Lung transplantation has become an important treatment modality

Transcription

1 Scientific investigations Prevalence of Sleep Disordered Breathing in Lung Transplant Recipients Virjanand S. Naraine, M.D. 1 ; T. Douglas Bradley, M.D. 1,2 ; Lianne G. Singer, M.D. 1, 1 Division of Respirology, Department of Medicine, University of Toronto, Canada; 2 Division of Clinical Investigation and Human Physiology, Toronto General Research Institute, University of Toronto, Toronto, Canada; Division of Respirology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada Study Objectives: Weight gain and obesity are common after lung transplantation. Despite associations between these conditions and sleep disordered breathing (SDB) in the general population, the prevalence and clinical impact of SDB in lung transplant recipients is unknown. The study objective was to determine the prevalence and clinical correlates of SDB in a cohort of lung transplant recipients. Methods: Single-center cross-sectional study. Overnight polysomnography, sleep questionnaires, and anthropomorphic measurements were conducted on 24 lung recipients transplanted at least one year previously. The primary outcome was the prevalence of SDB, defined as an apnea-hypopnea index (AHI) 10 per hour. Results: The prevalence of SDB was 6%. Obstructive sleep apnea (OSA) was observed in 8% and central sleep apnea (CSA) in 25%. Among all subjects, the mean AHI was 19.7 ± 24.4 events/hour and the average weight gained after transplant was 10.5 ± 12. kg. Subjects with SDB had a higher systolic blood pressure (15 ± 12 vs. 124 ± 1 mm Hg, p = 0.045), body mass index (BMI) (28.2 ±.7 vs ± 4.0 kg/m 2, p = 0.008) and arousal index (28.0 ± 26.9 vs ± 6.4 per hour, p = 0.025) compared to the non-sdb group. Cyclosporine use was associated with CSA (p = 0.006). Recipients with OSA had a greater change (pre to post transplant) in BMI (5.8 ± 4.6 vs. 2.0 ± 2.9 kg/m 2, p = 0.05) compared with non-sdb subjects. Conclusions: Sleep disordered breathing is highly prevalent after lung transplantation. Polysomnography should be considered in lung transplant recipients, especially if they have gained weight. Keywords: Sleep apnea, lung transplant, hypertension, polysomnography Citation: Naraine VS; Bradley TD; Singer LG. Prevalence of sleep disordered breathing in lung transplant recipients. J Clin Sleep Med 2009;5(5): Submitted for publication June, 2008 Submitted in final revised form April, 2009 Accepted for publication April, 2009 Address correspondence to: Lianne G. Singer, M.D., Assistant Professor of Medicine, University of Toronto, Medical Director, Lung Transplant Program, Toronto General Hospital, 585 University Avenue, NCSB 11C-1194, Toronto, Ontario M5G 2N2; Tel: (416) ; Fax: (416) ; lianne.singer@uhn.on.ca Journal of Clinical Sleep Medicine, Vol.5, No. 5, Lung transplantation has become an important treatment modality for end stage respiratory failure. Over the years, refinements in patient selection, surgical techniques, and intensive care management, combined with the evolution of more effective immunosuppressive regimens, have resulted in modest gains in post-transplant survival rates. 1 Lung transplant recipients are now living longer to develop chronic, adverse medical conditions, such as hypertension (prevalence as high as 74% after the first year transplanted) 1,2 and depression (prevalence as high as 58%). Although immunosuppressive drugs are an important cause of these problems, avoidance of these drugs is not feasible, as it would lead to early graft loss. In addition to the direct effects of immunosuppressive drugs, another potential mechanism links transplantation with adverse outcomes. Transplantation is associated with weight gain, 2 which may predispose to sleep disordered breathing (SDB), particularly obstructive sleep apnea (OSA). SDB describes a group of disorders of respiratory pattern or ventilation during sleep, with OSA being the most common subtype. 4 Weight gain and obesity are causal factors in OSA, and a graded increase exists in OSA prevalence with increasing body mass index, neck circumference, and waist-to-hip ratio. 5,6 Approximately 1 in 5 adults has at least mild OSA, and 1 in 15 has moderate to severe OSA. 7 OSA is an independent risk factor for the development of hypertension 8 and a cause of cardiovascular morbidity and mortality. 7,9,10 OSA has also been associated with depression 11 and impaired cognitive function. 