192 Volume 6 ‘ Number 2 - 1995

Sleep Disorders in Patients on Continuous AmbulatoryPeritoneal ,2

Edward Stepanski,3 Mark Faber, Frank Zorick, Robert Basner, and Thomas Roth

E. Stepanski. R. Basner. Center for Sleep and Ventila-tory Disorders. University of Illinois Hospital. Chicago. IL

M. Faber. F. Zorick. T. Roth. Sleep Disorders and Re-search Center. Division of Nephrology and Hyperfen-sion. Henry Ford Hospital. Detroit. Ml

(J. Am. Soc. Nephrol. 1995; 6:192-197)

ABSTRACTSleep complaints, habits, and medical history weresurveyed in 81 patients chronically receiving continu-

ous ambulatory peritoneal dialysis. Seventy-three per-cent of the sample reported insomnia, and 52% re-ported unintentional napping during the day.Behavioral factors (such as caffeine or alcohol use) orthe severity of concurrent medical disease did notaccount for the sleep problems. Eighteen of thesepatients subsequently underwent polysomnographyand objective measurement of daytime sleepiness.Clinically significant sleep apnea syndrome waspresent in 1 1 . The presence of sleep apnea wasassociated with increased levels of psychologicaldistress and daytime sleepiness. Periodic leg move-

ments during sleep were also frequently observed buthad minimal effect on sleep quality. Implications ofthese findings for clinical practice are discussed.

Key Words: Insomnia. sleep apnea. ESRD. dialysis. restless legs

syndrome

C hronic renal dialysis, despite its successful pro-

bongation of life, often falls to eliminate the per-

vasive feelings of fatigue ( 1 ,2), “tiredness” ( 1 ), and

disturbed sleep ( 1 ,3,4) reported in up to 50% of ESRD

patients. Clearly, these nonspecific symptoms can beassociated with multiple, diverse causes such as car-

diac or pulmonary disease, anemia (5), and depres-

slon (6,7). The potential importance of these symp-

toms lies not only in their demonstrated association

with patients’ perceived quality of life (3) but in the

positive correlation between quality-of-life measures

and survival (8).

Primary sleep disorders may also be important con-

� Received November 29. 1993. Accepted March 30. 1995.2 PortIons of this study were presented at the 12th Notional CAPD conference,

Seattle. WA. 1992. and the 12th InternatIonal Congress of Nephrology, Jerusalem,

Israel, 1993.

3 Dr. E. stepanskl, center for 5leep and Ventilafory DIsorders, University of Illinois

Hospital. M/C 787, 1 740 West Taylor Street, chicago. IL 60612.

1046.6673/0602.0192$03.O0/OJournal of the American Society of NephrologyCopyright C 1995 by the American Society of Nephrology

tributors to sleep complaints in ESRD. Restless legs’

syndrome and periodic leg movements (PLM) during

sleep have been described in patients with uremia (9).Another primary sleep disorder, sleep apnea, has

recently been documented in patients with ESRD orrenal insufficiency ( 10). About 70% of the hemodialy-

sis patients studied had sleep-disordered breathing(5DB) (i.e. , > 30 apneas or hypopneas per night),

which were clinically significant (i.e. , more than 100apneic events per night) In 40% of the sample. Subse-

quent studies reported similar incidences of sleep

apnea in patients receiving hemodlalysis and contin-

uous ambulatory peritoneal dialysis (CAPD) (11,12).

This study attempts to further characterize the ex-

tent and severity of subjective sleep complaints in

CAPD patients and investigates their association with

the medical history, concurrent disease status, and

symptoms ofdepression. In addition, for the subgroup

of the sample who subsequently volunteered to un-dergo polysomnography, objective evaluation of sleep

parameters was also carried out to assess the preva-

lence of primary sleep disorders. Finally, this sub-

group was also used to examine the functional signif-

icance of these findings by objectively measuring

daytime sleepiness and collecting psychometric data.

METHODS

Subjects

All patients currently receiving CAPD in the Henry FordHospital CAPD Program were recruited for this study. Of the

1 10 patients in this population, 81 participated in the first

phase of the study (41 men/40 women). The average age ofthis sample was 48.7 yr (± 15.2 SD) with a range of 22 to 85

yr. The average body mass index (kg/rn2) of the sample was

26.5 (±5.4 SD). The primary cause of renal failure was

diabetes in 23 of 8 1 , hypertension in 38 of 8 1 , glomerubone-phnitis in 7 of 8 1 , collagen vascular disease in 2 of 8 1 , andunknown in 1 1 of 8 1 patients.

