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(Chest. 2005;127:794-802.)
© 2005 American College of Chest Physicians

Nocturnal Continuous Positive Airway Pressure Improves Ventilatory Efficiency During Exercise in Patients With Chronic Heart Failure*

Michael Arzt, MD; Martina Schulz, MD; Roland Wensel, MD; Sylvia Montalvàn, MD; Friedrich C. Blumberg, MD; Günter A. J. Riegger, MD and Michael Pfeifer, MD

* From the Department of Internal Medicine II (Drs. Arzt, Wensel, Montalvàn, Blumberg, Riegger, and Pfeifer), Pneumology, University of Regensburg, Regensburg; and Lungenfachklink Donaustauf (Dr. Schulz), Donaustauf, Germany.

Correspondence to: Michael Arzt, MD, 65 High Park Ave #2012, Toronto, ON, M6P 2R7, Canada; e-mail: michael.arzt{at}utoronto.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Objectives: Chronic heart failure is closely related to impaired cardiorespiratory reflex control, including decreased ventilatory efficiency during exercise (E/CO2-slope) and central sleep apnea (CSA). Continuous positive airway pressure (CPAP) and nocturnal oxygen therapy alleviate CSA. The aim of the present study was to compare the effects of nocturnal CPAP and oxygen therapy on E/CO2-slope.

Design and setting: Prospective controlled trial at a university hospital.

Patients: Twenty-six stable patients with chronic heart failure and CSA.

Intervention and measurements: Ten patients received nocturnal oxygen, and 16 patients were assigned to CPAP treatment. At baseline and after 12 weeks of treatment, symptom-limited cardiopulmonary exercise testing was performed on a cycle ergometer. Expiratory gas was analyzed breath by breath for evaluation of ventilation and ventilatory efficiency in combination with arteriocapillary blood gas analysis during rest and exercise.

Results: CPAP treatment significantly reduced the E/CO2-slope (31.2 ± 1.6 vs 26.2 ± 1.0, p = 0.005) and improved the left ventricular ejection fraction (LVEF) [31.7 ± 2.6% vs 35.7 ± 2.7%, p = 0.041]. CPAP treatment significantly reduced the apnea-hypopnea index (AHI) [35.9 ± 4.0/h vs 12.2 ± 3.6/h, p = 0.002]. Peak oxygen consumption (O2) [16.2 ± 1.1 L/min/kg vs 16.3 ± 1.2 L/min/kg, p = 0.755] remained similar after CPAP treatment. Oxygen therapy reduced the AHI (28.8 ± 3.2/h vs 8.7 ± 4.1/h, p = 0.019), but did not improve exercise capacity (peak O2, 15.4 ± 1.5 L/min/kg vs 15.6 ± 1.9 L/min/kg, p = 0.760), LVEF (30.9 ± 2.4% vs 32.5 ± 2.3%, p = 0.231), or the E/CO2-slope (30.0 ± 1.5 vs 29.8 ± 1.5, p = 0.646).

Conclusion: Nocturnal CPAP and oxygen therapy alleviate CSA to a similar degree. Only CPAP therapy may improve ventilatory efficiency during exercise and may have favorable effects on LVEF. Therefore, our data suggest that CPAP is advantageous compared to oxygen in the treatment of CSA in patients with chronic heart failure.

Key Words: continuous positive airway pressure • exercise • heart failure • oxygen • sleep apnea • ventilation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Enhanced ventilatory efficiency during exercise (E/CO2-slope) is a characteristic feature of patients with chronic heart failure and is associated with symptom status and a poor prognosis.1234567 In chronic heart failure patients, impaired pulmonary gas exchange89 and abnormal hyperventilation lead to an increase in the slope of the ratio between minute ventilation (E) and carbon dioxide output (CO2) during exercise (E/CO2-slope). Both abnormalities have been related to low pulmonary blood flow, increased pulmonary arterial and wedge pressure,89 and abnormal ventilatory stimuli including augmented chemosensitivity10111213 and ergoreflex sensitivity.14