12 Despite the high prevalence of cardiovascular and psychiatric conditions among lung transplant recipients; SDB as a potential contributor is not well studied in this population. If SDB is present in transplant recipients, it is conceivable that treatment may, in the long run, mitigate adverse cardiovascular and neuropsychological outcomes, as it has done in the general population. 9,12,1 We undertook this cross-sectional study to estimate the prevalence, pattern (central or obstructive), severity, and clinical impact of SDB in lung transplant recipients. We hypothesized that SDB is highly prevalent after transplantation, and that this SDB would be primarily obstructive and would be associated with post-transplant weight gain and obesity. Subjects METHODS Lung transplant recipients visiting the Toronto General Hospital Transplant Clinic for routine annual follow-up as-

2 VS Naraine, TD Bradley, LG Singer sessments from July October 2004 were invited to participate. English-speaking adult subjects who were stable outpatients and first-time lung recipients transplanted within the previous 1 5 years were included. This post-transplantation interval was chosen because maximum weight gain tends to occur between 6 and 12 months post-transplant. 14,15 Subjects were excluded if they required high flow rates (> 6 L/min via nasal prongs) of oxygen, if they required noninvasive positive pressure ventilation, or if they were diagnosed with acute graft dysfunction requiring hospital admission. Subjects who met the inclusion / exclusion criteria and agreed to participate in the study completed one face-to-face interview, during which their demographic information was obtained. All subjects who agreed to participate, regardless of sleep history or symptoms of sleep apnea, underwent overnight level 1 polysomnography. Routine first-line immunosuppression in our program includes prednisone, cyclosporine, and azathioprine, though alternative agents are used for complications such as recurrent acute rejection, bronchiolitis obliterans, or intractable side effects. The protocol was approved by the institutional research ethics board, and informed consent was obtained from participants. Measurements Data collected included age, sex, diagnosis, medications and dosages, pulmonary function results, oxygen requirement, arterial blood gases, SDB symptoms (including morning headaches, snoring, restless sleep, witnessed apneas, and excessive daytime somnolence), smoking, and alcohol use. Height and weight, body mass index (BMI), neck and waist circumference, waist-to-hip ratio, and hip girth were measured using standard procedures. 16 The degree of weight gain post-transplant was defined as the absolute change in BMI (post-transplant BMI minus pre-transplant BMI). The Epworth Sleepiness Scale was used to assess daytime somnolence, with a score > 10 indicative of excessive daytime sleepiness. 17 Sleep Studies Level 1 overnight polysomnography was performed and scored by trained sleep technicians using standard techniques and scoring criteria for sleep stages and arousals. 18,19 Thoracoabdominal movements and tidal volume were measured by calibrated respiratory inductance plethysmography (Respitrace; Ambulatory Monitoring; Ardsley, NY) according to recommendations of the AASM Task Force of 1999 that prevailed at the time our study was performed in Oxyhemoglobin saturation (SpO 2 ) was measured continuously using a pulse oximeter (Nellcor N200; Nellcor Puritan Bennett Inc). Transcutaneous PCO 2 (PtcCO 2 ) was recorded with a transcutaneous capnograph (Kontron Medical). Obstructive apneas were defined as the absence of tidal volume excursion 10 sec accompanied by out-of-phase rib cage and abdominal movements. Obstructive hypopneas were defined as 50% reduction in tidal volume from baseline, with out-of-phase thoracoabdominal movements, persisting for at least 10 s. 20 Central apneas and hypopneas were similarly defined, except that during apneas there were no thoracoabdominal movements and during hypopneas no out-of-phase thoracoabdominal movements. The apnea-hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of sleep. To make our results comparable to those of the 2 most relevant studies on sleep apnea prevalence in lung transplant candidates or recipients by Malouf et al 21 and Pascual et al, 22 we used the same AHI of 10 as they did to identify subjects as having SDB. Subjects were further characterized as