- Email: [email protected]
Sleep apnea in heart transplant recipients: type, symptoms, risk factors, and response to nasal continuous positive airway pressure
Sleep Apnea in Heart Transplant Recipients: Type, Symptoms, Risk Factors, and Response to Nasal Continuous Positive Airway Pressure Emmanouil S. Brilakis, MD,a Eric J. Olson, MD,b Christopher G. A. McGregor, MD,c and Lyle J. Olson, MDa Background: We determined the type, symptoms, and risk factors for sleep apnea in heart transplant recipients and the response to nasal continuous positive airway pressure. Methods: A retrospective study on heart transplant recipients with sleep apnea was conducted in a tertiary care medical center with follow-up telephone interviews. Between February 1988 and August 1998, 147 patients underwent orthotopic heart transplantation at our institution. Seventeen patients (11.6%) who were suspected of having sleep apnea underwent polysomnography at a mean interval of 17.5 months after transplantation. Results: All were diagnosed with sleep apnea: 13 had obstructive sleep apnea and 4 had mixed sleep apnea. Mean age at polysomnography was 50.8 years (range, 24 – 67 years). The patients presented with snoring (100%), excessive daytime somnolence (65%), witnessed apneas (53%), and morning fatigue (53%). Sixteen (94%) had a mean weight gain of 10.4 kg after transplantation, and 1 patient lost 14.6 kg. In the 11 patients with obstructive sleep apnea who underwent nasal continuous positive airway pressure titration, significant improvements occurred in the apnea-hypopnea index (decreased from 37.6 to 10.4; p ⫽ 0.01) and mean arousal index (decreased from 44.5 to 19.4; p ⫽ 0.01). Only 2 of the 8 patients with sleep apnea for whom nasal continuous positive airway pressure was recommended continued to use it at the time of telephone follow-up. Conclusions: Sleep apnea, especially obstructive sleep apnea, occurs frequently in heart transplant recipients. Obstructive sleep apnea appears to present in the typical manner, and although a positive response to nasal continuous positive airway pressure can be documented by polysomnography, long-term use of nasal continuous positive airway pressure may be low. J Heart Lung Transplant 2000;19:330–336.
T
he term sleep apnea describes several syndromes characterized by disordered respiration during sleep that result in intermittent disruptions in gas exchange and sleep fragmentation.1 Encompassed syndromes include obstructive sleep apnea
(OSA), central sleep apnea and mixed sleep apnea.1 OSA describes repetitive episodes of airflow cessation because of upper airway occlusion, whereas central apnea is defined by lack of airflow and absent respiratory effort. The combination of ob-
From the aDivision of Cardiovascular Diseases and Internal Medicine, bDivision of Pulmonary and Critical Care Medicine and Internal Medicine, and cDivision of Cardiovascular Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota Submitted November 9, 1999; accepted January 10, 2000.
Reprint requests: Lyle J. Olson, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 55905. Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00067-X
330
The Journal of Heart and Lung Transplantation Volume 19, Number 4
structive and central features is termed “mixed apnea.” According to cross-sectional studies, sleep apnea is common in the general population.1– 4 Sleep apnea has been associated with neurobehavioral deficits and cardiovascular diseases, including hypertension,5–7 arrhythmias8 –12 including bradyarrhythmias,9 atrial fibrillation,10,11 and ventricular arrhythmias,11,12 and heart failure.13 However, the strength of these associations has been questioned recently.14 Sleep apnea, both obstructive and central, is common in patients with heart failure.11,13–17 Sleep apnea in heart transplant recipients has not been studied extensively (2 published abstracts,18,19 5 published papers: 2 case series20,21 and 3 case reports22–24). Some events of the posttransplant period (eg, the weight gain with the use of glucocorticoids) could precipitate or exacerbate OSA,20 and OSA itself could adversely affect the transplanted heart.21,22 We did a retrospective study with follow-up telephone interviews of 17 heart transplant recipients with sleep apnea in a tertiary care institution to determine the type, presenting symptoms, and risk factors for sleep apnea, as well as the response to nasal continuous positive airway pressure (nCPAP).
MATERIALS AND METHODS Data Collection Using the Mayo Clinic Rochester medical record registry and cross-index system, we performed a retrospective analysis of patients who underwent heart transplantation at our institution between February 1988 and August 1998 and were diagnosed subsequently with sleep apnea. A patient was diagnosed with sleep apnea if the apnea-hypopnea index (AHI), defined as the number of apneas or hypopneas per hour of sleep, was more than 5 and the symptoms were consistent. Clinical data abstracted from patient records included general demographic information, the etiology of heart failure, and the presenting symptoms. OSA data for risk factors were also collected, including anthropometric information, upper airway abnormalities, cushingoid features, and family history of OSA. Information about the modifiable OSA risk factors was recorded before heart transplantation and at the time of polysomnography. The study was approved by the Institutional Review Board of our institution before the data collection.
Polysomnography Each patient with suspected sleep disorder breathing underwent a comprehensive consultation in the
Brilakis et al.
331
Mayo Sleep Disorders Center, including a laboratory-based, technologist-attended, split-night sleep study. Electroencephalographic (C3-A2 or C4-A1, Fz-Cz, Cz-Oz), submental and anterior tibialis electromyographic, electro-oculographic, and electrocardiographic activity were recorded. Oxyhemoglobin saturation was measured by ear oximetry (Biox 3700 or 3704; Ohmeda, Louisville, CO). Oronasal airflow was monitored with thermocouples. Thoracic and abdominal respiratory activity were monitored by inductive plethysmography (Respitrace; Ambulatory Monitoring, Ardsly, NY). Snoring was assessed by a microphone attached to the patients’ bedclothes in proximity to the neck. A multichannel polygraph (Model 8-20D or 78D; Grass Instruments, Quincy, MA) was used to record the data. Apneas were defined as episodes of airflow cessation lasting for at least 10 seconds. They were considered obstructive if accompanied by continued respiratory effort, central in the absence of respiratory effort (as judged by lack of excursions in the thoracoabdominal plethysmography signals), or mixed if there was an initial lack of effort and a terminal obstructive component. Hypopneas were defined as episodes of oxyhemoglobin desaturation of at least 2% associated with a qualitative reduction in airflow lasting for at least 10 seconds. AHI was calculated separately for the 2 sleep position categories (supine and non-supine). Periodic limb movements were scored by standard criteria.25 A patient was diagnosed with periodic limb movement disorder if the periodic limb movement index (number of periodic limb movements per hour of sleep) was more than 5 and the symptoms were consistent. Sleep was scored in 30-second epochs according to standard criteria.26 Polysomnographic data abstracted included the AHI, arousal index (number of arousals per hour of sleep), sleep efficiency (total sleep time divided by the total time in bed), percentage of the total sleep time that oxygen saturation by pulse oximetry was less than 90%, and periodic limb movement index. For those patients who underwent a trial of nCPAP, the above indices were recorded before and after application of nCPAP.
