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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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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 (
E), 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, E, CO2, and lactate over time fell (p < 0.05); slopes of Borg- E, E- CO2, E-lactate
were unchanged. At a standardized time near end-exercise, O2 reduced dyspnea 2.0 ± 0.5 Borg units, CO2 0.06 ± 0.03 L/min, E 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.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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). However, responses to this intervention are highly variable and are unpredictable in any given individual (6). 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).
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 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 above-listed dynamic physiological and psychological variables.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
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, 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 exercise test. In a subsequent visit, subjects performed two constant-load 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.
Procedures
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 subject'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 corrections 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 [
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 [E], respiratory frequency [fR], VT, inspiratory capacity
[IC], IRV, oxygen consumption [O2], carbon dioxide production [CO2],
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.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subject characteristics are summarized in Table 1 (18). 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.
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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 O2 after 4.1 ± 0.9 min
(Table 2). Although endurance time increased significantly by
4.7 ± 1.4 min (p < 0.001) during 60% O2, peak values for O2
(n = 7, where technically satisfactory) and CO2 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).
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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 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
While breathing room air, mean peak E was low at only 23.0 ± 3.5 L/min; the small increase in E during exercise was accomplished almost exclusively through an increase in fR, because
VT was severely constrained from above (minimal IRV) and
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).
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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 included (Figures 2 and 3) E (p = 0.015), lactate (p = 0.14),
CO2 (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). O2 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): O2 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 E
correlated strongly with the fall in CO2 (r2 = 0.86, p < 0.0005).
The fact that E/CO2 and E/lactate slopes were not altered
with hyperoxia also supports the notion that these variables
changed in proportion to each other (Figure 5).
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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 reduction 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
in resting CO2 (IRV versus CO2, r = 0.81, p = 0.003)
and, in turn, E (IRV versus E, 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 E/time (r = 0.626, p = 0.039) 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(E) (r2 = 0.98) and 0.24e0.13(E) (r2 = 0.99) on
RA and O2, respectively. Therefore, Borg ratings of dyspnea
intensity and ventilation were reduced proportionally within
this relationship during hyperoxia.
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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.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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). E/CO2
slopes were identical on RA and oxygen; therefore, the reduction of E at isotime correlated strongly with simultaneous
CO2 reduction (Figure 5). Thus, reduced CO2 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 CO2,
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 reduced submaximal E 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 exercise: 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 E-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 E (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-E 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 (Figure 6). Borg-E 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). 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 disabled 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.
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Footnotes |
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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: odonnell{at}post.queensu.ca
(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 5-10, 2000.Acknowledgments: The authors acknowledge Dr. Emma Hollingworth for valuable assistance in patient recruitment and testing in this study.
Supported by the Ontario Thoracic Society. Denis O'Donnell holds a career scientist award from the Ontario Ministry of Health.
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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