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Original Research: CARDIOVASCULAR DISEASE |

Mechanisms of Periodic Breathing During Exercise in Patients With Chronic Heart Failure* FREE TO VIEW

Piergiuseppe Agostoni, MD, PhD; Anna Apostolo, MD; Richard K. Albert, MD, FCCP
Author and Funding Information

*From Centro Cardiologico Monzino (Dr. Apostolo), IRCCS, Istituto di Cardiologia, Università di Milano, Milan, Italy; Department of Medicine (Dr. Agostoni), University of Washington, Seattle, WA; and Department of Medicine. Denver Health (Dr. Albert), and University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Piergiuseppe Agostoni, MD, PhD, Centro Cardiologico Monzino, IRCCS, Istituto di Cardiologia, Università di Milano, Via Parea 4, 20138 Milan, Italy; e-mail: piergiuseppe.agostoni@ccfm.it



Chest. 2008;133(1):197-203. doi:10.1378/chest.07-1439
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Published online

Background: Periodic breathing (PB) in heart failure (HF) is attributed to many factors, including low cardiac output delaying the time it takes pulmonary venous blood to reach the central and peripheral chemoreceptors, low lung volume, lung congestion, augmented chemoreceptor sensitivity, and the narrow difference between eupneic carbon dioxide tension and apneic/hypoventilatory threshold.

Methods and results: We measured expired gases, ventilation, amplitude, and duration of PB in 23 patients with PB during progressive exercise tests done with 0 mL, 250 mL, or 500 mL of added dead space. Periodicity of PB remained constant despite heart rate, oxygen consumption, and minute ventilation increasing. Within each PB cycle, starting from the beginning of exercise, the largest (peak) tidal volume approached maximum observed tidal volume, while the smallest (nadir) tidal volume increased as exercise power output increased. PB ceased when nadir tidal volume reached peak tidal volume. End-tidal carbon dioxide increased with added dead space, and PB ceased progressively earlier during the exercise done with increased dead space.

Conclusion: Circulatory delay does not contribute to the PB observed in exercising HF patients. The pattern of gradually increasing nadir tidal volume during exercise and the effect of dead space on both PB ceasing and end-tidal carbon dioxide suggest that low tidal volume and carbon dioxide apnea threshold are important contributors to PB that occurs during exercise in HF.

Figures in this Article

Periodic breathing (PB) in patients with chronic heart failure (HF) is attributed to a variety of factors, including low cardiac output resulting in lengthening of the time it takes pulmonary venous blood to reach the central or peripheral chemoreceptors, low lung volume, pulmonary congestion, augmented chemoreceptor sensitivity, and the narrow difference between the eupneic Paco2 and the apneic (or hypoventilatory) threshold.18

We reasoned that if PB was caused by circulatory delays adversely affecting peripheral chemoreceptors, the periodicity of PB should decrease as cardiac output increases. Because PB occurs during exercise in some patients with HF,911 we were able to test this hypothesis during exercise when cardiac output increases.12 We also evaluated the roles of low ventilation and small lung volumes by comparing ventilation and tidal volume at the beginning of exercise, at PB disappearance during exercise and at peak exercise. In addition, because widening the eupneic Paco2-hypocapnic apneic threshold by inhaling carbon dioxide or by breathing through added dead space stabilizes Cheyne-Stokes respiration (CSR) in patients with HF when they are awake or asleep,,7,1315 we also thought to assess the effect of adding dead space on the PB that occurs during exercise.

We studied 23 patients with severe chronic HF (New York Heart Association classification III) who had PB during rest and exercise. PB was defined as a cyclic fluctuation of ventilation for > 60% of exercise, with amplitude swings that were > 30% of the mean ventilation.1011 The protocol was approved by the Institutional Ethics Committee, and written informed consent was obtained from each patient.

All patients were required to be clinically stable for a minimum of 1 week. Patients were excluded if they had unstable angina, a history of having a myocardial infarction within the last 2 months, severe valvular disease, severe obstructive or restrictive lung disease (FEV1 and FVC < 60% of predicted value), symptomatic peripheral vascular disease, or orthopedic problems that limited exercise performance. Further exclusion criteria was evidence, both as history or actual signs or symptoms, of neurologic diseases such as dementia, stroke or any kind, of cerebrovascular disease. Prior to testing, left ventricular volume and ejection fraction were determined by echocardiography, pulmonary function was assessed, and arterial blood gases were measured while the patients were breathing air.

