are highly variable and are unpredictable in any given
individual (6–9). The mechanisms of improvement when
breathing oxygen are complex and poorly understood. Ultimately, the success of ambulatory oxygen therapy in COPD
likely depends on its net effect on integrated cardiopulmonary
function and symptom generation. Previous studies have identified several potential contributing factors that include (1) altered 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 (1–9).
It is a common clinical observation that some patients with
COPD and unequivocal ventilatory limitation to exercise
show marked improvements in exercise performance with ambulatory oxygen. To gain new insights into the mechanisms of
this improvement, we examined the effects of supplemental
Subjects
METHODS
We studied 11 clinically stable patients with advanced COPD (FEV1 ⬍
50% predicted) who met medical criteria for ambulatory O2 in Ontario (Ministry of Health’s 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 exercise limitation were excluded.
Study Design
This study was a randomized, double-blind, placebo-controlled, crossover 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 exercise test. In a subsequent visit, subjects performed two constantload exercise tests at approximately 50% of their previously determined 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 subjective responses and performing data analysis.
(Received in original form July 7, 2000 and in revised form November 27, 2000)
Procedures
Presented, in part, at the ALA/ATS International Conference, Toronto, May 5–10,
2000.
Subjects performed pulmonary function and cycle exercise tests as
previously described (7). In addition, subjects described their breathing 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 during 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 flow–volume loops were also placed relative to each sub-
Supported by the Ontario Thoracic Society. Denis O’Donnell holds a career scientist award from the Ontario Ministry of Health.
Correspondence and requests for reprints should be addressed to Denis O’Donnell, M.D., Richardson House, 102 Stuart Street, c/o Kingston General Hospital,
Kingston, ON, K7L 2V7 Canada. E-mail: [email protected]
Am J Respir Crit Care Med Vol 163. pp 892–898, 2001
Internet address: www.atsjournals.org
O’Donnell, D’Arsigny, and Webb: Lung Hyperinflation in Hypoxic COPD
TABLE 1. SUBJECT CHARACTERISTICS*
Parameter
Value
Male:female
Age, yr
Height, cm
Weight, kg
Body mass index, kg/m2
Modified baseline dyspnea index
·
Peak V O2, L/min (% predictededicted maximum)
·
Peak V O2, ml/kg/min
4:7
68 ⫾ 2
163 ⫾ 2
68 ⫾ 6
25.5 ⫾ 1.9
4.5 ⫾ 0.3 (severe)
0.47 ⫾ 0.09 (38)
7.2 ⫾ 1.1
Pulmonary function and gas exchange (% of predicted normal)
FEV1, L
0.65 ⫾ 0.06 (31)
FVC, L
1.59 ⫾ 0.11 (53)
FEV1/FVC, %
41 ⫾ 3 (59)
TLC, L
6.86 ⫾ 0.51 (127)
RV, L
5.07 ⫾ 0.50 (237)
FRC, L
5.64 ⫾ 0.50 (190)
IC, L
1.23 ⫾ 0.12 (50)
PImax, cm H2O
42 ⫾ 4 (59)
26.7 ⫾ 2.5 (666)
SRaw, cm H2O · s
DLCO, ml/min/mm Hg
6.9 ⫾ 0.8 (36)
PaO2 (room air), mm Hg
52.4 ⫾ 2.2
PaCO2 (room air), mm Hg
48.5 ⫾ 2.1
pH (room air)
7.41 ⫾ 0.02
HCO3 (room air), mM
28.1 ⫾ 1.7
*n ⫽ 11. Values represent means ⫾ SEM. Pulmonary function variables in parentheses represent the percentage of predicted normal values. Predicted normal values for
spirometry, lung volumes, DLCO, and PImax were those of Morris and associates (18),
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).
ject’s TLC, using concurrent IC measurements. IC maneuvers were carried out at the end of each 10-min resting baseline until three reproducible efforts were achieved (within 5%), every 2–3 min during exercise,
and at peak exercise. This has been found to be a reliable and responsive method of tracking acute changes in lung volume (10, 15, 16).