having obstructive sleep apnea (OSA) if 50% of the respiratory events of the night were obstructive, or having central sleep apnea (CSA) if 50% of the respiratory events of the night were central. Sample Size Calculation This study was envisioned as a pilot study to allow the estimation of SDB prevalence in lung transplant recipients, as a basis for planned future prospective studies. Assuming a prevalence similar to the reported OSA prevalence of 0.51 (using an AHI 10 cut-off) in heart transplant recipients, 2 and a population size of 200, we calculated that 24 subjects would allow a 95% confidence interval of 0.2 above and below our prevalence estimation. The study was not powered to examine for differences between SDB and non-sdb patients, and such analyses should be considered exploratory. Data Analysis The mean AHI and prevalence of SDB (using an AHI 10 cut-off) in the cohort were calculated. We calculated exact binomial 95% confidence intervals for proportions. The binomial test was used to compare the observed prevalence of SDB to the hypothesized prevalence of 20%, which is the prevalence of OSA in the general population. The analysis of variance (ANOVA) (or McNemar test for nonparametric data) was used to compare continuous variables between the SDB and non-sdb groups. Fisher exact test was used to compare categorical variables between groups. Spearman rank correlation test was used to estimate associations between continuous variables. SPSS 11.0 (SPSS Inc., Chicago, IL) and Stata 10 (StataCorp, College Station, TX) were used for analysis. Characteristics of Subjects RESULTS At study initiation, 87 recipients were alive who had been transplanted 1 5 years previously. Twenty-nine of these subjects attended the Transplant Clinic between July and October 2004, of whom 24 (16 males) agreed to participate in the study. The subjects who declined participation cited the inconvenience of an overnight sleep study ( subjects) or lack of interest (2 subjects). None of the subjects had a pre-transplant sleep study. Most of the subjects had bilateral lung transplants (21/24, 88%). Only 2 subjects, both in the non-sdb group, were using nasal supplemental oxygen (2 and 4 LPM, respectively). The characteristics of the subjects are shown in Table 1. Journal of Clinical Sleep Medicine, Vol.5, No. 5,

3 Table 1 Characteristics of the Subjects Sleep-Disordered Breathing in Lung Transplant Recipients Non SDB group (n = 9) SDB group (n = 15) OSA (n = 9) CSA (n = 6) Male (n, %) 5 (56) 8 (89) (50) Female (n, %) 4 (44) 1 (11) (50) Age (years) 4.8 (± 12.6) 56.7 (± 11.0)* 52.0 (± 8.1) Time since transplant (months) 7.8 (± 17.6) 24. (± 12.7) 19.8 (± 5.0) Transplant graft type (n, %) Single 1 (11) 1 (11) 1 (17) Double 8 (89) 8 (89) 5 (8) Transplant indication (n, %) Emphysema 0 4 (44)* 1 (17) IPF () 4 (44) 2 () CF 2 (22) 1 (11) 0 Misc diseases Ŧ 4 (44) 0 (50) Epworth Sleepiness Score 6.2 (± 4.1) 6.5 (± 4.5) 9.7 (± 7.5) Snoring (n, %) () 7 (78)* 4 (67) Prednisone dose (mg/d) 9.4 (± 6.4) 12.8 (± 4.2) 10.0 (± 7.9) Medication use (n, %) Opiates (22) 1 (11) 2 () Sedatives 5 (56) 4 (44) 4 (67) Cyclosporine 2 (22) 6 (67) 6 (100) $ Antihypertensive use 4 (44) 5 (56) 4 (67) Systolic BP (mm Hg) 12.6 (± 12.9) 17. (± 9.9)* 11. (± 14.2) Diastolic BP (mm Hg) 80.2 (± 7.6) 82.1 (± 2.8) 82.0 (± 10.0) BMI (kg/m 2 ) 24.0 (± 4.0) 28.8 (± 4.2)* 27.2 (± 2.7) $ Absolute change in BMI (kg/m 2 ) 2.0 (± 2.9) 5.8 (± 4.)* 2.7 (± 4.0) Neck circumference (cm) 6.6 (± 5.4) 40.9 (± 2.9) 7.7 (±.7) Waist/Hip Ratio 0.92 (± 0.1) 1.00 (± 0.1) 0.94 (± 0.09) Data are mean ± SD unless otherwise indicated. *p < 0.05 vs. non-sdb groups; $ p < 0.05 vs. non-sdb p < 0.05 vs. CSA groups; Ŧ bronchiolitis obliterans organizing pneumonia, broncho-alveolar cancer, pulmonary arterial hypertension, α-1 antitrypsin deficiency. Abbreviations: BMI = body mass index, BP = blood pressure, CF = cystic fibrosis, IPF = idiopathic pulmonary fibrosis, SDB = sleep disordered breathing Polysomnographic Data Among all subjects, the mean AHI was 19.7 ± 24.4 events/h. Distribution of the AHI stratified by 5 unit intervals is shown in Figure 1. SDB (using our AHI 10 cut-off) was present in 15/24 or 6% of subjects (95% confidence interval, 41% to 81%, p = , compared with hypothesized prevalence of 0.2). The SDB group had a higher arousal index. There were no statistically significant differences in other sleep variables. OSA was observed in 8% (mean AHI of 20.1 ± 14.2/h), and