To become familiar with the procedure, all patients underwent incremental cardiopulmonary exercise testing on a cycle ergometer using a ramp protocol that was personalized with the objective of having each patient reach maximum exercise in 8 to 10 min. After 60 s of unloaded pedaling at 60 revolutions per minute, work was continuously increased at a rate of 6 to 12 W/min starting at 0 W. Patients breathed through a mouthpiece (with the nose occluded) that was connected to a mass flowmeter that had a dead space of 54 mL. Minute ventilation, oxygen consumption, and carbon dioxide production were measured breath by breath at the mouth (V-max; SensorMedics; Yorba Linda, CA). ECG and heart rate were assessed continuously. The familiarization test was used to confirm or diagnose the presence of exercise-induced PB. Thereafter, in patients who met the exclusion/inclusion criteria, in random order, on different days, exercise testing was performed using a patient-specific protocol with no additional dead space and when 250 mL or 500 mL of additional dead space was added to the breathing circuit.

Since PB causes a periodicity in the measured oxygen consumption and minute ventilation, the increase in oxygen consumption and minute ventilation occurring during exercise was determined by comparing the average of the peak and nadir values observed in the first cycle (ie, during unloaded pedaling) with those in the last cycle of the test. The effect of progressive exercise on the amplitudes and variability of the tidal volume, minute ventilation, respiratory rate, and end-tidal carbon dioxide partial pressure (Petco2) was assessed by measuring the peak and nadir values seen during the first three cycles of loaded exercise. PB periodicity was measured using tidal volume as the reference variable. PB cessation was arbitrarily defined when amplitude swing of ventilation was < 10%.

Data are presented as mean ± SD. Results observed with 0 mL, 250 mL, or 500 mL of added dead space were analyzed using analysis of variance for repeated measures or with mixed modeling when patients had data missing from one of the three tests. Comparisons of initial and final values, and of peak and nadir values, were made using Student paired t test; p < 0.05 was considered to be significant.

Demographics of the patient population are summarized in Table 1 . No patient had resting hypoxemia (the lowest Pao2 measured at rest was 68 mm Hg). All patients but one had mild respiratory alkalemia, and 14 patients also had a mild metabolic alkalosis (defined as a serum bicarbonate > 25 mEq/dL). The duration of loaded exercise was 7.7 ± 1.5 min, 7.6 ± 1.6 min, and 6.9 ± 1.5 min with 0 mL, 250 mL, and 500 mL of added dead space, respectively. During the course of the test, heart rate, oxygen consumption, minute ventilation, and respiratory rate increased considerably (Table 2 ). Anaerobic threshold was not identifiable because of PB. All patients performed what they believed was a maximal test.

Periodicity of PB

The mean peak and nadir minute ventilation, tidal volume, respiratory rate, and Petco2 for the first three cycles of loaded exercise are summarized in Table 3 . All patients had amplitude variations that were evident from the onset of testing (Fig 1 ). The highest Petco2 values were concurrent with the nadirs of the tidal volume and the minute ventilation, and vice versa.

No Added Dead Space:

The number of PB cycles observed during the exercise test was 6.4 ± 1.5 (range, 4 to 10 cycles per patient). No difference was apparent in the periodicity, ie, the length of the cycle (61 ± 16 s) measured during unloading pedaling and the last cycle observed (– 2.6 ± 12 s, p = not significant). Respiratory rate periodicity was also evident in 14 patients, with the peaks appearing concurrently with the peaks in tidal volume and minute ventilation.

Added Dead Space, 250 mL:

The number of cycles observed was 6.4 ± 2.7 for 19 of 23 patients who showed PB for at least 2 min of loaded exercise under this condition. No difference was apparent in the periodicity measured during unloading pedaling (62 ± 18 s) and the last cycle observed (+ 0.5 ± 12 s). Respiratory rate periodicity was also evident in 14 patients.

Added Dead Space, 500 mL:

The number of cycles observed was 5.1 ± 1.6 for the 12 patients who showed PB for at least 2 min of loaded exercise under this condition. No difference was apparent in the periodicity measured during unloading pedaling (65 ± 21) and the last cycle observed (– 0.1 ± 18 s). Respiratory rate periodicity was also evident in eight patients.

