Research
Open Access

Nocturnal sleep, daytime sleepiness, and quality of life in stable patients on hemodialysis

  • Kathy P Parker1, 3Email author,
  • Nancy G Kutner2,
  • Donald L Bliwise3, 1,
  • James L Bailey4 and
  • David B Rye3, 1
Health and Quality of Life Outcomes20031:68

https://doi.org/10.1186/1477-7525-1-68

©  Parker et al; licensee BioMed Central Ltd. 2003

Received: 31 July 2003

Accepted: 21 November 2003

Published: 21 November 2003

Abstract

Background

Although considerable progress has been made in the treatment of chronic kidney disease, compromised quality of life continues to be a significant problem for patients receiving hemodialysis (HD). However, in spite of the high prevalence of sleep complaints and disorders in this population, the relationship between these problems and quality of life remains to be well characterized. Thus, we studied a sample of stable HD patients to explore relationships between quality of life and both subjective and objective measures of nocturnal sleep and daytime sleepiness

Methods

The sample included forty-six HD patients, 24 men and 22 women, with a mean age of 51.6 (10.8) years. Subjects underwent one night of polysomnography followed the next morning by a Multiple Sleep Latency Test (MSLT), an objective measure of daytime sleepiness. Subjects also completed: 1) a brief nocturnal sleep questionnaire; 2) the Epworth Sleepiness Scale; and, 3) the Quality of Life Index (QLI, Dialysis Version) which provides an overall QLI score and four subscale scores for Health & Functioning (H&F), Social & Economic (S&E), Psychological & Spiritual (P&S), and Family (F). (The range of scores is 0 to 30 with higher scores indicating better quality of life.)

Results

The mean (standard deviation; SD) of the overall QLI was 22.8 (4.0). The mean (SD) of the four subscales were as follows: H&F – 21.1 (4.7); S&E – 22.0 (4.8); P&S – 24.5 (4.4); and, F – 26.8 (3.5). H&F (rs = -0.326, p = 0.013) and F (rs = -0.248, p = 0.048) subscale scores were negatively correlated with periodic limb movement index but not other polysomnographic measures. The H&F subscale score were positively correlated with nocturnal sleep latency (rs = 0.248, p = 0.048) while the H&F (rs = 0.278, p = 0.030) and total QLI (rs = 0.263, p = 0.038) scores were positively associated with MSLT scores. Both of these latter findings indicate that higher life quality is associated with lower sleepiness levels. ESS scores were unrelated to overall QLI scores or the subscale scores. Subjective reports of difficulty falling asleep and waking up too early were significantly correlated with all four subscale scores and overall QLI. Feeling rested in the morning was positively associated with S&E, P&S, and Total QLI scores.

Conclusion

Selected measures of both poor nocturnal sleep and increased daytime sleepiness are associated with decreased quality of life in HD patients, underscoring the importance of recognizing and treating these patients' sleep problems.

Background

Considerable progress has been made in the treatment of chronic kidney disease (CKD). Yet, suboptimal quality of life continues to be a significant problem for patients receiving hemodialysis (HD). Several factors are believed to contribute to this problem including stress [3–5], depression and anxiety [6], anemia [7–9], the confines of treatment [3, 10], and vocational inactivity [7]. Sleep complaints and daytime sleepiness are also very prevalent in this group [11, 12], but their impact upon quality of life remains to be well characterized. In the general population, nocturnal and daytime sleep abnormalities adversely affect quality of life-related measures such as general health status [13], satisfaction with life [14], mood [15] and work performance [16]. Because sleep problems, such as insomnia, sleep apnea, and periodic limb movement disorder (see Table 1) are very prevalent in the HD population, information about their association with life quality is essential for the optimization of both interventions and clinical outcomes. Here we present a systematic exploration (that was part of a larger study previously reported [17]) of how quality of life is related to specific measures of nocturnal sleep and daytime sleepiness in a sample of stable HD patients. Our hypothesis was that reduced quality of life would be associated with poorer nocturnal sleep and increased daytime sleepiness.
Table 1

Definitions of Sleep Variables Measured in the Study [1, 2]

Brief Arousal – An abrupt change (3 to 14 seconds) from a "deeper" stage of NREM sleep to a "lighter" stage, or from REM sleep to wakefulness.

Brief Arousal Index – number of brief arousals/hour of sleep; normally < 15/hour

Excessive Daytime Sleepiness – Difficulty in maintaining the alert, awake state. Can be measured subjectively using questionnaires (such as the Epworth Sleepiness Scale; see text) or objectively (polysomnographically) using the Multiple Sleep Latency Test (see text).

Insomnia/Sleep Fragmentation (subjective) – difficulty initiating or maintaining sleep; often characterized by difficulty falling and/or staying asleep, early morning awakenings, or unrefreshing sleep.

Mean Sleep Latency – the average period of time from the start of a nap opportunity to the first epoch of sleep as measured by the Multiple Sleep Latency Test.

Periodic Limb Movement – a rapid partial flexion of the foot at the ankle, extension of the big toe, and partial flexion of the knee and hip[ that occurs during sleep. The movements occur with a periodicity of 5 to 90 seconds, lasting 0.5 to 5.0 seconds.

Periodic Limb Movement Index (PLMI) – number of periodic limb movements/hour of sleep.

Periodic Limb Movement with Arousal Index – number of limb movements/hour of sleep associated with an abrupt change from a deeper stage of NREM sleep to a lighter stage, or from REM sleep to wakefulness

Respiratory disturbance – Cessation (apnea) or reduction in breathing (hypopnea; airflow reduced by at least 50%) during sleep, lasting 10 seconds or longer, often associated with a fall in blood oxygen saturation.

Respiratory Disturbance Index (RDI) – number of apneas/hypopneas per hour of sleep.

Sleep Efficiency (SE) – The proportion of sleep in the episode filled by sleep; the ratio of TST to time in bed. Normal values range typically from 80% to 95% and decrease with age.

Sleep Latency (SL) – The onset of sleep defined as the first of three consecutive epochs of Stage 1 sleep or the first epoch of any other stage of sleep. Normal sleep latency averages < 20 minutes.