Procedure

Phase I. A sleep habits questionnaire and the Beck Depres-

sion Inventory were administered. The sleep questionnaire

assessed the subjective description of the usual sleep patternand habits known to affect sleep (see Table 1). A chart review

was conducted to provide data on the cause of the ESRD andconcurrent medical illness, as well as the results of recent

laboratory bloodwork and a list of current medications.

All subjects who completed the first phase of the studywere eligible for the second phase (i.e. , polysomnography).However, the second phase began about 6 months later, andmany patients were no longer receiving treatment in the

CAPD clinic. Patients were unavailable for the followingreasons: transplant (N = 12). hemodialysis (N = 6), death

(N = 5), and transferred to other medical centers (N = 6).Eighteen of the remaining 52 patients still on CAPD agreed toparticipate in the second phase of the study.

Stepanski et al

Journal of the American Society of Nephrology 193

TABLE 1 . Behaviors assessed with the sleepquestionnaire

Usual Sleep Duration and Sleep LatencyDifficulty Falling AsleepDifficulty Returning to Sleep After AwakeningDifficulty Staying Awake During the DayDaytime NappingFalling Asleep Unintentionally During the DayUsual Bedtime/Arising TimeSnoringStop Breathing EpisodesLeg TwitchingUse of Sleeping PillsAlcohol UseTobacco Use

Phase II. Objective recordings of sleep and daytime sleep-iness were obtained. Each patient spent two consecutivenights followed by 1 day in the sleep laboratory. All polysom-nographic recordings consisted of continuous monitoring of

unipolar electroencephalograms, (C3 and OZ), EOG, electro-myograph (submental and anterior tibialis), electrocardlo-gram, and nasal/oral airflow. Bedtimes were selected toclosely match that of the subject’s routine sleep schedule.Each recording period was fixed at 8 h in bed. The first nightserved as an adaptation night to allow the patient to adjust tosleeping in the laboratory for the first time. Only sleep andrespiratory parameters derived from the second night ofrecording were used in the analyses.

A Multiple Sleep Latency Test (MSLT) was performed after

the second night ofrecording to provide an objective measureof daytime sleepiness. The MSLT consists of having thesubject lie down in a darkened room for 20 mm or until Stage2 sleep is observed. These tests were conducted at 10:00a.m., 12:00 p.m., 2:00 p.m., 4:00 p.m.. and 6:00 p.m. On theday of the MSLT, patients were asked to complete the Mm-nesota Multiphasic Personality Inventory-Il (MMPI-II). Foursubjects did not complete enough test items (unanswereditems > 30) to allow for interpretation of the profile.

RESULTS

Subjective Description of Sleep

The percentage of patients reporting specific sleepsymptoms on the sleep questionnaire are listed in

Table 2. Reports of snoring, leg twitching, or an irreg-

ular sleep/wake schedule were not significantly cor-

TABLE 2. Self-reported sleep behaviors

S tympomOverall Group

(N=81)(%)

Sleep Onset Problem 59Sleep Maintenance Problem 73Falling Asleep Unintentionally 51Taking Daytime Naps 77Snoring 69Stop Breathing Episodes 9Leg Twitches 32Use of Sleeping Pills 13

related with complaints of insomnia or daytime sleep-

mess. Further, the presence of a sleep complaint was

not related to age, use of alcohol or tobacco, score on

the Beck Depression Inventory, duration of CAPD, or

general medical status (e.g. , number of admissions,

number of hospital days, blood chemistry values,

number of medications) (see Table 3).

Polysomnography

The 18 patients who participated in Phase II of the

study and underwent polysomnography did not differ

from the remaining 63 patients who participated inonly Phase I of the study with respect to age (48.8

versus 48.6 yr), BMI (26.0 versus 26.5), or reported

snoring (67 versus 64%). However, those patients

volunteering for polysomnography were more likely toreport insomnia (89 versus 71%) and excessive day-

time sleepiness (72 versus 60%). It is certainly possi-

ble that those patients who volunteered to undergo

Phase II (sleep testing) did so because of greater

concern about their sleep-wake function. This self-

selection might bias the sample in the direction of

finding more sleep disturbance than would have been

found in those patients declining to participate inPhase II. In addition, only 1 of the 18 patients com-

pleting Phase II had a diagnosis of diabetes mellitus.

Sleep parameter values from the second night of

recording are presented in Table 4. Data are shown for

the overall group, as well as for subgroups with andwithout significant 5DB. Sleep apnea was defined by a

respiratory events index (REI; the average number of

apneas or hypopneas per hour of total sleep time)�20. A review of individual patients finds that the

primary type of 5DB is as follows: obstructive apnea,

four patients; central apnea, four patients; and ob-

structive hypopnea, three patients. The amount of

5DB was stable across the two consecutive nights of

recording in this study. The mean REI on Night 1 was

37.4, which was comparable to the 34.8 for Night 2.