Another manifestation of altered ventilation associated with a poor prognosis in patients with chronic heart failure is central sleep apnea (CSA).1516 The largest studies1718 reported prevalence rates between 33% and 40% for CSA in patients with chronic heart failure. Stimulation of pulmonary vagal irritant receptors by pulmonary congestion1920 and augmented chemosensitivity to CO2212223 play a pivotal role in causing a chronically enhanced ventilatory drive. The typical periodic breathing cycles that characterize CSA occur as recurrent episodes of hyperventilation with subsequent reduction in PaCO2 below the apneic threshold.2224 The resulting arousals lead to severe disturbances in autonomic and cardiac function including atrial fibrillation, ventricular arrhythmias, and poor prognosis.15161825 We previously showed that the E/CO2-slope is increased in heart failure patients with CSA compared to those without, and that the E/CO2-slope correlates with the severity of CSA.26

Nocturnal oxygen and CPAP are two potent therapies that reduce central respiratory events in chronic heart failure and CSA. Only for CPAP therapy an additional improvement in cardiac function272829 could be shown. Furthermore, there is growing evidence that treatment with positive airway pressure can reduce augmented chemosensitivity to CO2.30 Cardiac function and augmented chemosensitivity to CO2 represent major pathomechanisms of CSA and impaired ventilatory efficiency during exercise. In spite of an effective reduction of nocturnal central respiratory events, apnea-related hypoxia, and exercise capacity31 in chronic heart failure patients with CSA, nocturnal oxygen treatment has not been reported to exert beneficial effects on cardiac function.323334

Therefore, we tested the hypothesis that, in contrast to nocturnal oxygen, CPAP therapy can improve cardiac function and ventilatory efficiency during exercise in chronic heart failure patients with CSA. This is the first study to compare the effects of nocturnal oxygen and CPAP treatment on cardiac function, exercise capacity, and ventilatory efficiency during exercise.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients
Inclusion criteria were chronic heart failure due to ischemic, hypertensive, or idiopathic dilated cardiomyopathy with a left ventricular ejection fraction (LVEF) < 45% as determined by resting echocardiography according to the guidelines of the American Society of Echocardiography or by radionuclide ventriculography by a single investigator who was blinded to the clinical data. Baseline and follow-up measurements were performed according to the same methodology in each subject. Furthermore, patients (New York Heart Association [NYHA] functional class II and III) were stable over the previous 3 months as documented by stable cardiac medication and no hospital admissions. Chronic heart failure patients with clinically important CSA (apnea hypopnea index [AHI], number of episodes per hour ≥ 15),18 diagnosed by laboratory-based polysomnography (Brainlap; Schwarzer; Munich, Germany) were included in the study. Exclusion criteria were a history of unstable angina, cardiac surgery, or documented myocardial infarction within 90 days of entry into the study.

A total of 134 consecutive ambulatory patients with chronic heart failure (file information) were screened for CSA by a portable computerized sleep diagnosis set (SOMNOcheck effort; Weinmann; Hamburg, Germany). In 39 chronic heart failure patients, CSA (AHI, number of episodes per hour ≥ 15) was diagnosed. These patients were evaluated based on the present study protocol. Four patients were excluded due to an LVEF > 45% by echocardiography. In three patients, CSA could not be confirmed in the study polysomnography. An additional six patients refused nocturnal CPAP or oxygen therapy.

Of the remaining 26 patients, the first 10 patients (depending on the date of screening) received nocturnal nasal oxygen treatment. The remaining 16 patients were assigned to nocturnal CPAP treatment. All patients gave written informed consent to participate in this prospective study, which had been previously approved by the ethics committee of our institution.

