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Jun 4, 2007 - Adrian Covic. Sleep-disordered breathing in patients with end-stage renal disease and long-term dialysis. Schlafbezogene Atmungsstörungen.
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Somnologie 11:211–215 (2007) DOI 10.1007/s11818-007-0309-5

Elena Corina Mucenica Daniela Boisteanu Josef Alexander Wirth Andrei Cernomaz Adrian Covic

Schlafbezogene Atmungsstörungen bei langjährigen Dialysepatienten mit finaler Nierenerkrankung 왘 Zusammenfassung Fragestellung: Bei Patienten mit finaler Nierenerkrankung ist eine hohe Prävalenz von Schlafstörungen (Insomnie, Periodische Beinbewegungen, Schlafapnoe) zu beobachten. Die Lebensqualität ist dadurch zusätzlich eingeschränkt und das kardiovaskuläre Risiko erhöht. Das Auftreten von schlafbezogenen Atmungsstörungen bei Patienten unter Langzeitdialyse wurde bisher nur wenig beleuchtet. Received: 27 June 2006 Accepted: 24 April 2007 Published online: 4 June 2007 E. C. Mucenica · D. Boisteanu · A. Cernomaz Clinical Hospital of Pneumology Iasi, Romania J. A. Wirth Institute of Sleep Diagnosis and Therapy Alfeld, Germany A. Covic Dept. of Nephrology,“Dr. C. I. Parhon” University Hospital Iasi Iasi, Romania A. Covic “Gr T. Popa” University of Medicine Iasi, Romania E. C. Mucenica (✉) Spitalul Clinic Pneumologie Iasi Str. Dr I. Cihac 30 Iasi, 6600, Romania E-Mail: [email protected]

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ORIGINAL ARTICLE

Sleep-disordered breathing in patients with end-stage renal disease and long-term dialysis

Patienten und Methodik: Wir rekrutierten 20 Patienten mit finaler Nierenerkrankung und einer mehr als 10 Jahre andauernden Hämodialyse. Es wurde die komplette Schlafanamnese, inklusive der Epworth Sleepiness Scale, erhoben sowie eine polysomnographische Untersuchung durchgeführt. Ergebnisse: Alle Patienten hatten einen gestörten Schlaf mit häufigem Erwachen (durchschnittl. Arousal Index = 19.1 ± 15.4 Ereignisse/Std., durchschnittl. Schlafeffizienz 79.3 % ± 11 %). Die gesamte Schlafzeit betrug 376 ± 90 min. Acht Patienten erfüllten die Diagnosekriterien für eine schlafbezogene Atmungsstörung, mit einem AHI von > 5/h. Wir fanden signifikante Unterschiede zwischen den zwei separierten Gruppen (Patienten mit vs. ohne schlafbezogene Atmungsstörungen) hinsichtlich des BMI, des Serumkreatinins und der Blut-Harnstoff-Stickstoff-Konzentration (BUN – blood urea nitrogen). Schlussfolgerung: Schlafbezogene Atmungsstörungen treten bei Patienten mit finaler Nierenerkrankung unter Langzeitdialyse (> 10 Jahre) im Vergleich zur Allgemeinbevölkerung häufiger auf. Möglicherweise ist dies eine Konsequenz aus der langjährigen Nierenerkrankung und aus der urämischen Milieuexposition.

왘 Schlüsselwörter Schlafbezogene Atmungsstörungen – Hämodialyse – Nierenerkrankung – Polysomnographie 왘 Summary Background It is proven that in patients with endstage renal disease (ESRD) the prevalence of sleep disorders (insomnia, periodic leg movement and sleep apnea) is high. This fact may contribute to an impaired quality of life and to an increased risk for cardiovascular diseases. However, only few published data are available with regard to sleepdisordered breathing in long-term hemodialysed patients. Patients and methods We recruited twenty patients with end-stage renal disease who had been dialysed for more than 10 years. Sleep disorders were confirmed by polysomnography, a sleep-questionnaire and the Epworth Sleepiness Scale. Results All patients had disturbed sleep with frequent awakenings (mean arousal index 19.1 ± 15.4 events/hour, mean sleep efficiency 79.3 % ± 11 %). Total sleep time in patients was 376 ± 90 min. Eight (40 %) patients met the criteria of sleep-disordered breathing (SDB) with an AHI of > 5/h and more than two major symptoms. We found significant differences between the two subgroups (patients with SDB vs. patients without SDB) due to body mass index, serum cre-

