Scientific investigations
Quantitative Analysis of Rest-Activity Patterns in Elderly Postoperative Patients with
Delirium: Support for a Theory of Pathologic Wakefulness
Sandra A. Jacobson, M.D.1; Patrick C. Dwyer, B.S.2; Jason T. Machan, Ph.D.3; Mary A. Carskadon, Ph.D.4
Sun Health Research Institute, Sun City, AZ; 2The Miriam Hospital, Providence, RI; 3Rhode Island Hospital, Providence, RI; 4Warren Alpert
Medical School of Brown University, E.P. Bradley Hospital Sleep Research Lab, E. Providence, RI
1
Study Objectives: To investigate the feasibility of using wrist actigraphy in a postoperative cohort of elderly patients (delirious versus
nondelirious), and to use actigraphy to help characterize diurnal restactivity patterns in this population.
Methods: This was a prospective postoperative study using wrist
actigraphy and clinical scales (DRS-R-98 and Mini-Mental State Examination). Actigraphy was continuous for 24 to 72 hours, and scales
were completed once daily. DSM-IV-TR criteria were used to diagnose
delirium and to separate the sample into delirium and nondelirium
groups. Groups were compared at inception (age, sex, time since surgery, number of medications, number of active medical conditions, and
presurgical sleep quality). For actigraphy analysis, a 24-hour sample
(taken when the DRS-R-98 score was highest) was used for each patient. Statistical analyses were performed on 6 rest-activity parameters
to examine group differences.
Results: Thirteen patients were studied: 6 with delirium and 7 without
delirium. The groups did not differ significantly at inception. Significant
group differences were found in diurnal rest-activity patterns: delirious patients showed fewer nighttime minutes resting, fewer minutes
resting over 24 hours, greater mean activity at night, and a smaller
amplitude of change in activity from day to night.
Conclusions: This is the first study to document a significant disruption of the diurnal rest-activity cycle among delirious patients using objective methods and quantitative analysis of activity. Rest and activity
consolidation were significantly reduced in delirious patients, as was
the amplitude of day-night differences in rest and activity. These findings are consistent with a state of pathologic wakefulness in delirium.
Keywords: Delirium, confusion, motor activity, sleep, sleep disorders,
circadian rhythm, chronobiology disorders
Citation: Jacobson SA; Dwyer PC; Machan JT; Carskadon MA. Quantitative analysis of rest-activity patterns in elderly postoperative patients with delirium: support for a theory of pathologic wakefulness. J
Clin Sleep Med 2008;4(2):137-142.
D
elirium is a syndrome of disturbed consciousness, cognition, and perception that develops acutely in the context
of medical disease and/or in the postoperative period.1 Symptoms include disorientation, memory problems, inattention,
incoherent speech, visual hallucinations, excessive daytime
somnolence, nighttime wakefulness (often total), and episodic
severe agitation. Although hyperactive, hypoactive, and mixed
subtypes have been posited,2 in fact the level of agitation may
wax and wane along with other symptoms over the course of a
24-hour period. Delirium is currently classified in DSM-IV-TR
as a cognitive disorder (along with dementia); however, it is the
disturbance in consciousness and psychotic symptoms (delusions and hallucinations) that better characterize the syndrome
and distinguish it from related conditions.
In our clinical experience, one of the most salient features
of delirium is that the patient appears to be asleep and awake
simultaneously. During a bedside interview, he might drop back
to his pillow and begin to snore in the middle of a sentence. He
is often disoriented and unable to maintain a coherent stream
of thought or action (“confused”), but these deficits fluctuate
over the course of a 24-hour period. Utterances are often rambling and incoherent; content of speech that is understandable
is reminiscent of dream content. For example, the patient may
believe he is being chased, or that he is trying to get somewhere
but cannot get there. At times, he may act out dreams, either
benignly (the assembly-line worker may go through his daily
motions over and over while lying in bed) or dangerously (the
patient may run out of his hospital room and fall down the stairs,
or may attack a nurse he perceives as a threat). He may swat at
his bedclothes because he sees rats (visual hallucinations). He
may refuse food and drink because he has the idea that someone
is trying to poison him (paranoid delusion). These signs and
symptoms may continue throughout the day and night or may
be more prominent during the evening or nighttime hours, a
phenomenon known as “sundowning.”
