Questions to be Addressed. Cognitive Decline after Surgery. Post Operative Cognitive Dysfunction 9/22/2012

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1 Questions to be Addressed Cognitive Decline after Surgery Dr Mervyn Maze MB ChB, FRCP, FRCA, FMedSci William K Hamilton Distinguished Professor of Anesthesia Chair, Department of Anesthesia and Perioperative Care, What is the Clinical Condition of Postoperative Cognitive Dysfunction (POCD)? What is the pathogenesis for POCD? Why does POCD not occur in all patients if trauma-induced inflammation is the cause? Why are Metabolic Syndrome patients at higher risk for POCD? University California San Francisco 1 2 Post Operative Cognitive Dysfunction Possible risk factors*» Age» Duration of anaesthesia» Second operation» Post-operative infections» Respiratory complications *Moller JT et al, Long-term postoperative dysfunction in the elderly. ISPOCD 1 Study Lancet 1998; 351:

2 P e r c e n ta g e (% ) Post Operative Cognitive Dysfunction Incidence Early Controls Patients Late *Moller JT et al, Long-term postoperative dysfunction in the elderly. ISPOCD 1 Study Lancet 1998; 351: International Study of Post Operative Cognitive Dysfunction (ISPOCD)Moller, J.T. et al The Lancet 1998; 351: patients aged at least 60 years undergoing major noncardiac surgery with general anaesthesia 25.8% of patients had POCD one week after surgery; 9.9% persisted 3 months postop Risk Factor: Infection Age as a Predictor of cognitive dysfunction after major noncardiac surgery Monk, T.G. et al Anesthesiology 2008; 108(1): patients undergoing major non-cardiac surgery with general anaesthesia 36.6% (18-39 yr), 30.4% (40-59 yr), 41.4% (>60 yr) patients had POCD at hospital discharge and 5.7%, 5.6% and 12.7% at 3 months postop respectively 6 Projection of the U.S. Population by Age Regional vs General: No Influence on Prevalence of POCD Population in millions Ages 85+ Ages Ages Bigler D et al. Mental function and morbidity after acute hip surgery during spinal and general anaesthesia Anaesthesia 1985; 40: Campbell DNC et al. A prospective randomized studyof local vs general anaesthesia for cataract surgery Anaesthesia 1993; 48: Ghoneim MM et al. Comparison of Psychologic and cognitive functions after general or regional anaesthesia Anesthesiology 1988; 69: Jhones MJT et al. Cognitive and functional competence after anaesthesia in patients aged over 60: controlled trial of general and regional anaesthesia for elective hip or knee replacements British Med. J. 1990; 300: Nielson WR et al. Long-term cognitive and social sequelae of general versus regional anesthesia during arthroplasty in the elderly. Anesthesiology 1990; 73: Williams-Russo P et al. Cognitive effects after epidural vs. general anesthesia in older adults. A randomised trial J. of the Amer. Med. Association 1995; 274:

3 Postoperative Cognitive Dysfunction Impairment established by Variety of cognitive tests No consensus on diagnostic criteria Use arbitrary statistical thresholds Risk Factors that increase Prevalence Age Infection Metabolic Syndrome Is POCD a Validated Clinical Construct? Avidan et al: Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness. Anesthesiology 2009 Avidan MS, Evers AS: Review of clinical evidence for persistent cognitive decline or incident dementia attributable to surgery or general anesthesia. J Alzheimers Dis 2011 Long-term consequences Loss of Job and/or independence Higher Mortality Rate Selnes et al:cognitive and Neurologic outcomes after coronary-artery bypass graft surgery. NEJM CAD patients with or without surgery, have similar cognitive decline Is POCD a Validated Disease? Cognition Anesthesia Surgery? Normal population At-risk population At-risk population with surgery? Age in Years Selnes et al Ann Thorac Surg

4 Animal model of Postoperative Cognitive Decline Projected Growth of Arthroplasty Surgery in the USA Why Overcome problem of controls Establish the independent contributions Anesthesia Surgery Validated by enhanced vulnerability Age Infection Metabolic Syndrome J Bone Joint Surg Am. 2007;89: Orthopedic Surgical model

5 Trace Fear Conditioning Surgery induces memory deficit in mice Contextual trace fear conditioning, POD 3 Cibelli M et al, Ann Neurol Peripheral Surgery Disrupts the Blood Brain Barrier Terrando et al, Annals of Neurology, 2011 S MLA+S Anesthesia Anesthesia + Surgery