Respiratory events were associated with minimal

oxygen desaturation. Waking oxygen saturation was96.6% (:t 1 .5 SD; range, 93 to 99), and the mean low

saturation was 86% (±7.7 SD; range, 72 to 96). Six

patients desaturated to below 85%, and only one had

more than 10 episodes to below 85% per hour of total

sleep time (TST). The number of episodes of desatura-

TABLE 3. Means (SD) from medical chart review andselected survey questions

ParameterOverall Group(N = 81)

Age 48.7 (15.2)Body Mass Index 26.5 (5.4)Subjective Average 1ST 6.7 (2.1)Beck Depression Score 10.7 (7.0)Creatinine Level 11.9 (4.6)Albumin Level 3.36 (0.49)Months on CAPD 24.0 (17.3)

Sleep Disorders in Dialysis Patients

194 Volume 6 . Number 2 . 1995

TABLE 4. Means (SD) for sleep parameters

P tarame er

Apnea(N = 11)

No Apnea(N = 7)

Overall Group(N = 18)

TST (mm)

% Stage 1

% Stage 2

% Stage 3-4

% Stage Rapid Eye Movement

Wake During Sleep (mm)

341.5(94.8)40.6

(13.6)42.6

(12.2)5.0

(6.9)11.8(5.5)93.8

393.9(24.7)

19.6(7.2)50.3(9.5)7.7

(7.4)22.5(3.3)52.2

361.9(78.7)32.4

(15.4)45.6

(11.6)6.0

(7.0)15.9(7.1)77.6

REI(37.9)54.6

(29.4)Range, 24-112

(27.6)3.7

(5.4)Range, 0-15

(39.3)34.8

(34.2)

Apnea Index 40.0(32.2)

Range, 1-98

1.8(3.0)

Range, 0-8

25.2(31.3)

MSLT 5.5(4.0)

Range, 1.4-13.4

7.7(2.9)

Range, 4.5-13.0

6.3(3.7)

tion below 85% per hour of TST was 2.7 (±7.0 SD;range, 0 to 28.6), and the number of minutes below

85% per hour of TST was 0.68 (± 1 .37 SD; range, 0 to4.9).

The subgroup of patients with significant 5DB were

more likely to report snoring (82%) and daytime sleep-

mess (82%) than were those patients without 5DB (43

and 29%, respectively). Among laboratory values, only

total serum CO2 was significantly different, with avalue of24.2 (±3.7) for the 5DB group, compared with

19.9 (±5.1) for the no-SDB group (t = 2.08; P < 0.05).

Six patients had clinically significant PLM, defined

as more than 25 PLM per hour ofTST. The presence ofsignificant PLM on the sleep recording was not pre-dicted by any sleep complaint. In fact, more patients

without PLM (27%) than with PLM (0%) reported leg

twitching at night. A comparison of values from labo-

ratory blood chemistry found a significant difference

In serum intact parathyrold hormone concentration,

as assayed by two site immunoradiometrlc assays

(Nichols Institute Diagnostics, San Juan Capistrano,

CA). Patients with PLM had a mean intact paathyroid

hormone of 803 ±273 compared with 343 ±332

pg/mL in those without PLM (t = 2.85, p < .0 1).

To study the effect of PLM on sleep, the subgroup

without significant 5DB has been further divided Into

those with (N = 3) and without (N = 4) significant PLM(Table 5). The sleep of the four patients having neitherbreathing abnormalities nor PLM is still shorter and

lighter than expected in normal sleepers.

Daytime FunctioningThe overall group was objectively sleepy during the

day, as measured by the MSLT (Table 4). Only two

TABLE 5. Sleep parameters in patients withoutsleep-disordered breathing

P tarameerWith PLM(N=3)

Without PLM(N=4)

TST(min) 381.0(16.7)

403.6(27.3)

%Stagel 21.5 18.1

% Stage 2(9.2)47.5(4.2)

(6.2)52.4

(12.4)% Stage 3/4 5.5

(7.4)9.3

(8.1)% Stage Rapid Eye Movement 25.5

(1.9)

20.2(1.7)

Sleep Efficiency 79.0(3.7)

84.2(5.8)

PLM Index 57.1(10.3)

0.0

MSLT 6.9(1.9)

8.2(3.7)

patients had average latencies in the normal range

(i.e. , longer than 10 min).