Electroencephalogram (EEG) findings confirm the similarities
of delirious states to sleep states. The delirious patient who is quietly confused and tending toward somnolence exhibits slowing
or dropout of the posterior dominant (alpha) rhythm and diffuse
Disclosure Statement
This was not an industry supported study. The authors have indicated no
financial conflicts of interest.
Submitted for publication June, 2007
Accepted for publication October, 2007
Address correspondence to: Sandra A. Jacobson, MD, Sun Health Research Institute, 10515 W Santa Fe Dr., Sun City, AZ 85351; Tel: (623) 9747395; Fax: (623) 875-6504; E-mail: [email protected]
Journal of Clinical Sleep Medicine, Vol. 4, No. 2, 2008
137
SA Jacobson, PC Dwyer, JT Machan et al
generalized slow-wave activity into the delta range (like slowwave sleep), even during backward counting.3 Eye movements
for this “hypoactive” patient tend to be slow, resembling those of
drowsiness.4 The aggressive and actively hallucinating individual (e.g., the patient in delirium tremens) shows an excess of lowvoltage fast activity and rapid eye movements (REM) identical to
those of REM sleep,5 often admixed with generalized slow-wave
activity. Although as yet unstudied, ultradian EEG rhythms may
be present in delirium as well and may correspond to the observed
“waxing and waning” of symptoms, a commonly observed pattern of episodic exacerbation of symptoms in delirium.
It has been speculated that delirium may represent the simultaneous appearance of wakefulness and REM sleep, constituting
a state of “pathologic wakefulness.”6 Except for a few studies
involving REM sleep in alcoholics,5,7 however, delirium has not
been systematically investigated from the standpoint of sleepwake activity and its disruption. Borbély posited 3 processes
underlying sleep-wake regulation: a homeostatic process, dependent on prior sleep and waking; a circadian clock-like process
that is independent of prior sleep and waking; and an ultradian
process involving a periodic alternation of non-REM (NREM)
and REM sleep.8 All three processes may be involved in delirium
pathogenesis. Among patients with esophageal and gastric cancer who have undergone surgery, even the pattern of clock gene
expression is altered in the postoperative period, with the magnitude of alteration dependent on the degree of surgical stress.9
Polysomnography (the gold standard for investigation of
sleep-wake abnormalities) is impractical to use in the study of
patients with delirium, primarily due to poor patient cooperation. Wrist actigraphy has been used to study sleep-wake activity in elderly nursing home patients with dementia and validated
using EEG.10 Although not a substitute for polysomnography,
actigraphy does provide useful information about ultradian patterns and usually is well tolerated. This study was undertaken to
investigate the feasibility of using wrist actigraphy in patients
with delirium and to begin to characterize sleep-wake abnormalities in this population, using automated methods.
study team. Each referred patient (or patient and family member) was given basic information about the study protocol. For
those willing to participate, informed consent was obtained using a consent form approved by the Institutional Review Board.
Patients were included if they were 65 years of age or older,
had recently undergone major surgery, and were able to give
informed consent or consent by proxy. Patients were excluded
if they were too medically ill or delirious to participate in the
evaluation (as determined by the need for urgent medical or
psychiatric intervention), exhibited limb tremor that would interfere with actigraphy assessment, or were unable to wear the
actigraph on the nondominant wrist.
Data Collection
Sources of data included medical records; reports from nursing staff, patient, and family or caregiver; and direct evaluation
and observation of the patient. Upon completion of the informed
consent process, the following baseline patient data were obtained during the acute postoperative period: demographic and
basic medical information (age, sex, type of surgery, medical
diagnoses, current medications); handedness as determined by
the Edinburgh Inventory11; cognitive screening using the MiniMental State Examination (MMSE),12 the Clock Drawing Test,13
and the Mental Alternation Test14; delirium screening using the
Delirium Rating Scale-R-98 (DRS-R-98)15 and the Confusion
Assessment Method16; and presurgical sleep assessment using
the Pittsburgh Sleep Quality Index (PSQI).17 These data were
entered to a Microsoft Access database for later analysis.
