Abstract
Heart failure is associated with Cheyne–Stokes breathing, which fragments patients' sleep. Correction of respiratory disturbance may reduce sleep fragmentation and excessive daytime sleepiness. This randomized prospective parallel trial assesses whether nocturnal-assist servoventilation improves daytime sleepiness compared with the control. A total of 30 subjects (29 male) with Cheyne–Stokes breathing (mean apnea–hypopnea index 19.8 [SD 2.6] and stable symptomatic chronic heart failure (New York Heart Association Class II–IV) were treated with 1 month's therapeutic (n = 15) or subtherapeutic adaptive servoventilation. Daytime sleepiness (Osler test) was measured before and after the trial with change in measured sleepiness the primary endpoint. Secondary endpoints included brain natriuretic peptide levels and catecholamine excretion. Active treatment reduced excessive daytime sleepiness; the mean Osler change was +7.9 minutes (SEM 2.9), when compared with the control, the change was −1.0 minutes (SEM, 1.7), and the difference was 8.9 minutes (95% confidence interval, 1.9–15.9 minutes; p = 0.014, unpaired t test). Significant falls occurred in plasma brain natriuretic peptide and urinary metadrenaline excretion. We conclude that adaptive servoventilation produces an improvement in excessive daytime sleepiness in patients with Cheyne–Stokes breathing and chronic heart failure. This study suggests improvements in neurohormonal activation with this treatment.
Cheyne–Stokes breathing is detectable in between 36 and 57% of patients with chronic heart failure (1, 2) and is associated with a number of secondary consequences. Each apnea is associated with arousal from sleep (3), which fragments the normal sleep process (2, 4). The syndrome of heart failure includes lethargy, fatigue and sleepiness, which are plausibly related to this. The repetitive apnea and arousal cycle also induces cyclic sympatheticoadrenal activation (5), an accepted predictor of mortality in heart failure (6). It is possible that correction of Cheyne–Stokes breathing may improve both daytime symptoms and the heart failure syndrome itself.
Adaptive servoventilation (ASV, Autoset-CS; ResMed Corp, San Diego, CA) is a novel therapy that could produce these benefits by correcting Cheyne–Stokes breathing. The ventilator aims to correct episodes of apnea and hypoventilation and subsequently reduce arousal, sleep fragmentation, and sympathetic activation. In observational studies, ASV is technically effective in controlling central apneas during sleep (7). However, there have been no randomized trials to confirm that controlling Cheyne–Stokes breathing is associated with clinical patient benefit. We have performed a randomized prospective comparison of therapeutic ASV with a subtherapeutic control in patients with stable chronic heart failure and Cheyne–Stokes breathing to assess whether ASV improves objectively measured excessive daytime sleepiness (primary end point), or plasma brain (B-type) natriuretic peptide (BNP) levels (a marker of heart failure severity), urinary catecholamine excretion, self-reported health status, and steering simulator performance (secondary end points). Statistical analysis was performed on “intention to treat” basis using SPSS version 10 (SPSS Inc., Chicago, IL). Unpaired t tests were used for normally distributed data and Mann–Whitney U tests were used for nonnormally distributed data. Results are mean (SEM) for normally distributed data and median (interquartile range) for nonnormally distributed data. Some of the results have been previously reported in an abstract (8).
This study was a prospective, parallel, randomized, double-blind trial performed at the Sleep and Respiratory Trials Units, Oxford Radcliffe Hospitals, UK. Additional detail on the methods is provided in an online supplement. Patients identified with a primary diagnosis of heart failure and stable drug therapy were contacted to invite them to participate. Current heart failure symptoms (New York Heart Association Class II–IV) were confirmed in subjects with more than 10 saturation dips greater than 3% per hour on overnight home pulse oximetry (Minolta 3i; AVL, Shaffhausen, Switzerland). These subjects then consented for the main study (approved by the Central Oxford Research Ethics Committee, number 99.218) and underwent overnight polysomnography performed by standard methods (9), health status questionnaires, and 24-hour urine collections. Additional details are provided in the online supplement.
