Copyright ©ERS Journals Ltd 2002 Assisted ventilation for heart failure patients with Cheyne-Stokes respiration1 Dept of Pulmonary and Intensive Care Medicine, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany. 2 Institute for Cardiovascular Research and 3 Dept of Respiratory Medicine, St James's University Hospital Leeds, Leeds, UK CORRESPONDENCE: T. Köhnlein, Otto-von-Guericke-Universität Magdeburg, Zentrum Innere Medizin, Pneumologie und Internistische Intensivmedizin, Leipziger Str. 44, D-39120, Magdeburg, Germany. Fax: 49 3916715420. E-mail: thomas.koehnlein@web.de Keywords: bilevel ventilation, central sleep apnoea syndrome, Cheyne-Stokes respiration, congestive heart failure, continuous positive airway pressure
Received: December 18, 2001
T. Köhnlein was funded with a long-term research fellowship from the European Respiratory Society.
Patients with chronic congestive cardiac failure (CCF) frequently suffer from central sleep apnoea syndrome (CSAS). Continuous positive airway pressure (CPAP) has been suggested as a treatment. The authors hypothesised that bilevel ventilation might be easier to initiate and superior to CPAP at correcting the sleep-related abnormality of breathing in patients with CCF. After excluding those with a history suggestive of obstructive sleep apnoea, 35 patients with CCF (left ventricular ejection fraction <35%) were screened with overnight oximetry and the diagnosis of CSAS was established with polysomnography in 18. Two 14-day cycles of CPAP (0.85 kPa (8.5 mbar)) or bilevel ventilation (0.85/0.3 kPa (8.5/3 mbar)) in random order, were compared in a crossover study. Sixteen patients (13 males), mean age 62.0±7.4 yrs completed the study. The pretreatment apnoea/hypopnoea index of 26.7±10.7 was significantly reduced by CPAP and bilevel ventilation to 7.7±5.6 and 6.5±6.6, respectively. The arousal index fell from 31.1±10.0 per hour of sleep to 15.7±5.4 and 16.4±6.9, respectively. Significant and equal improvements with CPAP and bilevel ventilation were found for sleep quality, daytime fatigue, circulation time and New York Heart Association class. The authors conclude that continuous positive airway pressure and bilevel ventilation equally and effectively improve Cheyne-Stokes respiration in patients with congestive cardiac failure. Central sleep apnoea syndrome (CSAS) with Cheyne-Stokes respiration (CSR) is common in patients with severe cardiac failure. Up to 45% of patients with a left ventricular ejection fraction of 40% may suffer from this breathing disorder during sleep 1, 2. Current concepts of the pathophysiology of CSR suggest it is caused by enhanced carbon dioxide sensitivity, delayed transfer of blood gas tension changes to the chemoreceptors and the influence of adjacent brain centres (circadian rhythms, sleep wake centre) upon the central control of breathing 3. CSR is characterised by periodic changes of tidal volume, resulting in 3060-s cycles of hyperventilation, alternating with hypoventilation or apnoea in a crescendo decrescendo pattern. The resumption of respiration from apnoea is associated with arousals and episodes of sympathetic activation. These episodes may occur several hundred times during the night in patients with severe CSAS 4. The repeated arousals prevent the patient from entering the deeper recuperative stages of sleep, which leads to daytime sleepiness and fatigue. Activation of the sympathetic nervous system coincides with low levels of blood and tissue oxygenation. Heart rate, blood pressure, and the calculated work load for the heart are periodically increased during sleep. As a consequence, the stress upon the failing heart is multiplied 5. Sympathetic activation is a well-documented, independent risk factor for progression of cardiac dysfunction and sudden cardiac death 6. Recent epidemiological studies have shown a significantly worse survival for patients with left heart insufficiency and CSAS 7, 8. Andreas et al. 9 concluded that CSR during sleep or wakefulness is associated with mortality or the need for transplantation within a few months. Therefore, treatment of CSR in combination with "optimised" medical therapy may influence the course of chronic heart failure, quality of life and the survival of patients 10. Continuous positive airway pressure (CPAP) and time-controlled bilevel ventilation (bilevel spontaneous/timed) are both used as symptomatic approaches to treat sleep disordered breathing, correct hypoxaemia, reduce arousals, decrease sympathetic tone, and improve sleep quality 11, 12. However, the application of CPAP to patients with CHF may be problematic 13, 14. CPAP requires a spontaneously breathing patient and will be ineffective for central apnoeas, whereas timed bilevel ventilation is able to ventilate a patient even in the absence of spontaneous respiratory effort. Furthermore, some patients find breathing out against positive pressure uncomfortable. Bilevel ventilation has been suggested as an alternative, but little is known about the efficacy or tolerance of bilevel ventilation in these patients and, in particular, it has not been compared to CPAP. The authors hypothesised that bilevel ventilation might be more effective than CPAP in terms of reducing pathological respiratory events and be better tolerated by patients. The aim of this prospective randomised, nonblinded, crossover, clinical trial was to compare the effect of CPAP and bilevel ventilation on the ventilatory pattern during sleep in a cohort of patients with CSAS during sleep. Secondary outcome parameters were the effect on blood oxygen saturation, arousals from sleep, sleep quality, circulation time, quality of life, daytime fatigue, and New York Heart Association (NYHA) functional class.
