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Keywords:

  • acidosis;
  • exercise;
  • hyperoxia;
  • lactate;
  • oxygen

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Background and objective:  The results of studies on the oxygen response in patients with COPD should provide important clues to the pathophysiology of exertional dyspnoea. We investigated the exercise responses to hyperoxia in relation to dyspnoea profile, as well as cardiopulmonary, acidotic and sympathetic parameters in 35 patients with stable COPD (mean FEV1 46% predicted).

Methods:  This was a single-blind trial, in which patients breathed 24% O2 or compressed air (CA) in random order during two incremental cycle exercise tests.

Results:  PaO2 and PaCO2 were higher (P < 0.0001 and P < 0.05, respectively) at each exercise point while patients were breathing 24% O2 compared with CA. At a standardized time point near peak exercise, use of O2 resulted in reduced plasma lactate and plasma noradrenaline concentrations (P < 0.01). Peak minute ventilation/indirect maximum voluntary ventilation was similar while breathing 24% O2 and CA. At peak exercise, the dyspnoea score, pH and plasma noradrenaline concentrations were similar while breathing 24% O2 and CA. The dyspnoea—ratio (%) of Δoxygen uptake (peak minus resting oxygen uptake) curve reached a break point that occurred at a similar exercise point while breathing 24% O2 or CA.

Conclusions:  Regardless of whether they breathed CA or 24% O2, patients with COPD did not develop ventilatory compensation for exertional acidosis, and the pH values measured were similar. Hyperoxia during a standardized exercise protocol did not alter the pattern of exertional dyspnoea in these patients, compared with breathing CA, although hyperoxia resulted in miscellaneous effects.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Exertional dyspnoea is a major symptom in most patients with COPD and it affects their activities of daily living. Ventilatory limitation in conjunction with exertional dyspnoea is an important reason for curtailing of exercise by COPD patients, and oxygen therapy improves their exercise performance while relieving exertional dyspnoea.1 Several studies have provided evidence supporting the benefit of supplemental O2 during exercise. However, responses of patients with COPD to this intervention have been variable and conflicting results have been reported in different populations. Possible mechanisms that may lead to improved exercise performance in these patients are: (i) an altered central perception of exertional dyspnoea; (ii) reduced ventilation; (iii) improved muscle function; and (iv) cardiovascular effects.2–11

The mechanisms underlying exertional dyspnoea in patients with respiratory disease are considered to be multifactorial.12 We previously showed that patients with IPF, as well as those with sequelae of pulmonary tuberculosis (TBsq), who limited their exercise primarily because of exertional dyspnoea may be unable to compensate for exertional acidosis, resulting in cessation of exercise under normoxic conditions when a certain pH is reached.13,14 Furthermore, the dyspnoea and sympathetic break points during exercise occurred similarly in both patient groups at the lactate threshold point.13,14 Identification of the phenomena that might explain the mechanisms of exertional dyspnoea is of considerable importance for patients with TBsq and IPF. We postulated that despite using supplemental O2 during exercise, patients with COPD may not develop ventilatory compensation in response to exertional acidosis, and would therefore stop exercising when a specific pH is reached.

We therefore compared exercise responses to compressed air (CA) and 24% O2 in terms of dyspnoea pattern, as well as cardiopulmonary, acidotic and sympathetic parameters, in a randomized, single-blind study of patients with stable COPD. We also investigated whether the dyspnoea break point, which was identified while patients were breathing CA during exercise, was also affected while they were breathing 24% O2.

METHODS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Subjects

The study included 35 patients with COPD (FEV1/FVC < 70%), who developed exertional dyspnoea while performing routine tasks. All patients had a history of smoking. None had qualified for long-term oxygen therapy before the time of cardiopulmonary exercise testing (CPET). At the time of CPET, 20 patients were receiving a long-acting muscarinic antagonist, six patients were receiving a long-acting β2-agonist, and five patients were receiving inhaled corticosteroids. The inclusion criteria for this study were: (i) clinical stability (no respiratory infection for at least 4 weeks before CPET); (ii) ability to tolerate CPET for at least 4 min (that is, ≥4 measurement points) to ensure adequate evaluation; (iii) exercise limitation due primarily to exertional dyspnoea during CPET (that is, breathing discomfort either alone or in conjunction with leg discomfort was the primary reason for stopping exercise); and (iv) absence of any other significant pathology, including neuromuscular, cardiac and/or peripheral vascular disease, malignancy or anaemia. Table 1 shows the characteristics of the participants.

Table 1.  Baseline characteristics of the patients with COPD (n = 35)
  1. Data are means (SD) unless stated otherwise.