After polysomnography, subjects fulfilling the study entry criteria remained in hospital for a further 2 days to complete baseline assessments and institute the trial therapy. Blood samples were taken at 8:30 a.m., and patients underwent Osler tests of daytime vigilance at 9:00 a.m. and 2:00 p.m. After the 9:00 a.m. Osler test, subjects underwent training on the steering simulator before proceeding to a 30-minute test run. Two-dimensional and M-mode echocardiography was performed.
During their stay, subjects learnt about the ventilator and were fitted with a mask before a daytime acclimatization session and then received subtherapeutic and therapeutic Autoset CS (ResMed Corp) on alternate nights in random order. After the second night, 4 weeks treatment with therapeutic or subtherapeutic ASV was allocated by the selection of a presealed and numbered envelope. At 4 weeks, subjects reattended for repeat assessments, and, ASV hour meters were read to calculate mean nightly usage (see further details in the online supplement).
Therapeutic ASV was delivered from the Autoset CS, set to its default settings (expiratory pressure 5 cm H2O, inspiratory pressure support between 3 and 10 cm H2O, backup respiratory rate 15 breaths per minute). Subtherapeutic ASV was delivered from an identical machine, adapted to deliver a nominal 1.75 cm H2O pressure with little pressure support ventilation (minimum, 0.75; maximum, 2.75).
The primary outcome was the change in the patients' objective degree of sleepiness measured using a behavioral sleep resistance challenge, the Osler test (10). Secondary outcome measures included BNP, urinary catecholamine excretion, self-reported health status (Epworth sleepiness score, short-form 36, and the chronic heart failure questionnaire), and steering simulator performance (Stowood Scientific Instruments, Oxford, UK). To ensure the study remained double blind, the specialist nurse who performed outcome assessments was unaware of the treatment assignment.
Of the 30 patients randomized, 20 had ischemic or coronary heart disease and 10 had dilated cardiomyopathy (four of these presumed secondary to hypertension), with 12 having atrial fibrillation and 14 having a past history of hypertension (Table E1). No changes were made to patients' medications during the trial. The mean apnea–hypopnea index per hour of recording was similar between groups (Tables 1
Therapeutic ASV Mean (SD) | Subtherapeutic ASV Mean (SD) | |
|---|---|---|
| (n = 15, 15 male) | (n = 15, 14 male) | |
| Age, yr | 71.4 (8.6) | 70.9 (7.9) |
| Body mass index, kg/m2 | 26.8 (4.6) | 25.6 (4.1) |
| NYHA symptom score | 2.7 (0.6) | 2.9 (0.7) |
| Left ventricular ejection fraction, % | 36.5 (11.5) | 33.0 (11.3) |
| Apnea/hypopnea index, per hour | 24.7 (11.3) | 23.3 (13.3) |
| SaO2 dips > 3%, per hour | 23.1 (13.4) | 20.7 (11.2) |
| Epworth sleepiness score | 10.5 (4.7) | 9.7 (3.8) |
| ASV compliance, hours per night | 5.0 (1.7)* | 3.9 (2.3) |
During the trial, four subjects withdrew in the subtherapeutic group (detailed in Figure 1) and none withdrew in the therapeutic group. The data for all outcomes were analyzed on intention to treat with baseline data used for follow-up with no change assumed in subjects who withdrew. The subjects' baseline characteristics and compliance data are shown in Tables 1 and E1. The study groups were well matched for baseline characteristics.
Therapeutic ASV produced a clinically and statistically significant improvement in objectively measured sleepiness quantified by the Osler test when compared with the subtherapeutic control. Change in duration of wakefulness with therapeutic ASV was +7.9 minutes (SEM, 2.9), change with subtherapeutic ASV was −1.0 minutes (SEM, 1.7), and the difference was 8.9 minutes (95% confidence interval for difference, 1.9–15.9 minutes; p = 0.014, unpaired t test) (Figure 2)
Figure 2. Maintenance of wakefulness test (Osler test) results. Subtherapeutic adaptive servoventilation (ASV) is shown in the left-hand columns and therapeutic ASV is shown in the right-hand columns. Data are presented individually in open circles, with the group median and interquartile ranges also being present. Therapeutic ASV improves objective sleepiness, whereas subtherapeutic control produces no change. (Mean difference, 8.9 minutes; 95% confidence interval, 1.9–15.9; p = 0.014; unpaired t test.)
