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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2013

Open Access 01-12-2013 | Research

Preoperative cerebrospinal fluid cytokine levels and the risk of postoperative delirium in elderly hip fracture patients

Authors: Dunja Westhoff, Joost Witlox, Leo Koenderman, Kees J Kalisvaart, Jos F M de Jonghe, Mireille F M van Stijn, Alexander P J Houdijk, Inge C M Hoogland, Alasdair M J MacLullich, David J van Westerloo, Diederik van de Beek, Piet Eikelenboom, Willem A van Gool

Published in: Journal of Neuroinflammation | Issue 1/2013

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Abstract

Background

Aging and neurodegenerative disease predispose to delirium and are both associated with increased activity of the innate immune system resulting in an imbalance between pro- and anti-inflammatory mediators in the brain. We examined whether hip fracture patients who develop postoperative delirium have altered levels of inflammatory mediators in cerebrospinal fluid (CSF) prior to surgery.

Methods

Patients were 75 years and older and admitted for surgical repair of an acute hip fracture. CSF samples were collected preoperatively. In an exploratory study, we measured 42 cytokines and chemokines by multiplex analysis. We compared CSF levels between patients with and without postoperative delirium and examined the association between CSF cytokine levels and delirium severity. Delirium was diagnosed with the Confusion Assessment Method; severity of delirium was measured with the Delirium Rating Scale Revised-98. Mann–Whitney U tests or Student t-tests were used for between-group comparisons and the Spearman correlation coefficient was used for correlation analyses.

Results

Sixty-one patients were included, of whom 23 patients (37.7%) developed postsurgical delirium. Concentrations of Fms-like tyrosine kinase-3 (P=0.021), Interleukin-1 receptor antagonist (P=0.032) and Interleukin-6 (P=0.005) were significantly lower in patients who developed delirium postoperatively.

Conclusions

Our findings fit the hypothesis that delirium after surgery results from a dysfunctional neuroinflammatory response: stressing the role of reduced levels of anti-inflammatory mediators in this process.