Protocol and Intervention
All patients underwent cardiopulmonary exercise testing, polysomnography, and echocardiography. The tests were done by two different investigators blinded to the clinical data. Data were obtained at baseline and after 12 weeks of nocturnal CPAP or oxygen therapy. Medication was kept constant throughout the study period. Patients assigned to CPAP were brought into the sleep laboratory to administer CPAP at a target pressure of 8 to 12 cm H2O. For reasons of acclimatization, CPAP (Somnocomfort; Weinmann) was applied to patients at 4 cm H2O for 1 h while awake. During the first night starting at 4 cm H2O, CPAP pressure was increased in 1- to 2.5-cm H2O increments to the highest level the patient could tolerate (≤ 12 cm H2O). On the second night, CPAP was applied with the highest tolerated level of the first night. Patients were sent home at this pressure level and were instructed to use CPAP for at least 6 h per night. The mean nightly usage was calculated by CPAP hour meters. Adequate compliance was defined as ≥ 3 h of daily use, averaged over the 12-week treatment period. We chose this cut-off point since short-term studies273035 have shown that the use of CPAP for ≥ 3 h is associated with significant improvement in LVEF and other physiologic variables in chronic heart failure patients with CSA. Compliance with CPAP therapy was adequate in 14 patients. Two patients who had a daily use < 3 h were withdrawn from the study. Patients assigned to the oxygen treatment group received 2 L/min nasal oxygen (Braun Meditec; Ludwigsburg, Germany).

Exercise Testing
Symptom-limited exercise testing was performed on an electronically braked cycle ergometer (Ergometrics 900; Ergoline; Windhagen, Germany). Pulmonary gas exchange analysis was measured breath by breath by a metabolic card (Oxycon Champion; Jaeger-Toennies; Hoechberg, Germany). Therefore, E was measured in terms of body temperature (37°C) atmospheric pressure water saturated, and corrected to standard temperature (0°C) and pressure, dry, so that the E/CO2-slope could be calculated in standard temperature and pressure, dry. The E/CO2-slope was calculated for each subject as the slope of the regression line relating E to CO2 output (CO2) during exercise testing and was used as an index of the ventilatory response to exercise. The ratio of E to CO2 reveals a linear relationship over a wide range; the nonlinear part of this relationship after onset of acidotic drive to ventilation was excluded.2 The arteriocapillary PCO2 was obtained before and at peak exercise.

Polysomnography
At baseline and after 12 weeks of therapy, sleep studies were performed on all patients who met initial inclusion criteria, recording body position, eye and leg movements, cardiotachography, nasobuccal airflow, chest and abdominal effort, and pulse oximetry (Brainlap; Schwarzer). Sleep stages were determined using standard criteria.36 Apneas and hypopneas were scored according to the established criteria for our laboratory.26 An episode of apnea was defined as a cessation of inspiratory airflow for ≥ 10 s. In the case of CSA, excursions of the rib cage and abdomen also cease; while in obstructive apnea, despite existing breathing excursions of the rib cage and abdomen, oronasal airflow is absent. Hypopnea was defined as a > 50% reduction in airflow or thoracoabdominal excursions lasting at least 10 s, resulting in a ≥ 4% drop in arterial oxygen saturation (SaO2). The AHI describes the number of episodes of apnea and hypopnea per hour. Clinically important CSA was defined as an AHI ≥ 15 episodes per hour with obstructive sleep apnea events < 25% of total AHI.1826

Statistical Analysis
All data were analyzed using statistical software (Version 11.0; SPSS; Chicago, IL). To assess differences between patients with CPAP and those with oxygen treatment, the Mann-Whitney U test was used. {chi}2 analysis was used to calculate proportions. Data before and after the treatment period were compared using the Wilcoxon log-rank test. A two-sided p value < 0.05 was considered to indicate statistical significance.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patient Characteristics
Patients of the CPAP and oxygen treatment groups did not differ significantly with respect to age, body mass index, spirometry, exercise capacity, cardiac function, or sleep characteristics (Table 1 ). Both cohorts were also similar with respect to their medication (Table 1). Eighty-six percent of the patients assigned to CPAP had ischemic cardiomyopathy compared to 80% in the oxygen group. The prevalence of atrial fibrillation was similar in both groups (Table 1).


