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Aspects of acute hospital admission in the elderly
de Rooij, S.E.J.A.
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Citation for published version (APA):de Rooij, S. E. J. A. (2006). Aspects of acute hospital admission in the elderly.
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Download date: 17 Jun 2020
C H A P T E RR 5
CYTOKINE SS AN D ACUT E PHAS E RESPONSE IN
HOSPITALIZE DD ELDERL Y PATIENT S WITH DELIRIU M
S O P H I AA E. D E R O O I J , B A R B A R A C. VAN M U N S T E R ,
J O H A N N AA C. K O R E V A A R A N D M A R C E L L E V I
submitted submitted
91 91 AspectsAspects of acute hospital admission in the elderly
CHAPTERR 6
Deliriumm is frequently diagnosed in acutely hospitalized patients. The pathophysiology
off delirium is poorly understood but is generally considered the result of an imbalance in
neurotransmitterr systems. Raised levels of cytokines occur in common causes of delirium,
suchh as infection. Animal studies show that proinflammatory cytokines induce a reduced
activityy of the cholinergic system. We hypothesize that inflammatory mediators may
playy a role in the pathogenesis of delirium. Al l consecutive patients of 65 years and older,
acutelyy admitted to die department of Medicine, were invited. The presence of delirium was
determinedd within 48 hrs after admission by experienced geriatric physicians. C-reactive
proteinn and cytokines (IL-lfi , IL-6, T N F - Ö, IL-8, and IL-10) were determined. In total,
1855 eligible patients were included, mean age was 79 years, 42% were male, and 34.6 %
developedd delirium. Compared to patients without delirium, delirious patients were
older,, and experienced more often pre-existent cognitive impairment. In delirious
patientss significantly more IL-6 levels (53% vs 31%) and IL-8 levels (45% vs 22%) were
abovee the detection limit . After correction for infections, these differences were still
significant.. Proinflammatory cytokines may contribute to the pathogenesis of delirium
inn acutely admitted elderly patients.
93 3 AspectsAspects of acute hospital admission in the elderly
CHAPTERR 6
INTRODUCTION N
IInfectionss in humans are characterised by local, systemic and central nervous system
(CNS)) effects. The effects of inflammation and infection on the ageing brain are highly
complex.. The mechanisms, however, that mediate the behavioural effects of peripherally
releasedd cytokines on the brain, often described as sickness behaviour, have partly been
elucidatedd over the past decade 3,4,6,24 Cytokines, a diverse group of peptide molecules
thatt regulate cell and tissue functions, are responsible for sickness behaviour including
malaise,, fatigue and reduced appetite. These cytokines, mainly interleukin 1 (IL-l a and
IL-lfi) ,, IL-6 and tumour necrosis factor (TNF)-a, are supposed to act on the brain by
aa fast neural pathway and a slower humoral pathway 2^. The proinflammatory IL-1 is
ablee to induce its own synthesis and the synthesis of other cytokines that potentiate its
effectt (e.g.TNF-a and IL-6, IL-8) or antagonize its effect (IL-10). Proinflammatory
cytokiness are involved in the production of IL-1 in the brain 5>6 and peripheral and central
administrationn of IL-1 ft in animal studies induced all components of sickness behaviour l .
Inn humans a high serum 11-6 and also other cytokines have been associated with neuro-
psychiatricc illness like cognitive decline in dementia 22, and depression 20 and cognitive
declinee and fatigue in cancer 28>29.
Delirium,, an acute neuropsychiatric syndrome, characterized by deranged conscious-
ness,, cognitive and attentional disturbances with a typical fluctuating course, is also
hypothesizedd to be induced by circulating cytokines 931, Although a variety of factors
iss associated with delirium, such as psychiatric illness, older age, and cerebral vascular
disease,, the pathophysiology of delirium remains poorly understood. Interestingly, delirium
hass been recognized as a frequent manifestation of infections in the elderly ^ . Delirium
usuallyy disappears as the underlying illness causing delirium has been resolved and is a
fullyy reversible phenomenon similar to cytokine-induced sickness behaviour 27. Moreover,
animall studies have demonstrated that cytokines can cause a reduction in the acetyl-
94 4 AspectsAspects of acute hospital admission in the elderly
CHAPTERR 6
cholinergicc pathways 37 which are supposed to be impaired in delirium11 Based on this
informationn delirium may be considered as a distinct part of sickness behaviour that can
bee seen as the outward expression of a potentially reversible episode of brain inflammation
andd is triggered by peripheral immune stimulation 7,9,31,34 _ These and other studies
resultedd in several hypotheses suggesting that cytokines may be involved in the pathogenesis
off delirium 8,10>31. There are, however, no data on the association between peripheral
cytokinee levels and delirium.