Age, years70.4 (5.7)
Gender, males/females35/0
BMI, kg/m221.3 (4.0)
Pulmonary function 
 FEV1, L1.13 (0.45)
 FEV1, % predicted43.1 (17.4)
 FEV1/FVC, %46.1 (13.5)
 VC, L2.91 (0.64)
 VC, %91.6 (21.8)

Study design

The randomized, single-blind protocol was approved by the institutional review board. After providing written informed consent, patients were familiarized with all procedures, which comprised two CPETs in random order. Patients breathed either O2 (fraction of inspired O2 (Fio2) 24%) or CA (Fio2 21%), were allowed to recover for 30 min (washout) and then breathed the alternative mixture. During CPET, patients breathed through a mask attached to a low resistance, two-way, non-rebreathing valve (total dead space, 150 mL) that was supplied with 24% O2 or CA from gas cylinders through a 200-L Douglas bag. Patients were blinded as to which oxygen concentration they were breathing. CPETs were performed in the afternoon, and patients avoided caffeine, heavy meals, alcohol and excessive physical exertion before CPET.

CPET

Symptom-limited exercise tests were conducted using an electronically braked cycle ergometer (CV-1000SS, Lode, Groningen, The Netherlands) and a CPET system (Vmaxs-29C, CareFusion 207, Palm Springs, CA, USA).13,14 Testing consisted of 2-min increments to 10 W, performed to exhaustion. Expired gas data was monitored breath-by-breath and 30-s averages were obtained at rest, at 2-min intervals during exercise, and at the end of exercise. In addition, dyspnoea (Borg scale), intensity of leg fatigue and arterial blood gases were measured at rest, during the last 15 s of each stage of exercise, and at the end of exercise. Blood gases and plasma noradrenaline and lactate levels were measured as described previously.13,14

Pulmonary function testing

Pulmonary function testing was performed using an Autospirometer System 9 (Minato Medical Science; Osaka, Japan) within 2 weeks prior to CPET, as previously described.13,14

Data and statistical analysis

Break point

The break point was determined for each patient using the intersection of two lines on plots of individual dyspnoea-oxygen uptake (inline image), lactate inline image, and noradrenaline inline imagecurves obtained during exercise. To illustrate the relationship between the cardiorespiratory parameters and standardized oxygen uptake, namely the ratio (%) of Δoxygen uptake (inline image) (peak inline image − resting inline image) that occurs during exercise, the values of the parameters at each ratio of inline imagewere calculated for each patient, by linear interpolation between adjacent measurement points, as described previously.13,14

Sample size and Statistical analysis

It was estimated that a sample size of at least 34 patients would be needed to detect a change in the Borg dyspnoea scale of 1 with supplemental 24% O2. This was calculated using an estimated SD of 2, as determined in our laboratory, for a one-sample two-tailed t-test, with α = 0.05 and a power of 0.80.

Data are expressed as means ± SD or SEM, unless otherwise indicated. Differences in exercise parameters while breathing CA or 24% O2 were analysed using paired t tests. The statistical significance of differences due to interaction between exercise phase and the oxygen mixture were determined by repeated measures analysis of variance. All statistical analyses were performed using StatView 5.0 software (Abacus Concepts, Berkeley, CA, USA). P values <0.05 were regarded as significant.

RESULTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Resting responses to oxygen

When patients were breathing 24% O2, heart rate and plasma NE were lower, whereas O2 pulse (inline image rate), PaO2 and PaCO2 at rest were higher (Table 2 and Fig. 1).

Table 2.  Cardiopulmonary responses to incremental exercise in patients with COPD while breathing 24% O2 or compressed air (CA)
 RestIsotimePeak exercise
CAFio2 24%CAFio2 24%CAFio2 24%
  1. Data are means (SD).

  2. P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 comparing data for CA with that for Fio2 24% at each exercise point.

  3. CA, compressed air; f, breathing frequency; Fio2, fraction of inspired oxygen; HCO3-, bicarbonate ion; HR, heart rate; isotime, standardized endurance time during exercise; LT, lactate; MVV, maximum voluntary ventilation; NE, noradrenaline; THR, target heart rate; inline image, minute ventilation; inline image, oxygen uptake; VT, tidal volume.