Amplitude of PB

Although there was considerable patient-to-patient variation, on average the swings in amplitude tended to decrease with each cycle (Table 4 ).16 The peak tidal volume at the onset of exercise was 92 to 94% of the highest tidal volume observed anytime during the test, and changed very little during the course of the exercise. The nadir value gradually increased. When the nadir value approached the peak value, PB ceased and this occurred at a tidal volume that was 89 to 95% of the maximum tidal volume observed, consistent with the idea that the maximum tidal volume was limited by the inspiratory capacity (Table 5 , Fig 1, middle panel). The point at which PB ceased seemed to be less strongly related to a limitation in minute ventilation as, even with 500 mL of added dead space, the minute ventilation at which PB stopped was only 72 ± 13% of the maximum ventilation observed in each patient’s test (Table 5).

Duration of PB

The duration of PB decreased with increasing dead space (Table 6 , Fig 2 ), but in 9 of 23 patients PB continued throughout the entire test when the exercise was performed with no added dead space. Petco2 at the time PB stopped increased with increasing dead space (Table 6).

The important findings of this study are as follows: (1) the periodicity of PB during exercise in patients with chronic HF was constant during the course of the test; (2) PB stopped when the nadir of the tidal volume swings approached the peak tidal volume, the latter of which was very close to the maximal tidal volume observed; (3) PB stopped well before maximal ventilation was reached; (4) increasing dead space caused PB to disappear earlier in the course of exercise, but at a slightly higher Petco2; and (5) periodicity in respiratory rate was seen in many but not all of our patients. We recognized that our exercise tests were done on a cycle ergometer with subjects pedaling at 60 revolutions per minute, and that the ergometer used and the rate of pedaling might influence our results. Indeed, it will be interesting to reassess exercise-induced PB subjects and compare cycle ergometer exercise vs treadmill exercise.

CSR is characterized by repetitive gradual increases and subsequent gradual decreases of ventilation followed by periods of apnea17 and occurs in patients with a variety of diseases and conditions. PB in HF patients has a similar increase and decrease in ventilation but without periods of apnea. Both ventilatory patterns may have the same mechanistic explanations, with PB being a less severe form of CSR.1011 This idea is supported by Ponikowski et al,4 who found no difference in age, gender, cause of HF, functional class, left ventricle ejection fraction, maximum oxygen consumption, autonomic balance, and peripheral chemosensitivity in HF patients with CSR and those with PB. Furthermore CSR and PB have been found at different times in the same patient.1011,18 Although the explanatory mechanisms may be the same in CSR and PB, the present report deals only with PB observed in awake HF patients at rest and during exercise.

A number of theoretical models have been developed in an attempt to integrate the various clinical observations into a comprehensive mechanistic explanation of CSR.14,8,1920 All of these include a controlling system, a controlled system and feedback loop, and all function such that the system will oscillate spontaneously if there is a delay in the feedback loop (ie, a prolonged circulation time) or if the controlling system sensitivity (ie, ventilatory drive) is greatly increased. Francis and colleagues,8 evaluated as factors favoring PB in HF patients increased chemoreceptor sensitivity, a long lag time for pulmonary venous blood to reach the chemoreceptors, low ventilation, low cardiac output, a high alveolar-to-atmospheric carbon dioxide difference, and small lung volumes and identified chemoreflex sensitivity and delay time as causes of PB. We evaluated the role of circulation time, pulmonary congestion, apnea threshold and carbon dioxide sensitivity, alveolar-to-atmospheric carbon dioxide difference and lung volume as possible causes of PB.

Circulation Time

Whether prolonged circulation time causes CSR in HF has been debated for nearly 100 years.21 Several studies2030 suggested a major role of delayed circulation time on PB generation, while others13,20,23,3132 speak against this possibility. Our patients were able to exercise for an average of 7.7 ± 1.5 min to an average of 66 ± 21 W. Despite the fact that all were receiving β-blockers, their heart rates increased by a mean of 49%. Accordingly, although we did not measure cardiac output or circulation time, the former should have increased and the latter should have decreased during the course of the test, decreasing the time it takes for pulmonary venous blood to reach the peripheral chemoreceptors. On average, exercise had no effect on the periodicity of PB, a result that is quite inconsistent with the idea that delayed stimulation of peripheral chemoreceptors is an important cause of PB in HF. None of the previous reports5,9,2223,3334 commented on the periodicity of PB, but several reports,5,9,22,3334 included PB tracings that were quite similar to ours. We cannot exclude the importance of delayed circulation time on stimulation of the central chemoreceptors because an increase in cardiac output during exercise might not result in an increase in cerebral blood flow in patients with HF,35perhaps as a result of autoregulation.3637 Although none of our patients had resting hypoxemia, we did not measure oxygen saturation during exercise and therefore cannot comment on the potential role exercise-induced hypoxemia might have had on our results. Hypoxemia during exercise in HF patients is unusual, however, even when HF is severe.3839 In conclusion, our data suggest that delayed feedback, at least to the peripheral chemoreceptors, is not a critical factor of the model in the majority of HF patients with PB during exercise.