Total Sleep Time (TST) – The amount of actual sleep time in a sleep episode; the time is equal to the total sleep episode less the awake time; average normal TST is 7.5 hours.

Methods

Sample

The School of Medicine's Internal Review Board and appropriate HD unit physicians and administrators approved the protocol. Because we sought to study relationships among quality of life and sleep variables in patients with CKD receiving intermittent HD independent of the effects of other major chronic illnesses, potential subjects with histories of cardiac disease, chronic lung disease, arthritis, organic brain disease, drug/alcohol abuse, or past psychiatric disorders [1] requiring treatment were excluded from participation. Because of potential drug-related effects on sleep and wakefulness [18], those subjects routinely taking medications known to modulate central nervous system state such as beta-blockers (low lipid-soluble agents were allowed, e.g. atenolol), other antihypertensives such as clonidine and methyldopa, and antidepressants, sedatives, hypnotics, activating agents, or pain medications were also excluded. Finally, potential subjects were screened via a structured interview to exclude those with a history of or current treatment for sleep apnea syndrome, restless legs syndrome, or periodic limb movement disorder. The final sample included 46 stable, otherwise healthy HD patients recruited from 26 HD units in the Atlanta metropolitan area (see Table 2). According to Cohen [19], using a one-tailed test and an alpha level = 0.05, a sample of 46 provided a power of approximately 85% to detect a medium effect size (rs = 0.40).
Table 2

Demographic/Clinical/Dialysis-Related Features of the Sample

Demographic Variables

Mean (SD*) or n**

Median

Range

Age

51.6 (10.8)

52.0

32.0 to 74.0

Gender (n)

   

• Males

24

  

• Females

22

  

Race (n)

   

• Black

36

--

--

• White

10

  

Marital Status (n)

   

• Married

27

--

--

• Divorced

4

  

• Single

15

  

Years of Education

12.3 (2.0)

12.0

7.0 to 18.0

Clinical Variables

   

Etiology of Renal Failure (n)

   

• Diabetes

15

--

--

• Hypertension

22

  

• Glomerulonephritis

3

  

• Other

6

  

BUN (mg/dL)

65.0 (16.8)

63.0

39.3 to 105.0

Creatinine (mg/dL)

12.0 (2.8)

12.4

3.6 to 17.5

Sodium (meq/L)

139.9 (3.0)

139.5

132.3 to 147.3

Potassium (meq/L)

4.9 (0.7)

4.6

3.8 to 6.4

CO2 (meq/L)

20.6 (2.8)

20.7

13.8 to 27.7

Calcium (mg/dL)

9.5 (0.8)

9.6

7.5 to 11.4

Phosphorous (mg/dL)

5.4 (1.5)

5.3

2.8 to 10.5

Hematocrit (%)

35.8 (3.2)

36.2

28.9 to 43.2

Ferritin (μ/L)

549.1 (394.3)

515.0

13.4 to 1764.0

PTH (pg/ml)

222.9 (197.7)

184.5

13.0 to 1144.0

Body Mass Index (kg/m2)

26.8 (5.6)

26.8

17.0 to 40.1

• Black Males (n = 18)

25.8 (5.1)

 

18.8 to 36.8

• Black Females (n = 18)

28.0 (5.8)

 

17.0 to 40.1

• White Males (n = 6)

25.3 (6.1)

 

20.7 to 36.6

• White Females (n = 4)

27.3 (7.1)

 

18.3 to 35.5

Days hospitalized

2.2 (3.3)

0

0 to 12

Dialysis Variables

   

Kt/V

1.5 (0.3)

1.5

1.1 to 2.6

Treatment time (minutes)

219.0 (24.1)

220.0

165.0 to 270.0

Shift

   

• 1

18

--

--

• 2

13

  

• 3

15

  

Months on HD

37.5 (36.0)

28.5

5.0 to 184.0

* SD = standard deviation, ** = number

Demographic and Clinical Features of the Sample

Demographic, clinical, and dialysis related information was obtained via chart review. Monthly laboratory reports were collected for three months immediately prior to inclusion and the values cited in this report represent the means (± SD; standard deviation) for this period. Exceptions include parathyroid hormone (PTH intact) and ferritin, which were measured once during the three-month period. Body mass index (BMI) was calculated using the patient's estimated dry weight (ideal weight at optimal fluid balance) at the time of consent. All subjects received HD three times a week on one of three shifts (based on when a majority of their treatment occurred; shift 1 – 6 am to 10 am; shift 2 – 10 am to 2 pm; shift 3 – 2 pm to 6 pm) for periods of three to five hours. All subjects were metabolically stable and adequately dialyzed [20] (see Table 2).

Evaluation of Nocturnal Sleep and Daytime Sleepiness

On the night of a HD treatment day (i.e., 6 to 12 hours post treatment), all subjects were asked to complete brief nocturnal and daytime sleep questionnaires and to undergo one night of laboratory-based nocturnal polysomnography (PSG) followed by a daytime PSG nap study (Multiple Sleep Latency Test; MSLT). These subjective and objective measures target the most common nocturnal and daytime sleep complaints and primary sleep disorders seen in HD patients [21](see Table 3).
Table 3

Common Sleep Problems/Disorders in Hemodialysis Patients: Comparison of Subjective and Objective Measures

Problem

Subjective (prior six months)

Objective (one night of PSG and daytime MSLT)

Insufficient sleep

Amount of sleep typically obtained

Total sleep time

Insomnia/Sleep Fragmentation

Difficulty:

 
 

• Falling asleep

Nocturnal sleep latency

 

• Staying asleep

Sleep efficiency

 

• Early morning awakenings

Arousals

 

• Unrefreshing sleep

 

Daytime sleepiness

Frequency of daytime napping

Nocturnal sleep latency

 