Time, s  506 (192)529 (207)550 (203)
Dyspnoea, Borg scale0.1 (0.4)0.1 (0.2)6.9 (2.0)5.8 (2.8)7.7 (1.3)7.8 (1.8)
f, breaths/min21 (5)20 (5)32 (6)29 (5)*33 (6)31 (5)*
VT, mL719 (153)765 (212)1190 (325)1232 (305)1203 (328)1233 (320)
inline image, L/min14.6 (3.5)14.8 (3.2)37.8 (11.8)35.7 (9.8)*38.4 (8.6)37.5 (10.6)
inline image, mL/min282 (53)305 (63)*870 (274)881 (245)891 (294)919 (246)
inline image52.4 (12.1)50.2 (14.6)45.5 (8.3)41.6 (8.1)***44.4 (8.5)41.6 (8.1)***
HR, beats/min88 (12)85 (11)*119 (15)117 (13)120 (15)120 (15)
inline image, mL/beat3.2 (0.7)3.6 (0.9)**7.4 (2.3)7.5 (1.9)7.4 (2.3)7.7 (1.8)
pH7.417 (0.03)7.419 (0.062)7.363 (0.042)7.362 (0.045)7.358 (0.045)7.353 (0.044)
PaO2, mm Hg76.4 (10.1)93.7 (12.7)****59.1 (10.9)76.5 (15.2)****58.6 (10.9)75.5 (15.2)****
PaCO2, mm Hg38.5 (5.5)39.5 (5.6)*42.5 (7.1)43.4 (7.6)*42.9 (7.5)44.1 (7.5)*
HCO3-, mEq/L24.5 (2.5)24.7 (2.3)23.9 (2.8)24.2 (2.7)23.7 (2.9)24.1 (2.6)*
Plasma LT, mg/L129 (48)124 (43)308 (108)279 (97)**326 (125)308 (102)
Plasma NE, ng/mL0.71 (0.25)0.67 (0.22)*2.05 (1.08)1.78 (0.98)*2.23 (1.06)2.10 (1.48)
inline imagemax/MVV, %    104 (28)102 (28)
HR max/THR, %    80 (11)80 (10)
image

Figure 1. Ratios (%) of the Δoxygen uptake (inline image) curve for cardiopulmonary parameters in COPD patients. Cardiopulmonary responses are plotted against the ratio (%) of inline imageduring exercise. inline image, increment in inline imagebetween resting and peak exercise; open symbols, compressed air; solid symbols, 24% O2. Square symbols show dyspnoea, lactate or noradrenaline break points with error bars. Dyspnoea, noradrenaline and lactate break points while breathing compressed air were determined in 29, 29 and 30 patients, respectively, and while breathing 24% O2 in 31, 29 and 33 patients, respectively. Data are means ± SEM. P < 0.05, P < 0.01, §P < 0.001, P < 0.0001, for differences between compressed air and 24% O2 at each exercise point. None of the cardiopulmonary parameters differed significantly, due to interaction between exercise phase and inhalation of compressed air or 24% O2, as assessed by repeated measures analysis of variance.

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Peak exercise responses to oxygen

The distribution of reasons for stopping exercise did not differ when breathing 24% O2 or CA. Most patients stopped primarily because of dyspnoea (24% O2, 74% vs CA, 80%), and fewer patients stopped because of a combination of dyspnoea and leg discomfort (24%O2, 26% vs CA, 20%), regardless of the gas being inhaled. The endurance time was increased by 6 ± 18% (mean ± SD) while breathing 24% O2. PaO2, PaCO2 and HCO3- concentration were significantly higher, and respiratory frequency (f) and minute ventilation inline imagewere significantly lower while breathing 24% O2 compared with CA. Other peak exercise parameters, including dyspnoea score, pH and plasma NE were similar with 24% O2 and CA (Table 2 and Fig. 1). The mean changes in PaCO2 from rest to peak exercise were similar with 24% O2 and CA (mean ± SD: 24% O2, 4.6 ± 4.2 mm Hg vs CA, 4.4 ± 4.2 mm Hg), and were strongly correlated (r = 0.608, P < 0.0001). Five patients experienced a decrease in PaCO2 at peak exercise while breathing CA. The observed peak inline image/indirect maximum voluntary ventilation (FEV1 × 35) was similar with 24% O2 and CA.

Isotime exercise responses to oxygen

The dyspnoea score was relatively decreased in response to 24% O2 (P = 0.0647). The inline imagefell while patients were breathing 24% O2, as a result of a concurrent significant decrease in f, resulting in a decreased inline image. Plasma lactate and NE were significantly reduced while breathing 24% O2 compared with CA (Table 2).

Break point during exercise in response to oxygen

The break points in the cardiopulmonary parameters while breathing 24% O2 or CA were compared using standardized oxygen uptake (Fig. 1 and Table 3). A break point in the dyspnoea, NE or LT ratios of the inline imagecurve occurred while patients were inhaling 24% O2 during exercise. These break points occurred at a similar point in the exercise cycle while breathing CA. The break points in the standardized oxygen uptake curves were not shifted when patients were breathing 24% O2, and the dyspnoea pattern during exercise was similar while breathing 24% O2 or CA.