Pulmonary Congestion

Christie and Hayward40attributed PB to pulmonary congestion because they were able to induce it by occluding a pulmonary vein. This idea is supported by studies showing that the frequency and duration of central apnea in patients with HF correlates with the pulmonary capillary wedge pressure and that changing the pulmonary capillary wedge pressure is associated with inverse changes in the Paco2,41 and that cardiac resynchronization (which by improving cardiac failure, likely reduces pulmonary congestion) improves CSR.30,42 Our findings would argue against pulmonary congestion being involved, however, because the PB that we observed abated in the later stages of exercise in most of our patients at a time when pulmonary congestion should have been increasing rather than decreasing.16,43

Apnea Threshold and Carbon Dioxide Sensitivity

Apnea can be produced in normal subjects by forced hyperventilation.44 One hypothesis attributes the apneic phase of CSR (and presumably the hypoventilatory phase of PB) to the preceding period of hyperventilation which reduces the Paco2 below the apneic threshold.,34 Our observation that the amplitude and duration of the PB were different depending on whether the patients were exercising with 0 mL, 250 mL, or 500 mL of added dead space, while their Petco2 values increased, suggests that the carbon dioxide apnea threshold may be an important contributor to PB.

Alveolar-to-Atmospheric Carbon Dioxide Difference

An increased alveolar-to-atmospheric carbon dioxide difference has been reported as a possible cause of PB.8 Adding dead space, however, increases the alveolar-to-atmospheric carbon dioxide difference, yet we found that this caused the PB to disappear earlier.

Lung Volume

Our observation that PB ceased at lower levels of exercise when patients breathed through added dead space, and that it did so when tidal volumes closely approached the maximum tidal volume observed, is consistent with the idea that low lung volume is an important contributor to PB, as suggested by Francis and colleagues.8

PB during exercise does not seem to depend on circulation time (at least with respect to the peripheral chemoreceptors) but seems to depend on patients reaching their apnea thresholds. The peak tidal volume generated during PB seems to be determined by the patient’s maximum tidal volume, and the nadir tidal volume (and therefore the amplitude difference) seems to be a function of intrinsic metabolic rate (as PB stops when the metabolic rate increased to point that near-maximum tidal volume is required for carbon dioxide homeostasis).

Abbreviations: CSR = Cheyne-Stokes respiration; HF = heart failure; PB = periodic breathing; Petco2 = end-tidal carbon dioxide partial pressure

The authors have no conflicts of interest to disclose.

Table Graphic Jump Location
Table 1. Patient Demographics*
* 

Data are presented as No. or mean ± SD. ACE = angiotensin-converting enzyme; Dlco = diffusion capacity of the lung for carbon monoxide.

Table Graphic Jump Location
Table 2. Effect of Added Dead Space on Heart Rate, Oxygen Consumption, Minute Ventilation, and Respiratory Rate*
* 

Data are presented as mean ± SD. Start = unloaded pedaling.

 

p < 0.001 vs start.

Table Graphic Jump Location
Table 3. Peak and Nadir Respiratory Variables at the Beginning of Loaded Exercise*
* 

Data are presented as mean ± SD for first three cycles of loaded exercise.

 

Subjects who showed cycling of the examined variable.

 

p < 0.001 vs peak value.

Figure Jump LinkFigure 1. From top to bottom: Ventilation (VE), tidal volume (Vt), and Petco2 vs time during exercise in a typical patient with no added dead space. The white arrow indicates the beginning of loaded pedaling, and the black arrow indicates its end. The workload reached was 62 W.Grahic Jump Location
Table Graphic Jump Location
Table 4. Effect of Exercise and Dead Space on Ventilatory Amplitudes*
* 

Data are presented as mean ± SD; p < 0.05 for all.