CSA in 25% (mean AHI of 41.1 ± 8.1/h) of subjects (Table 2). The prevalence of SDB at an AHI 5 was 8%. Potential Clinical Predictors Subjects with SDB were older (54.8 ± 9.9 vs. 4.8 ± 12.6 years, p = 0.048), had been transplanted more recently (22.5 ± 10. vs. 7.8 ± 17.6 months, p = 0.048), snored more frequently (7 vs. %, p = 0.05), were more likely to be on cyclosporine (80% vs. 22%, p = 0.009), and had better lung function (% predicted FEV ± 0.6 vs ± 0.24, p = 0.01) than subjects without SDB. All subjects with pre-transplant emphysema (n = 5) had SDB in the post-transplant period. No differences between the 2 groups were found in gender, current prednisone dosage, renal function, waist-hip ratio, or neck circumference. Among all subjects, the mean weight gained after transplant was 10.5 ± 12. kg (an 18% increase over the pre-transplant value), with a mean change in BMI of.6 ± 4.0 kg/m 2. SDB subjects had higher post-transplant BMI than subjects without SDB (28.2 ±.7 vs ± 4.0 kg/m 2, p = 0.008), but change in BMI did not differ significantly between the 2 groups (4.5 ± 4. vs. 2.0 ± 2.9 kg/m 2, p = 0.2). However, in the subgroup with OSA, the change in BMI was significantly greater than in the non-sdb group (5.8 ± 4. vs. 2.0 ± 2.9 kg/m 2, p = 0.05; Figure 2). Similarly, although there was no significant correlation between the change in BMI and overall AHI (Spearman rank (rs) = 0.20, p = 0.), a trend existed between change in BMI and the obstructive AHI (rs = 0.97, p = 0.055). Subjects with CSA all used cyclosporine (100% vs. 22%, p = 0.006) and had a higher BMI (27.2 ± 2.7 vs ± 4.0 kg/m 2, p = 0.0) than the non-sdb group. Sedative, opiate, or antidepressant use was not more common in subjects with CSA than in the non-sdb subjects. No significant differences were found in nocturnal SpO 2, transcutaneous PCO 2, renal function, or arterial blood gases between subjects with CSA and those without SDB. Most subjects had pre and post transplant echocardiograms, without any evidence of significant left ventricular dysfunction that would potentially predispose them to CSA. Of 24 subjects, 2 had pre-transplant echocardiograms, with left ventricular ejection fraction > 60% in 21 and 40% to 60% in 2 subjects respectively. Eleven of 24 had post-transplant echocardiograms with left ventricular ejection fraction > 60% in 9 and 40% to 60% in 2 subjects, respectively. Journal of Clinical Sleep Medicine, Vol.5, No. 5,

4 VS Naraine, TD Bradley, LG Singer Table 2 Polysomnographic Findings in Subjects with and without SDB Non-SDB group (n = 9) SDB group (n = 15) OSA (n = 9) CSA (n = 6) Total sleep time (min) 7 (± 59.) 18. (± 51.0) 12.7 (± 58.) Sleep efficiency (%) 81.6 (± 9.5) 80.2 (± 1.4) 77.9 (± 7.7) Arousal index (n/h) 10.4 (± 6.5) 21.4 (± 16.) 8.0 (± 7.6) $ AHI (n/h) 4.9 (± 2.6) 20.1 (± 41.1 (± 8.1) $ Obstructive event index (n/h).8 (± 2.7) 17.8 (± 7.7 (± 8.5) Central event index (n/h) 1.2 (± 1.1) 2. (± (± 8.9) $ Apnea index (n/h) 0.5 (± 0.7) 5.1 (± 19.9 (± 24.) $ Hypopnea index (n/h) 4.5 (± 2.6) 15.0 (± 5.)* 21. (± 15.2) $ PLM index (n/h) 4.8 (± 14.0) 2. (± 4.6) 14.5 (± 21.4) Mean SpO 2 (%) 9.7 (± 2.9) 96.4 (± 94.8 (± 2.1) SpO 2 < 90% (%TST) 10.9 (± 24.5) 0.61 (± 1.1) 1.8 (± 1.5) Mean PtcCO 2 (mm Hg) 8.7 (±.7) 8.9 (± 6.9) 8.7 (± 2.8) Data are mean ± SD unless otherwise indicated. *p < 0.05 vs. non-sdb groups; $ p < 0.05 vs. non-sdb p < 0.05 vs. CSA groups. Abbreviations: AHI = apnea-hypopnea index, PLM = periodic leg movements, SpO 2 = oxygen saturation, SDB = sleep-disordered breathing, PtcCO 2 = transcutaneous carbon dioxide 17% 8% 6% 6 * Number of subjects to <5 5 to<10 10 to <15 15 to <20 20 to <25 25 to <40 40 AHI (n/hr) 50% 25% 1% 1% Non-SDB SDB OSA CSA Mean change in BMI (kg/m2) Figure 2 Pre- to post-transplant change in BMI (kg/m 2 ) categorized according to type of sleep disordered breathing (SDB) (OSA = obstructive sleep apnea, CSA = central sleep apnea) (*denotes a significant difference [p = 0.05] compared to the non-sdb group) Figure 1 Histogram showing distribution of the apnea-hypopnea index. The number and percent of subjects in various categories are shown. Potential Clinical Consequences Fifty-four percent (9/15 SDB subjects and 4/9 non-sdb subjects) were taking at least one antihypertensive medication. Subjects with SDB had higher systolic blood pressure than those without SDB (14.9 ± 11.7 vs ± 12.9 mm Hg, p = 0.045). The differences in systolic blood pressure were even greater