Trial registration

The Effect of Taurine on Morbidity and Mortality in the Elderly Hip Fracture Patient.
Registration number: NCT00497978. Local ethical protocol number: NL16222.094.07.
Literature
1.
2.
Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA: Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA 2010, 304:443–451.CrossRefPubMed
3.
Maldonado JR: Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 2008, 24:789–856. IxCrossRefPubMed
4.
Eikelenboom P, Hoogendijk WJ, Jonker C, van TW: Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer’s disease. J Psychiatr Res 2002, 36:269–280.CrossRefPubMed
5.
Cunningham C, Maclullich AM: At the extreme end of the psychoneuroimmunological spectrum: delirium as a maladaptive sickness behaviour response. Brain Behav Immun 2013, 28:1–13.CrossRefPubMed
6.
Inouye SK, Charpentier PA: Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996, 275:852–857.CrossRefPubMed
7.
Helmy SA, Wahby MA, El-Nawaway M: The effect of anaesthesia and surgery on plasma cytokine production. Anaesthesia 1999, 54:733–738.CrossRefPubMed
8.
Gonzalez-Martinez H, Rodriguez L, Najera O, Cruz D, Miliar A, Dominguez A, Sanchez F, Granial J, Gonzalez-Torres MC: Expression of cytokine mRNA in lymphocytes of malnourished children. J Clin Immunol 2008, 28:593–599.CrossRefPubMed
9.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW: From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008, 9:46–56.CrossRefPubMedPubMedCentral
10.
van Gool WA, van de Beek D, Eikelenboom P: Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 2010, 375:773–775.CrossRefPubMed
11.
Nightingale S, Holmes J, Mason J, House A: Psychiatric illness and mortality after hip fracture. Lancet 2001, 357:1264–1265.CrossRefPubMed
12.
Lemstra AW, Kalisvaart KJ, Vreeswijk R, van Gool WA, Eikelenboom P: Pre-operative inflammatory markers and the risk of postoperative delirium in elderly patients. Int J Geriatr Psychiatry 2008, 23:943–948.CrossRefPubMed
13.
Adamis D, Lunn M, Martin FC, Treloar A, Gregson N, Hamilton G, Macdonald AJ: Cytokines and IGF-I in delirious and non-delirious acutely ill older medical inpatients. Age Ageing 2009, 38:326–332.CrossRefPubMed
14.
Beloosesky Y, Hendel D, Weiss A, Hershkovitz A, Grinblat J, Pirotsky A, Barak V: Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci 2007, 62:420–426.CrossRefPubMed
15.
Kalisvaart KJ, de Jonghe JF, Bogaards MJ, Vreeswijk R, Egberts TC, Burger BJ, Eikelenboom P, van Gool WA: Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc 2005, 53:1658–1666.CrossRefPubMed
16.
Witlox J, Kalisvaart KJ, de Jonghe JF, Verwey NA, van Stijn MF, Houdijk AP, Traast HS, MacLullich AM, van Gool WA, Eikelenboom P: Cerebrospinal fluid beta-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture. J Am Geriatr Soc 2011, 59:1260–1267.CrossRefPubMed
17.
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI: Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990, 113:941–948.CrossRefPubMed
18.
Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N: Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci 2001, 13:229–242.CrossRefPubMed
19.
Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME: A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993, 119:474–481.CrossRefPubMed
20.
Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB: The neuroinflammatory hypothesis of delirium. Acta Neuropathol 2010, 119:737–754.CrossRefPubMed
21.
Licinio J, Wong ML, Gold PW: Localization of interleukin-1 receptor antagonist mRNA in rat brain. Endocrinology 1991, 129:562–564.CrossRefPubMed
22.
Tarkowski E, Liljeroth AM, Nilsson A, Minthon L, Blennow K: Decreased levels of intrathecal interleukin 1 receptor antagonist in Alzheimer’s disease. Dement Geriatr Cogn Disord 2001, 12:314–317.CrossRefPubMed
23.
Lampa J, Westman M, Kadetoff D, Agreus AN, Le ME, Gillis-Haegerstrand C, Andersson M, Khademi M, Corr M, Christianson CA, Delaney A, Yaksh TL, Kosek E, Svensson CI: Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice. Proc Natl Acad Sci U S A 2012, 109:12728–12733.CrossRefPubMedPubMedCentral
24.