When the informed consent process was complete, the actigraph (Octagonal Basic Motionlogger, Ambulatory Monitoring, Inc., Ardsley, NY) was placed on the wrist of the patient’s
nondominant hand and left in place for 24 to 72 hours while the
patient continued usual activities. This device, which resembles
a wristwatch, captures a simple count of wrist/forearm movements within 1-minute epochs and stores these data internally.
On the day that data capture was complete and the monitor
was removed, data were downloaded for analysis to a personal
computer using Act Millenium software (Ambulatory Monitoring, Inc). For patients in whom more than 24 hours of actigraphy data had been collected, the 24-hour period during which
the DRS-R-98 score was highest was used for analysis. An automated sleep-wake scoring algorithm was applied using the
Action W-2 software package (Ambulatory Monitoring, Inc.).
“Rest” versus “active” designations were based on the Sadeh
algorithm,18 which has been validated to distinguish estimated
sleep and wake in healthy control subjects. In the absence of
such validation in the elderly postoperative population, it was
decided that the less specific terms “rest” and active” would
be more appropriately applied. Activity variables examined included the total number of minutes active during the daytime
hours (0600 to 2200), the total number of minutes resting during
the nighttime hours (2200 to 0600), the total time resting in 24
hours, the mean activity count during the daytime, the mean activity count during the nighttime, and the 24-hour amplitude of
the activity rhythm (the absolute value of the difference between
mean activity count at night and mean activity count in day).
The following daily clinical assessments were made: DRSR-98 score; note of any change in the patient’s medical condi-
Methods
Identification and Enrollment of Subjects
The study was performed in compliance with the Declaration
of Helsinki. The research protocol was reviewed and approved
by the Institutional Review Board, Office of Research Administration, Miriam Hospital, Providence, RI. Informed consent
was obtained from patients capable of consenting; in cases in
which the patient was judged unable to consent because of confusion or memory impairment, consent was obtained from the
designated proxy (family member), and assent was obtained
from the patient.
The study team attended surgical and nursing rounds to brief
surgeons, nurses, and other involved staff regarding the intent
and logistics of the study before enrollment was initiated. Patients were identified and consented postoperatively, and all patient evaluations commenced during the postoperative period.
On a daily basis during the study period, nursing staff on four
units providing postsurgical care were asked to refer postoperative elderly patients who indicated a willingness to talk to the
Journal of Clinical Sleep Medicine, Vol. 4, No. 2, 2008
138
Delirium: Pathological Wakefulness
A
B
Figure 1—Sample actigraphy plots (raw data) for 6 study subjects in the (a) delirious and 6 study subjects in the (b) control patients groups.
Plots begin and end at midnight, except for the last 2 control subjects, who were studied for 24 hours from midday to midday.
tion or medications; note of any abnormalities in vital signs or
laboratory values; evidence of pulmonary congestion, constipation, dehydration or fluid overload; or pain complaints. Abnormalities in any of these variables were brought to the attention
of the primary treating team, per usual clinical routine, for optimal patient management and treatment.
Medications administered during the study period were
grouped into one of the following categories: antihistamines,
antibiotics/antifungals, cancer drugs, asthma/chronic obstructive pulmonary disease drugs, gastrointestinal drugs, anticholinergics, opioids, benzodiazepines/benzodiazepine-like hypnotics, antipsychotics, antihypertensives, hypoglycemics/insulin,
and miscellaneous/other. Categories were counted to provide a
measure of overall medication burden. Specific note was made
regarding the administration of opioid, benzodiazepine, and antipsychotic medications.
the proportion of patients who reported pain, and the proportion
of patients who were administered opioids, benzodiazepines, or
antipsychotics. T-tests were also performed to compare groups
on each of 6 activity parameters. The association between each
parameter and DRS-R-98 severity scores was examined by computing the Pearson correlation coefficient.
