**3.9 Medications and other substances**

Medications and other substances which may cause insomnia include beta-blockers, bronchodilators, corticosteroids, CNS stimulants, Tagamet, cardiovascular drugs, neurological drugs, alcohol, caffeine and nicotine (Merlino et al., 2006; Rosenthal, 1998; Unruh et al., 2006). Most prescribed as well as over-the-counter medications produce side effects which are either sedating or stimulating. Drugs which cause daytime sleepiness include analgesics, benzodiazepines and antihistamines (Rosenthal, 1998; Unruh et al., 2006). According to recent investigations, the use of hypnotic medication in dialysis patients is rather modest: 8–10% (De Santo et al., 2005; De Santo et al., 2001). In a large study, the reported use of sleep-inducing medication was even lower—3.6% (Merlino et al., 2006). However, dialysis patients with severe sleep disorders use specific medication more frequently (24%) (De Santo et al., 2005). Improved hemodialysis techniques, socioeconomical disparities in the studied populations, and reluctance by nephrologists to prescribe psychotropic medication may explain these disparities. However, we must be aware that chronic auto-administration of hypnotic medication may be more frequent in

cardiovascular disease (CVD), which causes roughly 50% of deaths (Covic et al., 2006). A study by Mucsi et al. (2004), demonstrated that comorbidities are independent predictors of sleep disturbances in patients on maintenance dialysis. According to another study, the average Charlson Comorbidity Index (CCI) in patients without sleep disorders was 4.10, while scores in patients with subclinical and clinically overt sleep disorders were 6.10 and 6.81, respectively (De Santo et al.,2005). This highly significant association in the Italian HD population was maintained regardless of age. To conclude so far, any in-depth research on

Sleep difficulties are closely correlated with older age in patients with chronic uremia (Iliescu et al., 2003). Yoshioka et al.(1993) found that advanced age and long-term dialysis therapy directly affected patients experiencing sleep problems. The disorders are similar to those described in the general population, where the prevalence and severity of sleep disorders are also associated with old age. Each decade of age increases the risk of insomnia by 239%, and the risk of overt clinical insomnia by 51% (De Santo et al., 2005). Mollaoğlu (2004) reported a negative correlation between age and sleep quality, with sleep quality decreasing with advanced age in their study of 105 HD patients. In addition, communitybased studies have shown that sleep quality could be deteriorated in elderly patients due to increased frequency of physical diseases, multiple drug use, primary sleep disturbances, or

The psychiatric condition most commonly causing sleep disorders is depression that may affect up to 50% of this patient population (Covic et al., 2006). The relationship between depression and sleep disorders is well known both in the general population and in patients undergoing hemodialysis (İliescu et al.,2003). Depression can be a cause, as well as a result, of insomnia. Dialysis patients with a Pittsburg Quality Index Sleep score of >5 (patients with a "difficult sleep") have a prevalence of overt depression of 20%, while among ESRD patients

Medications and other substances which may cause insomnia include beta-blockers, bronchodilators, corticosteroids, CNS stimulants, Tagamet, cardiovascular drugs, neurological drugs, alcohol, caffeine and nicotine (Merlino et al., 2006; Rosenthal, 1998; Unruh et al., 2006). Most prescribed as well as over-the-counter medications produce side effects which are either sedating or stimulating. Drugs which cause daytime sleepiness include analgesics, benzodiazepines and antihistamines (Rosenthal, 1998; Unruh et al., 2006). According to recent investigations, the use of hypnotic medication in dialysis patients is rather modest: 8–10% (De Santo et al., 2005; De Santo et al., 2001). In a large study, the reported use of sleep-inducing medication was even lower—3.6% (Merlino et al., 2006). However, dialysis patients with severe sleep disorders use specific medication more frequently (24%) (De Santo et al., 2005). Improved hemodialysis techniques, socioeconomical disparities in the studied populations, and reluctance by nephrologists to prescribe psychotropic medication may explain these disparities. However, we must be aware that chronic auto-administration of hypnotic medication may be more frequent in

reporting a normal sleep**,** the prevalence of depression is almost nil (İliescu et al.,2003).

the quality of sleep in renal patients must consider the magnitude of comorbidities.

lifestyle modifications (Brandenberger et al., 2003; Kamel & Gammack 2006).

**3.7 Age** 

**3.8 Depression** 

**3.9 Medications and other substances** 

ESRD patients compared to the general population. Moreover, according to recent data from the CHOICE incident dialysis population, use of benziodiazepines is associated with altered sleep quality during the first year of dialysis. Although this study was unable to distinguish between cause and effect, more effective dialysis and cognitive behavioral therapy have been suggested in patients with sleep disorders in need of sleep-inducing medication (Unruh et al., 2006). Moreover, many antidepressants actually cause paradoxical restlessness, therefore systematic administration of these drugs should be subjected to close clinical follow-up, which should be easy to accomplish in hemodialysis patients.