Wee performed a study amongst consecutive elderly patients acutely admitted to the
hospitall to compare the expression patterns of pro- and anti-inflammatory cytokines in
patientss with and without delirium.
METHODSS AND MATERIALS
PATIENTS S
Al ll consecutive patients aged 65 years or older, acutely admitted to the Department of
Medicinee of the Academic Medical Centre, Amsterdam, a 1024-beds university teaching
hospital,, were invited. Patients were excluded from the study if they were unable to
speakk or understand Dutch or English, if they or their relatives did not give permission
forr the study, if they came from or were transferred to another ward, or left the ward
withinn 48 hours. Before enrolment, informed consent was obtained from the patient or
substitutee decision-maker. The hospital s Medical Ethics Committee approved the study.
PROCEDURES S
Memberss of the team completed a multidisciplinary evaluation for all study participants
withinn 48 hrs after admission. The team was composed of a geriatric physician, a fellow
inn geriatric medicine, and research nurses trained in geriatric medicine. Demographic
95 5 AspectsAspects of acute hospital admission in the elderly
C H A P T E RR 6
andd clinical data were collected. The reason for admission was collected and expressed
inn International Classifications of Diseases (ICD) code. Five cytokines, namely IL-lfi ,
IL-6,, IL-8, IL-10, and TNF-a, and C-reactive protein as a marker of the acute phase
response,, were measured in a blood sample taken in the morning within one week after
admission.. The blood samples were centrifuged and serum was stored at -80 C until
determination.. Cytokine concentrations (TNF-a, IL-lfê, IL-6, IL-8, and IL-10) were
measuredd using a cytometric bead array immunoassay (BD Biosciences Pharmingen,
Sann Diego, CA). Considering the dilutions at which the samples were tested, actual
detectionn limits were for TNF-a 2.5 pg/mL, for IL-lf i 80 pg/mL, for IL-6 10 pg/mL,
forr IL-8 20 pg/mL, and for IL-10 10 pg/mL.
Withi nn 48 hrs after admission, research nurses interviewed patients, medical and
nursingg staff At the time of hospital admission cognitive impairment was recorded by
twoo validated instruments (MMSE, IQCODE). The MMSE (Mini Mental State
Examination)) is the internationally most widely used bed-side screening instrument for
detectionn of cognitive impairment in the elderly 12. The MMSE measures cognitive
functioningg on a scale of 0 (poor) to 30 (excellent), with a score less than 24 indicating
cognitivee impairment.
Thee IQCODE (Informant Questionnaire on COgnitive DEcline) assesses the possible
presencee of dementia before hospital admission based on the response of an informant
whoo had known the patient for at least 10 years and could assess any decline in memory
orr cognition ï8'1^. The informant was asked to recollect the situation 2 weeks before the
illnesss leading to the hospital admission and to compare it with the situation 10 years
before.. The score is an average of the 16-item scores, each rated from 1 (much improved)
too 5 (much worse). Patients with a mean score of 3.9 or more were considered to have serious
cognitivee impairment. Final classification for having pre morbid cognitive impairment was
basedd on an earlier diagnosis of dementia or on the MMSE score for patients without
96 96 AspectsAspects of acute hospital admission in the elderly
CHAPTERR 6
delirium,, whereas for patients with delirium, the combination of both instruments
(MMSEE and IQCODE) was applied if no earlier diagnosis of cognitive impairment was
available.. In case of conflicting outcome, the score of the IQCODE was used.
Thee physician scored the presence of delirium within 48 hrs after admission with
thee CAM (Confusion Assessment Method). The CAM is a structured interview of delirium
symptomss based on the Diagnostic and Statistical Manual of Mental Disorders criteria
(DSM-III-R) .. This instrument has been found reliable, sensitive and specific [1990]
andd a valid Dutch version was available [accepted for publication].
Functionalityy was measured by the modified Katz-ADL scale, a 15-item scale develop-
edd for use in a geriatric population 36. The Katz-ADL consists of one scale for patients
andd one for their relative or informant. The Katz-ADL as scored by the patient was
used.. In case this score was missing, the Katz-ADL score of the informant was taken.
Oncee more, the informant was asked to recall the situation before admission.