Epworth Sleepiness Scale

Multiple Sleep Latency Test

Periodic Limb Movement Disorder

Waking from legs kicking

Periodic limb movements/hour

Sleep Apnea Syndrome

Waking from gasping/choking

Apneas/hour

PSG = polysomnography, MSLT = Multiple Sleep Latency Test

The questionnairse asked subjects to estimate the amount of sleep they typically obtained each night over the past six months. In addition, they were asked to rate, on a scale from 1 (rarely) to 5 (always), the following: how often they had trouble falling asleep, waking up during the night, and waking up too early and not being able to fall asleep again; how often they felt rested in the morning; how often they napped; and, how often they awoke at night from kicking of the legs and gasping/choking. If the subject marked the "do not know" option, the response was coded 0 (missing data). Content validity of the questionnaire is supported by the fact that it targeted major domains of subjective sleep quality measured by several other sleep instruments [22–26] and included specific questions used in a large population-based study of sleep [27]. In addition, it captured perceptions of two polysomnographic measures of interest in this population – limb movements and apneas (see Table 3). Subjects also completed the Epworth Sleepiness Scale (ESS), an inventory designed to evaluate a patient's general level of subjective sleepiness – or more specifically, chance of dozing in real life situations [28, 29]. The range of possible scores on the ESS is 0 to 24, with higher scores indicating greater levels of subjective sleepiness. A score > 11 is often used to identify individuals with significant subjective sleepiness levels [30]. Acceptable validity, test-retest reliability, and internal consistency reliability of the ESS have been reported [28, 29].

The PSG consisted of a standard montage (electrode placement) of electroencephalography (EEG) (C3/A2 or C4/A1 and O2/C3 or O1/C4), monopolar left and right electrooculography (EOG) referenced to the opposite mastoid, surface mentalis electromyography (EMG), respiratory airflow and effort, electrocardiography (ECG), anterior tibialis EMG, and pulse oximetry. All recordings were made on a Grass Model 78 polysomnograph recorded with a paper speed of 10 mm/sec and scored in 30-second epochs. Sleep variables calculated for each subject included: Total sleep time (TST, minutes); sleep efficiency (SE = TST/time in bed × 100); the percentage of TST spent in stages 1, 2, 3 & 4, and REM (rapid-eye-movement) sleep [31]; and the latency to three consecutive epochs of sleep (sleep latency, SL, minutes). Periodic leg movements and movements with arousals [32], apneas, and total brief arousals [33] were scored using conventional criteria. The brief arousals, apneas, limb movements, and limb movements with arousals observed were expressed as the number of events per hour of sleep. All PSGs were scored by the same certified polysomnographic technician and verified by the Director of the Sleep Disorders Center.

The morning following the nocturnal PSG, daytime sleepiness was quantified using the Multiple Sleep Latency Test (MSLT) following standard procedures [34]. Approximately 1.5 to 2 hours after awakening, subjects were allowed five 20 – minute nap opportunities at 2-hour intervals across the day. The SL on any given nap opportunity was defined as the time from lights out to the first 30-second epoch scored as sleep. Each nap was terminated after 20 minutes or after a maximum of 15 minutes from sleep onset. The average SL across all naps was calculated and expressed as the mean sleep latency. The range of possible mean sleep latency scores on the MSLT is 0 to 20 minutes, with a low score indicating greater sleepiness. According to the International Classification of Sleep Disorders (ICSD), a mean sleep latency ≤ 5 minutes suggests "severe or pathological" sleepiness, a mean sleep latency between 5 minutes and 10 minutes suggests "moderate sleepiness", and a mean sleep latency > 10 minutes suggests "mild or normal sleepiness". An alternative schema also used to interpret MSLT scores is based on supporting evidence derived from comparisons of normal subjects to patients with sleep abnormalities[15, 35–37] and uses a MSLT score < 8 minutes as indicative of abnormal sleepiness.

Evaluation of Quality of Life

Quality of life was defined as a person's sense of well-being reflecting satisfaction or dissatisfaction with the areas of life that are deemed important. Immediately before the nocturnal PSG, all subjects completed the Quality of Life Index (QLI, Dialysis Version) developed by Ferrans and Powers [38, 39], a questionnaire consisting of 64 items divided into two sections. The first section assesses how satisfied the subject is with 32 aspects of life while the second assesses the importance of those same aspects. Responses to the satisfaction items range from "very satisfied" (6) to "very dissatisfied" (1). Responses to the importance items range from "very important" (6) to "very unimportant" (1). Scores are calculated by weighting each satisfaction response with its paired importance response. Overall QLI scores and four subscale scores are calculated: Health & Functioning, Social & Economic, Psychological & Spiritual, and Family. The range of scores on the overall scale and the subscales scores is 0 to 30 with a higher score indicating a better quality of life.

The instrument has excellent validity and reliability [38]. Content validity was established by administering a questionnaire that included sixty-four items applicable to both healthy graduate students and dialysis patients (n = 88). Six items relative to dialysis were added and the instrument was administered to dialysis patients (n = 37). Correlations between the instrument and an overall satisfaction with life question of 0.75 (graduate students) and 0.65 (dialysis patients) supported criterion-related validity. Support for reliability was provided by test-retest correlations of 0.87 (graduate students) and 0.81 (dialysis patients) and Cronbach alphas of 0.93 (graduate students) and 0.90 (dialysis patients)[40].

Data Analysis

Descriptive statistics were used to summarize all data. Because examination of the data revealed that they did not meet the assumption of normality necessary for the use of parametric statistical tests, nonparametric procedures were used. Differences in quality of life scores in groups of patients based on categorical variables were detected using the Mann Whitney-U (two categories) or the Kruskal-Wallis (three or more categories) procedures [41]. Correlations between quality of life scores and interval/ratio/ordinal measures were performed using the Spearman rho (rs) correlation procedure (one-tailed test; our hypothesis was that poorer nocturnal sleep and increased daytime sleepiness would be associated with decreased quality of life) [41]. Internal consistency reliability of the QLI in this sample was supported by Cronbach's alphas of 0.91 for the overall scale and 0.80, 0.94, 0.81, and 0.91, respectively, for the Health & Functioning, Social &Economic, Psychological & Spiritual, and Family subscales. Results were also similar to those previously reported in a larger, more representative sample of HD patients (see Table 4) [38]. The significance level was set at α = 0.05. Because of the exploratory nature of this study, we chose not to use the Bonferroni correction for multiple correlations and to accept the greater possibility of making a Type II error [22].
Table 4

Quality of Life Index Scores Reported by HD Sample in This Study and by HD Patients Studied by Ferrans/Powers*

Scale

Study Sample (n = 46)