Alcohol is widely used as a sleep aid. Although it does shorten sleep latency, it also causes sleep fragmentation, decreased REM, REM rebound and early morning awakenings. The use of alcohol combined with hypnotics may exacerbate sleep difficulties even more (Rosenthal, 1998). Alcohol and (particularly) tobacco abuse is highly associated with increased prevalence of sleep disorders in ESRD (Merlino et al., 2006). Caffeine and other stimulants such as nicotine have been shown to increase sleep latency and sleep fragmentation, and to decrease total sleep time (Rosenthal, 1998). Current smoking is also related with decreases in sleep quality during the first year of dialysis therapy in incident patients (Unruh et al., 2006). Caffeine intake appears to have no significant impact on insomnia in ESRD (Sabbatini et al., 2002).

### **4. Sleep quality and evaluation of sleep in hemodialysis patients**

Sleep quality is an important clinical construct for two major reasons. First, complaints about sleep quality are common; epidemiological surveys indicate that 15-35 % of the adult population complain of frequent sleep quality disturbance, such as difficulty falling asleep or difficulty maintaining sleep. Second, poor sleep quality can be an important symptom of many sleep and medical disorders (Buysse et al., 1989).

Sleep quality" is sometimes used to refer to a collection of sleep measures including total sleep time (TST), sleep onset latency (SOL), degree of fragmentation, total wake time, sleep efficiency, and sometimes sleep disruptive events such as spontaneous arousals or apnea. The widely employed Pittsburgh Sleep Quality Index (PSQI), for example, provides a measure of global sleep quality based on a respondent's retrospective appraisal (past month) of an array of sleep measures, including sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction (Krystal & Edinger, 2008). Sleep quality is also sometimes inferred from a collection of objective indices taken from polysomnography (PSG). PSG is the most valid and accurate way to assess sleep. Measures derived from PSG include: (a) total sleep time, (b) sleep efficiency (ratio of time spent asleep/time in bed), (c) sleep latency (time to fall asleep after lights out), (d) amount of wake time during sleep periods (waking after sleep onset, WASO), (e) number of awakenings, and (f) amount of each sleep stage ( Landis al., 2002).

Among these objective indices are measures such as sleep onset latency, total sleep time, wake time after sleep onset, sleep efficiency, and number of awakenings that correspond to like measures taken from various available self-report instruments (e.g., sleep diaries, PSQI, etc.) (Buysse et al., 2006). However, PSG also provides a number of measures that reflect the architecture of sleep such as the percentage or temporal amounts of stage 1 sleep, stage 2 sleep, slow wave sleep or rapid eye movement (REM) sleep. Despite having no self-report analogues, these latter measures also have been employed by some as indices of sleep quality (Krystal & Edinger, 2008).

Sleep in Patients with ESRD Undergoing Hemodialysis 417

view, psychological, behavioural and pharmacologic interventions that promote sleep will

The above studies results show that the sleep characteristics of hemodialysis patients need to be routinely evaluated. In addition to medical treatment to eliminate the sleep problems of hemodialysis patients and increase their sleep quality, the implementation of sleep hygiene interventions that can play a part in the regularity of patients' sleep could also be beneficial. These interventions would include an environment with a comfortable room temperature and ventilation, minimal noise, a comfortable bed, and proper lighting. These interventions should apply to each patient's personal routines (Mollaoglu & Mollaoglu,

Proper management of sleep problems in ESRD patients requires in the first instance a proper identification of sleep abnormalities (extensively discussed above). Although significant research has been done to characterize sleep abnormalities in hemodialysis patients (Holey et al., 1992; De Santo et al., 2005; Merlino et al., 2006), little has been published regarding proper treatment. In the absence of guidelines, nephrologists rely largely on some published data and on opinion-based medicine. Sleep problems lower quality of life and contribute to physical and mental health problems. Sleep disorders and lack of sleep are an under treated threat to the public health. Sleep professionals have recognized the behavioral components of sleep disorders for decades, yet most patients

Periodic clinical assessment of sleep complaints should become routine for dialysis staff. Early identification of sleep problems and interventions to improve sleep quality is essential, because sleep disturbance that persists for a long period of time could decrease general health and functioning (Sabbatini et al., 2003; Tatomir et al., 2007). Increasing evidence supports the effectiveness of both pharmacologic and nonpharmacologic therapies for sleep problems (Edinger et al., 2001; Montgomery & Dennis, 2004; Smith et al., 2002).