Telephone Interviews Patients alive in December 1998 were contacted by telephone to determine continued use of nCPAP or the reason for discontinuing nCPAP. They were also asked about any change of sleep apnea-related symptoms (snoring, morning fatigue, paroxysmal nocturnal dyspnea, and excessive daytime sleepi-
332
Brilakis et al.
The Journal of Heart and Lung Transplantation April 2000
TABLE I Characteristics of the patients who were diagnosed with sleep apnea after heart transplantation Patient
Age, yr
Type of sleep apnea
AHI
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
48 52 63 66 25 47 49 36 55 67 24 54 63 48 59 64 44
OSA OSA† OSA† OSA OSA OSA OSA OSA OSA† OSA† OSA OSA† OSA Mixed Mixed Mixed Mixed
81 16 31 47 78 53 19.3 84 53 6 6 16 8 10 24 37 70
Dead*
Cause of heart failure Rheumatic CM CAD CAD Dilated CM Dilated CM Amyloidosis Amyloidosis Sarcoidosis CAD CAD Congenital CM Dilated CM CAD CAD Dilated CM Dilated CM CAD
Yes
Yes Yes Yes Yes
AHI, apnea-hypopnea index; CAD, coronary artery disease; CM, cardiomyopathy; OSA, obstructive sleep apnea. *Dead at the time of the interview (December 1998). † Coexistent periodic limb movement disorder.
ness) between the time of the initial diagnosis of sleep apnea and the time of the interview. Daytime sleepiness was quantified by the Epworth sleepiness scale.27
Statistics The mean AHI, mean arousal index, mean sleep efficiency, and mean percentage of total sleep time that oxygen saturation by pulse oximetry was less than 90% were recorded before and after nCPAP and compared by paired 2-sample t test for means. The sub-groups of patients with OSA and with mixed sleep apnea were analyzed separately. Posttransplantation survival for the patients with sleep apnea and the rest of the heart transplant recipients was calculated by the Kaplan-Meier method and compared by use of the log-rank test. Statistical differences in data were considered significant if p values were less than 0.05 for 2-sided alternatives.
have sleep apnea, all were white, and all except one were men. Mean age at diagnosis was 50.8 years. Thirteen of the patients (76%) had OSA, and 4 (24%) had mixed sleep apnea. Five patients (29%) with OSA also had periodic limb movement disorder, with a mean periodic limb movement index of 54. Two of those 5 patients had concomitant daytime restless leg syndrome. Patient symptoms (new or worsening) that prompted referral for polysomnography included snoring, excessive daytime sleepiness, witnessed apneas and morning fatigue (Table II). Ten of the patients (59%) had at least 1 symptom before heart transplantation.
TABLE II Prevalence of proposed sleep apnearelated symptoms before and after heart transplantation in 17 patients Patients, no. (%)
RESULTS Between February 1988 and August 1998 147 patients underwent orthotopic heart transplantation at our institution. One- and 5-year actuarial patient survival (Kaplan-Meier) were 94.3 ⫾ 2.0 and 84.0 ⫾ 3.6, respectively. Polysomnography was performed in 17 patients (11.6%) at a mean interval of 17.5 months (range, 2–51 months) after heart transplantation (Table I). All patients tested were found to
Symptom Snoring Excessive daytime sleepiness Witnessed apneas Morning fatigue
Present at polysomnography
Present before heart transplantation
17 (100) 11 (65)
10 (59) 3 (18)
9 (53) 9 (53)
3 (18) 0
The Journal of Heart and Lung Transplantation Volume 19, Number 4
Brilakis et al.
333
TABLE III Split-night polysomnographic
TABLE IV Change of symptoms and Epworth
variables* without and with nasal continuous positive airway pressure in 15 heart transplant recipients with sleep apnea
sleepiness score* of heart transplant recipients with sleep apnea treated with nasal continuous positive airway pressure according to the continuation of nasal continuous positive airway pressure at the time of the telephone interview
Variable
Without nCPAP
With nCPAP
P†
Patients, no. (%)
Patients with OSA (n ⫽ 11) AHI Arousal Index Sleep efficiency, % % TST ⬍90% saturation
38 ⫾ 29 10 ⫾ 12 45 ⫾ 25 19 ⫾ 8 80 ⫾ 12 84 ⫾ 8 24 ⫾ 28 2⫾3 Patients with mixed apnea (n ⫽ 4)
0.013 0.012 0.24 0.016
AHI Arousal Index Sleep efficiency, % % TST ⬍90% saturation
35 ⫾ 26 40 ⫾ 24 70 ⫾ 27 11 ⫾ 13
0.68 0.44 0.90 0.27
26 ⫾ 22 25 ⫾ 18 69 ⫾ 23 4⫾5
*Values are given as mean ⫾ SD. † Paired t test for means. AHI, apnea-hypopnea index; nCPAP, nasal continuous positive airway pressure; OSA, obstructive sleep apnea; TST, total sleep time.
Mean body mass index (BMI) at polysomnography was 26.6 (range, 19.7–31.1). Eleven patients (65%) had a BMI greater than 25, and 4 (24%) had a BMI greater than 30. A mean weight gain of 10.4 kg (range, 0.9 –24) was observed after transplantation in 16 patients (94%), whereas 1 patient lost 14.6 kg. This patient was subsequently diagnosed with Addison disease. Craniofacial abnormalities (narrowed lateral or anteroposterior pharyngeal diameters or both, nasal septum deviation, retrognathia, low-hanging soft palate) were present in 11 patients (65%). Insulin-requiring diabetes mellitus developed in 4 patients (24%) after heart transplantation. Cushingoid features (dorsocervical or central obesity) were present in 10 patients (59%). Three patients (18%) reported a positive family history of OSA. At the time of polysomnography, 14 patients (82%) were receiving a mean dose of 15 mg of prednisone, and 16 patients (94%) were receiving cyclosporine. Thirteen patients had OSA. Eleven OSA patients consented to a trial of nCPAP during the polysomnogram. The mean nCPAP pressure requirement was 8.6 cm H2O (range, 5–11). Ten of the 11 patients had significant improvement of their sleep continuity during the nCPAP titration. The mean AHI, mean arousal index, and mean percentage of time that oxygen saturation was lower than 90% also significantly improved (Table III).