Ferrans &Powers Study (n = 349)*

 

Mean (SD)

Range

Internal Consistency**

Mean (SD)

Range

Internal consistency

Health & Functioning Subscale ***

21.1 (4.7)

10.29–29.54

0.80

18.64 (5.7)

2.8–30.0

0.87

Social & Economic Subscale

22.0 (4.8)

10.71–30.0

0.94

21.29 (5.4)

3.2–30.0

0.82

Psychological & Spiritual Subscale ***

24.5 (4.4)

15.07–30.0

0.81

21.60 (6.7)

0.9–30.0

0.90

Family Subscale

26.8 (3.5)

18.0–30.0

0.91

25.25 (5.1)

0.0–30.0

0.77

Total QOLI Score ***

22.8 (4.0)

14.53–29.67

0.91

20.7 (4.8)

7.3–29.8

0.90

* [38], ** Cronbach's alphas, *** p = 0.005, 0.007, 0.005 respectively: t-test

Results

The demographic, clinical, and dialysis-related features of the sample are included in Table 2. Similar to national statistics for HD patients [42], the mean age was 51.6 (10.8) years with a relatively even gender distribution; diabetes and hypertension were the most common causes of CKD. Unlike the national population of HD patients, a majority of subjects in this sample were black reflecting the racial composition of the available population. Subjects had a relatively high level of education because of the need to read and complete study questionnaires.

The mean total QLI and the four subscale scores are reported in Table 4. Overall QLI, the Health & Functioning, and the Psychological & Spiritual scale scores were significantly higher than those reported by Ferrans & Power (t-test) in a larger randomly selected sample of HD patients [38], probably reflecting the overall stable condition and otherwise general good health of this sample. Also similar to the Ferrans & Powers study, subjects were most satisfied with their Family quality of life; relationships among children/spouses/significant others and family's happiness were both the most satisfying and most important. Correlations between items of satisfaction and importance regarding children (rs = 0.41, df = 44, p = 0.005), family (rs = 0.28, df = 44, p = 0.038), and spouse (rs = 0.61, df = 44, p = 0.000) were statistically significant. Health & Functioning life quality was the least satisfying and job satisfaction, ability to travel, and amount of stress/worries in life ranked lowest in this regard. However, these items were also among the least important, possibly reflecting adjustment to the life constraints imposed by the disease and its treatment [38].

There were no significant differences in total QLI or subscale scores in groups of subjects based on gender, race, marital status, etiology of renal failure, or treatment time of day. There were also no significant relationships detected between these scores and age, years of education, the number of days hospitalized in the past year, or other parameters measured listed in Table 2.

Data from the nocturnal and daytime sleep questionnaires are presented in Table 5. Subjects estimated sleeping an average of 6.3 hours (377.7 ± 78.9 minutes) per night and most reported having difficulty falling asleep, waking up at night, or waking too early in the morning "sometimes". Subjects were typically unaware that their legs kicked during the night and only rarely experienced gasping or choking. Most subjects reported that they also "sometimes" napped and felt rested during the day. The mean ESS Scale score was 7.4 ± 4.6 suggesting normal subjective daytime sleepiness levels. However, 30.4% (n = 14) had scores ≥ 11, suggesting that clinically significant sleepiness was a problem for many of the subjects [17].
Table 5

Subjective (Questionnaires) Measures of Nocturnal Sleep and Daytime Sleepiness

Variable

Mean

Median

Mode

Typical sleep duration

377.7 (78.9)

360.0

420.0

How often they felt rested upon awakening in the morning*

3.0 (1.0)

3.0

3.0

How often they had trouble *:

   

• Falling asleep

2.9 (1.2)

3.0

3.0

• Waking up at night

2.5 (1.2)

2.0

2.0

• Waking up too early and not being able to fall asleep

2.8 (1.1)

3.0

3.0

How often legs kicked or twitched*

1.9 (1.0)

2.0

1.0

How often awake gasping/choking*

1.6 (1.0)

1.0

1.0

How often they napped*

2.7 (1.1)

3.0

3.0

Epworth Sleepiness Scale

7.4 (4.6)

7.0

6.0

* 0 = don't know (classified as missing data and not included in the analyses), 1 = never, 2 = rarely, 3 = sometimes, 4 = most of time, 5 = always

Data from the nocturnal PSGs are presented in Table 6. The mean TST for the group was 5.6 hours (335.8 ± 64.8 minutes) with a SE of 78.2% ± 14.0, values lower than normative data reported for individuals of the same gender and similar in age [43] but consistent with the results of other PSG studies in HD patients [44, 45]. General features of nocturnal sleep, including percentage of time spent in the various stages of sleep, were unremarkable. Mild sleep apnea (RDI < 15 apnea/hour) [2] and periodic limb movement disorder (PLMI < 25 limb movements/hour) [1] characterized the group despite clinical screening to eliminate subjects with these problems. The average MSLT score was 10.2 ± 4.2 minutes; 15 of the subjects (32.6%) had scores less than 8 minutes and 6 (13.0%) had pathologic daytime sleepiness (MSLT scores < 5 minutes), indicating that objectively measured daytime sleepiness was also a problem for many of the subjects [1, 15, 17, 36, 37]. There were no significant univariate relationships noted between subjective and objective measures of sleep.
Table 6

Polysomnographic Measures of Nocturnal Sleep and Daytime Sleepiness

Variable

Mean (SD)

Median

Total Sleep Time (minutes)

335.8 (64.8)

343.0

Sleep Efficiency (%)

78.2 (14.0)

82.4

Sleep Latency (minutes)

31.1 (37.6)

15.9

RDI (events/hour)

13.1 (20.4)

5.4

PLMI (events/hour)

23.0 (36.7)

5.5

PLMs with arousals (events/hour)

9.3 (13.2)

2.4

BAI (events/hour)

30.9 (24.2)

21.1

Mean Sleep Latency (min)

10.2 (4.2)

10.3

RDI = respiratory disturbance index, PLMI = periodic limb movement index, PLMs = periodic limb movements, BAI = brief arousal index