between the OSA and non-sdb groups (17. ± 9.9 vs ± 12.9 mm Hg, p = 0.024) (Figure ). Among all subjects there was no significant correlation between the AHI and systolic blood pressure (rs = 0.8, p = 0.065). There were no differences in the frequency of restless sleep, morning tiredness, non-restorative sleep, witnessed apneas, nocturnal choking, or Epworth Sleepiness Score between the SDB and non-sdb groups. DISCUSSION This cross-sectional study indicated that SDB is very common (6%) among the Toronto lung transplant cohort, and is moderate in severity (mean AHI of 20). Obstructive sleep apnea was seen in 8% (9/24) of subjects. An unexpectedly high prevalence of CSA (25% of our subjects) was also seen. The high prevalence of SDB found in our study underscores the importance of screening lung transplant recipients for characteristics that may warrant overnight sleep studies. We have identified some potential clinical predictors. Older, heavier recipients with worse hypertension were more likely to have SDB. Snoring, a marker for upper airway instability 6 during sleep, was more prevalent in our SDB subjects and may be secondary to fatty infiltration of the pharynx related to corticosteroid use. 24 Emphysema as a transplant indication was associated with post-transplant SDB, although it is unknown if these subjects had SDB while on the transplant waiting list (none of our subjects had sleep studies prior to transplantation). Notably, the ESS did not reliably predict SDB and is, therefore, not a sensitive indicator for screening for SDB in this patient population. A secondary aim of our study was to investigate the association between weight gain and SDB in lung transplant recipients. The mean weight gain of 18% after transplant seen in our study would predict an approximate 2% increase in the AHI and a 6-fold increase in the odds of developing moderate-to-severe SDB (AHI 15), as seen in the Wisconsin cohort study of the Journal of Clinical Sleep Medicine, Vol.5, No. 5,

5 Sleep-Disordered Breathing in Lung Transplant Recipients general population. 25 As expected, we showed a trend between change in BMI and the obstructive event index, and transplant recipients with OSA had a greater change in BMI than non- SDB subjects (Figure 2). The relationship between corticosteroid use and weight gain is a well-recognized entity in the general population and solid organ transplant recipients. 2,7,26,27 However, we could not analyze the association between prednisone use and degree of weight gain or development of SDB, as our data reflected prednisone dose at time of study entry. Typically, the prednisone dosage of lung transplant recipients decreases over time. The tendency for subjects with SDB to have been transplanted more recently might suggest that current dose, rather than cumulative exposure, is more closely associated with SDB. If an association between post-transplant weight gain, corticosteroid use, and OSA is confirmed in future studies, early screening of lung transplant recipients for OSA and treatment strategies that would minimize weight gain might prevent the complication of OSA after transplantation. It is also intriguing to consider the role that other immunosuppressive drugs may play in the development of post-transplant SDB. Our findings would suggest that cyclosporine use is associated with the presence of CSA. However, it would be premature to conclude this based on our study. In our lung transplant program, all patients are started on cyclosporine after transplantation and switched to alternate agents later if required. As time goes on, the dosages of other drugs may also be reduced, and some drugs are discontinued. Therefore, there are a number of potential confounding factors including time since transplant and other medications. Despite the numerous central nervous system effects of cyclosporine, no exact mechanism by which it predisposes to CSA is reported in the literature. The high prevalence of CSA in our cohort and the association with cyclosporine use seems an isolated finding, as other studies on lung transplant recipients, 21,28,29 albeit also limited by small sample sizes, did not report such findings. Moreover, studies addressing SDB in other solid organ (heart, kidney) transplant recipients who used cyclosporine failed to report or identify it as a predictor for SDB (or CSA). 2,0,1 Hypertension is extremely common after lung transplantation with a prevalence of 50% to 74% at one year post lung transplant. 