Statistical Analysis
Results are presented as means ⫾ SEM. A statistical significance of
0.05 was used for all analyses, with appropriate Bonferroni correc-
TABLE 2. SYMPTOM-LIMITED PEAK EXERCISE
Endurance time, min
Dyspnea intensity, Borg rating
Leg discomfort, Borg rating
Reason for stopping exercise, number of subjects:
Breathlessness
Leg discomfort
Both
Other
HR, beats/min
SaO2, %
PaO2, mm Hg
PaCO2, mm Hg
Lactate, mM
·
V CO2, L/min
·
V E, L/min
· ·
V E/ V CO2
fR, breaths/min
VT, L
ICdyn, L
IRV, L
Dynamic lung hyperinflation (DH), L
EILV, %TLC
Room Air
60% O2
4.1 ⫾ 0.9
5.2 ⫾ 0.7
4.1 ⫾ 0.8
8.8 ⫾ 1.3*
5.0 ⫾ 0.8
4.5 ⫾ 0.8
8
5
0
3
3
1
0
2†
112 ⫾ 5
110 ⫾ 4
82 ⫾ 2
99 ⫾ 0.1*
45.9 ⫾ 2.8 244.7 ⫾ 10.4*
53.3 ⫾ 3.0
58.0 ⫾ 5.0*
2.9 ⫾ 0.4
2.8 ⫾ 0.4
0.54 ⫾ 0.09 0.53 ⫾ 0.09
23.0 ⫾ 3.5
22.4 ⫾ 2.9
45.0 ⫾ 2.2
45.4 ⫾ 4.2
30.0 ⫾ 2.0
28.6 ⫾ 2.2
0.77 ⫾ 0.11 0.80 ⫾ 0.10
1.07 ⫾ 0.13 1.25 ⫾ 0.16‡
0.30 ⫾ 0.04 0.45 ⫾ 0.08‡
0.26 ⫾ 0.07 0.21 ⫾ 0.08
95 ⫾ 1
93 ⫾ 1‡
* p ⬍ 0.01, significant difference between room air and 60% O 2.
†
Other reasons for stopping exercise included general “tiredness” (n ⫽ 1) and discomfort on the bicycle seat (n ⫽ 1).
‡
p ⬍ 0.05, significant difference between room air and 60% O 2.
893
tions for multiple comparisons. Before treatment comparisons were
made, the possibility of sequence effects was evaluated (17). Treatment comparisons were made using paired t tests. Exercise endurance
was evaluated as total cumulative work performed [Σ work rate [%
predicted maximum] ⫻ minutes); exercise slopes were expressed as
means of individual regression lines; isotime exercise was defined as
the highest equivalent minute of exercise completed during both tests.
Pearson correlations were used to establish associations between
change in endurance (⌬Work) with hyperoxia and concurrent changes
in relevant independent variables (i.e., dyspnea, leg discomfort, minute
·
ventilation [VE], respiratory frequency [fR], VT, inspiratory capacity
·
·
[IC], IRV, oxygen consumption [VO2], carbon dioxide production [VCO2],
lactate, PaO2, PaCO2). Stepwise multiple regression analysis was carried
out with these variables and possible covariates (baseline lung function and gas exchange) to establish the best equation for improvement
in exercise endurance. Similar analyses were carried out to examine
interrelationships between changes in dyspnea intensity, ventilation,
operational lung volumes, breathing pattern, and other relevant cardioventilatory parameters.
RESULTS
Subject characteristics are summarized in Table 1 (18–22). No
significant sequence effects were found in this study with respect to exercise responses (i.e., measurements of exercise endurance, symptom intensity, ventilation and metabolic responses), thereby allowing a valid analysis of treatment effects
in response to supplemental O2.