[More] [Minimize]Therapeutic ASV produced a reduction in serum BNP when compared with the subtherapeutic control. The median change in BNP with therapeutic ASV was −56 pg/ml (interquartile range, −238 to −16), with no change in subtherapeutic ASV (0, interquartile −24 to +71; p = 0.001, Mann–Whitney U test).
There was reduced metadrenaline excretion with therapeutic ASV. Change in metadrenaline with therapeutic ASV was −14.3 (4.4) nmol/mmol creatinine, change with subtherapeutic ASV was +4.9 (6.3) nmol/mmol creatinine, and the difference was 19.2 (95% confidence interval for difference, 3.5–35.0 nmol/mmol creatinine; p = 0.019, unpaired t test). There was no difference in metnoradrenaline excretion; change with therapeutic ASV was −34.2 (20.0) nmol/mmol creatinine, change with subtherapeutic ASV was −2.2 (12.8), and the difference was 32.0 (95% confidence interval for difference, −16.6 to +80.6; p = 0.188, unpaired t test) (Tables 2
Therapeutic ASV | Subtherapeutic ASV | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Change with
Therapeutic ASV
(n = 15) | Change with
Subtherapeutic ASV
(n = 15) | p Value | |||
| Daytime sleepiness Osler, min | 26.1 (3.3) | 34.0 (2.3) | 29.9 (2.7) | 28.9 (3.2) | +7.9 (2.9) | −1.0 (1.7) | 0.014 | ||
| BNP, pg/ml | 363 (234–875) | 278 (187–493) | 318 (73.2–975) | 311 (113–1286) | −56.0 (−238–−16.0) | 0.0 (−24.0–+71.0) | 0.001 | ||
| Metadrenaline, nmol/mmol creatinine | 60.6 (6.1) | 45.2 (4.1) | 93.1 (12.2) | 98.4 (12.1) | −15.4 (4.6) | +5.3 (6.8) | 0.018 | ||
| Metnoradrenaline, nmol/mmol
creatinine | 190.0 (37.6) | 153.2 (20.9) | 279.4 (45.1) | 277.1 (41.1) | −36.6 (21.3) | −2.3 (13.7) | 0.19 | ||
There were no statistically significant changes in any of the questionnaire assessments of health status or sleepiness with either therapeutic or subtherapeutic treatment (Table E3). Two of the 30 subjects did not drive, and these subjects did not perform the driving simulator assessments. There were no statistically significant changes in any of the driving assessments (Table E3).
Within the subtherapeutic group, three subjects withdrew from the trial after wearing the machine initially, and one subject did not wear the machine after the baseline in-hospital assessments. Machine use was a little lower in the subtherapeutic group (Tables 1 and E1). The median overnight pressure delivered by the therapeutic machine was 10.0 (interquartile range, 9.5–10.5) cm H2O, compared with a median pressure of 2.5 (2.5–3.0) for the subtherapeutic machine, p value less than 0.001. We also calculated that the pressure–time index (median overnight pressure × average compliance per night) for the therapeutic group median was 50.4 (35.2–61.1) cm H2O hours per night versus 7.1 (3.7–12.2) cm H2O hours per night for the subtherapeutic group (p < 0.001, Mann–Whitney U test). Therapeutic ASV was technically more effective in controlling the Cheyne–Stokes breathing when compared with the subtherapeutic control; average apnea/hypopnea index measured by the ASV machines was 5.0 (1.4) per hour on therapeutic ASV, average on subtherapeutic ASV was 20.6 (2.3) per hour, and the difference was 15.6 (2.3) per hour (95% confidence interval, 10.9–20.3 per hour; p < 0.001, paired t test). Similarly in subjects who attended for the follow-up, the machine-recorded apnea/hypopnea index was lower in the subjects receiving therapeutic ASV (5.4 [1.9]) than with subtherapeutic ASV (14.7 [3.2]), and the difference was 9.3 (95% confidence interval, 2.1–16.5 per hour; p = 0.01, unpaired test).