1,2 The hypertension is often difficult to control and may increase the long-term risk of cardiovascular disease. 2 Although hypertension in lung transplant recipients is generally attributed to immunosuppressive use or renal dysfunction, our findings suggest that OSA may contribute to this extremely high prevalence. Studies in the general population have suggested that hypertension is more difficult to control in OSA patients than in nonapneic patients, and patients with hypertension refractory to maximal medical therapy have a very high prevalence of OSA. 4 This pattern is reflected in our study, since an increasing AHI was associated with an increasing number of antihypertensive medications. Logan and coworkers 5 found that nasal continuous positive airway pressure (ncpap) treatment of OSA in non transplanted subjects significantly reduced blood pressure, which suggests that ncpap treatment of OSA in transplant recipients may improve control of drug-resistant hypertension. The prevalence of CSA in the general population is < 1%, 6 while in heart failure patients it ranges from % to 40%. 7,8 systolic BP (mm Hg) non-sdb OSA CSA Figure Systolic blood pressure measurements in subjects with obstructive sleep apnea (OSA), central sleep apnea (CSA) or no sleep disordered breathing (non-sdb) (*denotes a significant difference [p = 0.024] compared to the non-sdb group) Possible mechanisms in lung transplant recipients include altered chemoreceptor sensitivity, changes in respiratory drive, lung denervation affecting the control of breathing, or medication use (opiates, anxiolytics, and immunosuppressants). Although chemoreceptor instability causing CO 2 fluctuations around the apneic threshold during sleep contributes significantly to the cyclical hypocapnic form of CSA, 9 we did not find any significant differences between the CSA and non-sdb subjects in terms of nocturnal transcutaneous CO 2 measurements or daytime arterial PCO 2 values. Sedative, opiate, and/ or antidepressant use, which can predispose to CSA, was not more common in subjects with CSA. Similarly, although only 11/24 of subjects had post-transplant echocardiograms, left ventricular function was well preserved and was unlikely to be the pathogenic mechanism of CSA. The prevalence of SDB has been better studied in heart transplant than in lung transplant recipients, and our data more closely resemble those of the former. 2,0 Javaheri et al found that 6% (16/45) had at least moderate OSA (defined as an AHI 15 per hour). If an AHI 10 threshold was chosen, the prevalence increased to 51% (2/45), very similar to our finding. OSA post heart transplant was associated with post-transplant weight gain, excessive daytime sleepiness, hypertension, and poorer health-related quality of life. 2 Brilakis et al. studied 17 heart transplant recipients who were suspected of having SDB and found that all had it (1 had OSA and 4 had mixed sleep apnea) and nasal CPAP treatment was effective in reducing the AHI and arousal index. 0 Prior studies addressing SDB in lung transplant recipients were limited by small sample size, selection bias, and different definitions of SDB. Shea et al. 28 compared 8 heart-lung transplant recipients to normal subjects and found that none of the transplanted patients had SDB. None of the patients were recipients of lung transplants only, and selected sleep periods were analyzed, not the total sleep time. Chhajed 29 found 24% (2/96) of lung transplant recipients had OSA (defined as AHI > 5/h) but this study was designed to identify patients who would * Journal of Clinical Sleep Medicine, Vol.5, No. 5,

6 VS Naraine, TD Bradley, LG Singer benefit from nasopharyngeal oxygen supplementation during bronchoscopy. There was also selection bias as sleep studies were requested on those patients who had clinical symptoms of OSA or had a pre-transplant diagnosis of OSA. It is unclear whether the recipients develop de novo SDB after transplant or have a worsening of their already elevated pretransplant AHI. A recent study attempted to address this issue, by examining the prevalence of SDB in subjects on the lung transplant waiting list; a 6% prevalence (42/117 subjects) was reported. 