Results
Thirteen patients were studied and were classified according to DSM-IV-TR criteria as delirious (n = 6) or not delirious (n = 7). Figure 1 displays the 24-hour actigraphy plot for
each patient. Table 1 shows demographic and other baseline
data for 12 of the 13 subjects (last control subject omitted for
space reasons). The 2 groups did not differ significantly in demographic characteristics, including age (t11 = +0.86, p = 0.41),
mean score on the Pittsburgh Sleep Quality Index (reflecting
premorbid sleep) (t11 = -0.33, p = 0.75), mean number of active medical problems (t11 = -0.76, p = 0.47), mean number of
administered medication groups (t11 = -0.4, p = 0.70), time since
surgery (t11 = +0.95, p = 0.37), or the percentage of patients administered opioids during the study period (83% of the delirium
group and 86% of the control group; Fisher exact p = 1.0).
Table 2 shows clinical evaluation data for each patient, along
with group summary data. Significant differences were found
between the groups in mean MMSE score (t11 = -2.86, p = 0.016),
mean DRS-R-98 Total Score (t11 = +7.77, p = 0.0001), and mean
DRS-R-98 Severity Score (t11 = +4.14, p = 0.002). Nonsignifi-
Data Analysis
Statistical analyses were performed using SPSS (SPSS, Inc.,
Chicago, IL) and the VassarStats statistical computation Website
(http://faculty.vassar.edu/lowry/VassarStats.html). T-tests were
performed to compare groups with regard to the following demographic variables: age, PSQI score, number of active medical
conditions, number of medication groups, and time since surgery;
and the following clinical variables: MMSE score, DRS-R-98 total score, and DRS-R-98 severity score. Fisher exact test was used
to examine group differences in the proportion of men to women,
Journal of Clinical Sleep Medicine, Vol. 4, No. 2, 2008
139
SA Jacobson, PC Dwyer, JT Machan et al
Table 1—Demographic and Baseline Data
Patient Group
Age
Sex
PSQI Score
001
D
73
F
4
007
D
72
M
5
009
D
82
M
4
010
D
86
M
4
014
D
87
M
7
016
D
85
F
12
Mean (SD)
81 (6.7)
6.0 (3.2)
003
C
67
M
2
005
C
79
F
6
006
C
78
M
10
011
C
91
F
9
012
C
73
F
4
013
C
71
M
14
015
C
82
M
2
Mean (SD)
77 (7.9)
6.7 (4.5)
Active medical
problems
2
4
4
4
3
7
4.0 (1.7)
4
3
7
3
4
7
5
4.7 (1.7)
Medication
groups
5
4
7
4
3
6
4.8 (1.5)
7
3
4
6
6
5
5
5.1 (1.3)
Time since
surgery, d
2
3
1
10
1
1
3 (3.5)
1
2
2
2
1
1
3
1.7 (0.8)
Type of
surgery
Hip ORIF
Hip ORIF
Abdominal
CABG
Hip ORIF
Thoracotomy
Hip ORIF
Hip ORIF
Hip ORIF
Hip ORIF
AAA repair
BKA
CABG
PSQI refers to Pittsburgh Sleep Quality Index; AAA, abdominal aortic aneurysm; BKA, below-the-knee amputation; CABG, coronary artery
bypass grafting; ORIF, open reduction, internal fixation.
cant differences were found in the percentage of patients reporting pain at the time of clinical assessment (83% of delirium
group versus 57% of the control group; Fisher exact p = 0.56),
percentage of patients administered benzodiazepine medications during the study period (17% of the delirium group versus
29% of the control group; Fisher exact p = 1.0), and percentage who took antipsychotic medications (33% of the delirium
group versus 0% of the control group; Fisher p = 0.19).
Table 3 shows activity data for each patient, along with
group summary data. The groups showed significant differences in rest-activity patterns. Based on the Sadeh algorithm,
delirious patients, compared with control patients, showed (1)
a significantly lower number of nighttime minutes at rest (t11 =
-4.74, p = 0.00061), (2) a significantly lower number of minutes
at rest over the 24-hour period (t10 = -2.52, p = 0.031), (3) a significantly higher mean activity count at night (t11 = +3.96, p =
0.0023), and (4) a significantly smaller amplitude of change in
mean activity from day to night (t11 = -3.01, p = 0.012).
