Sleep-related breathing disorders impair quality of life in haemodialysis recipients

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1 Nephrol Dial Transplant (2002) 17: Original Article Sleep-related breathing disorders impair quality of life in haemodialysis recipients Bernd M. Sanner 1, Martin Tepel 1, Martina Esser 1, Joerg Klewer 1, Beate Hoehmann-Riese 1, Walter Zidek 1 and Bernhard Hellmich 2 1 Department of Medicine I, Marienhospital Herne, Ruhr University Bochum and 2 Department of Medicine, Ruhr University Bochum, Universitaetsklinik Bergmannsheil, Germany Abstract Background. It is well known that the quality of life of haemodialysis recipients is often severely compromised. So far, the influence of sleep-related breathing disorders on the quality of life of patients receiving maintenance dialysis has not been evaluated. Methods. Quality of life as assessed by the Medical Outcomes Study Short Form-36 (SF-36) and the Nottingham Health Profile Part 1 (NHP1) was determined in 33 patients (20 males, 13 females; median age 66 years (95% CI 22 82)) with end-stage renal disease treated with haemodialysis. Additionally, polygraphy with a validated eight-channel ambulatory recording unit was performed. Results. Twenty-one patients (63.6%) had a clinically significant sleep-related breathing disorder with a median apnoeauhypopnoea index of 13.3 ( )uh and a median oxygen saturation during sleep of 92.5 (88 97)%. In three out of eight subjective measures of the SF-36 (vitality, social functioning and mental health) and in one out of six subjective measures of the NHP1 (emotional reactions), patients without sleeprelated breathing disorders had a higher quality of life than patients with this disorder (P-0.05 each). Furthermore, the severity of the sleep-related breathing disorder as indicated by the apnoeauhypopnoea index significantly correlated with the following quality of life measures: physical functioning, social functioning, role limitation due to physical and emotional problems, general health and vitality (SF-36), and also with pain, sleep, social isolation and emotional reactions (NHP1) (P-0.05 each). Conclusions. We conclude that sleep-related breathing disorders independently influence the quality of life of patients receiving maintenance dialysis. Keywords: dialysis; quality of life; sleep Introduction In patients with end-stage renal disease, initiation of long-term dialysis treatment increases survival [1], but quality of life remains impaired compared with successful renal allotransplantation [2]. Therefore, researchers and clinicians generally agree that quality of life, its determinants and treatment options that may preserve subjective well-being merit continued investigation [2]. Patients with end-stage renal disease have a high incidence of sleep disorders, especially of periodic limb movements in sleep and sleep-related breathing disorders [3,4]. It is known that patients with sleep-related breathing disorders are prone to an increased cardiovascular morbidity and mortality [5]. Up to 70% of patients with end-stage renal disease have pathologic breathing patterns during the night [6]. So far, the influence of sleep-related breathing disorders on the quality of life in patients receiving maintenance dialysis has not been evaluated. We therefore determined the quality of life using two quality of life measures in consecutive haemodialysis recipients and analysed the impact of sleep-disordered breathing. Since different quality of life scales measure different aspects of health decrement, and since it is not clear which of the standard measures is most suited to measuring the quality of life in patients with end-stage renal disease, we were interested in seeing how two different scales perform in this situation. Subjects and methods Correspondence and offprint requests to: Prof. Dr Bernd M. Sanner, Department of Medicine I, Marienhospital Hoelkeskampring, Ruhr University Bochum, D Herne, Germany. bernd.sanner@ruhr-uni-bochum.de Patients Men and women were eligible for the study if they were at least 18 years of age, had end-stage renal disease, and had # 2002 European Renal Association European Dialysis and Transplant Association