The correlations between the quality of life scores and subjective and polysomnographic nocturnal/daytime sleep variables appear in Table 7. Increased perceived difficulty falling asleep and waking up early in the morning were negatively associated with total QLI scores and all four subscale scores. Feeling more rested in the morning was positively associated with Social & Economic (rs = 0.325, df = 44, p = 0.014), Psychological & Spiritual (rs = 0.319, df = 44, p = 0.015), and Total QLI (rs = 0.332, df = 44, p = 0.012) scores. ESS scores were unrelated to quality of life measures. Health & Functioning scores were positively correlated with nocturnal sleep latency (rs = 0.248, df = 44, p = 0.048) while MSLT scores were positively correlated with both Health & Functioning (rs = 0.278, df = 44, p = 0.030) and the total QLI scores (rs = 0.263, df = 44, p = 0.038). These findings collectively indicate that less daytime sleepiness was associated with better quality of life. Although increased numbers of periodic limb movements (PLMI) were associated with lower Health & Functioning (rs = -0.326, df = 44, p = 0.013) and Family (rs = -0.248, df - 44, p = 0,048) subscale scores, no other relationships were noted between PSG and quality of life measures.
Table 7

Correlations between Measures of Nocturnal Sleep/Daytime Sleepiness and Quality of Life Scores

Variable

Health & Functioning

Social & Economic

Psychological & Spiritual

Family

Total QLI

Subjective measures (questionnaires) *

Typical sleep duration (n = 46)

--

rs = 0.301

P = 0.022

--

--

--

How often they had trouble :

     

• Falling asleep (n = 45)

rs = - 0.387

p = 0.004

rs = - 0.402

p = 0.003

rs = - 0.422

p = 0.002

rs = - 0.497

p = 0.000

rs = - 0.472

p = 0.001

• Waking up at night (n = 44)

--

--

--

--

--

• Waking up at night and not being able to get back to sleep (n = 45)

rs = - 0.426

p = 0.002

rs = - 0.480

p = 0.000

rs = - 0.373

p = 0.006

rs = - 0.461

p = 0.001

rs = - 0.496

ps = 0.000

How often they felt rested upon awakening in the morning (n = 46)

--

rs = 0.325

p = 0.014

rs = 0.319

p = 0.015

--

rs = 0.332

p = 0.012

Nocturnal kicking/twitching (n = 30)

--

--

--

--

--

Nocturnal gasping/choking (n = 41)

--

--

--

--

--

How often they napped (n = 46)

--

--

--

--

--

Epworth Sleepiness Scale (n = 46)

--

--

--

--

--

Objective Measures (polysomnography) **

Total Sleep Time (min)

--

--

--

--

--

Sleep Efficiency (%)

--

--

--

--

--

Sleep Latency (min)

rs = 0.248

p = 0.048

--

--

--

--

RDI (events/hour)

--

--

--

--

--

PLMI (events/hour)

rs = -0.326

p = 0.013

--

--

rs = -0.248

p = 0.048

--

PLMs with arousal (event/hour)

rs = -0.247

p = 0.049

--

--

--

--

BAI (events/hour)

--

--

--

--

--

Mean Sleep Latency (min)

rs = 0.278

p = 0.030

--

--

--

rs = 0.263

p = 0.038

*those subjects who responded that "don't know" (0) were excluded from the analysis, **all analyses include all subjects (n = 46)

Discussion

Numerous studies in the general population have demonstrated that poor or reduced amounts of nocturnal sleep and excessive daytime sleepiness adversely affect a variety of quality of life and functional health status indicators [15, 46–50]. Both problems have also recently been associated with cardiovascular disease [46–49], the most common cause of death in the HD population [42]. However, although sleep disorders and excessive daytime sleepiness [51] are very prevalent in the HD population, limited information is available with regard to the extent to which these problems affect life quality. Previous reports suggest that poor subjective sleep[52, 53] and sleep-related breathing disorders [54] have adverse effects, but the scope of these studies with regard to sleep measures is limited. Thus, we examined how quality of life is related to both subjective and objective measures of nocturnal sleep and daytime sleepiness in a sample of stable HD patients.

Perhaps the most important finding of this study is that selected indicators of poor nocturnal sleep and increased daytime sleepiness are associated with reduced quality of life. Sleep complaints that characterize insomnia [52, 55], including difficulty initiating sleep, early morning awakenings, and feeling unrefreshed in the morning, are particularly important. A recent study by Williams et al. [52], also noted that complaints of insomnia were associated with pain, depression, and decreased physical functioning. These findings suggest that the assessment and treatment of insomnia-related complaints should be included in any overall plan of care designed to optimize quality of life as well as other important clinical outcomes. Numerous pharmacological and/or cognitive behavioral techniques are efficacious for treatment of insomnia but controlled clinical trials designed to evaluate their effectiveness in HD patients remain to be conducted [56–59].

Relationships between TST (measured subjectively or via PSG) and quality of life measures were not observed, although subjects obtained an average of only 6 hours of sleep per night. Excessive daytime sleepiness and decreased functional status are prevalent in health community samples that are sleep restricted to this extent [15, 35, 46–50, 60, 61]. We also found that subjective reports of napping less and PSG measures indicating less daytime sleepiness were associated with higher quality of life. Because sleep requirements vary, overall perceived sleep quality, including subjective responses to sleep and the ability to function optimally during the day, may be more important than absolute amount of sleep obtained. It is interesting to note that Kripke et el. recently demonstrated an increased risk of mortality associated with chronic nocturnal sleep periods less than or equal to six hours [62]. In a 10-year follow-up from NHANES I, Qureshi et al. also found an increase in stroke in persons who reported greater than eight hours or less than six hours per night [63]. Increased napping has also been associated with increased mortality in the elderly [64, 65]. Studies designed to examine the relationship between specific nocturnal and daytime sleep measures and these other important clinical outcomes remain to be conducted with the HD population.

Subjects were typically unaware that their legs kicked or twitched during the night. Nonetheless, PSG revealed that periodic limb movements were prevalent in this sample. Greater numbers of movements and movements with arousals per hour were associated with decreased Health & Functioning subscale scores, an observation consistent with previous reports of increased morbidity and mortality in HD subjects with limb movements [66, 67]. Moreover, it is possible the association of increased limb movements and decreased family subscale scores may reflect spousal problems with and/or reaction to nocturnal kicking and sleep problems as marital discord is often seen when one of the partners has a sleep disorder. Because of the high prevalence of both sleep abnormalities and divorce in the HD population, investigations of the effects of sleep problems on marital relationships represents an important area for future research. In contrast to a previous report [54], we did not find a significant relationship between apnea and quality of life measures, most likely because those with a strong history of or receiving treatment for the condition were systematically eliminated from participation in this study.