21 These authors were also able to compare pre- and post-transplant sleep studies in some subjects, and found a 29% (4/14) incidence of SDB post-transplantation. The definition of SDB used makes direct comparison to our study difficult. Malouf et al. 21 defined SDB as either a respiratory disturbance index (RDI) of 10 or 10% of total sleep time (TST) with SpO 2 90% in the presence of an awake oxygen saturation 90% or both. Hence, most of the SDB subjects (60% or 25/42) were so defined based on nocturnal hypoxemia which is consistent in patients with chronic respiratory failure (i.e., on a transplant waiting list), where the typical breathing abnormality during sleep is hypoventilation as opposed to OSA. 40 Another study, in which AHI 10 was considered abnormal, examined 17 patients on a lung transplant waiting list and compared them to healthy controls. 22 The waiting list patients had a mean AHI (6.1 ± 6 events/h) that was similar to the control group. These findings would suggest that SDB develops after transplantation, but requires confirmation in a prospective study. Such prospective studies would clarify the timing of onset of SDB, and this may shed light on its mechanisms. For example, development of early SDB after transplantation would suggest immunosuppressive use or lung denervation as causes of SDB, while development of SDB later after transplantation would implicate weight gain or obesity as potential causative factors. Our study is subject to a number of limitations. First, since we did not perform sleep studies prior to transplantation, we could not determine the relationship of the presence of SDB prior to transplantation to that post transplantation. Second, because the study was cross-sectional, we could not determine risk factors for, and the incidence of, SDB post transplantation. In addition, we could not determine the potential effects that SDB might have on clinical outcomes, such as lung rejection or death rates. Third, the sample size was limited and did not allow for sufficient statistical power to perform multivariate analysis to control for potential confounding factors with respect to determining independent predictors of SDB. In summary, we found a high prevalence of SDB, both OSA and CSA, in an unselected cohort of lung transplant recipients. The presence of OSA was associated with higher systolic blood pressure and higher post-transplant BMI and greater post-transplant weight gain, while the presence of CSA was associated with cyclosporine use. We propose increased vigilance and screening for SDB, particularly OSA, in transplant recipients as it may be an under-recognized and treatable cause of posttransplantation hypertension. Our data underscore the need to systematically determine the incidence, clinical predictors, and consequences of SDB in lung transplant recipients in order to identify those who would benefit most from early intervention. We hope that our prevalence estimates can be used to design larger, prospective cohort studies which would ideally include pre- and post-transplant polysomnography, to better understand this complex and important problem. ABBREVIATIONS AHI - apnea-hypopnea index BMI - body mass index CSA - central sleep apnea FEV 1 - forced expiratory volume in 1 second ncpap - nasal continuous positive airway pressure OSA - obstructive sleep apnea PLM - periodic leg movement PtcCO 2 - transcutaneous carbon dioxide SpO 2 - oxyhemoglobin saturation (measured by pulse oximetry) SDB - sleep disordered breathing ACKNOWLEDGMENTS This study was supported by a Block Term Grant (Dr. L. Singer) from the Ontario Thoracic Society. Project institution: University Health Network (Toronto General Hospital), Toronto, Canada Disclosure Statement This was not an industry supported study. The authors have indicated no financial conflicts of interest. REFERENCES 1. Trulock EP, Edwards LB, Taylor DO. The Registry of the ISHLT: twenty-first official adult heart transplant report J Heart Lung Transplant 2004;2: Singer LG, Brazelton TR, Doyle RL, Morris RE, Theodore J. Weight gain after lung transplantation. J Heart Lung Transplant 200;22: Olbrisch ME, Benedict SM, Ashe K, Levenson JL. Psychological assessment and care of organ transplant patients. J Consult Clin Psychol 2002;70: American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999;22: Douglas NJ, Polo O. Pathogenesis of obstructive sleep apnoea/ hypopnoea syndrome. Lancet 1994;44: Sakakibara H, Tong M, Matsushita K, Hirata M, Konishi Y, Suetsugu S. Cephalometric abnormalities in non-obese and obese patients with obstructive sleep apnoea. Eur Respir J 1999;1: Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165: Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000;28: Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 200;48: He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 85 male patients. Chest 1988;94:9-14. Journal of Clinical Sleep Medicine, Vol.5, No. 5,