Fourteen patients completed the MMPI-II. Mean

scale scores fell in the normal range but were elevated

for the Hypochondriasis and Health scales. These

scales are concerned with somatic symptoms. A com-

paison of the MMPI-II scores of those patients with(N = 8) and without (N = 6) apnea found significant

differences on the Depression Scale (62. 1 versus 51.5;

t = 3.03; P < 0.01) and Psychasthenia (anxiety) Scales

Stepanski et al

Journal of the American Society of Nephrology 195

(59.9 versus 44.7; t = 3.76; P < 0.008). In both cases,

the apnea patients had the more pathologic scores.

DISCUSSION

The survey data confirm a high prevalence of bothinsomnia and daytime sleepiness in patients with

ESRD undergoing treatment with CAPD. The preva-

lence of self-reported insomnia in this population is

higher in this study than has previously been reported

(3,4, 13). This may be attributable to a difference in

methodology in that this study specifically evaluated

several different aspects of sleep/wake functioning(i.e. , sleep initiation, sleep maintenance, daytime

alertness). Perhaps more surprising than the highprevalence of Insomnia is that 52% of patients report

falling asleep unintentionally during the day. In effect,not only do many patients report disturbed nocturnal

sleep, but they also experience daytime impairment asa consequence. Despite the high prevalence of sleep

complaints and the associated daytime symptoms,most patients were not receiving treatment for this

problem. Only 13% of patients reported using hyp-notic medication, and only 3 patients (4%) had been

referred to a sleep disorders center for evaluation.

Behavioral factors and psychiatric disorders did not

appear to predict sleep disturbance. The prevalence ofreported poor sleep was not different in those patients

with good sleep habits versus those with bad habits.The polysomnographic data collected found that,

overall, the group slept poorly and was abnormallysleepy during the day. The most important contribut-

ing factor to the poor sleep appeared to be frequent

episodes of 5DB. Using 20 or more events per hour of

sleep as a cutoff, 6 1% ( 1 1 of 18) of the sample had

clinically significant SDB. Previous studies of patientson hemodlalysis ( 1 0, 1 1) and CAPD ( 1 2) reported sim-

ilar percentages of patients with apnea, although a

threshold of only five events per hour of sleep was

used. Thus, the patients In this study actually had

higher amounts of 5DB than were described in prey-

ous reports. This is especially remarkable given the

fact that two of those studies ( 1 0, 1 2) specifically

sought out symptomatic patients, although the p0551-

bility that the most severely affected patients were

self-selected for PSG In this study has been mentioned

already. Our CAPD-apnea patients are similar to

those reported in other studies of patients with ESRD

in that a spectrum of central, mixed, and obstructiverespiratory events have been found (10,12,14,15).

The presence of abnormal breathing was associatedwith fragmented sleep, as evidenced by increased

Stage 1 sleep, decreased rapid eye movement sleep,and Increased wakefulness during the night. These

changes in sleep architecture are consistent withthose changes found In non-ESRD samples of patients

with sleep apnea syndrome ( 16). There is also evidenceof morbidity associated with the 5DB in the form of

increased daytime sleepiness and psychological dis-tress. The apnea subgroup was significantly more

likely to report symptoms of anxiety and depressionthan were other ESRD patients without apnea.

In some cases, abnormal breathing responded to a

standard treatment for obstructive apnea. Three pa-

tients from the CAPD sample with significant obstruc-tive apnea were treated with nasal Continuous Posi-

tive Airway Pressure (CPAP) subsequent to study

participation. Sleep was significantly improved in

each case. Although TST did not change (376 versus370 mm), sleep quality improved as demonstrated by

a decrease in percent Stage 1 sleep from 45 to 20%

and an increase in percent Stage rapid eye movement

sleep from 6 to 15%. The average RE! decreased from77 to 6. Therefore, it appears that, at least in selected

patients, traditional treatment with CPAP for obstruc-

tive apnea is a viable option. A recent study reports

that nasal CPAP was also beneficial in ESRD patientshaving primarily central or mixed apneas (14).

One patient with continuous central apneas (RE! =

6 1) refused a trial on CPAP. This patient was treated

with temazepam, 30 mg at bedtime, but a sleep re-

cording failed to show improved sleep, despite his verypoor basal sleep (TST = 82 min; Stage 1 = 66%). Thispatient was restudied after cadaveric renal transplan-

tation. The apnea had resolved (RE! = 6), and sleep

was vastly improved (TST = 413 min; Stage 1 = 27%).