Symptom change
Continued nCPAP (n ⫽ 2)
Stopped nCPAP (n ⫽ 6)
Snoring improvement 2 (100) 5 (83) Witnessed apneas improvement 2 (100) 4/5 (80) Morning fatigue improvement 2 (100) 2 (33) Paroxysmal nocturnal dyspnea 2 (100) 3/5 (60) improvement Epworth sleepiness score* At polysomnography 21.5 ⫾ 3.53 23 ⫾ 5.44 At telephone interview 14.5 ⫾ 2.12 21.5 ⫾ 4.5 *Values are given as mean ⫾ SD. nCPAP, nasal continuous positive airway pressure.
Four patients had mixed sleep apnea and underwent nCPAP titration. The mean nCPAP pressure requirement was 6.8 cm H2O (range, 5–9). No statistically significant differences in the polysomnographic indices were detected with nCPAP (Table III). Telephone interviews were conducted in December 1998, a mean of 54 months (range, 37–73) after polysomnography. Eleven of the 17 patients with sleep apnea were alive. One patient was not found, and another refused to participate. Nine patients were interviewed by telephone (8 had OSA and 1 had mixed sleep apnea). Eight of the 9 patients had been advised to use nCPAP. However, only 2 patients were still compliant with that recommendation at the time of the interview. Of the 6 patients who stopped nCPAP, 5 did so because of discomfort or inconvenience and 1 because of cost. Snoring, witnessed apneas, morning fatigue, paroxysmal nocturnal dyspnea, and excessive daytime sleepiness (estimated by using the Epworth sleepiness scale) improved in both groups (Table IV). Three- and 5-year post-transplant survival were 88% and 75%, respectively, for the patients with sleep apnea and 89% and 85% for the remaining heart transplant recipients (p ⫽ 0.092, log-rank test).
DISCUSSION Sleep apnea, primarily OSA, is common in the general population. The most widely cited preva-
334
Brilakis et al.
lence estimate comes from a community-based survey of middle-aged Wisconsin state employees in which 4% of men and 2% of women were found to have OSA, defined as AHI greater than 5 and daytime sleepiness.2 Prevalence of sleep apnea in heart transplant recipients has been reported to range between 2.5% and 43%.18 –20 Sleep apnea was present in 11.6% of our population, yet its prevalence was almost certainly underestimated because universal screening was not performed. Only patients with typical OSA symptoms (n ⫽ 17) underwent polysomnography, and sleep apnea was found in all of them. Underdetection of sleep apnea remains an important public health issue. Reasons for inadequate identification include the non-specific nature of many of the symptoms, the unavailability of collateral history from a bed partner, and the lack of formal sleep education for most health care providers. In the case of heart transplant recipients, the difficulties diagnosing sleep apnea may be compounded by the use of multiple medications, which may affect sleep, and the complexity of the posttransplant course. Central sleep apnea is common in patients awaiting heart transplantation.17 Even in the setting of stable congestive heart failure, periodic breathing with central apneas followed by crescendo-decrescendo respiration (Cheyne-Stokes breathing) may occur in 40% to 50% of patients mostly during stages 1 and 2 of non-rapid eye movement sleep.28,29 Central sleep apnea is thought to result primarily from an increased propensity of heart failure patients to hyperventilate, which maintains the PCO2 tenuously close to the apneic threshold.30 The ventilatory instability manifests clinically as paroxysmal nocturnal dyspnea, insomnia, and daytime sleepiness and is possibly a marker of increased mortality in heart failure patients.31–33 Cheyne-Stokes respiration usually resolves after heart transplantation.34,35 In this report and in others,19,20 OSA was the predominant form of sleep apnea post-transplant. Upper airway obstruction during sleep is the result of a complex interaction of anatomic, neuromuscular and mechanical factors.36 The strongest risk factors for OSA in the general population are obesity and male sex. Obesity is thought to act through upper airway fat deposition and thoracoabdominal mass loading. Androgenic hormones may alter upper airway musculature or central respiratory drive.2 These risk factors were well represented in our heart transplant patients found to have sleep apnea. All except one were men and 16 of the 17
The Journal of Heart and Lung Transplantation April 2000
patients had gained an average of 10 kg since transplant. Conventional craniofacial risk factors for OSA were also common in our population. Several features associated with the post-transplant period may influence the modifiable risk factors for OSA, as suggested by Klink and colleagues.20 Central adiposity due to glucocorticoid administration may increase the propensity to upper airway narrowing during sleep. Cushingoid features were present in 59% of our sleep apnea patients (10 of 17), and 82% (14 of 17) were receiving prednisone at the time of polysomnography. Diabetes mellitus simultaneously developed post-transplant in 24% of the patients (4 of 17). Diabetes has been implicated in the pathogenesis of OSA.37 The commonly used post-transplant combination of glucocorticoids and cyclosporine may negatively modulate insulin release and action, which could aggravate both OSA and diabetes mellitus.20 All of the patients, except one, were receiving cyclosporine at the time of polysomnography. The treatment of choice for most cases of OSA is nCPAP,38 yet initial acceptance of and compliance with nCPAP have been problematic occasionally. Initial studies incorporating objective measures of compliance demonstrated that patients tended to subjectively overestimate nCPAP use and that actual use was frequently sub-optimal.39,40 However, a more recently reported study of more than 500 patients with an AHI greater than 15 revealed an initial acceptance rate for nCPAP of 79% and an objectively documented acceptance rate of greater than 85% over 7 years.41 The poor compliance with nCPAP in our cohort is striking and difficult to explain retrospectively. The telephone follow-up disclosed that the majority of patients discontinued the use of nCPAP because of inconvenience. Admittedly, side effects from the pressure and nasal interfaces are common. Other potential explanations for poor compliance include insufficient nCPAP titration during the split-night protocol or overshadowing of the importance of nCPAP by other post-transplant challenges. Finally, it is possible that prednisone dose tapering with the concomitant weight loss contributed to the spontaneous improvement of the patients’ symptoms, obviating the need for nCPAP. To the best of our knowledge, this study is the first to reveal a high prevalence (29%) of periodic limb movement disorder in heart transplant recipients. Periodic limb movements are repetitive, stereotypic actions primarily of the legs that cause symptoms as a result of sleep fragmentation.1 Periodic limb
The Journal of Heart and Lung Transplantation Volume 19, Number 4
movements have been reported to occur in association with medical conditions, including heart failure. Hanly and Zuberi-Khokhar42 noted that approximately 50% of their severe, stable heart failure patients had periodic limb movements during sleep. The same authors reported the case of a patient with heart failure and periodic limb movement disorder, who improved after heart transplantation.23 Conclusions regarding the impact of heart transplantation on periodic limb movements cannot be drawn from our data given the lack of pre-transplant polysomnography in our patients. The repetitive intrathoracic pressure changes, hypoxia, and sleep fragmentation characteristic of OSA could negatively impact the transplanted heart. Heart transplant recipients with sleep apnea may be at increased risk for arrhythmias because the bradycardiac response to apnea and hypoxia is abolished.21 Although there are no large-scale longitudinal studies on the consequence of sleep apnea on heart transplant recipients, data are emerging to suggest that it may be deleterious to both quality of life and survival: a heart transplant recipient with severe OSA was reported to develop cor pulmonale.22 Post-transplant survival appeared to be worse in our patients with sleep apnea, though the difference was not statistically significant. Screening all heart transplant recipients with polysomnography, the standard for diagnosis, is impractical. Other methods for a rapid assessment of the risk for sleep apnea are necessary. In severe cases, a careful history (eliciting the presence of snoring, witnessed apneas, daytime somnolence, and morning fatigue) and physical examination (focusing on the presence of obesity, cushingoid features, and craniofacial abnormalities) may be enough to prompt referral for polysomnography. For less obvious cases, there are mathematical models that can predict the presence of OSA. One such model has been proposed recently by Kushida et al.43 It is a morphometric model, which combines measurements of the oral cavity with BMI and neck circumference to estimate the risk for OSA. Routine use of such a model could increase the rate of sleep apnea detection in the pre-transplant and the post-heart transplant settings. From this retrospective review, we conclude that sleep apnea, especially OSA, is common in heart transplant recipients. Heart transplant recipients with OSA have typical risk factors and present with the classic symptoms. Compliance with nCPAP may be poor despite polysomnographic evidence of efficacy. Given the common thread of immunosuppres-
Brilakis et al.