7 Sleep-Disordered Breathing in Lung Transplant Recipients 11. Ohayon MM. The effects of breathing-related sleep disorders on mood disturbances in the general population. J Clin Psychiatry 200;64: McFadyen TA, Espie CA, McArdle N, Douglas NJ, Engleman HM. Controlled, prospective trial of psychosocial function before and after continuous positive airway pressure therapy. Eur Respir J 2001;18: Douglas NJ. Treatment of the obstructive sleep apnea/hypopnea syndrome: the effect on blood pressure. Sleep 2004;27: Blumke M, Keller E, Eble F, Nausner M, Kirste G. Obesity in kidney transplant patients as a risk factor. Transplant Proc 199;25: Baker AM, Levine TB, Goldberg AD, Levine AB. Natural history and predictors of obesity after orthotopic heart transplantation. J Heart Lung Transplant 1992;11: Lohman T, Roche A, Martorell R. Measurement descriptions and techniques. In: Lohman TG, Roche AF, Martorell R, eds. Anthropometric standardization reference manual. Champaign, IL: Human Kinetics Books; Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14: Rechtschaffen A, Kales A, eds. A manual of standardized terminology, technique and scoring system for sleep stages of human subjects. Los Angeles, CA: Brain Information Service/Brain Research Institute; EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 1992;15: Gould GA, Whyte KF, Rhind GB, et al. The sleep hypopnea syndrome. Am Rev Respir Dis 1988;17: Malouf MA, Milross MA, Grunstein RR, et al. Sleep-disordered breathing before and after lung transplantation. J Heart Lung Transplant 2008;27: Pascual N, Jurado B, Rubio JM, Santos F, Lama R, Cosano A. Respiratory disorders and quality of sleep in patients on the waiting list for lung transplantation. Transplant Proc 2005;7: Javaheri S, Abraham WT, Brown C, Nishiyama H, Giesting R, Wagoner LE. Prevalence of obstructive sleep apnoea and periodic limb movement in 45 subjects with heart transplantation. Eur Heart J 2004;25: Horner RL, Mohiaddin RH, Lowell DG, et al. Sites and sizes of fat deposits around the pharynx in obese patients with obstructive sleep apnoea and weight matched controls. Eur Respir J 1989;2: Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000;284: Holley JL, Shapiro R, Lopatin WB, Tzakis AG, Hakala TR, Starzl TE. Obesity as a risk factor following cadaveric renal transplantation. Transplantation 1990;49: Augustine SM, Baumgartner WA, Kasper EK. Obesity and hypercholesterolemia following heart transplantation. J Transpl Coord 1998;8: Shea SA, Horner RL, Banner NR, et al. The effect of human heart-lung transplantation upon breathing at rest and during sleep. Respir Physiol 1988;72: Chhajed PN, Aboyoun C, Malouf MA, et al. Management of acute hypoxemia during flexible bronchoscopy with insertion of a nasopharyngeal tube in lung transplant recipients. Chest 2002;121: Brilakis ES, Olson EJ, McGregor CG, Olson LJ. Sleep apnea in heart transplant recipients: type, symptoms, risk factors, and response to nasal continuous positive airway pressure. J Heart Lung Transplant 2000;19: Molnar MZ, Szentkiralyi A, Lindner A, et al. High prevalence of patients with a high risk for obstructive sleep apnoea syndrome after kidney transplantation--association with declining renal function. Nephrol Dial Transplant 2007;22: Bostom AD, Brown RS, Jr., Chavers BM, et al. Prevention of post-transplant cardiovascular disease--report and recommendations of an ad hoc group. Am J Transplant 2002;2: Hirshkowitz M, Karacan I, Gurakar A, Williams RL. Hypertension, erectile dysfunction, and occult sleep apnea. Sleep 1989;12: Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001;19: Logan A, Tkacova R, Perlikowski S, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J 200;21: Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med 1998;157: Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160: 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: Dempsey JA. Crossing the apnoeic threshold: causes and consequences. Exp Physiol 2005;90: Becker HF, Piper AJ, Flynn WE, et al. Breathing during sleep in patients with nocturnal desaturation. Am J Respir Crit Care Med 1999;159: Journal of Clinical Sleep Medicine, Vol.5, No. 5,