Subjects Successive patients of both sexes, aged 1880 yrs, were screened in a cardiac outpatient clinic at the Leeds Teaching Hospitals National Health Service (NHS) Trust (Leeds, UK) between April and November 2000.
Patients with a >1 yr history of chronic left heart failure, in NYHA functional class II and III due to ischaemic heart disease or dilated cardiomyopathy, qualified for the study. Furthermore, inclusion criteria were a left ventricular ejection fraction of Exclusion criteria included any pulmonary or neurological disease that might affect ventilation or the control of breathing (such as central alveolar hypoventilation syndrome, chronic obstructive pulmonary disease, pulmonary fibrosis, chronic infections in the respiratory tract, previous stroke, transient ischaemic attack, neuropathy and tumour). Further exclusion criteria were myocardial infarction within 6 months of study entry, severe ventricular arrhythmia, atrial fibrillation 16, cardiac valve replacement, current smoking, known or a strong clinical suspicion of obstructive sleep apnoea (>10 obstructive apnoeas per hour of sleep or >10% of all detected apnoeas being obstructive in nature), diabetes mellitus, and (suspicion of) alcohol or drug abuse. Patients with any noncardiologic medication that would have a possible influence on the control of breathing (e.g. sedatives, tranquillisers, theophylline) were also excluded. Any deterioration in the subject's condition as a result of participation in this study, judged by clinical assessment, polysomnography or from the patient's own impression, warranted immediate withdrawal from the study. The study was approved by the Local Research Ethics Committee of the Leeds Teaching Hospitals NHS Trust. Informed written consent was obtained from every patient prior to study entry.
Experimental protocol
CSR patients were randomised and entered a crossover study design (fig. 1
The polysomnographic studies at the beginning of each treatment cycle were performed to confirm the tolerance to the intervention and to exclude detrimental effects of CPAP or bilevel ventilation. Data for analysis in this study were obtained from the first polysomnography during spontaneous breathing and from the polysomnographies at the end of each treatment cycle.
Polysomnography
Circulation time was calculated as described in detail elsewhere 20. In brief, 15 randomly selected sequences with periodic breathing in sleep stage II were analysed for the time interval between the resumption of respiratory efforts and the nadir of the oxygen saturation at the finger tip of the index finger of the left hand (fig. 2
Symptom assessment Daytime sleepiness and fatigue were quantified with the Epworth sleepiness scale 21. Health status was assessed with the short-form health survey (SF)-36 quality-of-life questionnaire 22, a generic questionnaire, which has been used previously for evaluation of patients with chronic cardiac disease and obstructive sleep apnoea 23.
Continuous positive airway pressure and noninvasive ventilation The run time of all ventilators was recorded with an hour meter in the device recording the actual time the patient received assisted ventilation within the last fourteen 24-h cycles (not visible to the patient). Ultra Mirage masks (Resmed Inc.) or Respironics Special nasal masks (Respironics Inc.) were used according to the subject's preference.
Data analysis
A total of 330 chronic heart failure patients were considered for this study. Thirty five patients, meeting all inclusion and exclusion criteria were screened with overnight pulse-oximetry and 18 (51%) were found to have CSR. The diagnosis of central sleep apnoea and CSR was established, obstructive sleep apnoea excluded, with full polysomnography in all subjects. Two subjects withdrew after the first intervention night (CPAP in both cases) because of the inconvenience of the procedure. Sixteen patients (13 males) complied with all aspects of the protocol and completed the study. The mean age was 62.0±7.4 yrs (range 4977) and the mean BMI was 27.3±3.2 kg·m2 (range 20.732.3). The body weight of all subjects remained stable within ±1.5 kg throughout the study. All patients suffered from advanced left ventricular insufficiency; the mean left ventricular ejection fraction was 23.6±6.9% (range 1535). Eleven patients had severe coronary artery disease, with five of them having had coronary artery bypass surgery in the past. The remaining five subjects had severe, idiopathic dilated cardiomyopathy. At study entry, four subjects were in NYHA functional class II, and twelve in class III (table 1
The initial polysomnography revealed CSR in all subjects, averaging 37.1±16.6% of the total sleep time (TST). CSR was typically found in sleep stages I, II and occasionally during rapid eye movement (REM) sleep. In nearly all subjects the breathing pattern was unaffected during slow wave sleep (SWS). In one subject (no. 2), CSR was documented during wakefulness shortly before the onset of sleep. Obstructive respiratory events were rare, and in the whole study population the amount of snoring ranged 04% of the TST.
