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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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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.


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-


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


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


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


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)


IL-66 {% below DL)


IL-88 (% below DL)


IL-100 (% below DL)


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


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


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


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


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


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% %



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


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


CHAPTERR 6

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