With control of the nocturnal Cheyne–Stokes ventilation there was a reduction in daytime hyperventilation, and daytime CO2 rose in the therapeutic group from 4.9 (0.2) kPa at baseline to 5.4 (0.2) kPa at follow-up (p = 0.002, paired t test). There was no difference in 3% SaO2 dip rate with subtherapeutic ASV, with baseline value of 20.7 (2.9), follow-up value of 21.8 (4.8), and p value of 0.77, and daytime ventilation was unchanged, with baseline CO2 value of 5.0 (0.2), follow-up value of 4.9 (0.2), and p value of 0.57. No differences were seen in primary or secondary endpoints on paired samples t tests with the subtherapeutic control machine (Tables 2, E3, and E4; Figure 2).
This study demonstrates that patients with Cheyne–Stokes breathing and symptomatic chronic heart failure improve the time they can remain awake when they are given therapeutic ASV. This improvement of 8.9 minutes is confirmed to be a treatment effect by comparison with a robust control, subtherapeutic ASV, which did not change measured sleepiness. The change before and after therapeutic ASV treatment was proved to be significant with paired t tests. The improvement seen with therapeutic ASV is unlikely to be due to increased compliance as there was no relationship between machine use and sleepiness improvement overall or within either the therapeutic or the subtherapeutic groups.
The magnitude of this therapeutic effect is large. It is similar to the 7 minutes improvement produced by the treatment of obstructive sleep apnea with nasal CPAP therapy (12) and substantially larger than the 3 minute improvement seen with patients with narcolepsy treated with the routinely used alerting agent, Modafinil (13). In all, 77% of the 30 subjects at baseline had an abnormal Osler test result of less than 40 minutes. After therapeutic ASV, this had fallen to 40% of subjects, implying a “number needed to treat” to restore one subject to normality of only 2.5.
The size of the improvement in objectively measured sleepiness with therapeutic ASV has been calculated on an intention to treat basis, with no change in sleepiness from baseline being assumed in subjects with incomplete follow up data. If the results are analyzed only in the 26 subjects with complete Osler test data, the benefit from therapeutic ASV is little changed. Change in Osler test values with therapeutic ASV was +7.9 (2.9) and with subtherapeutic ASV was −1.3 (2.4), and the difference was 9.2 (95% confidence interval, 1–14.5; p = 0.03).
It is disappointing that the large primary endpoint benefit is not associated with subjective symptom benefit on the general or disease-specific health status questionnaires or in the driving simulator performance. The energy and vitality domain of the short-form 36 is sensitive to treatment effects in obstructive sleep apnea and might have been expected to be informative in Cheyne–Stokes breathing. In fact, in this study there is a weak trend toward this index showing improvement, with an effect size of 0.3 (mean change with therapeutic ASV, 3.3; SD of baseline, 11). Unfortunately, this trial is too small to assess whether this improvement is real, and it is possible that the duration of this trial was too short to have improved these quality of life endpoints. A larger study to clarify whether such a benefit is real would be clinically important as health status improvements with an effect size of above 0.2 are generally considered worthwhile (14). Such a study would require 340 subjects (α = 0.05; power, 90%). If ASV does improve health status to this extent, this would be a larger “quality of life” benefit than is seen with other well-established heart failure therapies such as angiotensin-converting enzyme ACE inhibitors (15).