The Pearson correlation of DRS Severity Scale scores and
activity parameters mirrored these differences between delirium and control groups, as shown in Table 4. A significant positive relationship was revealed for DRS Severity Scale score and
mean activity count at night. Significant negative relationships
were revealed for DRS Severity Scale score and (1) number of
nighttime minutes at rest, (2) number of minutes at rest over the
24-hour period, and (3) amplitude of change in mean activity
from day to night.
In summary, the study showed that the delirium and nondelirium groups were similar at baseline in demographics and
medical characteristics but differed in clinical measures that
reflected the presence of delirium (MMSE and DRS-R-98). In
addition, the delirious patients showed an abnormal pattern of
rest and activity that was correlated with delirium severity.
jective methods and quantitative analysis of activity. Compared
with nondelirious postoperative elderly patients, delirious patients displayed more nighttime activity and a smaller amplitude
of day-night difference in rest and activity. The disruption was
sufficiently robust to be discernible even by visual inspection of
individual actigraphy plots. These findings are consistent with a
proposed state of persistent pathologic wakefulness in delirium,
manifest by the simultaneous appearance of rest and activity, or
by rapidly alternating periods of rest and activity.
In the current nosology, the hallmark of delirium is a disturbance of consciousness with reduced clarity of awareness of
the environment. Disturbance in the sleep-wake cycle is considered an inconstant associated feature.1 In practice, the nature
of the “disturbance of consciousness” is poorly understood, and
the relegation of sleep-wake disturbance to “associated” status
implies that it can be dissociated from the more fundamental
disturbance in consciousness. It may be that a more informative approach would be to model delirium as a disorder that
primarily involves the simultaneous but incomplete expression of wakefulness and sleep,6 both REM and NREM. Other
features of the delirium syndrome could then be understood as
arising from this state of persistent pathologic wakefulness. For
example, disordered REM sleep and REM intrusion into the
waking state are believed to underlie the occurrence of visual
hallucinations.19-21 Even NREM sleep processes have been implicated in hallucinatory phenomena.22,23 Furthermore, there appears to be some similarity between the agitated, “acting-out”
behaviors of the delirious patient and the phenomena of REM
sleep behavior disorder.24
Delirium is a difficult clinical problem to study in a systematic way, in large part because of logistic and ethical concerns
raised in the course of studying incompetent patients who are
medically compromised and variably cooperative. Moreover, a
range of uncontrolled variables potentially confounds the study
of patients with multiple medical problems treated with multiple medications. As far as possible, in this pilot study, these
variables were taken into account. The delirium and nondelirium groups were found to be equivalent in terms of premorbid
Discussion
This is the first study to document a significant disruption of
the diurnal rest-activity cycle among delirious patients using obJournal of Clinical Sleep Medicine, Vol. 4, No. 2, 2008
140
Delirium: Pathological Wakefulness
Table 2—Clinical Evaluation Data
Patient Group
Score
001
D
007
D
009
D
010
D
014
D
016
D
Mean (SD)
003
C
005
C
006
C
011
C
012
C
013
C
015
C
Mean (SD)
MMSE
DRS
DRS
Pain
Medications
total score severity score Reported Administered Opioid
BZD
20
21
21
+
+
—
26
9
4
+
+
+
19
14
9
+
+
—
27
12
9
—
—
—
24
15
10
+
+
—
12
18
16
+
+
—
21.3 (5.6)
14.8 (4.3)
11.5 (6.0)
30
2
2
+
+
+
30
1
1
+
+
—
25
3
3
+
+
—
24
3
3
+
+
+
29
1
1
—
+
—
30
1
1
—
—
—
28
3
3
—
+
—
28.0 (2.5)
2.0 (1.0)
2.0 (1.0)
AP
—
—
+
—
—
+
—
—
—
—
—
—
—
AP refers to antipsychotics; BZD, benzodiazepines; DRS, Delirium Rating Scale-R-98; MMSE, Mini-Mental State Exam.