The most effective nonpharmacologic interventions tested to date include all or most of the following components: *sleep hygiene instruction, sleep restriction, stimulus control, relaxation* 

Sleep hygiene involves basic education on how the sleep environment, caffeine, alcohol, nicotine, food and exercise affect sleep (Smith et al., 2002). Sleep Hygiene is an educational approach designed to teach insomnia patients as well as the population at large how to maintain healthy behavioral habits which promote better sleep. It is important to understand that successful treatment is only possible if the patient complies with suggestions to improve sleep hygiene (*Edinger et al., 2001)*. Below are summarized tips for

Sleep only when sleepy. If you can't fall asleep within 20 min get up and do something

*training, and cognitive modification* **(**Edinger et al., 2001; Montgomery & Dennis, 2004).

represent a more than promising area for future research in hemodialysis patients.

**5. Management of sleep problems in hemodialysis patients** 

never get a proper diagnosis and treatment (Mollaoglu & Mollaoğlu, 2009).

Pharmacologic therapy are discussed in the sleep disorders section.

2009).

**5.1 Sleep hygiene** 

sleep hygiene *Sleep hygiene tips* 

boring until you feel sleepy,

Don't take nap sunless your doctor advises so.

Most of the recent studies on quality of sleep use different questionnaires assessing various aspects of sleep. The Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, and the Berlin Questionnaire are most frequently applied. Results derived from these questionnaires are limited by the subjective perception/sincerity of the patients, and thus are an imperfect substitute for more objective research methods on sleep in patients with chronic uremia (Chen et al, 2006; Iliescu et al., 2003; Mollaoglu & Mollaoglu, 2009; Sabbatini et al., 2003).

Researchers have documented that ESRD patients reported significantly poorer subjective quality of sleep in comparison to the general population (Holley et al., 1992; Parker, 2005). The reported prevalence of 'poor sleep', including sleep-wake complaints, sleep-disordered breathing and excessive sleepiness, in dialysis patients is in the range of 45–80% (Afshar et al., 2011; Parker, 1996; Walker et al., 1995; Wei et al., 2011 ). In a another study It was examined the quality of sleep in 89 subjects with ESRD on haemodialysis using the PSQI and found a prevalence of 'poor sleep' (global PSQI>5) of 71% (Iliescu et al., 2003). Also, decreased quality of sleep is common in dialysis patients and is associated with decreased health-related quality of life (Iliescu et al., 2003; Williams et al., 2002).

 The complex evaluation of sleep in patients with renal disease may be accomplished only by means of polysomnography. Polysomnography includes the comprehensive evaluation of the patient during sleep by electroencephalography, electrooculography, myography, quantification of respiratory efforts (by plethysmography), pulseoxymetry and noninvasive evaluation of CO2 blood level, and heart rate measuring (Tatomir et al., 2007). Parker et al. (2003) examined by polysomnography 16 patients with HD and 8 patients with pre-dialysis CKD. Dialysis patients, in comparison with non-dialyzed CKD subjects, have a shorter sleep time. The REM phase is also shortened, time until falling asleep is longer, and respiratory events are more frequent. The sleep latency period was double in renal patients without dialysis compared to those with dialysis. Moreover, the prevalence and severity of periodical limb movement is higher in dialysis patients, as well as the number of short-term awakening periods (Parker et al., 2003). The authors suggest that sleep disturbances may have a different etiology in dialyzed patients compared to pre-dialysis CKD subjects. Functional and psychological factors may play a more prominent role in the pre-dialysis group, whereas intrinsic sleep disruption (arousals, apneas and limb movements) secondary to intermittent daytime HD sessions may play a more prominent role in patients with chronic uremia. Taken as a whole, renal patients experience a significant reduction in sleep length and efficiency compared to the general population (Parker et al., 2005).

The studies have shown poor the quality of sleep in HD patients to be associated with female sex, older age, caffeine intake, recombinant erythropoietin therapy, pain, cardiovascular disease, physical functioning, larger body mass index (BMI), exercise, dialysis adequacy, parathyroid hormone, serum creatinine and quality of life (QOL) (Benz et al., 1999; Sabatini et al., 2002; Walker et al., 1995). Hanly et al*.* (2003) examined daytime sleepiness with multiple sleep latency tests in 24 haemodialysis patients and found strong correlation between sleep latency and BUN. In addition, psychological problems do represent crucial factors in influencing the quality of sleep in hemodialysis patients, as emphasized by all the previous studies in prevalent patients with renal disease, with depression playing a prominent role, followed by anxiety, sexual problems, financial strains, and isolation (İliescu et al., 2003; İliescu et al., 2004; Markou et al.,2006; Novak et al.,2006).