Conclusions

In summary, our results support our initial hypotheses that better sleep quality and less daytime sleepiness are associated with improved quality of life in stable HD subjects. The overall good health/stability and particular racial characteristics of the sample limit the generalizability of the results to the whole HD patient population. The small sample size may have also limited our ability to detect some relationships. Nonetheless, the data support findings from other studies that have linked general measures of disturbed sleep in HD subjects with a variety of quality of life related variables [7, 38, 68–71]. Some of these indicated that other clinical outcomes such as a dialysis patient's ability to learn and perform home dialysis [72–75]; spousal and family normalcy [75, 76]; anxiety and depression [77]; and days of disability [78] are associated with reduced sleep quality. Our results suggest that clinicians should specifically query about nocturnal sleep quality and daytime sleepiness as they are clinical variables essential to consider when designing a comprehensive treatment program aimed at optimizing the quality of life of HD patients.

Declarations

Acknowledgements

The study was supported by grant RO1 04340 from the National Institute of Nursing Research.

Authors’ Affiliations

(1)
Nell Hodgson Woodruff, School of Nursing
(2)
Department of Rehabilitation Medicine, Renal Division, Emory University
(3)
Department of Neurology, Renal Division, Emory University
(4)
Department of Medicine, Renal Division, Emory University

References

  1. ASDA: The International Classification of Sleep Disorders. Rochester, MN, American Sleep Disorders Association 1997.Google Scholar
  2. AASM: Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999, 22: 667–689.Google Scholar
  3. Wolcott DL, Nissenson AR: Quality of life in chronic dialysis patients: a critical comparison of continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis. Am J Kidney Dis 1988, 11: 402–412.PubMedGoogle Scholar
  4. Friedrich RM: Patient perception of distress associated with hemodialysis: a state survey. JANNT 1980, 7: 252–258.Google Scholar
  5. Eichel CJ: Stress and coping in patients on CAPD compared to hemodialysis patients. ANNA Journal 1986, 13: 9–13.PubMedGoogle Scholar
  6. Zimmermann PR, de Figueiredo CE, Fonseca NA: Depression, anxiety and adjustment in renal replacement therapy: a quality of life assessment. Clin Nephrol 2001, 56: 387–390.PubMedGoogle Scholar
  7. Wolcott DL, Nissenson AR, Landsverk J: Quality of life in chronic dialysis patients. Factors unrelated to dialysis modality. Gen Hosp Psychiatry 1988, 10: 267–277.PubMedGoogle Scholar
  8. Evans RW, Rader B, Manninen DL: The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. Cooperative Multicenter EPO Clinical Trial Group [see comments]. Jama 1990, 263: 825–830. 10.1001/jama.263.6.825PubMedGoogle Scholar
  9. Evans RW: Recombinant human erythropoietin and the quality of life of end-stage renal disease patients: a comparative analysis. Am J Kidney Dis 1991, 18: 62–70.PubMedGoogle Scholar
  10. Cameron JI, Whiteside C, Katz J, Devins GM: Differences in quality of life across renal replacement therapies: a meta-analytic comparison. Am J Kidney Dis 2000, 35: 629–637.PubMedGoogle Scholar
  11. Holley JL, Nespor S, Rault R: Characterizing sleep disorders in chronic hemodialysis patients. ASAIO Trans 1991, 37: M456–7.PubMedGoogle Scholar
  12. Walker S, Fine A, Kryger MH: Sleep complaints are common in a dialysis unit. Am J Kidney Dis 1995, 26: 751–756.PubMedGoogle Scholar
  13. Briones B, Adams N, Strauss M, Rosenberg C, Whalen C, Carskadon M, Roebuck T, Winters M, Redline S: Relationship between sleepiness and general health status. Sleep 1996, 19: 583–588.PubMedGoogle Scholar
  14. Pilcher JJ, Ginter DR, Sadowsky B: Sleep quality versus sleep quantity: relationships between sleep and measures of health, well-being and sleepiness in college students. J Psychosom Res 1997, 42: 583–596. 10.1016/S0022-3999(97)00004-4PubMedGoogle Scholar
  15. Dinges DF, Pack F, Williams K, Gillen KA, Powell JW, Ott GE, Aptowicz C, Pack AI: Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4–5 hours per night. Sleep 1997, 20: 267–267.PubMedGoogle Scholar
  16. Ulfberg J, Carter N, Talback M, Edling C: Excessive daytime sleepiness at work and subjective work performance in the general population and among heavy snorers and patients with obstructive sleep apnea. Chest 1996, 110: 659–663.PubMedGoogle Scholar
  17. Parker KP, Bliwise DL, Bailey JL, Rye DB: Daytime sleepiness in stable hemodialysis patients. Am J Kidney Dis 2003, 41: 394–402. 10.1053/ajkd.2003.50049PubMedGoogle Scholar
  18. Schweitzer PK: Drugs that disturb sleep and wakefulness. Principles and Practice of Sleep Medicine 3rd Edition (Edited by: Kryger MH, Roth T and Dement W C). Philadelphia, W.B. Saunders Company 2000, 441–461.Google Scholar
  19. Cohen J: Statistical power analysis for the behavioral sciences. 2nd Edition Hillsdale, NJ, Lawrence Erlbaum 1988.Google Scholar
  20. Daugirdas JT, Kjellstrand CM: Chronic hemodialysis prescription: a urea kinetic approach. Handbook of Dialysis 3rd Edition (Edited by: Daugirdas JT, Blake P G and Ing TS). Philadelphia, Lippincott Williams & Wilkins 2001.Google Scholar