6 Circulating macrophages penetrate into the hippocampus shortly after surgery Aseptic Trauma-induces Hippocampal Neuroinflammation that results in Transient Postoperative cognitive decline (PCD) DAPI CCR2 LTP disruption Cytokine release Terrando et al, Annals of Neurology, 2011 Glial activation Surgery-induced neuroinflammation Increase of IL s and PGE2 in the CSF» Buvanendran A et al, Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology. 2006;104(3): Increase of IL-6 in CSF after OP Coronary Artery Bypass Grafts» Kalman J et al, Elevated levels of inflammatory biomarkers in the cerebrospinal fluid after coronary artery bypass surgery are predictors of cognitive decline. Neurochem Intern 2006; 48: Does generation of trauma-induced brain inflammation produce a survival benefit to the injured organism? Pro-inflammatory cytokines in the Brain Fever Anorexia Lethargy Cognitive Decline Disinclination to indulge in procreative behavior Stay in cave Protected from predators Further injury 24 6

7 What causes the neuroinflammation to stop? Nathan and Ding, Cell, What causes persistent neuroinflammation? Continuing Provocation Perioperative infection Underlying Neurologic Disease Stroke Neurodegenerative Disorders Failure of Inflammation Resolving Mechanisms Prevention of Resolving Mechanism Enhances Postoperative Neuroinflammation Naive PHA S Surgery Alone Surgery + α7nachr antagonist Terrando et al, Annals of Neurology,

8 % freezing Surgery-induced cognitive decline is exaggerated by disrupting, and ameliorated by facilitating, resolution * * *** Human Risk Factors can be reproduced in animal model Infection exacerbates surgery-induced cognitive decline (Fidalgo et al Neurosci Letts 2011) Surgery-induced cognitive decline is enhanced with advanced age (Roszyk et al Exp Gerontol 2008) Metabolic Syndrome 0 N MLA PHA S MLA + S PHA + S Terrando et al, Annals of Neurology, Metabolic Syndrome Patients are Particularly Vulnerable to POCD Low Capacity (LCR) vs High Capacity Runner (HCR) Rats

9 Acute Postoperative Cognitive Decline is exacerbated in Metabolic Syndrome Morris Water Maze (MWM) test Path to locate submerged platform Swimming Speed is similar Pool for Water Maze Test 30 cm 1.5 m

10 Postoperative learning dysfunction persists at 5 months Time to locate platform in MWM Postoperative memory dysfunction persists at 5 months - MWM probe trial?

11 The exaggerated & persistent postoperative cognitive decline in Metabolic Syndrome is associated with dysfunction of the innate immune response LPS-stimulation of circulating immunocytes release more pro-inflammatory Cytokines in Rats with MetaS both pre and postoperation 1000 ** TNF-α levels in the Media (pg/ml) ** The exaggerated innate immune response in Metabolic Syndrome is associated with dysregulation of inflammation-resolution Cholinergic inhibition of LPS-stimulated TNF-α release is attenuated in the Metabolic Syndrome TNF-α change (%)

12 Postoperatively, LCR rats produce less inflammation-resolving Lipoxin A4 but more inflammation-enhancing leukotriene B4 Summary of Results with LCR vs HCR rats LCR rats have enhanced neuroinflammation and more severe and persistent cognitive decline LCR rats have disrupted α7 nachr-mediated inflammation-resolution mechanism cellular components are reduced cellular responses are reduced cellular ratios are inverted LCR rats have qualitatively different humoral inflammation-resolving response to surgery Are these results extrapolatable to Clinical Condition of POCD? Evidence for systemic and neuroinflammatory response to elective orthopedic surgery Immune system homeostatic mechanisms are less effective with advancing age Infection represents a second inflammatory hit that overwhelms resolving mechanism Metabolic Syndrome is characterized by disorder of resolution of inflammation and of abnormality in cholinergic function 47 Clinical Questions Can we prospectively identify surgical patients that will not resolve postoperative neuroinflammation and cognitive decline? Can we promote resolution of postoperative inflammation in patients that are at risk? Does failure to resolve inflammation produce other postoperative complications? Conversion from acute to chronic postoperative pain Thrombo-embolism Infection 48 12

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