The Influence of Orthopedic Surgery on Circulating Metabolite Levels, and their Associations with the Incidence of Postoperative Delirium.

The mechanisms underlying the occurrence of postoperative delirium development are unclear and measurement of plasma metabolites may improve understanding of its causes. Participants (n = 54) matched for age and gender were sampled from an observational cohort study investigating postoperative delirium. Participants were ≥65 years without a diagnosis of dementia and presented for primary elective hip or knee arthroplasty. Plasma samples collected pre- and postoperatively were grouped as either control (n = 26, aged: 75.8 ± 5.2) or delirium (n = 28, aged: 76.2 ± 5.7). Widespread changes in plasma metabolite levels occurred following surgery. The only metabolites significantly differing between corresponding control and delirium samples were ornithine and spermine. In delirium cases, ornithine was 17.6% higher preoperatively, and spermine was 12.0% higher postoperatively. Changes were not associated with various perioperative factors. In binary logistic regression modeling, these two metabolites did not confer a significantly increased risk of delirium. These findings support the hypothesis that disturbed polyamine metabolism is an underlying factor in delirium that warrants further investigation.

CSF Beta-amyloid 1-42 Concentration Predicts Delirium Following Elective Arthroplasty Surgery in an Observational Cohort Study.

OBJECTIVE: To test the hypothesis that APOE ε4 status and cerebrospinal fluid (CSF) Aß42, T-tau and P-tau would independently predict the risk of postoperative delirium. BACKGROUND: Delirium following surgery is common and associated with adverse outcomes. Age and cognitive impairment are consistent risk factors for postoperative delirium. METHODS: This observational cohort study recruited 282 participants aged 65 years or older, without a diagnosis of dementia, admitted for primary elective hip or knee arthroplasty. Cognitive tests were undertaken preoperatively, blood and CSF were sampled at the time of spinal anesthesia, and participants were assessed daily postoperatively for delirium. RESULTS: Increasing age (P = 0.04), preoperative comorbidity (P = 0.03), type of surgery (P = 0.05), intravenous opioid usage (P = 0.04), and low CSF Aß42 (P < 0.01) were independent predictors of postoperative delirium. CONCLUSIONS: This study is the first to show an independent association between CSF Aß42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease.

Cerebrospinal Fluid Spermidine, Glutamine and Putrescine Predict Postoperative Delirium Following Elective Orthopaedic Surgery.

Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (≥65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 ≤ 0.56; Q2 ≤ 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P < 0.05; FDR < 0.07), and performed well as CSF biomarkers (ROC > 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF Aß42 (ROC > 0.8), and spermidine significantly correlated with Aß42 (pearson r = -0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with Aß42, and this requires further investigation.

Observational cohort study examining apolipoprotein E status and preoperative neuropsychological performance as predictors of post-operative delirium in an older elective arthroplasty population.

Introduction: delirium following surgery is common and is associated with negative outcomes. Preoperative cognitive impairment has been shown to be a risk factor for post-operative delirium. Often the cognitive tests used are cumbersome. This study tests the hypothesis that the quantification of brain vulnerability, using Apolipoprotein E (ApoE) status and neuropsychological tests, both traditional and more easily administered, can quantify the risk of post-operative delirium following elective primary arthroplasty surgery. Methods: this observational cohort study recruited participants aged 65 years or older admitted prior to elective primary hip or knee arthroplasty. Baseline data was collected and participants underwent neuropsychological testing and had blood taken for ApoE genotyping preoperatively. Post-operatively participants were assessed daily for delirium using the Confusion Assessment Method (CAM) and charts were reviewed where possible for reports of delirium. Univariate and multivariate analyses of preoperative factors were undertaken to identify independent predictors of delirium. Results: between March 2012 and October 2014, 315 participants completed the study with an overall incidence of post-operative delirium of 40/315 (12.7%). Of these 18 fulfilled the CAM criteria for delirium and 22 were deemed delirious by consensus decision based on chart review. ApoE genotype was not associated with post-operative delirium in this cohort. Time taken to complete Colour Trails 2, errors in mini mental state examination and level of pain preoperatively were independent predictors of post-operative delirium. Conclusions: this study challenges the assertion that ApoE4 genotype predicts post-operative delirium. It replicates previous work suggesting cognitive impairment predicts post-operative delirium and shows for the 1st time that simple cognitive tests can be as effective as more detailed tests.

Differential region-specific regulation of central alpha 1-adrenoceptor binding following chronic haloperidol and clozapine administration in the rat.

RATIONALE: Many antipsychotics exhibit potent anti-alpha(1)-adrenergic receptor activity, which has been suggested to contribute to typical and atypical antipsychotic effects and to the production of centrally mediated side effects. OBJECTIVES: To assess the relative contribution of alpha(1)-adrenoceptors to the mechanism of action of haloperidol and clozapine and to identify possible sites of action. METHODS: We examined the effect of chronic haloperidol and clozapine treatment on alpha(1)-adrenoceptor characteristics in several rat brain regions. For comparison, D(2)-like dopamine receptor density in the striatum was also determined. RESULTS: Clozapine administration (25 mg/kg/day i.p., 21 days) significantly increased alpha(1)-adrenoceptor density in the frontal cortex (44%), remaining cortex (49%) and thalamus (93%) but binding levels in the hippocampus and spinal cord were unchanged relative to vehicle. Haloperidol treatment (1.5 mg/kg/day i.p., 21 days) also significantly increased the density of alpha(1)-adrenoceptor binding in the thalamus (73%), but had no effect on alpha(1)-adrenoceptor levels in any other region examined. alpha(1)-Adrenoceptor affinity in the cortex was not significantly altered by either antipsychotic treatment. Haloperidol, in contrast to clozapine, significantly upregulated dopamine D(2)-like binding in the striatum. CONCLUSIONS: Central alpha(1)-adrenoceptors are differentially regulated after chronic haloperidol and clozapine treatment. It is suggested that thalamic alpha(1)-adrenoceptors may represent a common anatomical locus contributing to the antipsychotic activity and/or alpha(1)-adrenoceptor centrally mediated side effects of both drugs, whereas the selective upregulation of cortical alpha(1)-adrenoceptor density by clozapine may contribute, in part, to its superior atypical properties.