Symptom-limited Exercise Endurance
Symptom-limited endurance exercise at 23 ⫾ 3 W (26 ⫾ 5% of
the predicted maximum work rate) on ·RA was severely curtailed at 38 ⫾ 7% predicted maximum VO2 after 4.1 ⫾ 0.9 min
(Table 2). Although endurance time increased significantly· by
values for VO2
4.7 ⫾ 1.4 min (p ⬍ 0.001) during 60% O2, peak
·
(n ⫽ 7, where technically satisfactory) and VCO2 did not change
significantly with added O2 (Table 2). Breathing 60% O2 during
exercise did not result in any significant change in peak Borg
ratings (23) of dyspnea or leg discomfort; however, slopes of
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 subjects stopped exercise because of breathlessness alone, whereas
the remaining three stopped because of a combination of both
breathing and leg discomfort. At the end of RA exercise, the
main descriptors used to describe dyspnea were “I feel a need
Figure 1. Slopes of Borg ratings of perceived breathlessness and leg effort were significantly reduced over time during exercise on 60% O2
compared with room air (RA, 21% O2) (p ⬍ 0.01). Exercise endurance
time also increased significantly on O2 (p ⬍ 0.01). Values represent
means ⫾ SEM. *p ⬍ 0.05, **p ⬍ 0.01, difference between values at
isotime.
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
VOL 163
2001
TABLE 3. STEADY STATE BREATHING DURING REST
Dyspnea intensity, Borg rating
HR, beats/min
BP systolic, mm Hg
BP diastolic, mm Hg
SaO2, %
PaO2, mm Hg
PaCO2, mm Hg
pH
·
V CO2, L/min
·
V E, L/min
fR, breaths/min
TE, s
VT, L
ICdyn, L
IRV, L
EILV, %TLC
Figure 2. Ventilatory responses to exercise over time in 11 patients
with severe, hypoxic COPD while breathing RA and 60% O2. Values
represent means ⫾ SEM. *p ⬍ 0.05, difference at isotime exercise.
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 discomfort); 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 bicycle 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
·
VE was low at only 23.0 ⫾
While breathing room air, mean peak
·
3.5 L/min; the small increase in VE during exercise was accomplished almost exclusively through an increase in fR, because
VT was severely constrained from above (minimal IRV) and
Figure 3. Tidal and maximal flow–volume loops while breathing room
air (A) and 60% O2 (B). At isotime during exercise, note reduced dynamic lung hyperinflation and increased IRV during O2.
Room Air
60% O2
0.8 ⫾ 0.2
94 ⫾ 3
123 ⫾ 6
74 ⫾ 3
88.5 ⫾ 1.9
56 ⫾ 3
44 ⫾ 3
7.41 ⫾ 0.01
0.21 ⫾ 0.03
11.0 ⫾ 1.1
19.3 ⫾ 1.5
2.28 ⫾ 0.26
0.60 ⫾ 0.07
1.33 ⫾ 0.13
0.73 ⫾ 0.13
88 ⫾ 2
0.9 ⫾ 0.3
87 ⫾ 2*
125 ⫾ 5
73 ⫾ 4
98.8 ⫾ 0.1†
244 ⫾ 9†
51 ⫾ 4*
7.39 ⫾ 0.01†
0.16 ⫾ 0.02
10.0 ⫾ 1.1
18.3 ⫾ 2.3
2.42 ⫾ 0.28
0.56 ⫾ 0.06
1.46 ⫾ 0.18
0.91 ⫾ 0.18
86 ⫾ 3
* p ⬍ 0.05, significant difference between room air and 60% O 2.
†
p ⬍ 0.01, significant difference between room air and 60% O 2.
below (increased EELVdyn) (Figure 2). In all subjects at rest
and throughout exercise, tidal expiratory flows met or exceeded 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 exchange responses to 60% O2 during exercise are shown in Figure 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/predicted TLC (p ⫽ 0.011), and IC% predicted (p ⫽ 0.031) (Table 5). To highlight these reductions that became more apparent 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
2
correlated strongly
with the fall
in VCO2 (r ⫽ 0.86, p ⬍ 0.0005).
·
·
·
The fact that VE/VCO2 and VE/lactate slopes were not altered
Figure 4. Gas exchange responses to exercise over time in 11 patients
with severe, hypoxic COPD while breathing RA and 60% O2. Values
represent means ⫾ SEM. *p ⬍ 0.05, difference at isotime exercise.