STATISTICALL ANALYSIS
Dataa were analyzed using SPSS-PC software version 11.5. Rating scale data were expressed
ass median scores and quartiles because of their distribution. Differences in baseline
characteristicss were tested with chi-square tests or with the Mann-Whitney U test,
p<< 0.05 was considered statistically significant.
RESULTS S
Duringg the inclusion period 576 patients aged 65 years and older were admitted. Of
thesee patients, 88 patients came from another ward, resulting in 488 eligible patients.
1822 patients were not included because no informed consent was provided or because
thee patients were unable to speak or understand Dutch or English, or because they were
977 _ _ ._ _ AspectsAspects of acute hospital admission in the elderly
C H A P T E RR 6
dischargedd within 48 hours. In total 306 patients were included, a random sample of
1855 patients was selected for the current study. Non-selected and selected patients were
similarr regarding mean age, the male/female ratio, and the frequency of patients with
delirium.. Baseline characteristics of the 185 selected patients with and without delirium
aree presented in Table 1. Mean age was 80 years, 42% were male, and 64 patients (34.6 %)
weree diagnosed with delirium. Patients with delirium were significantly older, had more
oftenn (pre-existing) cognitive impairment, and were more impaired in daily activities com-
paredd to patients without delirium. Table 1 also describes C reactive protein and five
differentt peripheral cytokines in non-delirious and delirious patients. The vast majority
hadd C-reactive protein levels above the detection limit , these levels showed no significant
differencee between patients with or without delirium (p=0.83). Nearly all patients had
TNF-,, IL-lf i and IL-10 levels below the detection limi t (88%, 99%, and 96% respec-
tively).. Significant more non-delirious patients had IL-6 levels below the detection limi t
(69%)) compared to delirious patients (47%; p=0.04). A similar finding was seen for IL-8;
moree non-delirious patients with a level below the detection limi t (78% versus 55%;
p=0.001).. Limiting the analyses to the serum concentrations above the detection limit ,
noo significant difference between delirious and non-delirious patients was observed for
IL- 66 nor for IL-8. Serum levels above detection limi t for CRP, IL-6 and IL-8 are pre-
sentedd in Figure 1.
Forr 48% of the delirious and 4 1% of the non-delirious patients an infection was the
reasonn of admission. This could have disturbed the comparison between both groups,
thereforee we repeated our analyses in the subgroups with or without an infection. First,
noo difference in the acute phase response was shown in both groups between delirious
andd non-delirious patients (Table 2). Furthermore, limiting to the patients with an
infection,, significant more patients without delirium had IL-6 levels below the detection
limi tt (p=0.03). This difference was borderline significant for the patients without an
9l 9l AspectsAspects of acute hospital admission in the elderly
CHAPTERR 6
infectionn (Table 3). Once more, the same difference was seen for IL-8 although not sig-
nificantt for the patients with an infection (p=0.08), as is shown in Table 4. Table 5
showss levels of IL-6 in delirious and non-delirious patients with and without cognitive
impairment.. Due to the restriction of the number of patients with detectable IL-6 we
weree only able to show a trend towards significance.
DISCUSSION N
Inn this sample of consecutive acutely hospitalized elderly patients, 34.6% met the criteria
forr delirium. Patients with delirium had significantly more often IL-6 and IL-8 levels
abovee the detection limit . These differences remained after stratifying for infectious
disease. .
Thiss is the first study that shows a relationship between peripherally measured cytokine
levelss and delirium as a symptom/exponent of sickness behaviour in acutely admitted
elderlyy patients. This finding is in line with some previous observations. One study
investigatedd the relationship between low baseline insuline growth factor (IGF)-l and
deliriumm in acutely hospitalized elderly subjects 3 8. IGF-1 is known as a neuroprotective
cytokine,, inhibiting cytotoxic cytokines. From the results of this study it was concluded
thatt below a certain level of IGF-1 the brain is vulnerable to cytotoxic effects of circulating
cytokines,, generated by an acute illness and presenting with delirium.
Furthermore,, it was shown that in patients with a neurodegenerative disorder such
ass in Alzheimer's disease cognitive function can be impaired by a systemic infection and
thatt this cognitive decline is preceded by raised serum levels of IL-lf i 16. In longitudinal
population-basedd studies increased serum levels of IL-6 were also associated with cog-
nitivee decline 32,35,39} D u t ^ y pathophysiological relationship (contribution to cognitive
declinee or consequence of (early) dementia) still remains unclear. In our population
9? ? AspectsAspects of acute hospital admission in the elderly
CHAPTERR 6
howeverr these results could not be reproduced in patients with cognitive impairment.