335
sants, OSA may be an important management issue across the post-transplant spectrum. REFERENCES 1. American Sleep Disorders Association. International classification of sleep disorders, revised: diagnostic and coding manual. Rochester, Minnesota: American Sleep Disorders Association; 1997. 2. Strohl KP, Redline S. Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 1996;154:279 – 89. 3. Strollo PJ Jr, Rogers RM. Obstructive sleep apnea. N Engl J Med 1996;334:99 –104. 4. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middleaged adults. N Engl J Med 1993;328:1230 –5. 5. Silverberg D, Oksenberg A, Iaina A. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and Obstructive Sleep Apnea: let their silence not be matched by the silence of the ordinary physician (letter). Arch Intern Med 1998;158:1272–3. 6. Worsnop CJ, Naughton MT, Barter CE, Morgan TO, Anderson AI, Pierce RJ. The prevalence of obstructive sleep apnea in hypertensives. Am J Respir Crit Care Med 1998;157: 111–5. 7. Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997;157:1746 –52. 8. Flemons WW, Remmers JE, Gillis AM. Sleep apnea and cardiac arrhythmias. Is there a relationship? Am Rev Respir Dis 1993;148:618 –21. 9. Koehler U, Fus E, Grimm W, et al. Heart block in patients with obstructive sleep apnoea: pathogenetic factors and effects of treatment. Eur Respir J 1998;11:434 –9. 10. Mooe T, Gullsby S, Rabben T, Eriksson P. Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis 1996;7:475– 8. 11. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97:2154 –9. 12. Javaheri S, Corbett WS. Association of low PaCO2 with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann Intern Med 1998;128:204 –7. 13. Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991;338:1480 – 4. 14. Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence. BMJ 1997;314:851– 60. 15. Bradley TD, Floras JS. Pathophysiologic and therapeutic implications of sleep apnea in congestive heart failure. J Card Fail 1996;2:223– 40. 16. 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;152:473–9. 17. Lofaso F, Verschueren P, Rande JL, Harf A, Goldenberg F. Prevalence of sleep-disordered breathing in patients on a heart transplant waiting list. Chest 1994;106:1689 –94.
336
Brilakis et al.
18. Shapiro CS, Romaker AM, Bresnahan DR Jr. Obstructive sleep apnea in cardiac transplant patients (abstract). Chest 1992;102:54S. 19. Ellahham SH, Nelson K, Schlutz MT, et al. Sleep-disordered breathing is common in cardiac transplant recipients (abstract). Chest 1992;102:54S. 20. Klink ME, Sethi GK, Copeland JG, Quan SF. Obstructive sleep apnea in heart transplant patients. A report of five cases. Chest 1993;104:1090 –2. 21. Madden BP, Shenoy V, Dalrymple-Hay M, et al. Absence of bradycardic response to apnea and hypoxia in heart transplant recipients with obstructive sleep apnea. J Heart Lung Transplant 1997;16:394 –7. 22. Nkere UU, Hall MC, Corris PA. Sleep apnoea/hypopnoea syndrome: a potential cause of graft failure following heart transplantation. Eur J Cardiothorac Surg 1998;13:203–5. 23. Hanly P, Zuberi N. Periodic leg movements during sleep before and after heart transplantation. Sleep 1992;15:489 –92. 24. Collop NA. Cheyne-Stokes ventilation converting to obstructive sleep apnea following heart transplantation. Chest 1993; 104:1288 –9. 25. The Atlas Task Force. Recording and scoring leg movements. Sleep 1993;16:748 –59. 26. Rechtschaffen A, Kales A, eds. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Bethesda, Maryland: U.S. Department of Health, Education, and Welfare, 1968. 27. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540 –5. 28. Javaheri S, Parker TJ, Wexler L, et al. Occult sleep-disordered breathing in stable congestive heart failure. Ann Intern Med 1995;122:487–92. 29. Naughton MT, Liu PP, Bernard DC, Goldstein RS, Bradley TD. Treatment of congestive heart failure and CheyneStokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995;151:92–7. 30. Naughton MT, Bradley TD. Sleep apnea in congestive heart failure. Clin Chest Med 1998;19:99 –113. 31. Andreas S, Hagenah G, Moller C, Werner GS, Kreuzer H.
The Journal of Heart and Lung Transplantation April 2000
32.
33.
34.
35.
36. 37. 38.
39.
40.
41.
42.
43.