  21. Parker KP: Sleep disturbances in dialysis patients. Sleep Med Rev 2003, 7: 131–143. 10.1053/smrv.2001.0240PubMedGoogle Scholar
  22. Perneger TV: What's wrong with Bonferroni adjustments. Bmj 1998, 316: 1236–1238.PubMed CentralPubMedGoogle Scholar
  23. Douglass AB, Bornstein R, Nino-Murcia G, Keenan S, Miles L, Zarcone V. P., Jr., Guilleminault C, Dement WC: The Sleep Disorders Questionnaire. I: Creation and multivariate structure of SDQ. Sleep 1994, 17: 160–167.PubMedGoogle Scholar
  24. Ellis BW, Johns MW, Lancaster R, Raptopoulos P, Angelopoulos N, Priest RG: The St. Mary's Hospital sleep questionnaire: a study of reliability. Sleep 1981, 4: 93–97.PubMedGoogle Scholar
  25. Buysse DJ, Reynolds C. F. d, Monk TH, Berman SR, Kupfer DJ: The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989, 28: 193–213. 10.1016/0165-1781(89)90047-4PubMedGoogle Scholar
  26. Snyder-Halpern R, Verran JA: Instrumentation to describe subjective sleep characteristics in healthy subjects. Res Nurs Health 1987, 10: 155–163.PubMedGoogle Scholar
  27. Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB, Blazer DG: Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995, 18: 425–432.PubMedGoogle Scholar
  28. Johns MW: A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991, 14: 540–545.PubMedGoogle Scholar
  29. Johns MW: Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep 1992, 15: 376–381.PubMedGoogle Scholar
  30. Johns MW: Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of wakefulness test and the epworth sleepiness scale: failure of the MSLT as a gold standard. J Sleep Res 2000, 9: 5–11. 10.1046/j.1365-2869.2000.00177.xPubMedGoogle Scholar
  31. Rechtschaffen A, Kales A: A manual of standardized terminology: Techniques and scoring system for sl;eep stages in human subjects. Washington, D.C., Institute of Healht Publication 1968., No. 204: Google Scholar
  32. ASDA: Recording and scoring of leg movements. Sleep 1993, 16: 759–759.Google Scholar
  33. ASDA: EEG arousals and examples: A preliminary report fro the Sleep Disorders Atla Task Force of the American Soddp disorders Association. Sleep 1992, 15: 174–184.Google Scholar
  34. ASDA: Guidelines for the Multiple Sleep Latency Test (MSLT): A standard measure of sleepiness. Sleep 1986, 9: 519–524.Google Scholar
  35. Chervin RD, Aldrich MS: The Epworth Sleepiness Scale may not reflect objective measures of sleepiness or sleep apnea. Neurology 1999, 52: 125–131. 10.1159/000023448PubMedGoogle Scholar
  36. Guilleminault C, Mignot E, Partinen M: Controversies in the diagnosis of narcolepsy. Sleep 1994, 17: S1–6.PubMedGoogle Scholar
  37. van den Hoed J, Kraemer H, Guilleminault C, Zarcone V. P., Jr., Miles LE, Dement WC, Mitler MM: Disorders of excessive daytime somnolence: polygraphic and clinical data for 100 patients. Sleep 1981, 4: 23–37.PubMedGoogle Scholar
  38. Ferrans CE, Powers MJ: Quality of life of hemodialysis patients. Anna J 1993, 20: 575–81; discussion 582.PubMedGoogle Scholar
  39. Ferrans CE, Powers MJ: Psychometric assessment of the Quality of Life Index. Res Nurs Health 1992, 15: 29–38.PubMedGoogle Scholar
  40. Ferrans CE, Powers MJ: Quality of life index: development and psychometric properties. ANS Adv Nurs Sci 1985, 8: 15–24.PubMedGoogle Scholar
  41. Burns N, Grove SK: Understanding Nursing Research. 3rd Edition Philadelphia, Saunders 2003.Google Scholar
  42. USRDS: United States Renal Data System 2000 Annual Data Report. Ann Arbor, MI, University of Michigan and National Institute of Diabetes and Digestive and Kidney Diseases 2000.Google Scholar
  43. Williams RL, Karacan I, Hursch CJ: EEG of human sleep: Clinical applications. New York, John Wiley & Sons 1974.Google Scholar
  44. Mendelson WB, Wadhwa NK, Greenberg HE, Gujavarty K, Bergofsky E: Effects of hemodialysis on sleep apnea syndrome in end-stage renal disease. Clin Nephrol 1990, 33: 247–251.PubMedGoogle Scholar
  45. Wadhwa NK, Mendelson WB: A comparison of sleep-disordered respiration in ESRD patients receiving hemodialysis and peritoneal dialysis. Adv Perit Dial 1992, 8: 195–198.PubMedGoogle Scholar
  46. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, Lebowitz MD, Pickering TG: Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. Jama 2000, 283: 1829–1836. 10.1001/jama.283.14.1829PubMedGoogle Scholar
  47. Newman AB, Nieto FJ, Guidry U, Lind BK, Redline S, Pickering TG, Quan SF: Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001, 154: 50–59. 10.1093/aje/154.1.50PubMedGoogle Scholar
  48. Newman AB, Spiekerman CF, Enright P, Lefkowitz D, Manolio T, Reynolds CF, Robbins J: Daytime sleepiness predicts mortality and cardiovascular disease in older adults. The Cardiovascular Health Study Research Group [see comments]. J Am Geriatr Soc 2000, 48: 115–123.PubMedGoogle Scholar
  49. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, O'Connor GT, Boland LL, Schwartz JE, Samet JM: Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001, 163: 19–25.PubMedGoogle Scholar
  50. Lyznicki JM, Doege TC, Davis RM, Williams MA: Sleepiness, driving, and motor vehicle crashes. Council on Scientific Affairs, American Medical Association [see comments]. Jama 1998, 279: 1908–1913. 10.1001/jama.279.23.1908PubMedGoogle Scholar
  51. Parker KP, Bliwise DL, Rye DB, Bailey JL: Daytime sleepiness in stable patients on chronic hemodialysis. American Journal of Kidney Diseases 2002, in press.Google Scholar