Nevertheless,, increased levels of IL-6 were also found in the cerebrospinal fluid of
patientss with late-onset Alzheimer disease 22. Consequently, in otherwise apparently
healthyy brains, cytokines may have no delirious effect, but when neuronal damage is
presentt such as in dementia, but also in cerebrovascular disease or even as a result of
ageingg of the brain 2, some cytokines may enhance neurodegenerative processes leading
too the syndrome of delirium, perhaps even irrespective of their circulating levels.
Firstt theories but later on also findings indicate that the pathophysiology of delirium
iss a consequence of imbalances of several neurotransmitter systems, resulting in reduced
synthesiss of acetylcholine in the brain 2,l4,26,33_ Peripheral signals activating central
pathwayss is not easy to understand, because cytokines are large lipophobic proteins or
peptides,, that do not easily cross the blood-brain barrier. Nevertheless, a recent study
showedd a temporarily elevation of IL-6 in the cerebrospinal fluid after cardiac surgery 2 L
Too allow blood-borne cytokines trespassing this barrier many hypotheses have been pro-
posed.. One of them may be the binding to the cerebral vascular endothelium 3 4.
Neuropathologicall studies have shown that systemic inflammation causes activation of
vascularr endothelial cells and perivascular cells 2^.
AA limitation of this study may be the number of patients with detectable levels of
cytokines,, nevertheless, we decided not to give cytokine levels below the detection limi t
thee level of the detection limit . Another limitation is the moment of obtaining of blood
samples,, not all but however the vast majority of the samples was taken within 3 days
afterr admission. Another limitation of our study is that the cytokines are measured in
peripherallyy obtained blood and therefore not necessarily reflect the local pathophysio-
logicall process in the brain during delirium. However, it is well established that release
off proinflammatory cytokines IL-lfi , IL-6 and TNF-a are supposed to induce a typical pattern
off behaviour response, which has been collectively referred to as sickness behaviour 1 , 3° .
AspectsAspects of acute hospital admission in the elderly
C H A P T E RR 6
Thee amounts of cytokines are normally high during acute infections in patients sho-
wingg sickness behaviour ' $, but there is growing evidence that low circulating levels of
inflammatoryy cytokines also may influence the CNS ^°. If this is the case in delirium is not
yett clear, but it might explain why in some patients with cytokine levels below detection
limi tt delirium was present.
Itt can be concluded that more research is necessary to study the possibility that inflam-
matoryy mechanisms are involved in pathogenetic pathways of delirium. The present
studyy suggested a role for proinflammatory cytokines in delirium, independent of infectious
diseases. .
ACKNOWLEDGMENTS S
Thee authors thank Tom van der Poll , Jenny Pater and Alex Vos for determination of
serumm inflammatory marker levels, for their comments and suggestions, Caroline van Rijn,
Marjoleinn van der Zwaan and Arja Giesbers for interviewing all patients and relatives.
I O I I
AspectsAspects of acute hospital admission in the elderly
C H A P T E RR 6
Tablee 1. Baseline characteristics of acutely admitted elderly patients with and without a prevalent deliriumm after acute admission.
Variabl e e
Numberr of patients
Agee (yrs)
Genderr {% male)
Cognitivee impaired (%)
Functionall impairment (number of (l)ADL
disabilities) )
00 limitations
1-33 limitations
4-66 limitations
77 or > limitations
Admissionn reason <%)
Infectiouss disease
Malignancy y
Diseasee of digestive system
Waterr and electrolyte disturbances
Cardiovascularr diseases
Other r
CRPP (% below detection limit)
(mg/L)) Median (IQR)
TNF-- a (% below detection limit)
(pg/mL)Mediann (IQR)
IL-1BB (% below DL)
(pg/mL)Mediann (IQR)
IL-66 {% below DL)
(pg/mL)Mediann (IQR)
IL-88 (% below DL)
(pg/mL)Mediann (IQR)
IL-100 (% below DL)
(pg/mL)Mediann (IQR)
Deliriu m m
64 4
81.2(7.1) )
34% %
62% %
3.1% %
9.2% %
15.4% %
72.3% %
48 8
g g
8 8
16 6
8 8
11 1
6% %
72.55 (30.5 -
89% %
-- 185.0)
4.8(2.8-10.0) )
98% %
--47% %
21.11 (12.9-
55% %
53.8(30.9--
94% %
13.8(10.8--
-- 39.2)
-79.1) )
-- 20.6)
Noo deliriu m
121 1
77.33 (8.0)
45% %
20% %
11.2% %
29.6% %
20.0% %
39.2% %
41 1
12 2
15 5
7 7
9 9
15 5
9% %
87.0(33.0--
88% %
) )
3.11 (2.8-5.4)
99% %
--69% %
19.9(12.9--
78% %
40.3(27.9--
96% %
20.3(15.8--
-- 30.6)
-559.8) )
-29.2) )
p-valu e e
0.002 2
0.16 6
<0.001 1
<0.001 1
0.33 3
0.53 3
0.83 3
0.77 7
0.68 8
0.64 4
0.04 4
0.88 8
0.001 1
0.83 3
0.52 2
0.29 9
Note:: p<0.05 is significant
1 02 2
AspectsAspects of acute hospital admission in the elderly
C H A P T E RR 6
Figur ee 1. Plots of CRP, IL-6 and IL-8 levels in delirious and non delirious patients.