Cheyne-Stokes respiration and prognosis in congestive heart failure. Am J Cardiol 1996;78:1260 – 4. Findley LJ, Zwillich CW, Ancoli-Israel S, Kripke D, Tisi G, Moser KM. Cheyne-Stokes breathing during sleep in patients with left ventricular heart failure. South Med J 1985;78:11–5. Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med 1996;153: 272– 6. Murdock DK, Lawless CE, Loeb HS, Scanlon PJ, Pifarre R. The effect of heart transplantation on Cheyne-Stokes respiration associated with congestive heart failure. J Heart Transplant 1986;5:336 –7. Braver HM, Brandes WC, Kubiet MA, Limacher MC, Mills RM Jr, Block AJ. Effect of cardiac transplantation on Cheyne-Stokes respiration occurring during sleep. Am J Cardiol 1995;76:632– 4. White DP. Sleep-related breathing disorder. 2. Pathophysiology of obstructive sleep apnoea. Thorax 1995;50:797– 804. Strohl KP. Diabetes and sleep apnea. Sleep 1996;19:S225– 8. American Thoracic Society. Indications and standards for use of nasal continuous positive airway pressure (CPAP) in sleep apnea syndromes. Am J Respir Crit Care Med 1994;150: 1738 – 45. Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:887–95. Reeves-Hoche MK, Meck R, Zwillich CW. Nasal CPAP: an objective evaluation of patient compliance. Am J Respir Crit Care Med 1994;149:149 –54. Krieger J, Kurtz D, Petiau C, Sforza E, Trautmann D. Long-term compliance with CPAP therapy in obstructive sleep apnea patients and in snorers. Sleep 1996;19:S136 – 43. Hanly PJ, Zuberi-Khokhar N. Periodic limb movements during sleep in patients with congestive heart failure. Chest 1996;109:1497–502. Kushida CA, Efron B, Guilleminault C. A predictive morphometric model for the obstructive sleep apnea syndrome. Ann Intern Med 1997;127:581–7.
T
he term sleep apnea describes several syndromes characterized by disordered respiration during sleep that result in intermittent disruptions in gas exchange and sleep fragmentation.1 Encompassed syndromes include obstructive sleep apnea
(OSA), central sleep apnea and mixed sleep apnea.1 OSA describes repetitive episodes of airflow cessation because of upper airway occlusion, whereas central apnea is defined by lack of airflow and absent respiratory effort. The combination of ob-
From the aDivision of Cardiovascular Diseases and Internal Medicine, bDivision of Pulmonary and Critical Care Medicine and Internal Medicine, and cDivision of Cardiovascular Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota Submitted November 9, 1999; accepted January 10, 2000.
Reprint requests: Lyle J. Olson, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 55905. Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00067-X
330
The Journal of Heart and Lung Transplantation Volume 19, Number 4
structive and central features is termed “mixed apnea.” According to cross-sectional studies, sleep apnea is common in the general population.1– 4 Sleep apnea has been associated with neurobehavioral deficits and cardiovascular diseases, including hypertension,5–7 arrhythmias8 –12 including bradyarrhythmias,9 atrial fibrillation,10,11 and ventricular arrhythmias,11,12 and heart failure.13 However, the strength of these associations has been questioned recently.14 Sleep apnea, both obstructive and central, is common in patients with heart failure.11,13–17 Sleep apnea in heart transplant recipients has not been studied extensively (2 published abstracts,18,19 5 published papers: 2 case series20,21 and 3 case reports22–24). Some events of the posttransplant period (eg, the weight gain with the use of glucocorticoids) could precipitate or exacerbate OSA,20 and OSA itself could adversely affect the transplanted heart.21,22 We did a retrospective study with follow-up telephone interviews of 17 heart transplant recipients with sleep apnea in a tertiary care institution to determine the type, presenting symptoms, and risk factors for sleep apnea, as well as the response to nasal continuous positive airway pressure (nCPAP).
MATERIALS AND METHODS Data Collection Using the Mayo Clinic Rochester medical record registry and cross-index system, we performed a retrospective analysis of patients who underwent heart transplantation at our institution between February 1988 and August 1998 and were diagnosed subsequently with sleep apnea. A patient was diagnosed with sleep apnea if the apnea-hypopnea index (AHI), defined as the number of apneas or hypopneas per hour of sleep, was more than 5 and the symptoms were consistent. Clinical data abstracted from patient records included general demographic information, the etiology of heart failure, and the presenting symptoms. OSA data for risk factors were also collected, including anthropometric information, upper airway abnormalities, cushingoid features, and family history of OSA. Information about the modifiable OSA risk factors was recorded before heart transplantation and at the time of polysomnography. The study was approved by the Institutional Review Board of our institution before the data collection.
Polysomnography Each patient with suspected sleep disorder breathing underwent a comprehensive consultation in the
Brilakis et al.
331
Mayo Sleep Disorders Center, including a laboratory-based, technologist-attended, split-night sleep study. Electroencephalographic (C3-A2 or C4-A1, Fz-Cz, Cz-Oz), submental and anterior tibialis electromyographic, electro-oculographic, and electrocardiographic activity were recorded. Oxyhemoglobin saturation was measured by ear oximetry (Biox 3700 or 3704; Ohmeda, Louisville, CO). Oronasal airflow was monitored with thermocouples. Thoracic and abdominal respiratory activity were monitored by inductive plethysmography (Respitrace; Ambulatory Monitoring, Ardsly, NY). Snoring was assessed by a microphone attached to the patients’ bedclothes in proximity to the neck. A multichannel polygraph (Model 8-20D or 78D; Grass Instruments, Quincy, MA) was used to record the data. Apneas were defined as episodes of airflow cessation lasting for at least 10 seconds. They were considered obstructive if accompanied by continued respiratory effort, central in the absence of respiratory effort (as judged by lack of excursions in the thoracoabdominal plethysmography signals), or mixed if there was an initial lack of effort and a terminal obstructive component. Hypopneas were defined as episodes of oxyhemoglobin desaturation of at least 2% associated with a qualitative reduction in airflow lasting for at least 10 seconds. AHI was calculated separately for the 2 sleep position categories (supine and non-supine). Periodic limb movements were scored by standard criteria.25 A patient was diagnosed with periodic limb movement disorder if the periodic limb movement index (number of periodic limb movements per hour of sleep) was more than 5 and the symptoms were consistent. Sleep was scored in 30-second epochs according to standard criteria.26 Polysomnographic data abstracted included the AHI, arousal index (number of arousals per hour of sleep), sleep efficiency (total sleep time divided by the total time in bed), percentage of the total sleep time that oxygen saturation by pulse oximetry was less than 90%, and periodic limb movement index. For those patients who underwent a trial of nCPAP, the above indices were recorded before and after application of nCPAP.
Telephone Interviews Patients alive in December 1998 were contacted by telephone to determine continued use of nCPAP or the reason for discontinuing nCPAP. They were also asked about any change of sleep apnea-related symptoms (snoring, morning fatigue, paroxysmal nocturnal dyspnea, and excessive daytime sleepi-
332
Brilakis et al.