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  		Table 1.. Characteristics of Chronic Heart Failure Patients With CSA Assigned to CPAP and Oxygen Therapy*

 
Sleep Characteristics
The AHI of chronic heart failure patients with CSA was reduced significantly with nocturnal CPAP as well as with oxygen therapy (Table 2 ). CPAP significantly improved the apnea index; the reduction in the hypopnea index from 16.1 ± 3.9 to 7.4 ± 2.1 failed to reach statistical significance (Table 2). Oxygen therapy lowered the apnea index from 11.1 ± 2.3 to 5.1 ± 3.7, although the difference was not statistically significant. Hypopneas were significantly limited by nocturnal oxygen (Table 2). Oxygen and CPAP therapy significantly improved the oxygen desaturation profile during sleep regarding the mean and the lowest SaO2 and the oxygen desaturation index (Table 2). The reduction of the arousal indexes in both treatment groups (oxygen, 29.5 ± 7.4 to 22.9 ± 6.6; CPAP, 23.4 ± 4.6 to 14.0 ± 1.9) failed statistical significance (Table 2). Sleep efficiency did not improve due to oxygen or CPAP treatment (Table 2).


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  		Table 2.. Effects of Oxygen and CPAP Treatment in Patients With Chronic Heart Failure and CSA*

 
Ventilatory Efficiency
Nocturnal CPAP treatment significantly improved the E/CO2-slope in chronic heart failure patients. The E/CO2-slope was reduced from 31.2 ± 1.6 at baseline to 26.2 ± 1.0 after 12 weeks of CPAP treatment (p = 0.005; Table 2, Fig 1 ). While the arteriocapillary and end-tidal PCO2 at rest were similar, the arteriocapillary PCO2 at peak exercise was significantly elevated after the CPAP treatment period compared to baseline data (Table 2).



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  		Figure 1.. The individual values of ventilatory efficiency (E/CO2-slope) of patients with chronic heart failure and CSA before (baseline) and after 12 weeks of CPAP (n = 14) and oxygen therapy (n = 10).

 
Oxygen treatment did not affect the E/CO2-slope during exercise (Table 2, Fig 1). Arteriocapillary and end-tidal PaCO2 at rest and at peak exercise did not significantly differ after 12 weeks of oxygen treatment compared to baseline data (Table 2).

Exercise Capacity and Cardiac Function
A significant improvement in the LVEF was found in the CPAP-treated chronic heart failure patients with CSA (Table 2, Fig 2 ). After 12 weeks of CPAP treatment, the NYHA functional class, the peak O2, and the maximal oxygen pulse remained similar (Table 2). Oxygen therapy did not significantly affect NYHA functional class, peak O2, maximal oxygen pulse, or LVEF (Table 2, Fig 2).



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  		Figure 2.. The individual values of LVEF in patients with chronic heart failure and CSA before (baseline) and after 12 weeks of CPAP (n = 14) and oxygen therapy (n = 10).

 
Characteristics of Patients With Improvement in E/CO2-slope After CPAP Treatment
We defined a reduction of > 2.6 in the E/CO2-slope as a relevant improvement in ventilatory efficiency during exercise. This cut-off level might be in the range of clinical relevance, since Kleber et al2 found differences in the E/CO2-slope of 3.2 between control subjects and chronic heart failure patients with NYHA functional class I. The difference between NYHA functional class I and II chronic heart failure patients was 3.7.2 Based on this definition, the CPAP-treated patients can be classified as seven responders and seven nonresponders. The patients with relevant improvement in the E/CO2-slope had a significantly lower ventilatory efficiency and peak O2 at baseline (Table 3 ). LVEF (29.1 ± 2.8% vs 34.3 ± 4.3%) and the maximal oxygen pulse (12.0 ± 1.3 mL per beat vs 13.4 ± 0.8 mL per beat) were more impaired in the responders compared to the nonresponders, although the difference was not statistically significant (Table 3). The number of central respiratory events and the mean SaO2 were similar in both groups (Table 3). The reduction in AHI and the apnea index due to CPAP therapy was more prominent in the responder group, but did not reach statistical significance (Table 3). Improvement in mean SaO2 did not differ between the responder group and the nonresponder group (Table 3).