Considering the strict linkage between some of these factors affecting sleep and hemodialysis, it is tempting to speculate that treating sleep problems, while improving the overall quality of life, might positively affect hemodialysis. In addition, with this point of

Most of the recent studies on quality of sleep use different questionnaires assessing various aspects of sleep. The Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, and the Berlin Questionnaire are most frequently applied. Results derived from these questionnaires are limited by the subjective perception/sincerity of the patients, and thus are an imperfect substitute for more objective research methods on sleep in patients with chronic uremia (Chen et al, 2006; Iliescu et al., 2003; Mollaoglu & Mollaoglu, 2009; Sabbatini et al., 2003). Researchers have documented that ESRD patients reported significantly poorer subjective quality of sleep in comparison to the general population (Holley et al., 1992; Parker, 2005). The reported prevalence of 'poor sleep', including sleep-wake complaints, sleep-disordered breathing and excessive sleepiness, in dialysis patients is in the range of 45–80% (Afshar et al., 2011; Parker, 1996; Walker et al., 1995; Wei et al., 2011 ). In a another study It was examined the quality of sleep in 89 subjects with ESRD on haemodialysis using the PSQI and found a prevalence of 'poor sleep' (global PSQI>5) of 71% (Iliescu et al., 2003). Also, decreased quality of sleep is common in dialysis patients and is associated with decreased

 The complex evaluation of sleep in patients with renal disease may be accomplished only by means of polysomnography. Polysomnography includes the comprehensive evaluation of the patient during sleep by electroencephalography, electrooculography, myography, quantification of respiratory efforts (by plethysmography), pulseoxymetry and noninvasive evaluation of CO2 blood level, and heart rate measuring (Tatomir et al., 2007). Parker et al. (2003) examined by polysomnography 16 patients with HD and 8 patients with pre-dialysis CKD. Dialysis patients, in comparison with non-dialyzed CKD subjects, have a shorter sleep time. The REM phase is also shortened, time until falling asleep is longer, and respiratory events are more frequent. The sleep latency period was double in renal patients without dialysis compared to those with dialysis. Moreover, the prevalence and severity of periodical limb movement is higher in dialysis patients, as well as the number of short-term awakening periods (Parker et al., 2003). The authors suggest that sleep disturbances may have a different etiology in dialyzed patients compared to pre-dialysis CKD subjects. Functional and psychological factors may play a more prominent role in the pre-dialysis group, whereas intrinsic sleep disruption (arousals, apneas and limb movements) secondary to intermittent daytime HD sessions may play a more prominent role in patients with chronic uremia. Taken as a whole, renal patients experience a significant reduction in sleep

health-related quality of life (Iliescu et al., 2003; Williams et al., 2002).

length and efficiency compared to the general population (Parker et al., 2005).

The studies have shown poor the quality of sleep in HD patients to be associated with female sex, older age, caffeine intake, recombinant erythropoietin therapy, pain, cardiovascular disease, physical functioning, larger body mass index (BMI), exercise, dialysis adequacy, parathyroid hormone, serum creatinine and quality of life (QOL) (Benz et al., 1999; Sabatini et al., 2002; Walker et al., 1995). Hanly et al*.* (2003) examined daytime sleepiness with multiple sleep latency tests in 24 haemodialysis patients and found strong correlation between sleep latency and BUN. In addition, psychological problems do represent crucial factors in influencing the quality of sleep in hemodialysis patients, as emphasized by all the previous studies in prevalent patients with renal disease, with depression playing a prominent role, followed by anxiety, sexual problems, financial strains, and isolation (İliescu et al., 2003; İliescu et al., 2004; Markou et al.,2006; Novak et al.,2006). Considering the strict linkage between some of these factors affecting sleep and hemodialysis, it is tempting to speculate that treating sleep problems, while improving the overall quality of life, might positively affect hemodialysis. In addition, with this point of view, psychological, behavioural and pharmacologic interventions that promote sleep will represent a more than promising area for future research in hemodialysis patients.

The above studies results show that the sleep characteristics of hemodialysis patients need to be routinely evaluated. In addition to medical treatment to eliminate the sleep problems of hemodialysis patients and increase their sleep quality, the implementation of sleep hygiene interventions that can play a part in the regularity of patients' sleep could also be beneficial. These interventions would include an environment with a comfortable room temperature and ventilation, minimal noise, a comfortable bed, and proper lighting. These interventions should apply to each patient's personal routines (Mollaoglu & Mollaoglu, 2009).