After 2 weeks of treatment, both CPAP and bilevel ventilation reduced CSR significantly from 37.1±16.6% to 14.1±17.5% (p<0.001) and 13.8±17.6% (p<0.001) of TST, respectively (fig. 3a
The average oxygen saturation was normal for all subjects across the night (94.4±1.8%), and did not change significantly with CPAP (94.6±1.9%, p=0.22) or bilevel ventilation (94.7±1.6%, p=0.645). However, in association with apnoeas and hypopnoeas, severe, short-term oxygen desaturation was documented. Before treatment, the total time spent with oxygen saturation <90% during sleep was 18.1±30.9 min, and this was significantly reduced with CPAP to 1.6±1.9 min (p<0.029) and with bilevel ventilation to 0.8±1.1 min (p=0.039) (fig. 3c
The influence of both interventions on haemodynamic parameters was assessed by calculating the average circulation time between the lungs and the left index fingertip. Before treatment the mean circulation time was 35.8±6.1 s, which decreased to 29.8±6.1 s (p<0.001) with CPAP and to 29.9±5.3 s (p<0.001) with bilevel ventilation (fig. 5
The average NYHA functional class for all subjects was estimated at 2.8±0.4 before treatment. After 14 days, the NYHA functional class had improved to 2.0±0.4 (p<0.003) with CPAP and to 1.9±0.5 (p<0.001) with bilevel ventilation. The mean Epworth sleepiness score before treatment was 12.3±2.6. This marker of daytime sleepiness was significantly reduced to 7.5±2.4 (p<0.001) and 7.1±2.5 (p<0.001) after CPAP or bilevel therapy, respectively. Health status, as assessed by the SF-36 questionnaire, showed a trend towards improvements in physical health and emotional health as well as in the categories of physical and social activity, but these did not reach statistical significance (fig. 6
In agreement with other reports 11, 14, 25, 26, the authors found that CPAP is an effective treatment for patients with CSR. This was manifested by significant improvements in the percentage of CSR during sleep, AHI, sleep quality, arousal index, mean circulation time, Epworth sleepiness score and the NYHA class. These results with CPAP are similar to previous studies in patients with heart failure. The reduction of hypopnoeas and apnoeas with CPAP was similar to that found in the work of Naughton et al. 27 and Javaheri 28. Javaheri 28 also measured arousals and oxygenation before and after CPAP treatment, and the author's responders to CPAP showed similar results to those observed in the subjects present in this study. The authors did not find that the more complicated and more expensive bilevel ventilation conferred any advantage. The finding that CPAP was well tolerated was surprising, since it has not been experienced by the authors in routine clinical practice. Only two subjects were unable to tolerate noninvasive positive pressure in this study, both withdrawing after 1 night of treatment with CPAP. The remaining 16 patients managed to fulfil all requirements of the protocol. There was not a high proportion of nonresponders to CPAP, as described by Javaheri 28, or bilevel ventilation. However, the baseline AHI in the patients in the current study (26.7±10.7, range 1546) was considerably lower than in the total cohort (51±23) in the study by Javaheri 28, but was close to the mean AHI of responders to CPAP (36±15) in the latter study 28. Similar effects of bilevel ventilation on CSA were demonstrated by Teschler et al. 29, who investigated four different treatment modes (oxygen, CPAP, bilevel ventilation and adaptive pressure support servo-ventilation) during 1 treatment night each. In contrast to the present study, Teschler et al. 29 did not find that CPAP was effective. The current study evaluated each treatment after a 12-day treatment period at home to rule out the influence of adaptation problems and first night effects on the assessment of the treatment mode. The daily ventilator use was satisfactory for both interventions. The run time for CPAP and bilevel ventilation exceeded the average daily run time from the authors' laboratory for patients with obstructive sleep apnoea syndrome (4.3 h·day1). The involvement of a full time doctor in the study might have resulted in greater involvement with the patient than would be seen in normal every day clinical practice and the relatively short period of 14 days might also have been a factor.