Verstraete K, Koch S, Ertugrul S, Vandenberghe I, Aerts M, Vandriessche G, Thiede C, Sawides SN: Efficient production of bioactive recombinant human Flt3 ligand in E. coli. Protein J 2009, 28:57–65.CrossRefPubMed
25.
Servet-Delprat C, Arnaud S, Jurdic P, Nataf S, Grasset MF, Soulas C, Domenget C, Destaing O, Rivollier A, Perret M, Dumontel C, Hanau D, Gilmore GL, Belin MF, Rabourdin-Combe C, Mouchiroud G: Flt3+ macrophage precursors commit sequentially to osteoclasts, dendritic cells and microglia. BMC Immunol 2002, 3:15.CrossRefPubMedPubMedCentral
26.
Colton CA: Immune heterogeneity in dendritic cells in the brain. J Neuroimmune Pharmacol 2013, 8:145–165.CrossRefPubMed
27.
Xiong W, Candolfi M, Liu C, Muhammad AK, Yagiz K, Puntel M, Moore PF, Avalos J, Young JD, Khan D, Donelson R, Pluhar GE, Ohifest JR, Wawrosky K, Lowenstein PR, Castro MG: Human Flt3L generates dendritic cells from canine peripheral blood precursors: implications for a dog glioma clinical trial. PLoS One 2010, 5:e11074.CrossRefPubMedPubMedCentral
28.
Whartenby KA, Calabresi PA, McCadden E, Nguyen B, Kardian D, Wang T, Mosse C, Pardoll DM, Small D: Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease. Proc Natl Acad Sci U S A 2005, 102:16741–16746.CrossRefPubMedPubMedCentral
29.
Brazel CY, Ducceschi MH, Pytowski B, Levison SW: The FLT3 tyrosine kinase receptor inhibits neural stem/progenitor cell proliferation and collaborates with NGF to promote neuronal survival. Mol Cell Neurosci 2001, 18:381–393.CrossRefPubMed
30.
Dehlin M, Bjersing J, Erlandsson M, Andreasen N, Zetterberg H, Mannerkorpi K, Bokarewa M: Cerebrospinal Flt3 ligand correlates to tau protein levels in primary Sjogren’s syndrome. Scand J Rheumatol 2013, 42:394–399.CrossRefPubMed
31.
Stout-Delgado HW, Yang X, Walker WE, Tesar BM, Goldstein DR: Aging impairs IFN regulatory factor 7 up-regulation in plasmacytoid dendritic cells during TLR9 activation. J Immunol 2008, 181:6747–6756.CrossRefPubMedPubMedCentral
32.
33.
Agrawal A, Agrawal S, Tay J, Gupta S: Biology of dendritic cells in aging. J Clin Immunol 2008, 28:14–20.CrossRefPubMed
34.
Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, Guidi I, Blankenstein MA, Bresolin N, Scarpini E: Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol 2006, 63:538–543.CrossRefPubMed
35.
Xia MQ, Bacskai BJ, Knowles RB, Qin SX, Hyman BT: Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer’s disease. J Neuroimmunol 2000, 108:227–235.CrossRefPubMed
36.
van MG, Henry S, Todoruk T, Sullivan A, Silva C, Rourke SB, Holden J, McArthur JC, Gill MJ, Power C: Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10. Virology 2004, 329:302–318.CrossRef
37.
Jones SA: Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 2005, 175:3463–3468.CrossRefPubMed
38.
39.
Morrow JD, Opp MR: Sleep-wake behavior and responses of interleukin-6-deficient mice to sleep deprivation. Brain Behav Immun 2005, 19:28–39.CrossRefPubMed
40.
Butterweck V, Prinz S, Schwaninger M: The role of interleukin-6 in stress-induced hyperthermia and emotional behaviour in mice. Behav Brain Res 2003, 144:49–56.CrossRefPubMed
41.
Bluthe RM, Michaud B, Poli V, Dantzer R: Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice. Physiol Behav 2000, 70:367–373.CrossRefPubMed
42.
Baier PC, May U, Scheller J, Rose-John S, Schiffelholz T: Impaired hippocampus-dependent and -independent learning in IL-6 deficient mice. Behav Brain Res 2009, 200:192–196.CrossRefPubMed
43.
Bauer S, Kerr BJ, Patterson PH: The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci 2007, 8:221–232.CrossRefPubMed
44.
45.
Ershler WB, Keller ET: Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 2000, 51:245–270.CrossRefPubMed
46.
47.
Strauss S, Bauer J, Ganter U, Jonas U, Berger M, Volk B: Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer’s disease patients. Lab Invest 1992, 66:223–230.PubMed
48.
Papassotiropoulos A, Hock C, Nitsch RM: Genetics of interleukin 6: implications for Alzheimer’s disease. Neurobiol Aging 2001, 22:863–871.CrossRefPubMed
49.
Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, Zubair AC, Dickson D, Golde TE, Das P: Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J 2010, 24:548–559.CrossRefPubMedPubMedCentral
50.