Table Graphic Jump Location
Table 5. Minute Ventilation and Tidal Volume at the Beginning of Loaded Exercise and at PB Cessation*
* 

Data are presented as mean ± SD percentage of maximum.

Table Graphic Jump Location
Table 6. Time and Petco2 at Which PB Ceased During Exercise*
* 

Data are presented as mean ± SD.

 

p < 0.05 vs no added dead space.

 

p < 0.05 vs 250 mL added dead space.

Figure Jump LinkFigure 2. Tidal volume and workload vs time with no added dead space (top panel), 250 mL of added dead space (middle panel), and 500 mL added dead space (bottom panel) in a typical patient. The white arrow indicates the beginning of loaded pedaling, and the black arrow indicates its end. The workload reached is reported. DS = dead space. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Dr. Douglas Bradley reviewed some of the primary data and suggested a number of analytic approaches. Angela Keniston assisted with statistical analysis.

Cherniack, NS, Longobardo, GS (1973) Cheyne-Stokes breathing: an instability in physiology control.N Engl J Med288,952-957. [PubMed] [CrossRef]
 
Khoo, MCK, Kronauer, RE, Strohl, KP, et al Factors inducing periodic breathing in humans: a general model.J Appl Physiol1982;53,644-659. [PubMed]
 
Topor, ZL, Vasilakos, K, Younes, M, et al Model based analysis of sleep disordered breathing in congestive heart failure.Respir Physiol Neurobiol2007;155,82-92. [PubMed]
 
Ponikowski, P, Anker, SD, Chua, TP, et al Oscillatory breathing patterns during wakefulness in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity.Circulation1999;100,2418-2424. [PubMed]
 
Piepoli, MF, Ponikowski, PP, Volterrani, M, et al Aetiology and pathophysiological implications of oscillatory ventilation at rest and during exercise in chronic heart failure.Eur Heart J1999;20,946-953. [PubMed]
 
Hanly, P, Zuberi, N, Gray, R Pathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure: relationship to arterial Pco2.Chest1993;104,1079-1084. [PubMed]
 
Xie, A, Skatrud, JB, Puleo, DS, et al Apnea-hypopnea threshold for CO2in patients with congestive heart failure.Am J Respir Crit Care Med2002;165,1245-1250. [PubMed]
 
Francis, DP, Wilson, K, Davies, LC, et al Quantitative general theory for periodic breathing in chronic heart failure and its clinical implications.Circulation2000;102,2214-2221. [PubMed]
 
Kremser, CB, O’Toole, MF, Leff, AR Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy.Am J Cardiol1987;59,900-905. [PubMed]
 
Corra’, U, Giordano, A, Bosimini, E, et al Oscillatory ventilation during exercise in patients with chronic heart failure: clinical correlates and prognostic implications.Chest2002;121,1572-1580. [PubMed]
 
Corra’, U, Pistono, M, Mezzani, A, et al Sleep and exertional periodic breathing in chronic heart failure: prognostic importance and interdependence.Circulation2006;113,44-50. [PubMed]
 
Agostoni, P, Cattadori, G, Apostolo, A, et al Noninvasive measurement of cardiac output during exercise by inert gas rebreathing technique: a new tool for heart failure evaluation.J Am Coll Cardiol2005;46,1779-1781. [PubMed]
 
Steens, RD, Millar, TW, Xiaoling, S, et al Effect of inhaled 3% CO2on Cheyne-Stokes respiration in congestive heart failure.Sleep1994;17,61-68. [PubMed]
 
Lorenzi-Fihlo, G, Rankin, F, Bies, I, et al Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure.Am J Respir Crit Care Med1999;159,1490-1498. [PubMed]
 
Khayat, RN, Xie, A, Patel, AK, et al Cardiorespiratory effects of added dead space in patients with heart failure and central sleep apnea.Chest2003;123,1551-1560. [PubMed]
 
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Figures

Figure Jump LinkFigure 1. From top to bottom: Ventilation (VE), tidal volume (Vt), and Petco2 vs time during exercise in a typical patient with no added dead space. The white arrow indicates the beginning of loaded pedaling, and the black arrow indicates its end. The workload reached was 62 W.Grahic Jump Location
Figure Jump LinkFigure 2. Tidal volume and workload vs time with no added dead space (top panel), 250 mL of added dead space (middle panel), and 500 mL added dead space (bottom panel) in a typical patient. The white arrow indicates the beginning of loaded pedaling, and the black arrow indicates its end. The workload reached is reported. DS = dead space. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Patient Demographics*
* 

Data are presented as No. or mean ± SD. ACE = angiotensin-converting enzyme; Dlco = diffusion capacity of the lung for carbon monoxide.