2 Sleep-related breathing disorders in dialysis patients been receiving maintenance haemodialysis treatment for at least 3 months. Criteria for exclusion were uncontrolled hypertension, malfunction of the vascular access (haemodialysis blood flow -300 mlumin, high return venous pressure anduor recirculation )15%), stroke, seizures, symptomatic ischaemic heart disease or congestive heart failure, the presence of severe associated disease, anaemia unrelated to chronic renal failure, use of sedatives and muscle relaxants, or refusal to participate in the study. Evaluation of health-related quality of life Two well established questionnaires were used to evaluate health-related quality of life: the Nottingham Health Profile Part 1 (NHP1) and the Medical Outcomes Study Short Form-36 (SF-36). Physicians instructed patients how to fill out the forms, and all patients completed them at home on a non-dialysis day. The Nottingham Health Profile Part 1 The Nottingham Health Profile measures patients perception of their own health in terms of quality of life [7]. The Nottingham Health Profile has been widely used, and a number of different national versions have been produced. The questions were translated into and validated in German [8]. Part 1 measures the subjective health status by asking for responses ( yes or no ) to a test of 38 simple statements relating to six dimensions of social functioning: emotional reactions, energy, pain, physical mobility, sleep and social isolation. All statements are related to limitations of activity or aspects of distress. The answers are weighted with specific values, which enable a score from 0 to 100 for each dimension. A high score indicates a high degree of limitation. The scores are usually presented as a profile and not added to an overall score. SF-36 health survey questionnaire SF-36 is a 36-item questionnaire that measures physical functioning, mental health, energy and vitality, pain, and general perception of health [9,10]. For each variable, scores are coded, summed, and transformed onto a scale from 0 (worst possible health) to 100 (best possible health). Two summary scores are calculated: physical (physical component summary) and emotional well-being (mental component summary). These summary scores replicate the results from the original eight variables of the SF-36. The SF-36 questionnaire has been used to measure decreased quality of life in several disorders, including end-stage renal failure and dialysis treatment [11]. Sleep study All patients underwent overnight polygraphy on a dialysis day. Sleep-related breathing disorders were established by a 1-night sleep study with a validated eight-channel ambulatory recording unit (POLY-MESAM unit; MAP, Martinsried, Germany) [12]. The sleep study consisted of continuous polygraphic recording from a three-way thermistor that measured nasaluoral airflow, and from non-invasive leads measuring abdominal and chest-wall movements, oxygen saturation, heart rate, tracheal sounds (microphone), body position and limb movements (surface electrodes positioned over the M. tibialis anterior). According to the commonly used clinical criteria [13], a breathing event was defined as abnormal if either a complete cessation of airflow lasting P10 s took place (apnoea) or if a reduction in respiratory airflow of P50% of the airflow lasting )10 s associated with a desaturation of )3% could be discerned (hypopnoea). Obstructive apnoea was defined as absence of airflow in the presence of paradoxical chestwall motion. The average number of episodes of apnoea and hypopnoea per hour (apnoeauhypopnoea index) was calculated, and the mean and minimum oxygen saturations during the night were determined. Sleep-related breathing disorder was diagnosed when the apnoeauhypopnoea index was P5uh. Sleep-related periodic EMG leg activity was scored according to standard criteria [14]. The average number of periodic limb movements per hour (periodic limb movement index) was calculated. The study protocol was approved by the local ethics committee. All patients gave their informed consent before entry into the study. Statistical analyses Results are presented as medians (95% confidence interval). All P values reported are two-tailed. Statistical analyses were performed with the computer software SPSS for Windows (SPSS, Chicago, IL, USA). Intergroup differences were analysed for significance with the Mann Whitney U-test with Bonferroni s correction for multiple comparisons. The relationships between quality of life measures and parameters indicative of the severity of sleep-related breathing disorders were explored first by bivariate regression analysis (Spearman rank correlation coefficients). To determine the independent association of quality of life measures with the severity of sleep-related breathing disorders in the presence of other factors affecting quality of life, stepwise linear regression analysis was performed in a second step. The multivariate statistical model was built in steps and was designed to