One other patient with primarily central apnea (RE! =

82, TST = 408, Stage 1 = 5 1%) was restudled post-

transplant. His RE! had decreased to 6, and the TSTwas 372 min with 21% Stage 1 sleep. These results

parallel those from a recent report describing two

patients with ESRD and apnea (one central, one ob-

structive) who both showed dramatic Improvement in

breathing during sleep after renal transplantation( 15). It is unlikely that the absence of peritoneal fluidplayed an important role In the posttransplant Im-

provement. Compared with “empty” nights, CAPD pa-

tients with dialysate instilled showed greater desatu-

ration, slighily less TST, and more wake-after-sleep

time but no increase in 5DB ( 12). If reproducible,

these data suggest that the high prevalence of central

and obstructive apnea in these patients is attributable

to factors corrected by transplantation but not dialy-

sis.Certain features of the CAPD-apnea group are atyp-

ical compared with other samples of patients with

significant sleep apnea. These are: ( 1 ) the lack of

obesity and sex bias in patients with obstructive

apnea, and (2) the young age of the patients withcentral apnea. Seventy-five percent (8 of 12) of the

men and 50% (3 of 6) of the women in the sample hadsignificant apnea. This suggests that mechanisms

other than those that produce apnea in non-ESRDsamples could be operating to produce the SDB in this

population. It has been suggested that renal failureitself may precipitate poor sleep because of an effect of“toxins” on the central nervous system and respira-

tory function ( 1 7). One model of apnea and periodic

breathing during sleep that would account for the

results of this study has been described by Longob-

Sleep Disorders in Dialysis Patients

196 Volume 6 ‘ Number 2 ‘ 1995

ado et al. ( 18). According to this model, apneas occur

because of “unstable operation of the feedback control

system governing breathing.” During non-rapid eyemovement sleep, in particular, there is increased reli-

ance on chemical stimuli in the control of ventilation

( 19), and several pathophysiologlc mechanisms In

ESRD patients could increase the likelthood of respi-

ratory instability and resultant apnea in such pa-

tients. Because of chronic metabolic acidosis, many

ESRD patients are hypocapnic, and such hypocapnia

may play a role in sleep-induced respiratory periodic-ity and apnea (20-22). However, obstructive respira-

tory events have been found to decrease (23) as well as

Increase (24) in patients with obstructive sleep apnea

after the induction of metabolic acidosis. Additionally,

our own CAPD-apnea patients appear to be moreacidotic compared with the nonapnea patients, as

measured by serum bicarbonate. However, this study

was not designed to address the acid-base status of

the patients at the time of the sleep study, and the

bicarbonate data are difficult to interpret without

arterial blood gases. Other common perturbations in

ESRD patients that could lead to respiratory Instabil-

ity during sleep include increased circulation time,

hypoxemia, and anemia (25).

In contrast to the effects ofSDB, the effect ofPLM on

sleep appears to be minimal in patients with ESRD. In

those patients without 5DB, sImilar sleep quantity

and quality are found in patients with and without

PLM. However, even patients without primary sleep

pathology do not have normal sleep.

There are many clinical implications for the man-

agement of sleep complaints in patients with renal

failure. There was no evidence that depression was aprimary cause of sleep complaints in this population.

Persistent complaints of disturbed sleep and impaireddaytime alertness should not be presumed to be sec-

ondary to restless legs’ syndrome. Although poten-tially useful in individual patients, trials of clonaz-

epam for PLMS or restless legs (26,27), or any other

benzodiazeplne medication, In a patient with obstruc-

tive apnea might increase the frequency of apneic

episodes and the severity of the associated hypoxemia

(28) and should only be carried out under close su-

pervision with P50 monitoring. ESRD patients pre-

senting with significant sleep-wake complaints, pa-

ticulaly if accompanied by daytime sleepiness,

should be referred for formal polysomnography to rule

out the possible presence of sleep apnea. These data

show that nasal CPAP is beneficial to ESRD patients

with obstructive sleep apnea, and another study re-

ports that CPAP also helps ESRD patients with central

apnea ( 14). Limited experience with renal transplan-

tation in these patients also suggests benefit ( 15). The

systematic diagnosis and treatment of sleep disorders

In patients on dialysis may be an important factor in

achieving functional rehabilitation and improved

quality of life in ESRD patients.

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Therefore �fyou seek the Patients health, look that you receive the urine diligently: and as soon as you can, presentit to the Physician, and be diligent to instruct him in all things that you can, and that he shall not have need to ask.And so no doubt, you shall receive great commodity of that art, to the health of man, and to the glory of God, whichhas given such knowledge to man.

Robert Record, The Urinal of Physick, printed by Gatrude Dawson, London, 1 65 1 . From the

collection of the Clendening Library of the History of Medicine, University of Kansas.