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atinine and blood urea nitrogen. Conclusions Sleep-disordered breathing is more frequent in longterm hemodialysed patients (> 10

years) than in general population. It is possibly a consequence of the long process of renal failure and the exposure to the uremic milieu.

Introduction In previous studies [10, 12] it could be proven that the prevalence of sleep disorders (sleep apnea, insomnia, restless legs syndrome, periodic leg movements) is high in patients with end-stage renal disease. Of patients undergoing hemodialysis 50–85 % suffer from non-recreative sleep characterized by difficulties in initiating and maintaining sleep [10]. Sleep apnea has been reported in 50 % up to 70 % of patients with end-stage renal disease (ESRD) [10] which is higher than the prevalence reported for the general population [15]. Conventional hemodialysis (CHD) and peritoneal dialysis do not reduce the prevalence of sleep apnea, while nocturnal hemodialysis (NHD) [4] improves the symptoms of sleep apnea in patients with ESRD. Kidney transplantation [1, 5, 7] had a curative effect with respect to sleep apnea in all studied cases. This fact may indicate that the pathophysiology of sleep apnea could be probably associated with the development of chronic renal failure within this population. Previous investigators observed both, central and obstructive breathing events, in patients with ESRD [8, 12, 14]. This suggests that the pathogenesis of ESRD is related to destabilization of central respiratory control as well as to upper airway obstruction. Numerous factors might contribute to the high frequency of sleep disorders in hemodialysed (HD) patients, such as uremia and metabolic changes in correlation with dialysis as well as autonomous neuropathy and instability of ventilatory control [2, 5, 8]. However, there are no published data concerning sleep-disordered breathing in patients with long-term hemodialysis. Therefore, the objective of this study was to assess the occurrence of sleep-disordered breathing in a group of long-term hemodialysed subjects (more than 10 years).

Methods The study population consisted of 20 patients receiving conventional hemodialysis (CHD) in a university-based out-patient clinic of nephrology. All HD subjects received dialysis treatment three days a week for 4 hours with at least a time span of 10 years (mean duration of HD 159.7 ± 40.7 months). They were adequately dialysed: Kt/V > 1.2 in all patients (Kt/V-number used to quantify hemodialysis and peritoneal dialysis treatment adequacy, corrected for body size) [3].

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왘 Key words sleep-disordered breathing – haemodialysis – renal disease – polysomnography