select only factors that correlated with the quality of life measures at a level of significance of O0.05 for the final multiple regression model. Results 1261 Thirty-three consecutive patients (20 males, 13 females) out of 78 patients with end-stage renal disease receiving maintenance dialysis were included in the study. As confirmed by clinical examination, patients were in a stable condition of health. No patient had significant pain, elevated temperature or other acute conditions. There were no shift workers in our population. The median age of patients was 66 years (range 22 82). Table 1 shows the characteristics of the patients included in the study. All patients studied received haemodialysis treatment with a total of between and 15 h of dialysis per week, equally divided into three sessions. Aetiology of renal failure among the patients studied was as follows: glomerulonephritis, 11 patients (33.3%); chronic pyelonephritis, seven (21.2%); diabetic nephropathy, six (18.2%); polycystic disease, three (9.1%); and other, including systemic lupus

3 1262 B. M. Sanner et al. erythematosus, toxic nephropathy and obstructive nephropathy, six (18.2%). Twenty-eight of the patients (84.8%) had systemic hypertension, 14 patients (42.4%) had coronary artery disease and 10 patients (30.3%) had diabetes mellitus. All hypertensive patients were treated with antihypertensive agents (19 with angiotensin-converting enzyme inhibitors, 18 with beta-blocking agents, 10 with calcium channel blockers, five with angiotensin receptor antagonists), 14 patients were treated with a diuretic agent, five with a nitrate, six with insulin, and 28 with recombinant human erythropoietin. Sleep study Twenty-one of the 33 patients (63.6%) had an apnoeauhypopnoea index of P5uh. In this subgroup, the median apnoeauhypopnoea index was 13.3uh (range ), the median oxygen saturation during the night was 92.5% (range 88 97), the minimum oxygen saturation during the night was 80% (range 63 93), and the time during the night with an oxygen saturation -90% was 8% (range 1 41). Twenty-two of the 33 patients (66.7%) had a periodic limb movement index of P5uh. In this subgroup, the median periodic limb movement index was 38.2uh (range 7 156). Patients with and without a sleep-related breathing disorder did not differ with respect to age, body mass Table 1. Patient characteristics of the 33 patients included in the study Characteristic Median (95% confidence interval) Age (years) 66 (22 82) Body mass index (kgum 2 ) a 22.8 ( ) Months on dialysis 48 (10 194) KtuV 1.4 ( ) Haemoglobin (gudl) 11.5 ( ) Creatinine (mgudl) 8.9 ( ) Urea nitrogen (mgudl) 150 (99 218) a Weight (kg) divided by the square of the height (m). index, months on dialysis, laboratory values (haemoglobin, creatinine, urea nitrogen), KtuV, smoking habits, use of alcohol, associated diseases (especially hypertension, coronary artery disease and diabetes mellitus), prescribed medication, or treatment with recombinant human erythropoietin. Evaluation of health-related quality of life As assessed by the SF-36 health survey questionnaire, bodily pain and general health showed the worst impairment in the whole study group. Patients with a sleep-related breathing disorder had a significantly lower quality of life in three out of eight subjective measures and in one out of two summary scores (Table 2). NHP1 explored six dimensions of perceived health. The worst perceived dimension was sleep, with a median score of 29 (range 0 100). In patients with a sleep-related breathing disorder, only the score emotional reactions was significantly worse than in patients without this disorder (27 (0 99) vs 0 (0 27); Ps0.01). To clarify the relationship between sleep-related breathing disorders and quality of life in patients with end-stage renal disease, correlation analyses were performed. The apnoeauhypopnoea index was used as a parameter indicative of the severity of the sleeprelated breathing disorder. There were significant correlations between the apnoeauhypopnoea index and the following scores of the SF-36: physical functioning (rs 0.39; P-0.05), social functioning (rs 0.53; P-0.005) (Figure 1A), role limitation due to physical problems (rs 0.38; P-0.05), role limitation due to emotional problems (rs 0.41; P-0.05), general health (rs 0.42; P-0.05), vitality (rs 0.39; P-0.05) and physical component summary score (rs 0.46; P-0.05). Furthermore, the apnoeau hypopnoea index significantly correlated with three of the six dimensions of the NHP1: pain (rs0.38; P-0.05), social isolation (rs0.40; P-0.05) and emotional reactions (rs0.57; P-0.001) (Figure 1B). In