895
O’Donnell, D’Arsigny, and Webb: Lung Hyperinflation in Hypoxic COPD
TABLE 4. RESPONSES AT ISOTIME DURING EXERCISE*
Dyspnea intensity, Borg rating
Leg discomfort, Borg rating
HR, beats/min
·
V CO2, L/min
·
V E, L/min
· ·
V E/ V CO2
fR, breaths/min
TI, s
TE, s
TI/Ttot
Midtidal expiratory flow, L/s
Midtidal inspiratory flow, L/s
VT, L
VT/IC, %
ICdyn, L
DH from rest, L
IRV, L
EILV/TLC, %
VD/VT, %
Lactate, mM
PaO2, mm Hg
PaCO2, mm Hg
PETCO2
Room Air
60% O2
Mean Difference
4.9 ⫾ 0.5
3.9 ⫾ 0.7
114 ⫾ 4
0.50 ⫾ 0.08
21.5 ⫾ 2.8
45.3 ⫾ 2.2
28.4 ⫾ 1.6
0.72 ⫾ 0.05
1.46 ⫾ 0.09
0.33 ⫾ 0.01
0.72 ⫾ 0.13
1.51 ⫾ 0.17
0.76 ⫾ 0.10
73 ⫾ 3
1.05 ⫾ 013
0.28 ⫾ 0.06
0.29 ⫾ 0.05
95 ⫾ 1
37 ⫾ 4
2.7 ⫾ 0.4
45.3 ⫾ 2.6
53.3 ⫾ 3.0
43.1 ⫾ 2.0
2.9 ⫾ 0.6
2.7 ⫾ 0.8
103 ⫾ 4
0.45 ⫾ 0.06
18.7 ⫾ 1.9
45.3 ⫾ 3.1
23.9 ⫾ 1.8
0.85 ⫾ 0.07
1.81 ⫾ 0.17
0.33 ⫾ 0.02
0.54 ⫾ 0.10
1.42 ⫾ 0.14
0.80 ⫾ 0.09
63 ⫾ 4
1.34 ⫾ 0.17
0.13 ⫾ 0.04
0.53 ⫾ 0.11
92 ⫾ 2
41 ⫾ 4
2.3 ⫾ 0.3
245.9 ⫾ 9.3
57.6 ⫾ 3.4
47.2 ⫾ 1.9
⫺2.0†
⫺1.2‡
⫺11†
⫺0.06‡
⫺2.8‡
0.04
⫺4.4†
0.13†
0.35†
0.00
⫺0.18‡
0.09
0.04
⫺10
0.29‡
⫺0.16§
0.25‡
⫺3‡
4
⫺0.5
200.6†
4.4†
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
changed in proportion to each other (Figure 5).
Operational Lung Volumes
Along with the decrease in ventilation during O2, there was a
corresponding decrease in midtidal expiratory flow rates that
allowed tidal flow–volume loops to shift rightward within the
maximal loop (Figure 3); that is, there was an increase in IC
and IRV at rest (see above) and throughout exercise. At isotime during exercise with O2, there was also a significant reduc-
TABLE 5. EXERCISE RESPONSE SLOPES
Room Air*
Symptom intensity
Dyspnea–time, Borg/min
·
Dyspnea– V E, Borg/L/min
Leg discomfort–time, Borg/min
·
Leg discomfort–V CO2
Slopes over time
·
V E–time, L/min/min
·
V CO2–time
Lactate–time
fR–time
VT–time
IC–time
IC% predicted–time
IRV–time
IRV% predicted TLC–time
HR% predicted max–time
Slopes expressed against ventilation
·
F– V E
·
VT– V E
·
IC– V E
·
IRV– V E
·
V E–lactate
· ·
V E– V CO2
60% O2*
p Value
1.47 ⫾ 0.29
0.79 ⫾ 0.34
1.20 ⫾ 0.25
10.2 ⫾ 7.0
0.53 ⫾ 0.13
0.32 ⫾ 0.08
0.70 ⫾ 0.15
10.5 ⫾ 3.5
0.004
NS†
0.006
NS
3.13 ⫾ 0.66
0.09 ⫾ 0.02
0.5 ⫾ 0.1
3.2 ⫾ 0.7
0.03 ⫾ 0.03
⫺0.10 ⫾ 0.04
⫺3.9 ⫾ 1.4
⫺0.14 ⫾ 0.04
⫺2.5 ⫾ 0.7
3.3 ⫾ 0.7
1.54 ⫾ 0.31
0.04 ⫾ 0.01
0.3 ⫾ 0.1
1.4 ⫾ 0.4
0.02 ⫾ 0.01
⫺0.02 ⫾ 0.01
⫺0.0 ⫾ 0.0
⫺0.03 ⫾ 0.02
⫺0.7 ⫾ 0.3
1.9 ⫾ 0.5
0.015
0.021
0.014
0.002
NS
0.055
0.031
0.013
0.011
0.002
1.41 ⫾ 0.57
0.00 ⫾ 002
⫺0.08 ⫾ 0.05
⫺0.08 ⫾ 0.04
9.9 ⫾ 3.3
33.0 ⫾ 2.9
0.63 ⫾ 0.19