The Journal of Heart and Lung Transplantation April 2000
TABLE I Characteristics of the patients who were diagnosed with sleep apnea after heart transplantation Patient
Age, yr
Type of sleep apnea
AHI
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
48 52 63 66 25 47 49 36 55 67 24 54 63 48 59 64 44
OSA OSA† OSA† OSA OSA OSA OSA OSA OSA† OSA† OSA OSA† OSA Mixed Mixed Mixed Mixed
81 16 31 47 78 53 19.3 84 53 6 6 16 8 10 24 37 70
Dead*
Cause of heart failure Rheumatic CM CAD CAD Dilated CM Dilated CM Amyloidosis Amyloidosis Sarcoidosis CAD CAD Congenital CM Dilated CM CAD CAD Dilated CM Dilated CM CAD
Yes
Yes Yes Yes Yes
AHI, apnea-hypopnea index; CAD, coronary artery disease; CM, cardiomyopathy; OSA, obstructive sleep apnea. *Dead at the time of the interview (December 1998). † Coexistent periodic limb movement disorder.
ness) between the time of the initial diagnosis of sleep apnea and the time of the interview. Daytime sleepiness was quantified by the Epworth sleepiness scale.27
Statistics The mean AHI, mean arousal index, mean sleep efficiency, and mean percentage of total sleep time that oxygen saturation by pulse oximetry was less than 90% were recorded before and after nCPAP and compared by paired 2-sample t test for means. The sub-groups of patients with OSA and with mixed sleep apnea were analyzed separately. Posttransplantation survival for the patients with sleep apnea and the rest of the heart transplant recipients was calculated by the Kaplan-Meier method and compared by use of the log-rank test. Statistical differences in data were considered significant if p values were less than 0.05 for 2-sided alternatives.
have sleep apnea, all were white, and all except one were men. Mean age at diagnosis was 50.8 years. Thirteen of the patients (76%) had OSA, and 4 (24%) had mixed sleep apnea. Five patients (29%) with OSA also had periodic limb movement disorder, with a mean periodic limb movement index of 54. Two of those 5 patients had concomitant daytime restless leg syndrome. Patient symptoms (new or worsening) that prompted referral for polysomnography included snoring, excessive daytime sleepiness, witnessed apneas and morning fatigue (Table II). Ten of the patients (59%) had at least 1 symptom before heart transplantation.
TABLE II Prevalence of proposed sleep apnearelated symptoms before and after heart transplantation in 17 patients Patients, no. (%)
RESULTS Between February 1988 and August 1998 147 patients underwent orthotopic heart transplantation at our institution. One- and 5-year actuarial patient survival (Kaplan-Meier) were 94.3 ⫾ 2.0 and 84.0 ⫾ 3.6, respectively. Polysomnography was performed in 17 patients (11.6%) at a mean interval of 17.5 months (range, 2–51 months) after heart transplantation (Table I). All patients tested were found to
Symptom Snoring Excessive daytime sleepiness Witnessed apneas Morning fatigue
Present at polysomnography
Present before heart transplantation
17 (100) 11 (65)
10 (59) 3 (18)
9 (53) 9 (53)
3 (18) 0
The Journal of Heart and Lung Transplantation Volume 19, Number 4
Brilakis et al.
333
TABLE III Split-night polysomnographic
TABLE IV Change of symptoms and Epworth
variables* without and with nasal continuous positive airway pressure in 15 heart transplant recipients with sleep apnea
sleepiness score* of heart transplant recipients with sleep apnea treated with nasal continuous positive airway pressure according to the continuation of nasal continuous positive airway pressure at the time of the telephone interview
Variable
Without nCPAP
With nCPAP
P†
Patients, no. (%)
Patients with OSA (n ⫽ 11) AHI Arousal Index Sleep efficiency, % % TST ⬍90% saturation
38 ⫾ 29 10 ⫾ 12 45 ⫾ 25 19 ⫾ 8 80 ⫾ 12 84 ⫾ 8 24 ⫾ 28 2⫾3 Patients with mixed apnea (n ⫽ 4)
0.013 0.012 0.24 0.016
AHI Arousal Index Sleep efficiency, % % TST ⬍90% saturation
35 ⫾ 26 40 ⫾ 24 70 ⫾ 27 11 ⫾ 13
0.68 0.44 0.90 0.27
26 ⫾ 22 25 ⫾ 18 69 ⫾ 23 4⫾5
*Values are given as mean ⫾ SD. † Paired t test for means. AHI, apnea-hypopnea index; nCPAP, nasal continuous positive airway pressure; OSA, obstructive sleep apnea; TST, total sleep time.
Mean body mass index (BMI) at polysomnography was 26.6 (range, 19.7–31.1). Eleven patients (65%) had a BMI greater than 25, and 4 (24%) had a BMI greater than 30. A mean weight gain of 10.4 kg (range, 0.9 –24) was observed after transplantation in 16 patients (94%), whereas 1 patient lost 14.6 kg. This patient was subsequently diagnosed with Addison disease. Craniofacial abnormalities (narrowed lateral or anteroposterior pharyngeal diameters or both, nasal septum deviation, retrognathia, low-hanging soft palate) were present in 11 patients (65%). Insulin-requiring diabetes mellitus developed in 4 patients (24%) after heart transplantation. Cushingoid features (dorsocervical or central obesity) were present in 10 patients (59%). Three patients (18%) reported a positive family history of OSA. At the time of polysomnography, 14 patients (82%) were receiving a mean dose of 15 mg of prednisone, and 16 patients (94%) were receiving cyclosporine. Thirteen patients had OSA. Eleven OSA patients consented to a trial of nCPAP during the polysomnogram. The mean nCPAP pressure requirement was 8.6 cm H2O (range, 5–11). Ten of the 11 patients had significant improvement of their sleep continuity during the nCPAP titration. The mean AHI, mean arousal index, and mean percentage of time that oxygen saturation was lower than 90% also significantly improved (Table III).
Symptom change
Continued nCPAP (n ⫽ 2)
Stopped nCPAP (n ⫽ 6)
Snoring improvement 2 (100) 5 (83) Witnessed apneas improvement 2 (100) 4/5 (80) Morning fatigue improvement 2 (100) 2 (33) Paroxysmal nocturnal dyspnea 2 (100) 3/5 (60) improvement Epworth sleepiness score* At polysomnography 21.5 ⫾ 3.53 23 ⫾ 5.44 At telephone interview 14.5 ⫾ 2.12 21.5 ⫾ 4.5 *Values are given as mean ⫾ SD. nCPAP, nasal continuous positive airway pressure.
Four patients had mixed sleep apnea and underwent nCPAP titration. The mean nCPAP pressure requirement was 6.8 cm H2O (range, 5–9). No statistically significant differences in the polysomnographic indices were detected with nCPAP (Table III). Telephone interviews were conducted in December 1998, a mean of 54 months (range, 37–73) after polysomnography. Eleven of the 17 patients with sleep apnea were alive. One patient was not found, and another refused to participate. Nine patients were interviewed by telephone (8 had OSA and 1 had mixed sleep apnea). Eight of the 9 patients had been advised to use nCPAP. However, only 2 patients were still compliant with that recommendation at the time of the interview. Of the 6 patients who stopped nCPAP, 5 did so because of discomfort or inconvenience and 1 because of cost. Snoring, witnessed apneas, morning fatigue, paroxysmal nocturnal dyspnea, and excessive daytime sleepiness (estimated by using the Epworth sleepiness scale) improved in both groups (Table IV). Three- and 5-year post-transplant survival were 88% and 75%, respectively, for the patients with sleep apnea and 89% and 85% for the remaining heart transplant recipients (p ⫽ 0.092, log-rank test).