Wyss-Coray T: Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006, 12:1005–1015.PubMed
51.
Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N: A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 2010, 68:930–941.CrossRefPubMed
52.
Plaschke K, Fichtenkamm P, Schramm C, Hauth S, Martin E, Verch M, Karck M, Kopitz J: Early postoperative delirium after open-heart cardiac surgery is associated with decreased bispectral EEG and increased cortisol and interleukin-6. Intensive Care Med 2010, 36:2081–2089.CrossRefPubMed
53.
Munster BC, Aronica E, Zwinderman AH, Eikelenboom P, Cunningham C, Rooij SE: Neuroinflammation in delirium: a postmortem case–control study. Rejuvenation Res 2011, 14:615–622.CrossRefPubMedPubMedCentral
54.
de Rooij SE, van Munster BC, Korevaar JC, Levi M: Cytokines and acute phase response in delirium. J Psychosom Res 2007, 62:521–525.CrossRefPubMed
55.
Ott M, Davis AT, Vanderkolk W, Resau JH, Deheer DH, Jones CB, Stouffer C, Kubek EW: The protective effect of the blood brain barrier from systemic cytokines in an animal femur fracture model. J Trauma 2007, 63:591–595.CrossRefPubMed
56.
Lee YB, Satoh J, Walker DG, Kim SU: Interleukin-15 gene expression in human astrocytes and microglia in culture. Neuroreport 1996, 7:1062–1066.CrossRefPubMed
57.
Gomez-Nicola D, Valle-Argos B, Nieto-Sampedro M: Blockade of IL-15 activity inhibits microglial activation through the NFkappaB, p38, and ERK1/2 pathways, reducing cytokine and chemokine release. Glia 2010, 58:264–276.CrossRefPubMed
58.
Rentzos M, Zoga M, Paraskevas GP, Kapaki E, Rombos A, Nikolaou C, Tsoutsou A, Vassipoulos D: IL-15 is elevated in cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia. J Geriatr Psychiatry Neurol 2006, 19:114–117.CrossRefPubMed
59.
Maclullich AM, Edelshain BT, Hall RJ, de VA, Howie SE, Pearson A, Middleton SD, Gillies F, Armstrong IR, White TO, Cunningham C, de Rooji SE, van Munster BD: Cerebrospinal fluid interleukin-8 levels are higher in people with hip fracture with perioperative delirium than in controls. J Am Geriatr Soc 2011, 59:1151–1153.CrossRefPubMedPubMedCentral
60.
de JW, Prakken BJ, Bijlsma JW, Kuis W, Rijkers GT: Improved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibodies. J Immunol Methods 2005, 300:124–135.CrossRef
61.
Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ: The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab 2011, 31:658–670.CrossRefPubMed
62.
63.
Chuang D, Power SE, Dunbar PR, Hill AG: Central nervous system interleukin-8 production following neck of femur fracture. ANZ J Surg 2005, 75:813–816.CrossRefPubMed
64.
Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze : Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 2010, 68:360–368.CrossRefPubMedPubMedCentral
65.
Pollmacher T, Hinze-Selch D, Mullington J: Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J Clin Psychopharmacol 1996, 16:403–409.CrossRefPubMed
66.
Pollmacher T, Hinze-Selch D, Fenzel T, Kraus T, Schuld A, Mullington J: Plasma levels of cytokines and soluble cytokine receptors during treatment with haloperidol. Am J Psychiatry 1997, 154:1763–1765.CrossRefPubMed
67.
Kim YK, Kim L, Lee MS: Relationships between interleukins, neurotransmitters and psychopathology in drug-free male schizophrenics. Schizophr Res 2000, 44:165–175.CrossRefPubMed
68.
Rapaport MH, Doran AR, Nelson DL, McAllister C, Magliozzi JR, Paul SM: Haloperidol and soluble interleukin-2 receptors. Biol Psychiatry 1991, 30:1063–1064.CrossRefPubMed
69.
Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS: Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun 2006, 20:532–545.CrossRefPubMed
70.
Metadata
Title
Preoperative cerebrospinal fluid cytokine levels and the risk of postoperative delirium in elderly hip fracture patients
Authors
Dunja Westhoff
Joost Witlox
Leo Koenderman
Kees J Kalisvaart
Jos F M de Jonghe
Mireille F M van Stijn
Alexander P J Houdijk
Inge C M Hoogland
Alasdair M J MacLullich
David J van Westerloo
Diederik van de Beek
Piet Eikelenboom
Willem A van Gool
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2013
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-10-122

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