r r t t n n e e c c n n o o c c
P P R R C C
450 0
400 0
350H H
300 0
250 0
200-| |
150 0
100--
50--
0 0
l4f*i --
" i l l "
HI I
CRPP concentration for patients with and withoutt a delirium, limited to the patients with a
CRPP level above 3 mg/L.
t t n n e e c c n n o o c c
400 0
300-i i
200 0
100 0 75-r r
50--
25 5
0 0 > > »«V»\V«'»* *
IL-66 concentration for patients with and withoutt a delirium, limited to the patients with a
IL-66 level above 10 pg/mL
103 3 AspectsAspects of acute hospital admission in the elderly
C H A P T E RR 6
t t n n e e c c n n 0 0 c c
2600--
600-L L 600600 T OUU-r r
350-^ ^ 100-L L 100-r r
50--• • : : • •
IL-88 concentration for patients with and withoutt a delirium,limited to the patients with a
IL-88 level above 20 pg/mL
Tablee 2. CRP, mg/L separate for patients with or without infection as admission reason (limited to patientss above detection limit).
CRP,CRP, mg/L Infectio n n Noo infectio n
Deliriumm No delirium Delirium No delirium
255 39 21 40
166.0(40.0-252.5)) 114.0(53.0-228.0) 44.0(17.5-77.0) 53.5(28.3-128.0)
0.888 0.54
NumberNumber of patients
Mediann (IQR)
p-value e
DL== detection limit, p<0.05 is significant
104 4 AspectsAspects of acute hospital admission in the elderly
CHAPTERR 6
Tablee 3. IL-6, pg/mL separate for patients with or without infection as admission reason (limited to patientss above detection limit).
IL-6,IL-6, pg/ml Infectio n n Noo infectio n
Deliriumm No delirium Delirium No delirium
Numberr of patients 17 15 17 23
Mediann (IQR) 21.9(12.7-38.5) 19.8(13.6-29.8) 14.6(12.4-44.5) 20.1(12.9-32.8)
p-valuee 0.66 0.87
%% below DL 45% 70% 49% 68%
p-valuee 0J33 O06
DL== detection limit, p<0.05 is significant
Tablee 4. IL-8, pg/mL separate for patients with or without infection as admission reason (limited to patientss above detection limit).
IL-8,IL-8, pg/mL Infectio n n Noo infectio n
Deliriumm No delirium
Numberr of patients 14 13
Mediann (IQR) 48.4 (31.0- 63.4) 29.7 (25.6 - 381.7)
p-valuee 0.52
%% below DL 55% 74%
p-valuee 0J38
Delirium m
15 5
56.77 (29.2-148.6)
0.78 8
5% %
0.006 6
Noo delirium
14 4
102.5(27.4-1145.2) )
80% %
DL== detection limit, p<0.05 is significant
105 5 AspectsAspects of acute hospital admission in the elderly
C H A P T E RR 6
Tablee 5. IL-6, pg/mL separate for patients with or without cognitive impairment (patients above detectionn limit).
IL-6,IL-6, pg/mL Cognitiv e impairmen t No cognitiv e impairmen t
Deliriumm No delirium Delirium No delirium
Numberr of patients 20 6 10 29
Mediann (IQR) 21.2(13.1-36.2) 13.1(11.6-19.6) 15.2(11.5-40.9) 20.9(13.2-37.4)
p-valuee 0.08 0.26
p<0.055 is significant
106 6 AspectsAspects of acute hospital admission in the elderly
CHAPTERR 6
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