Table 3—Activity Data
Patient Group
001
D
007
D
009
D
010
D
014
D
016
D
Mean (SD)
003
C
005
C
006
C
011
C
012
C
013
C
015
C
Mean (SD)
Minutes
Minutes
Total 24-hour
active daytime resting nighttime Rest (min)
735
13
238
673
296
583
926
20
54
878
93
175
926
14
48
671
157
446
801.5 (122.3)
98.9 (112.3)
257.3 (216.3)
895
272
337
727
430
663
696
351
615
748
420
632
463
344
841
886
228
302
—a
449
—
735.8 (157.6)
356.3 (83.5)
565.0 (206.8)
Mean activity
count daytime
72.64
72.14
102.03
146.34
119.78
117.50
105.1 (29.0)
124.68
86.59
94.27
112.59
48.59
87.55
63.67
88.3(26.3)
Mean activity
count nighttime
70.73
28.11
119.99
94.27
116.29
105.13
89.1(34.7)
58.83
12.53
43.96
18.86
26.44
38.26
8.82
29.7(18.2)
24-hour Amplitude
(MACday – MACnight)
1.91
44.03
17.96
52.03
3.49
12.37
22.0(21.2)
65.85
74.07
50.31
93.73
22.15
49.29
54.85
58.6(22.5)
This patient’s record was missing a 2.5-hour segment of daytime recording. MAC refers to mean activity count.
a
sleep quality (as assessed by the PSQI), number of active medical problems, number of medication groups, time since surgery
(with 1 clear outlier in the delirium group), and type of surgery.
In future studies, attempts will be made to capture the actual severity of medical illness, using a scale such as the Modified Cumulative Illness Rating Scale.25 To determine whether data from
the 1 patient in the delirium group who was 10 days postoperative (the outlier) influenced the final statistics, all tests were run
with and without this patient’s data included, and no differences
were found in the results. In the course of the study, the delirium and non-delirium groups were found to be equivalent in
terms of the number of patients reporting pain, and the number
administered opioid, benzodiazepine, or antipsychotic medications. MMSE scores were of course significantly lower in the
delirium group because of the presence of delirium. It was not
possible to determine the prevalence of preexisting cognitive
impairment in either group except by history from patient and
family or caregiver; when this history was taken into account,
the groups were not different at baseline. Finally, although it
Journal of Clinical Sleep Medicine, Vol. 4, No. 2, 2008
Table 4—Delirium Severity (DRS-R-98) and Activitya
r
No. minutes resting at night
-0.82
No. minutes resting over 24 hours -0.58
MAC at night
+0.69
Amplitude of day-night
difference in MAC
-0.72
n
13
12
13
p
0.0007
0.05
0.009
13
0.006
All tests 2-tailed Pearson correlations; DRS-R-98 refers to the
Delirium Rating Scale-R-98; MAC, mean activity count.
a
is true that the hospital is far from ideal as a sleep-promoting
environment, factors such as nighttime noise and light would
have affected all patients equally, since all were treated on the
same postsurgical units.
The methods used in this study—wrist actigraphy and daily
clinical assessments—were unobtrusive and therefore acceptable to patients, family, and involved medical personnel. The
automated nature of actigraphy recording made it feasible to
141
SA Jacobson, PC Dwyer, JT Machan et al
maintain data collection over several days, even when cooperation was minimal. Although actigraphy is limited in that it
cannot be used to stage sleep or to provide an EEG measure
of encephalopathy, there are several ways in which actigraphy
could be used in future studies of delirium. For example, actigraphy could provide an objective measure to gauge the effectiveness of delirium treatment in normalizing diurnal rhythms,
using current interventions (antipsychotics or benzodiazepines), or chronobiologic treatments (melatonin or bright light
therapy). Sleep-hygiene measures such as maintaining a quiet
dark room at night and providing a snack before bedtime could
be examined as simple and non-labor-intensive interventions.
Alternatively, attempts could be made to correlate the changes in rest-activity patterns detected by actigraphy to putative
neurochemical derangements in delirium, such as elevated levels of certain proinflammatory cytokines,26-28 increased serum
anticholinergic activity,29-31 or deviations in ultradian cortisol
rhythms.32,33
13.
14.
15.
16.
17.
18.
ACKNOWLEDGMENTS
19.
This work was supported by a Research Developmental
Grant Award from the Lifespan Corporation. The funding agency had no role in designing the study, collecting or analyzing
data, interpreting data, writing the paper, or making the decision to submit for publication.
Work was performed at The Miriam Hospital, 164 Summit
Ave., Providence, RI 02906
20.
21.
22.
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