This primary endpoint result is supported by improvements in two secondary endpoints, BNP and urinary metadrenaline excretion. At baseline the elevated BNP levels confirmed moderate to severe cardiac failure (16) (Tables 2 and E4), and the reduction in BNP with therapeutic ASV (median, −56 pg/ml; mean, −310 pg/ml) was comparable with that achieved in patients with similar severity of heart failure after their medical therapy is optimized (mean, −79.0 pg/ml) (17). These results suggest that as well as improving symptoms, ASV may improve cardiac volume loading conditions and so might lead to a reduction in cardiac morbidity (18).
The change in adrenaline metabolite excretion was surprising as previous trials in this area suggest that noradrenaline metabolites are more specifically increased with sleep-disordered breathing. With this small trial and the number of comparisons performed on the secondary endpoints, this may represent a chance finding. In support of previous trials, however, there was a weak trend toward reduced noradrenaline metabolite excretion in the therapeutic group, −36.6 (21.3) μmol/mmol/creatinine, versus the subtherapeutic controls, −2.3 (13.7) μmol/mmol/creatinine, and the p value was 0.19.
The improvements seen in BNP did not correlate with improved echocardiographic function. The echocardiography examinations used standard M Mode and two-dimensional views, but due to technical difficulties, ejection fraction was reported for both baseline and follow-up in 25 patients and fractional shortening in 23. Mitral regurgitation was reported in 28 of the patients: 3 severe, 10 moderate, and 15 mild. The reported ejection fraction was higher than expected compared with other trials in this area (11, 19–21) and when compared with functional class and BNP levels of the subjects studied. This may represent a bias with the methods used by the technicians performing the studies and could have limited the ability of the trial to demonstrate a change. Other trials have shown improved cardiac function over 3 months (11, 19), and it is possible that this study was too short to have shown a difference. Further large trials with more sophisticated cardiac imaging and functional assessment are needed in this area.
In contrast to previous reports, the prevalence of Cheyne–Stokes breathing in this study sample was lower than expected (2). The reasons for this may be that first there was no selection bias introduced through screening only patients with daytime symptoms, second the initial screening study was from community-based overnight oximetry with the saturation dip rate estimated from the full length of recording and no adjustment was possible for time in bed or asleep, which would tend to underestimate the prevalence of sleep-disordered breathing, and third there has been a recent trend toward more aggressive management of patients with cardiac failure, which may have reduced the prevalence of sleep-disordered breathing.
The patients studied here are typical of those with chronic heart failure. They are elderly, breathless, have objectively impaired left ventricular function, high levels of BNP, and require diuretic and vasodilator medication for symptom control (Table E1). Despite this typical clinical profile and clinically characteristic Cheyne–Stokes breathing, a significant minority of the episodes of sleeping apnea were associated with polysomnographic evidence of some pharyngeal airway collapse. Presumably, this airway collapse is due to falling pharyngeal muscle tone as the phasic afferent breathing–associated neural drive to these muscles declines as a central apnea develops (22, 23). As well as being physiologically interesting, the presence of airway collapse raises the possibility that some of the therapeutic benefits we have shown with ASV could be achieved by simply maintaining airway patency with positive airway pressure. There is a substantial literature to support positive airway pressure as a therapeutic candidate in chronic heart failure. It can sometimes improve cardiac loading conditions and ejection fraction, reduce the severity of Cheyne–Stokes breathing, and perhaps reduce clinical symptoms (11, 19–21, 24, 25). However, not all investigators have demonstrated such improvements (26).
The therapeutic role on CPAP in heart failure is currently being assessed in a clinical trial comparing it with ‘best supportive care’ (27). If this trial shows a therapeutic benefit from CPAP, then comparative studies of ASV versus CPAP will be required to define their relative therapeutic efficacies and to compare their cost/benefit ratios.
The patients studied here were identified by screening a population not primarily complaining of excessive sleepiness, though they all described the heart failure syndrome, which includes tiredness and exhaustion, possibly attributable to sleep disturbance. This contrasts with most trials in obstructive sleep apnea, where subjects have presented symptomatic and requesting treatment. This is confirmed by the baseline Epworth sleepiness score in this trial of 10, which is only mildly abnormal and substantially less than is seen in most obstructive sleep apnea trials (12, 28). In view of this mild sleepiness, the size of the effect we have seen on objective sleepiness is surprisingly large and might have been greater still had the trial focused on subjects complaining of greater sleepiness at baseline.
