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

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

doi:10.1186/1742-2094-10-122

Abstract

BackgroundAging 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.MethodsPatients 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.ResultsSixty-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.ConclusionsOur 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 registrationThe Effect of Taurine on Morbidity and Mortality in the Elderly Hip Fracture Patient.Registration number: NCT00497978. Local ethical protocol number: NL16222.094.07.

Highlights

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
Patients who developed delirium showed more signs of cognitive impairment, both immediately preoperative (MMSE) and before hospital admission (IQCODE-N). These patients were more dependent on caregivers with regard to the activities of daily living (ADL) and instrumental ADL (IADL) functioning
As levels of cytokines tend to fluctuate over time we investigated if time from admission to surgery influenced cerebrospinal fluid (CSF) cytokine levels

Summary

Introduction

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. The pathophysiological mechanism of delirium is largely activity of the innate immune system of the central nervous system (CNS), resulting in an imbalance between pro- and anti-inflammatory cytokines [9]. Microglia show a more reactive phenotype and release increased quantities of cytokines in the brain after peripheral stimulation [9]. This microglial response may be less well-regulated due to reduced cholinergic feedback in older persons, mediating the detrimental effects on prognosis [10]

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