DISCUSSION Sleep apnea, primarily OSA, is common in the general population. The most widely cited preva-
334
Brilakis et al.
lence estimate comes from a community-based survey of middle-aged Wisconsin state employees in which 4% of men and 2% of women were found to have OSA, defined as AHI greater than 5 and daytime sleepiness.2 Prevalence of sleep apnea in heart transplant recipients has been reported to range between 2.5% and 43%.18 –20 Sleep apnea was present in 11.6% of our population, yet its prevalence was almost certainly underestimated because universal screening was not performed. Only patients with typical OSA symptoms (n ⫽ 17) underwent polysomnography, and sleep apnea was found in all of them. Underdetection of sleep apnea remains an important public health issue. Reasons for inadequate identification include the non-specific nature of many of the symptoms, the unavailability of collateral history from a bed partner, and the lack of formal sleep education for most health care providers. In the case of heart transplant recipients, the difficulties diagnosing sleep apnea may be compounded by the use of multiple medications, which may affect sleep, and the complexity of the posttransplant course. Central sleep apnea is common in patients awaiting heart transplantation.17 Even in the setting of stable congestive heart failure, periodic breathing with central apneas followed by crescendo-decrescendo respiration (Cheyne-Stokes breathing) may occur in 40% to 50% of patients mostly during stages 1 and 2 of non-rapid eye movement sleep.28,29 Central sleep apnea is thought to result primarily from an increased propensity of heart failure patients to hyperventilate, which maintains the PCO2 tenuously close to the apneic threshold.30 The ventilatory instability manifests clinically as paroxysmal nocturnal dyspnea, insomnia, and daytime sleepiness and is possibly a marker of increased mortality in heart failure patients.31–33 Cheyne-Stokes respiration usually resolves after heart transplantation.34,35 In this report and in others,19,20 OSA was the predominant form of sleep apnea post-transplant. Upper airway obstruction during sleep is the result of a complex interaction of anatomic, neuromuscular and mechanical factors.36 The strongest risk factors for OSA in the general population are obesity and male sex. Obesity is thought to act through upper airway fat deposition and thoracoabdominal mass loading. Androgenic hormones may alter upper airway musculature or central respiratory drive.2 These risk factors were well represented in our heart transplant patients found to have sleep apnea. All except one were men and 16 of the 17
The Journal of Heart and Lung Transplantation April 2000
patients had gained an average of 10 kg since transplant. Conventional craniofacial risk factors for OSA were also common in our population. Several features associated with the post-transplant period may influence the modifiable risk factors for OSA, as suggested by Klink and colleagues.20 Central adiposity due to glucocorticoid administration may increase the propensity to upper airway narrowing during sleep. Cushingoid features were present in 59% of our sleep apnea patients (10 of 17), and 82% (14 of 17) were receiving prednisone at the time of polysomnography. Diabetes mellitus simultaneously developed post-transplant in 24% of the patients (4 of 17). Diabetes has been implicated in the pathogenesis of OSA.37 The commonly used post-transplant combination of glucocorticoids and cyclosporine may negatively modulate insulin release and action, which could aggravate both OSA and diabetes mellitus.20 All of the patients, except one, were receiving cyclosporine at the time of polysomnography. The treatment of choice for most cases of OSA is nCPAP,38 yet initial acceptance of and compliance with nCPAP have been problematic occasionally. Initial studies incorporating objective measures of compliance demonstrated that patients tended to subjectively overestimate nCPAP use and that actual use was frequently sub-optimal.39,40 However, a more recently reported study of more than 500 patients with an AHI greater than 15 revealed an initial acceptance rate for nCPAP of 79% and an objectively documented acceptance rate of greater than 85% over 7 years.41 The poor compliance with nCPAP in our cohort is striking and difficult to explain retrospectively. The telephone follow-up disclosed that the majority of patients discontinued the use of nCPAP because of inconvenience. Admittedly, side effects from the pressure and nasal interfaces are common. Other potential explanations for poor compliance include insufficient nCPAP titration during the split-night protocol or overshadowing of the importance of nCPAP by other post-transplant challenges. Finally, it is possible that prednisone dose tapering with the concomitant weight loss contributed to the spontaneous improvement of the patients’ symptoms, obviating the need for nCPAP. To the best of our knowledge, this study is the first to reveal a high prevalence (29%) of periodic limb movement disorder in heart transplant recipients. Periodic limb movements are repetitive, stereotypic actions primarily of the legs that cause symptoms as a result of sleep fragmentation.1 Periodic limb
The Journal of Heart and Lung Transplantation Volume 19, Number 4
movements have been reported to occur in association with medical conditions, including heart failure. Hanly and Zuberi-Khokhar42 noted that approximately 50% of their severe, stable heart failure patients had periodic limb movements during sleep. The same authors reported the case of a patient with heart failure and periodic limb movement disorder, who improved after heart transplantation.23 Conclusions regarding the impact of heart transplantation on periodic limb movements cannot be drawn from our data given the lack of pre-transplant polysomnography in our patients. The repetitive intrathoracic pressure changes, hypoxia, and sleep fragmentation characteristic of OSA could negatively impact the transplanted heart. Heart transplant recipients with sleep apnea may be at increased risk for arrhythmias because the bradycardiac response to apnea and hypoxia is abolished.21 Although there are no large-scale longitudinal studies on the consequence of sleep apnea on heart transplant recipients, data are emerging to suggest that it may be deleterious to both quality of life and survival: a heart transplant recipient with severe OSA was reported to develop cor pulmonale.22 Post-transplant survival appeared to be worse in our patients with sleep apnea, though the difference was not statistically significant. Screening all heart transplant recipients with polysomnography, the standard for diagnosis, is impractical. Other methods for a rapid assessment of the risk for sleep apnea are necessary. In severe cases, a careful history (eliciting the presence of snoring, witnessed apneas, daytime somnolence, and morning fatigue) and physical examination (focusing on the presence of obesity, cushingoid features, and craniofacial abnormalities) may be enough to prompt referral for polysomnography. For less obvious cases, there are mathematical models that can predict the presence of OSA. One such model has been proposed recently by Kushida et al.43 It is a morphometric model, which combines measurements of the oral cavity with BMI and neck circumference to estimate the risk for OSA. Routine use of such a model could increase the rate of sleep apnea detection in the pre-transplant and the post-heart transplant settings. From this retrospective review, we conclude that sleep apnea, especially OSA, is common in heart transplant recipients. Heart transplant recipients with OSA have typical risk factors and present with the classic symptoms. Compliance with nCPAP may be poor despite polysomnographic evidence of efficacy. Given the common thread of immunosuppres-
Brilakis et al.