From its earliest descriptions, Cheyne–Stokes breathing was recognized to be more frequent during sleep and associated with disturbed sleep. It is also associated with a greater severity of heart failure (29) and has often (29, 30), though not always (31), been found to be an independent predictor of poor prognosis. Despite this linkage with severity, it remains unclear whether Cheyne–Stokes breathing is worthy of treatment in its own right. This may be because other treatments are less effective than ASV in stabilizing breathing, making it difficult to identify treatment effects in small sized trials. Nocturnal supplemental oxygen reduces the severity of Cheyne–Stokes breathing by between 40 and 75% (25, 32) and simple CPAP by about 60% (33, 34). In a randomized trial comparing oxygen, simple CPAP, pressure support ventilation, and ASV for a single night, oxygen and CPAP reduced the number of sleeping apneas by 37 and 40%, respectively, whereas ASV reduced the number of apneas by 86% (7).
This trial now shows that ASV produces clinically significant symptom improvements in heart failure patients and may also improve the cardiac loading conditions. Thus, as well as showing some therapeutic efficacy for ASV, this trial contributes to the evidence that Cheyne–Stokes breathing is responsible for significant clinical symptomatology in its own right.
This trial shows that ASV is more effective than a subtherapeutic control in correcting Cheyne–Stokes breathing in chronic heart failure. After 1 month's therapy, this improvement is associated with clinically significant reduction in objectively measured daytime sleepiness, a fall in BNP (a marker of cardiac loading), and urinary metadrenaline excretion. These results suggest that this novel therapy produces useful clinical benefit in patients with chronic heart failure associated with Cheyne–Stokes breathing.
The authors wish to thank Professor H. Watkins, Dr. O. Ormerod, Dr. Y. Bashir, Dr. A. P. Banning, Dr. K. M. Channon, Dr. I. R. Arnold, Dr. C. P. Clifford, and Dr. P. Davey for allowing us to approach their patients, and Mr. A. Prothero for his assistance with the echocardiograms.
| 1. | Yasuma F, Nomura H, Hayashi H, Okada T, Tsuzuki M. Breathing abnormalities during sleep in patients with chronic heart failure. Jpn Circ J 1989;53:1506–1510. |
| 2. | Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation 1998;97:2154–2159. |
| 3. | Davies RJ, Bennett LS, Barbour C, Tarassenko L, Stradling JR. Second by second patterns in cortical electroencephalograph and systolic blood pressure during Cheyne-Stokes. Eur Respir J 1999;14:940–945. |
| 4. | Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA, Kryger MH. Respiration and abnormal sleep in patients with congestive heart failure. Chest 1989;96:480–488. |
| 5. | Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995;152:473–479. |
| 6. | Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819–823. |
| 7. | Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001;164:614–619. |
| 8. | Pepperell JCT, Maskell NA, Langford-Wiley BA, Crosthwaite N, Stradling JR, Davies RJO. Prospective randomized controlled trial of adaptive proportional assist ventilation v sub-therapeutic control in chronic heart failure with Cheyne-Stokes breathing [abstract]. Am J Respir Crit Care Med 2002;165:A248. |
| 9. | Rechtschaffen A, Kales A. A Manual of Standardised Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Washington, DC: National Institutes of Health; 1968. Publication No. 204. |
| 10. | Bennett LS, Stradling JR, Davies RJO. A behavioural test to assess daytime sleepiness in obstructive sleep apnoea. J Sleep Res 1997;6:142–145. |
| 11. | Naughton MT, Liu PP, Bernard DC, Goldstein RS, Bradley TD. Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995;151:92–97. |