0.03 ⫾ 0.01
⫺0.00 ⫾ 0.01
⫺0.03 ⫾ 0.01
11.3 ⫾ 4.2
33.3 ⫾ 6.9
NS
NS
NS
NS
NS
NS
* Values represent means ⫾ SEM.
†
NS ⫽ no significant difference between room air and 60% O 2.
tion in the extent of dynamic hyperinflation (⫺⌬ICdyn): ICdyn
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
(and IRV) were also increased for any given ventilation during exercise with O2 due, in part, to alterations in breathing
pattern. By stepwise multiple regression analysis, the fall in IC
at isotime was best predicted by the combination of an increase in resting IRV and a decrease in isotime breathing frequency (r2 ⫽ 0.83, p ⬍ 0.0005). Of note, the increase in IRV at
rest occurred,
in part, as a result of· associated small reductions
·
(⌬IRV versus ⌬V· CO2, r ⫽ ⫺0.81, p ⫽ 0.003)
in resting VCO
·2
and, in turn, VE (⌬IRV versus ⌬ VE, r ⫽ ⫺0.75, p ⫽ 0.008).
Mechanisms of Improved Exercise Endurance
and Relief of Breathlessness
Improvements in exercise endurance
(⌬Work) correlated best
·
with changes in the slopes of VE/time (r ⫽ ⫺0.626, p ⫽ 0.039)
· ·
·
Figure 5. VE/ VCO2 and VE/lactate relationships
did not change during
·
exercise with added O2. Changes ·in VE at isotime correlated significantly with concurrent changes in VCO2 (r ⫽ 0.93, p ⬍ 0.0005).
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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 isotime during exercise on O2 (⌬IRV ⫽ 0.08 ⫾ 0.11 L, ⌬IC ⫽
0.19 ⫾ 0.11 L). This was in contrast to the remaining six subjects 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).
Dyspnea–ventilation 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 exertional 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 exchange, PaO2, PaCO2, or ventilatory mechanics. Although perceived 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 important 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 reduction in ventilation.
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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 limiting ventilatory constraints on exercise and the onset of intolerable dyspnea. Third, modest changes in submaximal ventilation and dynamic ventilatory mechanics resulted in relatively
large improvements in symptom intensity and exercise capacity. Fourth, reduced submaximal ventilation was likely linked,
in part, to altered metabolic requirements under hyperoxic
conditions. Finally, hyperoxia resulted in additional, and potentially important, effects on cardiovascular function and
perceived leg discomfort.