contrast to the SF-36, correlation coefficients of the Table 2. SF-36 scores in patients with and without sleep-related breathing disorders SRBD No SRBD Statistical significance Physical functioning 35 (0 100) (mean 44) 68 (5 85) (mean 54) NS Social functioning 62.5 (0 100) (mean 50) 88 (63 100) (mean 84) Role limitations (physical problems) 0 (0 100) (mean 29) 75 (0 100) (mean 55) NS Role limitations (emotional problems) 0 (0 100) (mean 42) 100 (0 100) (mean 70) NS Bodily pain 41 (0 74) (mean 32) 50 (21 74) (mean 45) NS General health 35 (15 77) (mean 37) 34 (27 52) (mean 37) NS Mental health 60 (13 92) (mean 58) 76 (60 92) (mean 76) Vitality 35 (0 70) (mean 35) 55 (20 85) (mean 55) Mental component summary 22.8 ( ) (mean 22.6) 24.8 ( ) (mean 24.5) Physical component summary 23.7 ( ) (mean 23.8) 24.2 ( ) (mean 24.1) NS SRBDssleep-related breathing disorders; NSsnot significant. Values are given as medians (95% confidence interval) and means.

4 Sleep-related breathing disorders in dialysis patients Nottingham Health Profile were positive because the two scales run in opposite directions. In addition, multiple stepwise linear regression analysis ( forward stepwise entry ) was performed with quality of life indicators as the dependent variable and apnoeauhypopnoea index, periodic limb movement index, age, body mass index, months on dialysis, 1263 creatinine level, haemoglobin, urea nitrogen, KtuV, erythropoietin administration, gender and smoking as independent variables. The regression analysis disclosed that the significant correlations between the apnoeauhypopnoea index and most of the scores of the quality of life measures persisted even after correction for the other possible risk factors tested. Table 3 shows the results of two of the regression studies with emotional reactions (a measure of the Nottingham Health Profile) and social functioning (a measure of the SF-36 health survey questionnaire) as the dependent variables. Discussion Fig. 1. (A) Social functioning (a measure of the SF-36 health survey questionnaire) plotted against apnoeauhypopnoea index (rs 0.53; P-0.005). (B) Emotional reactions (a measure of the Nottingham Health Profile) plotted against apnoeauhypopnoea index (rs0.57; P-0.001). Although quality of life has been recognized as an important parameter in evaluating the different forms of renal replacement therapy [2], to our knowledge sleep-related disorders have not yet been addressed in the studies on quality of life in end-stage renal disease. Conversely, in the general population sleep-related disorders have been generally accepted as an important factor influencing quality of life [15]. We therefore felt it necessary to study the impact of sleep-related breathing disorders on quality of life in end-stage renal disease patients, especially as quality of life is often severely limited in these patients. The most important finding of our study is that sleep-related breathing disorders have a major impact on quality of life in patients with end-stage renal disease. The relationship of the apnoeauhypopnoea index with most of the quality of life measures even after adjustment for age, gender, body mass index, time on dialysis, haemoglobin and comorbidity indicates that patients with high apnoeauhypopnoea indices have a worse physical and mental health status than patients on maintenance dialysis without disturbed breathing during the night. In this context, it has to be acknowledged that the polygraphic studies we performed in our patients tend to underestimate the degree of sleep-related breathing disorders [12]. This is due to the fact that with the POLY-MESAM device the time of sleep cannot be verified. The total recording time may therefore Table 3. Factors related to two of the quality of life scores Dependent variable Forward stepwise linear regression: selected independent variables Corrected r 2a Standardized b coefficients (last steep) P value Emotional reactions 1: Apnoeauhypopnoea index Steep 1: (Nottingham Health Profile b ) 2: Body mass index Steep 2: Social functioning 1: Apnoeauhypopnoea index Steep 1: (SF-36 b ) 2: Body mass index Steep 2: a Corrected determination coefficients for regression steeps. b Higher scores in the Nottingham Health Profile, but lower scores in the SF-36 indicate worse functional status. None of the othere possible risk factors tested (periodic limb movement index, age, months on dialysis, creatinine level, haemoglobin, urea nitrogen, KtuV, erythropoietin administration, gender and smoking) was included in the stepwise multiple linear regression model because the significance level exceeded 0.05.