Table Graphic Jump Location
Table 2. Effect of Added Dead Space on Heart Rate, Oxygen Consumption, Minute Ventilation, and Respiratory Rate*
* 

Data are presented as mean ± SD. Start = unloaded pedaling.

 

p < 0.001 vs start.

Table Graphic Jump Location
Table 3. Peak and Nadir Respiratory Variables at the Beginning of Loaded Exercise*
* 

Data are presented as mean ± SD for first three cycles of loaded exercise.

 

Subjects who showed cycling of the examined variable.

 

p < 0.001 vs peak value.

Table Graphic Jump Location
Table 4. Effect of Exercise and Dead Space on Ventilatory Amplitudes*
* 

Data are presented as mean ± SD; p < 0.05 for all.

Table Graphic Jump Location
Table 5. Minute Ventilation and Tidal Volume at the Beginning of Loaded Exercise and at PB Cessation*
* 

Data are presented as mean ± SD percentage of maximum.

Table Graphic Jump Location
Table 6. Time and Petco2 at Which PB Ceased During Exercise*
* 

Data are presented as mean ± SD.

 

p < 0.05 vs no added dead space.

 

p < 0.05 vs 250 mL added dead space.

References

Cherniack, NS, Longobardo, GS (1973) Cheyne-Stokes breathing: an instability in physiology control.N Engl J Med288,952-957. [PubMed] [CrossRef]
 
Khoo, MCK, Kronauer, RE, Strohl, KP, et al Factors inducing periodic breathing in humans: a general model.J Appl Physiol1982;53,644-659. [PubMed]
 
Topor, ZL, Vasilakos, K, Younes, M, et al Model based analysis of sleep disordered breathing in congestive heart failure.Respir Physiol Neurobiol2007;155,82-92. [PubMed]
 
Ponikowski, P, Anker, SD, Chua, TP, et al Oscillatory breathing patterns during wakefulness in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity.Circulation1999;100,2418-2424. [PubMed]
 
Piepoli, MF, Ponikowski, PP, Volterrani, M, et al Aetiology and pathophysiological implications of oscillatory ventilation at rest and during exercise in chronic heart failure.Eur Heart J1999;20,946-953. [PubMed]
 
Hanly, P, Zuberi, N, Gray, R Pathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure: relationship to arterial Pco2.Chest1993;104,1079-1084. [PubMed]
 
Xie, A, Skatrud, JB, Puleo, DS, et al Apnea-hypopnea threshold for CO2in patients with congestive heart failure.Am J Respir Crit Care Med2002;165,1245-1250. [PubMed]
 
Francis, DP, Wilson, K, Davies, LC, et al Quantitative general theory for periodic breathing in chronic heart failure and its clinical implications.Circulation2000;102,2214-2221. [PubMed]
 
Kremser, CB, O’Toole, MF, Leff, AR Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy.Am J Cardiol1987;59,900-905. [PubMed]
 
Corra’, U, Giordano, A, Bosimini, E, et al Oscillatory ventilation during exercise in patients with chronic heart failure: clinical correlates and prognostic implications.Chest2002;121,1572-1580. [PubMed]
 
Corra’, U, Pistono, M, Mezzani, A, et al Sleep and exertional periodic breathing in chronic heart failure: prognostic importance and interdependence.Circulation2006;113,44-50. [PubMed]
 
Agostoni, P, Cattadori, G, Apostolo, A, et al Noninvasive measurement of cardiac output during exercise by inert gas rebreathing technique: a new tool for heart failure evaluation.J Am Coll Cardiol2005;46,1779-1781. [PubMed]
 
Steens, RD, Millar, TW, Xiaoling, S, et al Effect of inhaled 3% CO2on Cheyne-Stokes respiration in congestive heart failure.Sleep1994;17,61-68. [PubMed]
 
Lorenzi-Fihlo, G, Rankin, F, Bies, I, et al Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure.Am J Respir Crit Care Med1999;159,1490-1498. [PubMed]
 
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