  52. Williams SW, Tell GS, Zheng B, Shumaker S, Rocco MV, Sevick MA: Correlates of sleep behavior among hemodialysis patients. The kidney outcomes prediction and evaluation (KOPE) study. Am J Nephrol 2002, 22: 18–28. 10.1159/000046670PubMedGoogle Scholar
  53. Iliescu EA, Coo H, McMurray MH, Meers CL, Quinn MM, Singer MA, Hopman WM: Quality of sleep and health-related quality of life in haemodialysis patients. Nephrol Dial Transplant 2003, 18: 126–132. 10.1093/ndt/18.1.126PubMedGoogle Scholar
  54. Sanner BM, Tepel M, Esser M, Klewer J, Hoehmann-Riese B, Zidek W, Hellmich B: Sleep-related breathing disorders impair quality of life in haemodialysis recipients. Nephrol Dial Transplant 2002, 17: 1260–1265. 10.1093/ndt/17.7.1260PubMedGoogle Scholar
  55. Sabbatini M, Minale B, Crispo A, Pisani A, Ragosta A, Esposito R, Cesaro A, Cianciaruso B, Andreucci VE: Insomnia in maintenance haemodialysis patients. Nephrol Dial Transplant 2002, 17: 852–856. 10.1093/ndt/17.5.852PubMedGoogle Scholar
  56. Morin CM, Hauri PJ, Espie CA, Spielman AJ, Buysse DJ, Bootzin RR: Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 1999, 22: 1134–1156.PubMedGoogle Scholar
  57. Pallesen S, Nordhus IH, Kvale G, Nielsen GH, Havik OE, Johnsen BH, Skjotskift S: Behavioral treatment of insomnia in older adults: an open clinical trial comparing two interventions. Behav Res Ther 2003, 41: 31–48. 10.1016/S0005-7967(01)00122-XPubMedGoogle Scholar
  58. Phillips TG, Holdsworth J, Cook S: How useful is cognitive behavioral therapy (CBT) for the treatment of chronic insomnia? J Fam Pract 2001, 50: 569.PubMedGoogle Scholar
  59. Edinger JD, Wohlgemuth WK, Radtke RA, Marsh GR, Quillian RE: Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial. Jama 2001, 285: 1856–1864. 10.1001/jama.285.14.1856PubMedGoogle Scholar
  60. Roehrs T, Carskadon MA, Dement WC, Roth T: Daytime sleepiness and alertness. Principles and Practice of Sleep Medicine 3 rd Edition (Edited by: Kryger MH, Roth T and Dement WC). Philadelphia, W.B. Saunders Company 2000, 43–52.Google Scholar
  61. Webb WB, Agnew H. W., Jr.: The effects of a chronic limitation of sleep length. Psychophysiology 1974, 11: 265–274.PubMedGoogle Scholar
  62. Kripke DF: Sleep and mortality. Psychosom Med 2003, 65: 74. 10.1097/01.PSY.0000039752.23250.69PubMedGoogle Scholar
  63. Qureshi AI, Giles WH, Croft JB, Bliwise DL: Habitual sleep patterns and risk for stroke and coronary heart disease: a 10-year follow-up from NHANES I. Neurology 1997, 48: 904–911.PubMedGoogle Scholar
  64. Bursztyn M, Ginsberg G, Hammerman-Rozenberg R, Stessman J: The siesta in the elderly: risk factor for mortality? Arch Intern Med 1999, 159: 1582–1586. 10.1001/archinte.159.14.1582PubMedGoogle Scholar
  65. Bursztyn M, Ginsberg G, Stessman J: The siesta and mortality in the elderly: effect of rest without sleep and daytime sleep duration. Sleep 2002, 25: 187–191.PubMedGoogle Scholar
  66. Benz RL, Pressman MR, Hovick ET, Peterson DD: Potential novel predictors of mortality in end-stage renal disease patients with sleep disorders [see comments]. Am J Kidney Dis 2000, 35: 1052–1060.PubMedGoogle Scholar
  67. Benz RL, Pressman MR, Hovick ET, Peterson DD: A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study). Am J Kidney Dis 1999, 34: 1089–1095.PubMedGoogle Scholar
  68. Rozenbaum EA, Chaimovitz C, Bearman JE: Quality of life of patients on chronic dialysis. Isr J Med Sci 1984, 20: 104–108.PubMedGoogle Scholar
  69. Bremer BA, McCauley CR, Wrona RM, Johnson JP: Quality of life in end-stage renal disease: a reexamination. Am J Kidney Dis 1989, 13: 200–209.PubMedGoogle Scholar
  70. Bremer BA, Wert KM, Durica AL, Weaver A: Neuropsychological, physical, and psychosocial functioning of individuals with end-stage renal disease. Ann Behav Med 1998, 19: 348–352.Google Scholar
  71. Molzahn AE, Northcott HC, Dossetor JB: Quality of life of individuals with end stage renal disease: perceptions of patients, nurses, and physicians. Anna J 1997, 24: 325–33; discussion 334–5.PubMedGoogle Scholar
  72. Daly RJ, Hassall C: Reported sleep on maintenance haemodialysis. Br Med J 1970, 2: 508–509.PubMed CentralPubMedGoogle Scholar
  73. Levy NB>: Psychological problems of patients on hemodialysis. Psychotherapy and Psychosomatics 1979, 31: 260–266.PubMedGoogle Scholar
  74. Richmond JM, Lindsay RM, Burton HJ, Conley J, Wai L: Psychological and physiological factors predicting outcome on home hemodialysis. Clinical Nephrology 1982, 17: 109–113.PubMedGoogle Scholar
  75. Sweatman AJ, Baillod RA, Moorhead JF: Comparison of home dialysis and other treatments for chronic renal failure. The Practitioner 1974, 212: 56–66.PubMedGoogle Scholar
  76. Daley RJ, Hassall C: Reported sleep maintenance on haemodialysis. British Medical Journal 1970, 2: 508–509.Google Scholar
  77. Parker K: Dream content and subjective sleep quality in stable patients on chronic dialysis. ANNA Journal 1996, 23: 201–210.Google Scholar
  78. Hays RD, Kallich JD, Mapes DL, Coons SJ, Carter WB: Development of the kidney disease quality of life (KDQOL) instrument. Qual Life Res 1994, 3: 329–338.PubMedGoogle Scholar

Copyright

© Parker et al; licensee BioMed Central Ltd. 2003

This article is published under license to BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

Advertisement