5 1264 B. M. Sanner et al. considerably exceed the total sleep time. Since the apnoeauhypopnoea index is calculated using the total recording time in polygraphic recordings, values below the true apnoeauhypopnoea index may have been obtained in those cases where significant periods of wakefulness occurred. The authors are well aware that the relatively small sample size constitutes another limitation of the study, underlining the need for further prospective studies on quality of life issues in patients with end-stage renal disease. Sleep-related breathing disorders are common in the general population. It is estimated that at least 2 4% of middle-aged adults are affected [16]. The prevalence of disturbed breathing during the night is even higher in patients with end-stage renal disease [6]. The causes of this increased prevalence are unknown, and it is likely that the underlying pathomechanisms differ from those responsible in the general population. It was shown that the total number of disordered breathing events seems not to be acutely altered by conventional haemodialysis treatment [17]. On the other hand, the breathing disorder may resolve after successful kidney transplantation [18]. This suggests that the pathogenesis involves an unstable breathing pattern, possibly caused by an altered metabolic state, uraemia and changes in volume status [18]. Sleep-related breathing disorders are characterized by a recurrent obstruction of the upper airway. This results in episodic oxygen desaturations and disruption of the normal sleep pattern. The majority of patients affected by this disease have symptoms related to poor quality sleep, such as excessive daytime sleepiness and tiredness, lack of concentration and memory impairment. As a result, quality of life in these patients is impaired [15]. Impaired daytime performance and daytime sleepiness are also common symptoms of end-stage renal disease. Thus, in patients receiving maintenance haemodialysis treatment, the symptoms of an associated sleep-related breathing disorder frequently go unreported or may be misdiagnosed as uraemia, depression, chronic illness or insomnia. Nevertheless, sleep-related breathing disorders may have an additional influence on the quality of life in this population, as the results of our study demonstrate. This underlines the need for recording a careful history regarding sleep symptomatology in all patients with chronic renal disease. If necessary, an additional polygraphic or polysomnographic study should be undertaken. Interestingly, the complaints most heavily noted in end-stage renal disease patients with sleep-related breathing disorders were not obviously related to an impaired nocturnal sleep. Most markedly, social functioning was felt to be impaired, although there is no obvious explanation of why impaired sleep should primarily affect social functioning instead of physical ability. Potentially, it is this peculiar pattern of symptoms that may be responsible for the fact that most patients and their physicians have not recognized a relationship between impaired sleep and reduced quality of life. Social activities may be especially precious to patients and it may be for this reason that the social life subscale provided evidence of the most striking difference across the groups. It was shown in a study published recently that elimination of sleep-related breathing disorders by treatment with nasal continuous positive airway pressure may result in improvement in quality of life [19]. It remains to be seen whether nasal continuous positive airway pressure is also a potential treatment for sleep apnoea that might preserve quality of life in patients with end-stage renal disease especially in view of the fact that this treatment modality is much more readily available than renal transplantation as a means of reversing sleep-related breathing disorders. 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