Table 3.  Break point responses to incremental exercise in patients with COPD while breathing 24% O2 or compressed air
 Compressed airFio2 24%
mL/min%mL/min%
  1. Data are means (SEM).

  2. Dyspnoea, noradrenaline and lactate break points while breathing compressed air were determined in 29, 29 and 30 patients, respectively, and while breathing 24% O2 in 31, 29 and 33 patients, respectively.

  3. %, ratio of Δoxygen uptake (inline image) (peak inline image − resting inline image); Fio2, fraction of inspired oxygen.

Dyspnoea break point746 (39)71 (3)752 (33)71 (3)
Noradrenaline break point765 (39)74 (2)770 (33)73 (2)
Lactate break point743 (37)71 (3)769 (33)70 (3)

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

The present study demonstrated that patients with COPD did not develop ventilatory compensation in response to exertional acidosis, and therefore stopped exercising when a similar pH was reached while breathing either CA or 24% O2. Break points in the dyspnoea, NE and LT ratios of the inline imagecurves developed at a similar point in the exercise cycle while the patients were breathing CA, and breathing 24% O2 did not change any of these break points.

An important systemic response during exercise in patients with COPD may be the control of exertional acidosis. In the present study a similar peak inline image/indirect maximum voluntary ventilation was observed when patients were inhaling 24% O2 or CA. Both PaCO2 and HCO3- concentration were higher, in conjunction with a reduced inline imageat isotime under hyperoxic conditions, compared with inhalation of CA (Table 2), resulting in a significant reduction in plasma lactate levels at that time point. These results concurred with the findings of O'Donnell et al. in COPD patients,15,16 although others have reported conflicting findings regarding the effect of hyperoxia on ventilation and blood lactate levels in these patients.7,16,17 Notably, the present study showed no difference in pH at peak exercise between inhalation of 24% O2 or CA. We previously reported that patients with IPF and those with TBsq stopped exercising under normoxic conditions when a similar pH was reached.13,14 These findings suggest that exercise limitation in COPD is primarily due to respiratory mechanics, and that regardless of whether they exercise under hyperoxic or normoxic conditions, patients with COPD may be unable to compensate for exertional acidosis and are therefore forced to stop exercising when a specific pH is reached, although both lactate levels and PaCO2 vary during exercise.

This study extends previous findings regarding the dyspnoea break point in patients with IPF or TBsq, by showing that sympathetic and dyspnoea break points also occurred at a lactate threshold in patients with COPD, which may be important in determining the exercise program.13,14 It was previously reported that the point of lactate threshold in relation to the total exercise cycle depends, at least partly, on the ventilatory capacity of the study population.18,19 We demonstrated that hyperoxic conditions did not change the break points during a standardized exercise program in patients with COPD. Despite accumulating evidence regarding the mechanisms underlying the beneficial effects of O2 supplementation during exercise in COPD patients, many investigators have suggested that a direct reduction in peripheral chemoreceptor activation, with a consequent reduction in central medullary motor drive, is the primary mechanism by which hyperoxia results in reduced ventilation during exercise.8 In the present study, hyperoxia delayed the accumulation of plasma lactate, that is, metabolic acidosis, at the isotime exercise point, although the changes in lactate levels over the whole exercise cycle were not significant. In contrast, PaCO2 increased in conjunction with a decrease in inline image, the changes in which were fairly constant over the exercise cycle (Fig. 1). Given that hypoxaemia and/or hypercapnia result in changes in the sensitivity of peripheral chemoreceptors, the responses of which are linked to control of ventilatory drive,11,20,21 fixed hyperoxia may not change each break point during a standardized exercise program in patients with COPD, due to constant loading for exertional acidosis.

This study had important limitations. First, several studies have shown that O2 supplementation improves exercise performance. However, 24% O2 improved exercise endurance by only 6% in the present study, which is quite different from previous results. The dose-dependent effects of O2 may explain this discrepancy.22 In addition, differences in the ventilatory capacity of the study populations may have contributed to the discrepancy in the change in endurance among studies.3,7 Secondly, the effect of acidotic loading on ventilatory drive under hyperoxic conditions was not investigated. Further studies are required to establish the precise mechanisms underlying exertional dyspnoea in patients with COPD.

In conclusion, the key findings from the present study were that despite inhaling 24% O2 or CA, patients with COPD did not develop ventilatory compensation in response to exertional acidosis, and stopped exercising when a similar pH was reached. In addition hyperoxic conditions did not alter the pattern of exertional dyspnoea in patients with COPD during a standardized exercise program.

ACKNOWLEDGEMENTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

We thank Ms A. Yagi and Ms S. Sakaguchi for help with the CPET measurements.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
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