| 12. | Jenkinson C, Davies RJ, Mullins R, Stradling JR. Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 1999;353:2100–2105. |
| 13. | Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol 1998;43:88–97. |
| 14. | Cohen J. Statistical power for the behavioral sciences. New York: Academic Press; 1977. |
| 15. | Jenkinson C, Jenkinson D, Shepperd S, Layte R, Petersen S. Evaluation of treatment for congestive heart failure in patients aged 60 years and older using generic measures of health status (SF36 and COOP charts). Age Aging 1997;26:7–13. |
| 16. | Clerico A, Iervasi G, Del Chicca MG, Emdin M, Maffei S, Nannipieri M, Sabatino L, Forini F, Manfredi C, Donato L. Circulating levels of cardiac natriuretic peptides (ANP and BNP) measured by highly sensitive and specific immunoradiometric assays in normal subjects and in patients with different degrees of heart failure. J Endocrinol Invest 1998;21:170–179. |
| 17. | Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma amino-terminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126–1130. |
| 18. | Richards AM, Nicholls MG, Yandle TG, Frampton C, Espiner EA, Turner JG, Buttimore RC, Lainchbury JG, Elliott JM, Ikram H, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation 1998;97:1921–1929. |
| 19. | Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000;102:61–66. |
| 20. | Kohnlein T, Welte T, Tan LB, Elliott MW. Assisted ventilation for heart failure patients with Cheyne-Stokes respiration. Eur Respir J 2002;20:934–941. |
| 21. | Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation 2000;101:392–397. |
| 22. | Onal E, Burrows DL, Hart RH, Lopata M. Induction of periodic breathing during sleep causes upper airway obstruction in humans. J Appl Physiol 1986;61:1438–1443. |
| 23. | Weiner D, Mitra J, Salamone J, Cherniack NS. Effect of chemical stimuli on nerves supplying upper airway muscles. J Appl Physiol 1982;52:530–536. |
| 24. | Naughton MT, Rahman MA, Hara K, Floras JS, Bradley TD. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation 1995;91:6–31. |
| 25. | Krachman SL, D'Alonzo GE, Berger TJ, Eisen HJ. Comparison of oxygen therapy with nasal continuous positive airway pressure on Cheyne-Stokes respiration during sleep in congestive heart failure. Chest 1999;116:1550–1557. |
| 26. | Davies RJO, Harrington KJ, Ormerod OJM, Stradling JR. Nasal continuous positive airway pressure in chronic heart failure with sleep-disordered breathing. Am Rev Respir Dis 1993;147:630–634. |
| 27. | Bradley TD, Logan AG, Floras JS. Rationale and design of the Canadian Continuous Positive Airway Pressure Trial for Congestive Heart Failure patients with Central Sleep Apnea: CANPAP. Can J Cardiol 2001;17:677–684. |
| 28. | Pepperell JCT, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C, Stradling JR, Davies RJO. Ambulatory blood pressure following therapeutic and sub-therapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 2002;359:204–210. |
| 29. | Javaheri S. Central sleep apnea-hypopnea syndrome in heart failure: prevalence, impact, and treatment. Sleep 1996;19:S229–S231. |
| 30. | Lanfranchi PA, Braghiroli A, Bosimini E, Mazzuero G, Colombo R, Donner CF, Giannuzzi P. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999;99:1435–1440. |
| 31. | Andreas S, Hagenah G, Moller C, Werner GS, Kreuzer H. Cheyne-Stokes respiration and prognosis in congestive heart failure. Am J Cardiol 1996;78:1260–1264. |
| 32. | Staniforth AD, Kinnear WJ, Starling R, Hetmanski DJ, Cowley AJ. Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur Heart J 1998;19:922–928. |
| 33. | Naughton MT, Benard DC, Rutherford R, Bradley TD. Effect of continuous positive airway pressure on central sleep apnea and nocturnal PCO2 in heart failure. Am J Respir Crit Care Med 1994;150:6–604. |
| 34. | Javaheri S. Treatment of central sleep apnea in heart failure. Sleep 2000;23:S224–S227. |