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  		Table 3.. Characteristics of CPAP-Treated Patients With Chronic Heart Failure and CSA With (Responder) and Without (Nonresponder) Relevant Improvement in E/CO2-slope*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The novel findings of this study are that, in contrast to oxygen therapy, nocturnal CPAP treatment improves the E/CO2-slope during exercise and may have beneficial effects on cardiac function in patients with chronic heart failure and CSA. Moreover, improvement of the E/CO2-slope by CPAP therapy was most prominent in patients with impaired ventilatory efficiency and peak O2 at baseline. Despite this, CPAP did not exert favorable effects on exercise capacity as measured by peak oxygen uptake.

According to previous studies, nocturnal CPAP and oxygen therapy reduced the frequency of central respiratory events3132333437 and improved nocturnal desaturation profiles32 in patients with chronic heart failure similar effectively. In our study, nocturnal CPAP treatment was found to be superior to oxygen in alleviation of the exercise-induced hyperventilation represented by the E/CO2-slope. Furthermore, after 12 weeks of CPAP treatment, patients showed higher end-tidal and arteriocapillary PCO2 levels at peak exercise compared to baseline measurements, indicating a reduction in ventilatory drive to exercise and CO2. Neither CPAP nor oxygen therapy led to an increase in exercise capacity. These findings do not correspond to the observations of Andreas et al,31 who found a rise in peak oxygen uptake and ventilatory efficiency after 1 week of oxygen treatment. It is noteworthy that the study population of Andreas et al31 suffered from more severe heart failure (mean LVEF 17%), which might make changes in these parameters easier to detect. The present data reveal that 50% of the patients in the CPAP cohort showed possibly clinically relevant effects on the E/CO2-slope (defined as reduction > 2.6). These patients had a significantly impaired ventilatory efficiency and peak oxygen uptake at baseline compared to those patients with only minor changes in the E/CO2-slope. The objective of the study was not to clarify which chronic heart failure patients profit most from CPAP therapy, but even these preliminary data with a small sample size suggest that CPAP therapy might be more effective in patients with chronic heart failure and more impaired functional status.

In our study, CPAP therapy was found to be advantageous to nocturnal oxygen treatment in stabilizing ventilatory control during exercise as expressed by the E/CO2-slope in chronic heart failure patients with CSA, although both therapies reduce central respiratory events and improve nocturnal desaturation profiles with similar effectiveness. Therefore, potential mechanisms that could explain this difference between oxygen and CPAP therapy should be discussed:

First, CPAP therapy exerts effects on cardiac function, whereas oxygen does not. In our study, nocturnal CPAP ventilation significantly improved resting LVEF. The individual values reveal that 50% of the CPAP-treated patients had increased LVEF ≥ 3% independently of changes in heart rate. Therefore, the findings in our study represent a possible improvement in left ventricular function in some patients with chronic heart failure who receive CPAP treatment. The data of the present study are similar to the findings of a randomized controlled trial of CPAP treatment in 29 chronic heart failure patients with CSA by Naughton and colleagues,27 who found a mean improvement of LVEF in the CPAP treatment group of 7.7%. Improvement of cardiac function in chronic heart failure patients by CPAP is thought to be caused by a reduction in preload and afterload. The increased intrathoracic pressure reduces venous return to the right atrium and thereby diminishes cardiac preload.2838 The decrease of afterload could be explained by augmented inspiratory and systolic intrathoracic pressure swings in patients with chronic heart failure, contributing to an increase in left ventricular transmural pressure observed by Naughton et al.38 The augmentation of intrathoracic pressure by CPAP reduces the amplitude of intrathoracic pressure swings leading to a decrease of left ventricular transmural pressure and afterload.38 In chronic heart failure patients with elevated left ventricular filling pressures, this effect leads to augmented stroke volume.29 Because of the close relationship between pulmonary gas exchange and abnormal hyperventilation to pulmonary blood flow and cardiac filling pressures,89 improvement of cardiac function most likely contributes to improvement of ventilatory efficiency during exercise. Significant changes in LVEF coinciding with no changes in peak O2 is not inconsistent, since Maurer et al39 observed remarkable improvement in LVEF and cardiac output in chronic heart failure patients after ß-blocker treatment, which was not paralleled by an increase in peak O2.