All subjects underwent polysomnography (PSG) during the second dialysis-free interval of the week. The patients had to fill out a sleep history questionnaire and the Epworth Sleepiness Scale. Furthermore, we asked for the cause of the renal disease, for the duration of dialysis treatment expressed in months, for the dialysis schedule and their medications. After PSG we determined routine laboratory examination (blood urea nitrogen [BUN], serum creatinine and haemoglobin) before the next dialysis session began. The PSG consisted of a standard montage of electroencephalography (EEG) (C3/A2, C4/A1, O2/A1, O1/A2),of left and right electrooculography (ROC,LOC) referenced to the opposite mastoid, of surface mentalis electromyography (EMG), of electrocardiogram as well as of microphone for snoring and body position sensor. Respiratory airflow was recorded with thermistor and thoracic and abdominal movements with piezoelectric sensors. Oxygen haemoglobin saturation was monitored by pulse oximetry. Sleep stages and arousals were manually scored according to the criteria of Rechtschaffen et Kales [11].Polysomnography was performed with Embla System. Respiratory events were analyzed visually. Apneas and hypopneas were manually scored according to international criteria [13]. Apnea was defined as an interruption of airflow for at least 10 seconds. Obstructive apnea was scored according to the persistence of thoracoabdominal movements. Central apnea was scored according to the absence of thoracoabdominal movements. Hypopnea was defined as a decrease of airflow with at least 50 % for more than 10 s accompanied by a decrease in oxygen saturation of up to 4 % for more than 10 s. The apnea index (AI) was defined as the number of apneas/hour of sleep. Hypopnea index (HI) means the number of hypopneas/hour of sleep. The apnea-hypopnea index (AHI) considered the number of apneas and hypopneas/hour of sleep.The oxygen desaturation index (ODI) was defined as the number of events with a decrease in oxygen saturation of 4 % or more per hour of sleep. Sleep-disordered breathing was defined as an AHI ≥ 5 events/hour of sleep and existence of at least 2 typical symptoms (e. g. excessive daytime sleepiness). General sleep measurements obtained total sleep time (min), the percentage of total sleep time spent in non rapid eye movement sleep (NREM) and in stages 1 (S1)and 2 (S2), slow wave sleep (S3, S4) and rapid eye movement sleep (REM). To quantify the sleep stability and sleep quality sleep efficiency (total sleep time/time in bed x 100) and wake after sleep onset (%) were also measured.

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■ Statistical analysis

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Table 1 Subject characteristics

For descriptive purposes means and standard deviations were calculated. The statistical significance of mean differences between the study groups was assessed by using the non-parametric Mann-Whitney-U test. The level of significance was set at P < 0.05.

Results Twenty patients (12 males, 8 females), mean age 45.2 ± 8.2 (range 29–65) years were studied. The causes of renal failure were glomerulonephritis (n = 9), chronic interstitial nephritis (n = 2), hypertensive nephropathy (n = 5), others (n = 4). In Table 1 demographic and dialysis data of the participants are shown. Eight (40 %) patients showed evidence (mean AHI = 21.6 ± 17.012, range 7.4–55) and met the diagnostic criteria of sleep-disordered breathing (AHI > 5/hour, 2 major symptoms). In order to assess biochemical and demographic differences between the patients with and without sleep-disordered breathing we divided them in two groups (with and without sleepdisordered breathing). We found a significant higher body mass index (p = 0.03), BUN (p = 0.039) and serum creatinine levels (p = 0.04) in the group with sleep-disordered breathing. According to polysomnographical data, as shown in Table 2, all patients had disturbed sleep with frequent awakenings (mean arousal index = 19 ± 15.4/h), decreased sleep efficiency (79.3 % ± 11 %) and consequential fragmentations in sleep architecture. In addition,

Parameter

Mean value ± Std. Deviation Range

Number of patients 20 Epworth Sleepiness Scale Score 6 ± 1.5 Age (years) 45 ± 8 Male/Female 12/8 BMI (kg/m2) 22.82 ± 3.5 Months of HD 159.76 ± 40.79 kT/V 1.4 ± 0.08 Serum creatinine 10.5 ± 21.91 Blood urea nitrogen (BUN) 193 ± 45.8

0–14 29–65 17–31 120–246 1.2–1.5 8–14 131–268

BMI body mass index; Kt/V dialysis coefficient representing dialysis adequacy; HD haemodialysis

superficial sleep stages were predominant (S1: 13.5 ± 7.9 %, S2: 40.5 ± 7.5 %) accompanied by a large fraction of wake episodes during sleep time (20.7 ± 11.3 %). Total sleep time was reduced (376 ± 90min) compared to normal values [9]. All patients suffered from daytime fatigue. Excessive daytime sleepiness was found in 12 subjects (ESS > 10). Snoring occurred in 10 patients. Total sleep time and sleep efficiency did not differ between the two groups. The patients with sleep-disordered breathing had a greater proportion of S1 and S2 NREM sleep, a smaller proportion of slow wave sleep and a greater number of arousals from sleep. The respiratory data are shown in Table 3. In the group with sleep-disordered breathing mean AHI was 21.64 ± 17.01/h. Apneas and hypopneas were predomi-

