Anticholinergic Activity in Cerebrospinal Fluid and Serum in Individuals with Hip Fracture with and without Delirium Leiv Otto Watne, MD,a,b Roanna J. Hall, MRCP,c,d Espen Molden, PhD,e Johan Ræder, MD, PhD,b,f Frede Frihagen, MD, PhD,g Alasdair M. J. MacLullich, MRCP, PhD,c,d Vibeke Juliebø, MD, PhD,h Armika Nyman, MSc,e David Meagher, MD, PhD,i,j and Torgeir B. Wyller, MD, PhDa,b

OBJECTIVES: To examine whether anticholinergic activity (AA) in cerebrospinal fluid (CSF) and serum is associated with risk of delirium in individuals with hip fracture. DESIGN: Prospective cohort study. SETTING: Two university hospitals in Oslo, Norway, and Edinburgh, UK. PARTICIPANTS: Individuals admitted with acute hip fracture (N = 151). MEASUREMENTS: Participants were assessed daily for delirium using the Confusion Assessment Method (preoperatively and postoperative days 1–5 (all) or until discharge (participants with delirium)). Prefracture cognitive function was assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF at the onset of spinal anesthesia. AA in serum (SAA) and CSF samples was determined according to a muscarinic radio receptor bioassay. The association between AA measures and delirium was evaluated using logistic multivariate analyses. RESULTS: Fifty-two (54%) of the participants in Oslo and 20 (39%) in Edinburgh developed delirium. There was no statistically significant difference in AA between participants with and without delirium in Oslo (serum: 7.02 vs 6.08 pmol/mL, P = .54; CSF: 0.39 vs 0.48 pmol/mL,

From the aDepartment of Geriatric Medicine, Oslo University Hospital, b Institute of Clinical Medicine, University of Oslo, Oslo, Norway; c Edinburgh Delirium Research Group, University of Edinburgh, dCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; eDepartment of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, fDepartment of Anesthesiology, Oslo University Hospital, gDepartment of Orthopedic Surgery, Oslo University Hospital, hDepartment of Cardiology, Oslo University Hospital, Oslo, Norway; iCognitive Impairment Research Group, Centre for Interventions in Infection, Inflammation and Immunity, Graduate Entry Medical School, University of Limerick, and jDepartment of Psychiatry, University Hospital Limerick, Limerick, Ireland. Address correspondence to Dr. Leiv Otto Watne, Department of Geriatric Medicine, Oslo University Hospital, PO BOX 4950, Nydalen, N-0424 Oslo, Norway. E-mail: [email protected] DOI: 10.1111/jgs.12612

JAGS 62:94–102, 2014 © 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society

P = .26) or in Edinburgh (serum: 1.35 vs 1.62 pmol/mL, P = .76; CSF: 0.36 vs 0.31 pmol/mL, P = .93). Nor was there any difference in SAA (Oslo, P = .74; Edinburgh, P = .51) or CSF AA (Oslo, P = .21; Edinburgh, P = .93) when participants were subdivided into prevalent, incident, subsyndromal, and never delirium. Stratifying participants according to prefracture cognitive status (IQCODE) gave the same results. CONCLUSION: This is the first study of AA in CSF of individuals with and without delirium. The study does not support the hypothesis that central (CSF) or peripheral (serum) AA is an important mechanism of delirium in individuals with hip fracture. J Am Geriatr Soc 62:94–102, 2014.

Key words: delirium; cerebrospinal fluid; anticholinergic activity; hip fracture

D

elirium affects approximately 20% of hospitalized individuals.1 Elderly, frail individuals are at particularly high risk of delirium, and an incidence of up to 53% has been reported in individuals with hip fracture.2 Delirium is associated with mortality, risk of institutionalization, future dementia risk, and cognitive decline.3–5 There is no licensed drug treatment, but delirium seems to be preventable in many cases, in medical6 and surgical settings.7 The pathogenesis of delirium is poorly understood.8 Acetylcholine is involved in many of the symptoms that occur in delirium (attention, memory, sleep), and cholinergic deficiency in the brain is widely believed to play a pathophysiological role.9 The observation that use of medications with anticholinergic properties can induce delirium supports this belief.10 In 1980, a bioassay that makes it possible to measure anticholinergic activity (AA) in biological samples as atropine equivalents was developed.11 The assay has been used to assess the association between serum AA (SAA) and cognition. Several studies have found

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an association between high SAA and chronic (dementia and mild cognitive impairment) and acute (delirium) cognitive deficits.12,13 A positive association between SAA and delirium severity has also been reported,14 but there are also studies reporting no such association.15,16 Most studies assessing delirium and SAA are crosssectional, but a study of longitudinal assessments of the relationship between SAA and delirium was recently published.16 Individuals with hip fracture (N = 142) were followed for delirium pre- and postoperatively, and SAA was measured in serum taken at up to four different time points. When adjusting for risk factors, SAA was not associated with delirium. Serum anticholinergic activity measures peripheral AA and might not reflect central AA. The relationship between SAA and AA in the cerebrospinal fluid (CSF) has been assessed in three studies, all finding a significant correlation between SAA and CSF AA,17–19 but the sample sizes were small (54 participants total), and only some of the participants were cognitively assessed.17,19 Few, if any, of the participants developed delirium. Thus, AA in CSF from individuals with delirium has received limited investigation. The aim of this study was therefore to examine the hypothesis that higher anticholinergic activity in CSF and serum is associated with greater risk of delirium in individuals with hip fracture.

METHODS Participants were recruited from Oslo University Hospital, Oslo, Norway, from September 9, 2009, to May 13, 2011, and from the Royal Infirmary, Edinburgh, UK, from September 9, 2009, to April 27, 2011. In Oslo, all participants with proximal femur fractures were suitable for inclusion, regardless of age, prefracture function, cognitive status, and accommodation, including nursing home residents. Individuals were excluded if the fracture was the result of a high energy trauma (defined as a fall from more than 1 m) or the individual was terminally ill. The orthopedic surgeon on call included participants in the emergency room.20 In Edinburgh, individuals aged 60 and older a waiting surgery under spinal anaesthia for repair of a proximal femoral fracture were suitable for inclusion. Individuals were excluded if they had received corticosteroid treatment in the last 10 weeks, had significant communication difficulties or advanced Parkinson’s disease, were nursing home residents, were moribund at admittance, or had significant malignant or comorbid disease such that prognosis was that they had

Anticholinergic activity in cerebrospinal fluid and serum in individuals with hip fracture with and without delirium.

To examine whether anticholinergic activity (AA) in cerebrospinal fluid (CSF) and serum is associated with risk of delirium in individuals with hip fr...
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