The choice of pressure settings was guided by the possible impact of increased intrathoracic pressure on the cardiovascular system and this may have been a further reason for the good compliance with CPAP in this study. Buckle et al. 14 found that their congestive heart failure patients did not tolerate CPAP pressures of >0.50.75 kPa (57.5 mbar). In this study, relatively low pressures of 0.85 kPa (8.5 mbar) and 0.850.3 kPa (8.5/3 mbar) were chosen for CPAP or bilevel ventilation, respectively, similar to those of Naughton et al. 11, who used pressures from 0.51.25 kPa (5 to 12.5 mbar), because of the observation of Becker et al. 30 that there was a decrease in cardiac output with CPAP of >1 kPa (10 mbar) or with bilevel ventilation of The applied pressures in this study were effective in all subjects, regardless of the severity of CSR, their BMI or body constitution. Treatment of CSAS does not seem to be critically dependent on the applied pressure, in contrast to patients with obstructive sleep apnoea syndrome 31. The fact that ventilatory parameters during sleep were improved in all patients with the same settings suggests that the beneficial effects of positive intrathoracic pressure upon the failing heart are the predominant mechanism of benefit. In various studies, Bradley and co-workers 11, 26 demonstrated that CPAP is effective not only in improving respiratory events but also in reducing cardiac pre and after load, transmural pressure of intrathoracic blood vessels 32 and cardiac dimensions 33. The current finding of a reduction in circulation time is also consistent with improved cardiac performance. There were no adverse effects of assisted ventilation in the patients in this study. Hyperventilation is a major aspect of the pathophysiology of CSAS in chronic heart failure patients. CPAP and bilevel ventilation might further increase hyperventilation by reducing the work of breathing. Although ventilation was assessed by visual analysis of the ventilation signals in the polysomnography recordings only, hyperventilation was not detected with any intervention in any patient. Ventilation was regularised with CPAP and bilevel ventilation, i.e. the pre-existing pathological breathing pattern was improved in all subjects. This was true for the relatively low pressure settings in this study. In view of the satisfactory results, higher ventilatory pressures were not studied, and therefore no information on the effect of ventilatory pressure was obtained. Carbon dioxide tensions were not measured. Direct measurement is not feasible during sleep unless an arterial line is available, but this was not performed with respect to patient safety and comfort. Transcutaneous measurement techniques are not sufficiently responsive for patients with rapid alterations of their breathing pattern and the measurement of gas samples in the exhaled air stream in the nose is quick, but during CPAP or bilevel ventilation there is no undisturbed exhaled air stream for analysis 34. Assisted ventilation could theoretically worsen CSR by reducing the carbon dioxide tension in arterial blood below the apnoeic threshold. The fact that an improvement in CSR was found suggests that this did not occur even though carbon dioxide tensions were not measured. This was probably because of the low pressures that were chosen and higher pressures may have had a deleterious effect on CSR through this mechanism. The lack of a placebo limb is a potential limitation of this study. However, in other studies, CPAP has been shown to have a beneficial effect on CSR, but because implementation may be difficult, the primary interest was to compare CPAP and bilevel ventilation in CHF patients, and the addition of a placebo limb would have considerably added to the complexity of the protocol for the patients. This study does support the observation in other studies of a beneficial effect of assisted ventilation, even though it was not the primary aim of this study. One advantage of this study compared to previous work is that the selection of subjects was guided by restrictive inclusion and exclusion criteria to avoid the confounding effects of comorbidity. Previous studies with similar design 11, 28, 35 might have been biased, because they were not controlled for cofounders influencing the control of breathing, such as medication and stroke, or the underlying cardiac rhythm. Health status showed a trend towards improvement and no patient became worse with positive pressure ventilation. The generic questionnaire, SF-36, is probably not sensitive enough to detect changes that might be picked up with disease-specific questionnaires. The improvement in the NYHA functional class of many patients is a further indicator of improved physical health under either treatment. However, the estimation of the NYHA class by the investigators is subjective and therefore open to bias. In conclusion, this randomised, crossover, open clinical trial confirmed the finding of other authors of significant benefits of continuous positive airway pressure and bilevel ventilation in patients with stable chronic heart failure due to ischaemic heart disease or idiopathic cardiomyopathy and Cheyne-Stokes respiration. However, in the absence of a control group, the fact that this might have been because of other factors, such as closer observation, cannot be excluded. Continuous positive airway pressure and bilevel ventilation with low pressures were equally effective in improving sleep quality, blood oxygenation, arousals from sleep and daytime symptoms. Both interventions were well accepted over the 14-day treatment periods and these data do not suggest a role for bilevel ventilation, the equipment for which is more expensive than that for continuous positive airway pressure. Low pressures are effective and well tolerated. The impact of treatment on the pathophysiology of chronic heart disease and the long-term effects are still unknown, and the results of a multicentre Canadian study of continuous positive airway pressure in chronic left ventricular failure are therefore awaited 36. The data presented in this study support the use of continuous positive airway pressure as an effective treatment for reducing sleep disordered breathing in patients with cardiac failure.
The authors thank A. Lux for the statistical evaluation of the data. The authors also thank Resmed UK for loaning two VPAP II flow generators for this study.
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