Table 2 Polysomnographic sleep data of group 1 (patients with sleep-disordered breathing) and of group 2 (patients without sleep-disordered breathing) Group 1 (n1 = 8)

Group 2 (n2 = 12)

Parameter

Mean ± Std. Deviation

Range

Mean ± Std. Deviation

Range

P value

Total sleep time (min) S1 (%) S2 (%) Slow wave sleep (%) S3 (%) S4 (%) REM (%) Wake (%) Sleep efficiency (%) Arousal index (events/h) ESS BMI BUN Serum creatinine

346 ± 90 14.2 ± 7.7 41.9 ± 8.1 11.2 ± 4.7 7.7 ± 2.3 3.5 ± 2.4 13 ± 8.3 19.4 ± 10 77.8 ± 12 20.6 ± 10 8.3 ± 2.4 24.75 ± 3.69 213.5 ± 45.4 11.3 ± 1.94

222–508 4.6–25.2 30.8–49.9 4.5–23.2 4.5–11.6 0–11.6 1.9–26.3 9.2–39.4 61.5–89.6 4–64 2–14 21–31 145–268 8–14

376 ± 97 12.9 ± 8.5 39.2 ± 7.1 14.9 ± 8.8 9.9 ± 5.2 5 ± 3.6 11 ± 5.7 21.8 ± 12 79.3 ± 11 18.5 ± 12 4.7 ± 1.3 21.11 ± 2.5 165.6 ± 31.8 9.4 ± 1.3

245–523 4.3–32.8 29–46.7 1.4–27 1.4–17 0–10 3.8–20 7.5–38 60.6–90.5 3–34 0–10 17–25 131–211 8–11

ns ns ns ns ns ns ns ns ns ns ns 0.03 0.039 0.04

S1 sleep stage 1; S2 sleep stage 2; S3 sleep stage 3; S4 sleep stage 4; REM rapid eye movement sleep; Sleep efficiency total sleep time (TST) expressed as a proportion of total analysis time; ESS Epworth Sleepiness Scale; BMI body mass index; BUN blood urea nitrogen

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Table 3 Polysomnographic data of group 1 (patients with sleep related breathing disorders), and of group 2 (patients without sleep related breathing disorders) Group 1 (N = 8)

Group 2 (N = 12)

Parameter

Mean ± Std. Deviation

Range

Mean ± Std. Deviation

Range

P value

AHI (events/h) AIo (events/h) AIc (events/h) AIm (events/h) HI (events/h) ODI (events/h) Mean O2 saturation (%) Lowest O2 saturation (%)

21.64 ± 17.01 2.8 ± 1.85 1.87 ± 1.50 0.32 ± 0.24 16.65 ± 14.85 20.4 ± 22.92 94.7 ± 1.9 83.7 ± 5

7.4–55 0–7.6 0–5.6 0–3.5 4.5–47.8 5.1–73 90.9–97 72–88

10 ± 6.79 2.3 ± 1.35 0.92 ± 2.02 0.47 ± 0.42 7.6 ± 4.94 2.94 ± 0.98 96.3 ± 1.98 85.3 ± 5.9

2.6–19.2 0–10.8 0–3.9 0–3.5 2.2–15.4 0.3–4.6 93–98 75–94

ns ns ns 0.04 0.01 0.05 ns

AHI Apnea/hypopnea index = events/hour of sleep; AIo obstructive apnea index; Aic central apnea index; AIm mixed apnea index; HI hypopnea index; ODI oxygen desaturation index

nantly of obstructive type (91 %). A smaller proportion was classified as central (7 %) or mixed (2 %). In all patients the majority (> 70 %) of respiratory events had obstructive features (mean of obstructive apneic events AHIo: 13.7 ± 13/h). Mean oxygen saturation (SaO2) was 94.7 % ± 1.9 % and the lowest SaO2 was 83.7 % ± 5 % in patients with sleep-disordered breathing.