Second, CPAP leads to a reduction in sympathetic activity in chronic heart failure patients with CSA as measured by plasma norepinephrine concentrations30 and radiotraced cardiac norepinephrine spillover.40 These effects occur even in the daytime after nocturnal CPAP treatment,30 an effect that has not yet been shown for nocturnal oxygen therapy.

Third, ventilation with positive airway pressure is thought to reduce daytime chemosensitivity to CO2. Catecholamines are known to potentiate chemosensitivity, which is shown in healthy subjects during exercise41 and with noradrenaline infusion.42 Thus, the decrease in sympathetic activity by CPAP in patients with chronic heart failure and CSA makes a decrease in chemosensitivity very likely. CPAP therapy can slow down the respiratory drive during sleep in chronic heart failure patients with CSA leading to an increase in mean transcutaneous partial pressure of CO2.43 The chronic heart failure patients in our study had significantly elevated end-tidal and arteriocapillary PCO2 at peak exercise compared to baseline, indicating a reduction in ventilatory drive due to exercise and CO2. This finding might further indicate a carryover effect of nocturnal CPAP therapy on daytime chemosensitivity, which was also observed in a randomized trial with 20 chronic heart failure patients with CSA treated with anticyclic modulated ventilation. Anticyclic modulated ventilation caused a significant decrease in daytime central chemosensitivity to CO2 as assessed by Read’s rebreathing method13 after a 6-week treatment period (V. Töpfer, MD; unpublished data; May, 2003). Reduction in augmented chemosensitivity to CO2 most likely contributes to the improvement in ventilatory efficiency, since augmented chemosensitivity to CO2 is known to be one important ventilatory stimulus in heart failure patients.1011

Reduced ventilatory efficiency during exercise is strongly related to heart failure severity and poor prognosis.12340 It shares common pathophysiologic mechanisms with CSA, which itself is an independent marker of a poor prognosis.1112 In addition, even chronic heart failure patients with preserved exercise capacity (peak O2 ≥ 18 mL/kg/min) can have a remarkably enhanced ventilatory response to exercise associated with poor prognosis.1 We could show an improvement in CSA and the E/CO2-slope during exercise by nocturnal CPAP treatment. These effects correspond to the hypothesis that CPAP may improve the prognosis in patients with chronic heart failure and CSA, which has already been suggested by Sin et al35 in a study of 29 patients with chronic heart failure and CSA, but which has yet to be confirmed with a survival analysis in a larger study population.

A limitation of the present study is that assignment to the treatment groups was not randomized. Negative selection of patients in the oxygen-treated group is rather unlikely, because baseline characteristics were very similar to the CPAP group. Neither chronic heart failure patients with CPAP nor with supplemental oxygen therapy required a change in medication or changed body weight significantly, indicating adequate adherence to medical therapy and drinking restriction. It should be emphasized that the study was designed to detect different effects of oxygen and CPAP therapy on ventilation during exercise and cardiac function and not to detect mechanisms.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Nocturnal CPAP and oxygen therapy reduced the frequency of central respiratory events and improved nocturnal desaturation profiles in patients with chronic heart failure to a similar degree. Only CPAP therapy may improve ventilatory efficiency during exercise and may have favorable effects on LVEF. The effects on ventilatory efficiency during exercise are most prominent in chronic heart failure patients with more impaired functional status. Our data suggest that CPAP is advantageous compared to oxygen in the treatment of CSA in patients with chronic heart failure.


   Acknowledgements
 
The authors thank Ms. Christiane Cordes and Ms. Margit Rothaug for performing the cardiopulmonary exercise tests, and Ms. Astrid Braune for reporting of polysomnographic studies.


   Footnotes
 
Abbreviations: AHI = apnea hypopnea index; CPAP = continuous positive airway pressure; CSA = central sleep apnea; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; SaO2 = arterial oxygen saturation; CO2 = carbon dioxide output; E = minute ventilation; E/CO2-slope = ventilatory efficiency during exercise; O2 = oxygen consumption.

Received for publication April 8, 2004. Accepted for publication October 4, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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