335
sants, OSA may be an important management issue across the post-transplant spectrum. REFERENCES 1. American Sleep Disorders Association. International classification of sleep disorders, revised: diagnostic and coding manual. Rochester, Minnesota: American Sleep Disorders Association; 1997. 2. Strohl KP, Redline S. Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 1996;154:279 – 89. 3. Strollo PJ Jr, Rogers RM. Obstructive sleep apnea. N Engl J Med 1996;334:99 –104. 4. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middleaged adults. N Engl J Med 1993;328:1230 –5. 5. Silverberg D, Oksenberg A, Iaina A. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and Obstructive Sleep Apnea: let their silence not be matched by the silence of the ordinary physician (letter). Arch Intern Med 1998;158:1272–3. 6. Worsnop CJ, Naughton MT, Barter CE, Morgan TO, Anderson AI, Pierce RJ. The prevalence of obstructive sleep apnea in hypertensives. Am J Respir Crit Care Med 1998;157: 111–5. 7. Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997;157:1746 –52. 8. Flemons WW, Remmers JE, Gillis AM. Sleep apnea and cardiac arrhythmias. Is there a relationship? Am Rev Respir Dis 1993;148:618 –21. 9. Koehler U, Fus E, Grimm W, et al. Heart block in patients with obstructive sleep apnoea: pathogenetic factors and effects of treatment. Eur Respir J 1998;11:434 –9. 10. Mooe T, Gullsby S, Rabben T, Eriksson P. Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery. Coron Artery Dis 1996;7:475– 8. 11. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97:2154 –9. 12. Javaheri S, Corbett WS. Association of low PaCO2 with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann Intern Med 1998;128:204 –7. 13. Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991;338:1480 – 4. 14. Wright J, Johns R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the research evidence. BMJ 1997;314:851– 60. 15. Bradley TD, Floras JS. Pathophysiologic and therapeutic implications of sleep apnea in congestive heart failure. J Card Fail 1996;2:223– 40. 16. 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;152:473–9. 17. Lofaso F, Verschueren P, Rande JL, Harf A, Goldenberg F. Prevalence of sleep-disordered breathing in patients on a heart transplant waiting list. Chest 1994;106:1689 –94.
336
Brilakis et al.
18. Shapiro CS, Romaker AM, Bresnahan DR Jr. Obstructive sleep apnea in cardiac transplant patients (abstract). Chest 1992;102:54S. 19. Ellahham SH, Nelson K, Schlutz MT, et al. Sleep-disordered breathing is common in cardiac transplant recipients (abstract). Chest 1992;102:54S. 20. Klink ME, Sethi GK, Copeland JG, Quan SF. Obstructive sleep apnea in heart transplant patients. A report of five cases. Chest 1993;104:1090 –2. 21. Madden BP, Shenoy V, Dalrymple-Hay M, et al. Absence of bradycardic response to apnea and hypoxia in heart transplant recipients with obstructive sleep apnea. J Heart Lung Transplant 1997;16:394 –7. 22. Nkere UU, Hall MC, Corris PA. Sleep apnoea/hypopnoea syndrome: a potential cause of graft failure following heart transplantation. Eur J Cardiothorac Surg 1998;13:203–5. 23. Hanly P, Zuberi N. Periodic leg movements during sleep before and after heart transplantation. Sleep 1992;15:489 –92. 24. Collop NA. Cheyne-Stokes ventilation converting to obstructive sleep apnea following heart transplantation. Chest 1993; 104:1288 –9. 25. The Atlas Task Force. Recording and scoring leg movements. Sleep 1993;16:748 –59. 26. Rechtschaffen A, Kales A, eds. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Bethesda, Maryland: U.S. Department of Health, Education, and Welfare, 1968. 27. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540 –5. 28. Javaheri S, Parker TJ, Wexler L, et al. Occult sleep-disordered breathing in stable congestive heart failure. Ann Intern Med 1995;122:487–92. 29. Naughton MT, Liu PP, Bernard DC, Goldstein RS, Bradley TD. Treatment of congestive heart failure and CheyneStokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995;151:92–7. 30. Naughton MT, Bradley TD. Sleep apnea in congestive heart failure. Clin Chest Med 1998;19:99 –113. 31. Andreas S, Hagenah G, Moller C, Werner GS, Kreuzer H.
The Journal of Heart and Lung Transplantation April 2000
32.
33.
34.
35.
36. 37. 38.
39.
40.
41.
42.
43.
Cheyne-Stokes respiration and prognosis in congestive heart failure. Am J Cardiol 1996;78:1260 – 4. Findley LJ, Zwillich CW, Ancoli-Israel S, Kripke D, Tisi G, Moser KM. Cheyne-Stokes breathing during sleep in patients with left ventricular heart failure. South Med J 1985;78:11–5. Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med 1996;153: 272– 6. Murdock DK, Lawless CE, Loeb HS, Scanlon PJ, Pifarre R. The effect of heart transplantation on Cheyne-Stokes respiration associated with congestive heart failure. J Heart Transplant 1986;5:336 –7. Braver HM, Brandes WC, Kubiet MA, Limacher MC, Mills RM Jr, Block AJ. Effect of cardiac transplantation on Cheyne-Stokes respiration occurring during sleep. Am J Cardiol 1995;76:632– 4. White DP. Sleep-related breathing disorder. 2. Pathophysiology of obstructive sleep apnoea. Thorax 1995;50:797– 804. Strohl KP. Diabetes and sleep apnea. Sleep 1996;19:S225– 8. American Thoracic Society. Indications and standards for use of nasal continuous positive airway pressure (CPAP) in sleep apnea syndromes. Am J Respir Crit Care Med 1994;150: 1738 – 45. Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:887–95. Reeves-Hoche MK, Meck R, Zwillich CW. Nasal CPAP: an objective evaluation of patient compliance. Am J Respir Crit Care Med 1994;149:149 –54. Krieger J, Kurtz D, Petiau C, Sforza E, Trautmann D. Long-term compliance with CPAP therapy in obstructive sleep apnea patients and in snorers. Sleep 1996;19:S136 – 43. Hanly PJ, Zuberi-Khokhar N. Periodic limb movements during sleep in patients with congestive heart failure. Chest 1996;109:1497–502. Kushida CA, Efron B, Guilleminault C. A predictive morphometric model for the obstructive sleep apnea syndrome. Ann Intern Med 1997;127:581–7.