Discussion Our findings confirm the high frequency of sleep-disordered breathing in patients with ESRD as reported in previous studies with short-term dialysis [10, 12]. The majority of apneas and hypopneas we observed were obstructive. The results of Beecroft et al. [2] agree with our findings. Otherwise, some previous studies revealed a higher percentage of central and mixed apneic and hypopneic events [1, 10]. Although many hypotheses have been considered (uremic milieu, cytokines, autonomous neuropathy, altered respiratory chemoreflex responsiveness, airway oedema) [2, 5, 10] the pathogenesis of sleep-disordered breathing in patients with ESRD is unknown. The high prevalence of arousals and breathing related disorders in all included HD patients suggests that conventional hemodialysis may have unknown effects on sleep. The results of Hanly and Pierratos [5] support our findings. They proved that the administration of nocturnal hemodialysis (NHD) reduces significantly the incidence of sleep apnea in ESRD patients. It is probably a consequence of more stability in ventilation. Beecraft et al. [2] showed that one of the potential mechanisms of sleep apnea in ESRD should be the altered respiratory chemoreflex responsiveness. These data indicate that the sensitivity of central and of peripheral chemoreceptors is increased in patients with sleep apnea and ESRD. This may indicate a loss of stability in respiratory control. By increased sensitivity of ventilation and destabi-

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lized respiratory control uremic neuropathy may also be involved in the pathogenesis of sleep-disordered breathing. Although sleep-disordered breathing is clearly associated with ESRD, the natural history of this association has not been determined yet. In our patients affected by sleep-disordered breathing there was a predominance of obstructive events, followed by central and mixed events. These findings support the hypotheses that sleep related breathing disorders in patients with ESRD occur due to the central destabilization of ventilation control as well as to upper airway occlusion [2, 5]. Our study is limited by the small sample size. On the other hand the majority of previous studies regarding this topic had an equal sample size. An additional limitation of the study is the separation of the study population in the two groups – with and without sleep-disordered breathing. Some parameters, such as AHI and SO2-saturation are not comparable between these two groups to make a conclusion. It is just to characterize the patients more detailed. Nonetheless, our findings suggest that further exploration is warranted and that population-specific interventions may be indicated. Polysomnography is useful in stratifying HD patients according to their cardiovascular risk and their need of specific therapy (i. e. sleep hygiene and nose-throat-specific therapy, continuous positive airway pressure) [16]. In our study group (sleep related breathing disorders and ESRD) we found a low therapeutical compliance, probably because of the multiple morbidities, which can explain the rejection of the CPAP therapy.

Conclusions Sleep-disordered breathing in patients undergoing dialysis for more than 10 years is more frequent (40 %) than in general population (2–4 %). This might be the result of the prolonged exposure to the uremic milieu in ESRD

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patients undergoing HD. The pathogenesis of sleep-disordered breathing seems to be influenced by factors that are associated with renal failure and dialysis itself. Furthermore, the appearance of sleep disorders in ESRD might be of a different way than the mechanisms that cause sleep related breathing disorders in the general population.

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Further extended investigations should compare patients new on dialysis versus long-term dialysis and should take into account autonomic dysfunction and cardiovascular risk factors. ■ Acknowledgement We authors thank Ms. Dana Buck for language and editorial assistance.

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12. Stepanski E, Faber M, Zorick F, Basner R, Roth T (1995) Sleep disorders in patients on continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 26: 751–756 13. The report of American Academy of Sleep medicine Task Force (1999) Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 22(5): 667–689 14. Wadhwa NK, Mendelson WB (1992) A comparison of sleep-disordered respiration in ESRD patients receiving hemodialysis and peritoneal dialysis. Adv Perit Dial 8:195–198 15. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S (1993) The occurrence of sleep-disordered breathing among middle-aged adults. N Eng J Med 328: 1230–1235 16. Zoccali C, Mallamaci F, Tripepi G (2001) Sleep apnea in renal patients. J Am Soc Nephrol 12:2854–2859

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