Effects on Ventilatory Responses
Ventilatory limitation and the attendant severe breathing discomfort were the primary factors curtailing exercise in these
severely hyperinflated patients with chronic respiratory failure. Perusal of the tidal and maximal flow–volume loops on
room air confirmed their limited ability to increase ventilation
further when challenged with the increasing metabolic demands of exercise (Figure 3). Significant ventilatory constraints 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, reductions in submaximal ventilation, by an average of 11% at
isotime, with a significant time delay in reaching the peak ventilation 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 mechanism is direct reduction of peripheral chemoreceptor activation with consequent reduced central medullary motor
drive
·
·
(i.e., loss of the hypoxic stimulus to breathe) (1–4). VE/VCO2
slopes were
identical on RA and oxygen; therefore, the reduc·
simultaneous
tion
of VE at isotime correlated strongly with
·
·
VCO2 reduction (Figure 5). Thus, reduced VCO2 at rest and
during low levels of exercise could have been reflective of reduced 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 reflect reduced acid buffering effects because of reduced metabolic acidemia (7). With hyperoxia, oxygen delivery to the active peripheral muscles is increased for a given blood flow
with less reliance on anaerobic glycolysis. In our subjects, hyperoxia 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 further accumulation of lactate despite the large increases in cumulative work performed. However, the relative contribution
of reduced hypoxic drive
and altered metabolic loading to re·
duced submaximal VE during hyperoxia could not be determined in this study, but both mechanisms are likely to be instrumental.
Effects on Operational Lung Volumes
In conjunction with reduced ventilation–time slopes, oxygen
also resulted in a delay in dynamic hyperinflation during exer-
897
O’Donnell, D’Arsigny, 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 associated 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 hyperoxia among study subjects; those individuals who had only
minimal changes in endurance time were the ones whose measured ICdyn did not change on oxygen compared with RA. Patients 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 VE–time and lactate–time
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 reduced 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 combination of the above.
Comparison of tidal flow–volume loops at isotime during
exercise showed that midtidal expiratory flow rates were diminished on oxygen compared with RA, suggesting a persistence of expiratory flow limitation during oxygen, but at lower
operational lung volumes, as dictated by the reduced ventilatory demands. Previous studies have suggested a direct, but
mild, bronchodilator effect of hyperoxia in COPD (11). However, 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 airway 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 bronchodilator effect, this could be explained by alterations in respiratory timing (i.e., prolonged TE) for a given ventilation during 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.,
Borg–time slopes) on RA were those who had the greatest
alleviation of dyspnea during hyperoxia. Moreover, the responses 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 severe COPD (FEV1.0 ⫽ 37% predicted) but with only mild exercise 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
·
and exercise performance. Perusal of the Borg–VE slopes in
the previously studied group of patients with less severe disease (7) and our present study subjects helped to explain the
differences in the
magnitude of response to 60% oxygen (Fig·
ure 6). Borg–VE slopes become steeper as baseline mechanical 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 patients with more severe mechanical impairment and hypoxemia.
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 exercise–limiting symptom in several patients. In
a subgroup of five patients whose more prolonged exercise
was limited by a new symptom on hyperoxia, there were significant 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 weakened inspiratory muscles, reduced muscular effort of breathing, and enhanced neuromechanical coupling of the respiratory 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 activation in contributing to dyspnea relief in this study was impossible to quantify. The extent to which hypoxia directly contributed to unpleasant respiratory sensations during exercise,
independent of ventilatory muscle activity, is debated (5–8).
While there is strong evidence that hypercapnia can cause unpleasant sensations of “air hunger” independent of muscle activation in healthy subjects paralyzed by neuromuscular
blockade, and in ventilated quadriplegics with high cervical
spine transection, direct effects of hypoxia on respiratory sensation 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
ventilation–perfusion mismatching (note increased physiological 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 hunger” 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, hyperoxia may (1) improve oxygen delivery to the peripheral
muscles and possibly the ventilatory muscles, and thus delay
fatigue; (2) improve cardiovascular function; (3) improve central 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 achieving higher levels of cumulative work. In addition, 60% oxygen
significantly reduced perceived leg discomfort throughout exercise. However, the relative contributions of these various
physiological effects of hyperoxia to improved exercise endurance were impossible to quantify using this study design.
In summary, hyperoxia resulted in relatively large improvements 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 implication of our study is that in advanced COPD, modest reductions in ventilation and in operational lung volumes translate into clinically important dyspnea alleviation and enhanced
exercise capabilities.
12.
13.
14.
15.
Acknowledgment : The authors acknowledge Dr. Emma Hollingworth for
valuable assistance in patient recruitment and testing in this study.
16.
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