David A Scott Associate Professor St Vincent s Hospital Melbourne

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1 David A Scott Associate Professor St Vincent s Hospital Melbourne

3 2012 Controlled Quiet? Stress-free

4 What is Anaesthesia? Balanced General Anaesthesia Hypnosis Analgesia Amnesia Muscle Relaxation General Anaesthesia Lack of (Conscious) Sensation Lack of Awareness Medically Induced COMA

5 The brain is the target organ Volatile agents Intravenous anaesthetics Opioids Benzodiazepines

animal models Alcohol (Ethanol) Adult Wernicke s Encephalopathy, Cerebral atrophy Foetus - Foetal

6 Toxicity of CNS Depressants Volatile Substance Abuse Petrol (gasoline) / Glue / Paint solvents (toluene) Acute - excitation / death Chronic - Long term cognitive dysfunction Reproducible in animal models Alcohol (Ethanol) Adult Wernicke s Encephalopathy, Cerebral atrophy Foetus - Foetal alcohol syndrome Combined NMDA antagonism and GABAA agonism Why expect that anaesthesia is inconsequential?

7 Perioperative Neurotoxicity - Neonatal What risk for the elderly?

8 Postoperative Cognitive Dysfunction (POCD) Subtle changes in neuropsychological (cognitive) function which follow surgery and anaesthesia

9 Cognitive function 100 POCD 0 Pre-surg Day 7 Day 90 Surgery & Anaesthesia

Neurologic and Neuropsychological Morbidity Following Major Surgery: Comparison of Coronary Artery Bypass and Peripheral Vascular Surgery Pamela J.

10 Neurologic and Neuropsychological Morbidity Following Major Surgery: Comparison of Coronary Artery Bypass and Peripheral Vascular Surgery Pamela J. Shaw, MRCP, et al. Discharge post-surgery Coronary Bypass (n=312) Non Cardiac (n=50) Neurological 61% 18% Neuropsychological 79% 31% Severe 24% 0% (Stroke 1987;18: )

11 Cardiac Surgery The Heart Lung Machine 1970 s / 80 s CVA 1 3% Cerebral Oedema (Pump Brain) Microemboli 1990 s onwards Biocompatible circuits Arterial filters

12 The Heart-Lung Machine Van Dijk et al JAMA 2002; 287:

13 Off-Pump versus On-Pump Cognitive Decline Off-Pump (n=142) On-Pump (n=139) 3-months 21% 29% RR 0.65 [95% CI ] P= months 30.8% 33.6% RR 0.88 [95% CI ] P=0.69 Van Dijk et al JAMA 2002; 287: Cognitive Decline Off-Pump (n=58) On-Pump (n=166) 1-week 55% 47% P=0.283 Liu et al Anesth Analg 2009 : 109(4): Factors other than CPB may cause cognitive decline after CABG anaesthetic type or surgical trauma could be a cause of cognitive decline

14 Off-pump vs On-pump NEJM 366;16 nejm.org april 19, 2012

Type of Anaesthetic and POCD 1 Week 3 Months 12 Months Low Dose Fentanyl (n=168) 35/148 23.

8% p-value 0.031 0.24 0.62 Silbert B, Scott D, Evered L et al. The ANTIPODES study.

anaesthesia for on-pump cardiac surgery (n=117) A sevoflurane-based anaesthesia was associated with

15 Type of Anaesthetic and POCD 1 Week 3 Months 12 Months Low Dose Fentanyl (n=168) 35/ % 20/ % 24/ % High Dose Fentanyl (n=158) 19/ % 19/ % 18/ % p-value Silbert B, Scott D, Evered L et al. The ANTIPODES study. Anesthesiology (2006) 104(6): Cognitive function after sevoflurane- vs propofol-based anaesthesia for on-pump cardiac surgery (n=117) A sevoflurane-based anaesthesia was associated with better short-term postoperative cognitive performance than propofol esp. in the presence of cerebral desauration Schoen et al. BJA 106 (6): (2011)

Depth of Anaesthesia Cerebral Protection Barbiturates Propofol Hypothermia Anaesthetic Depth as a Predictor of Adverse Outcomes Cumulative MAC Monk T et al.

16 Depth of Anaesthesia Cerebral Protection Barbiturates Propofol Hypothermia Anaesthetic Depth as a Predictor of Adverse Outcomes Cumulative MAC Monk T et al. Anesth Analg 2005; 100: 4-10 Kertai M et al. Anesthesiol 2010; 112: Triple Low Saager L, Sessler D et al. Anesthesiol 2009; 111: A880 Not associated with POCD Steinmetz et al. (2010). Acta Anaesthesiol Scand 54(2):

17 Regional Anaesthesia versus General Anaesthesia - ISPOCD Regional General One week 12.5% 19.7% 3 months 13.9% 14.3% Rasmussen L, et al. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand, 2003;47:

18 Cardiac, Non-cardiac and Regional 3 months CABG % Keizer AM, Hijman R, Kalkman CJ, et al. Acta Anaesthesiol Scand 2005;49: Silbert BS, Scott DA, Evered LA, et al. Anesthesiology 2006;104: Non-cardiac % Moller JT, Cluitmans P, Rasmussen LS, et al. Lancet 1998; 351: Monk TG, Weldon BC, Garvan CW, et al. Anesthesiology 2008;108:18 30 RA 13.9% Rasmussen L, Johnson T, Kuipers HM, et al. Acta Anaesthesiol Scand, 2003;47:

19 POCD incidence Control CABG THJR n=34 n=312 n=161 Day 7 6% 43% 17% CA n=167 3 mths 0% 16% 16% 21% Evered LA, Scott DA, Silbert BS, Maruff P. Post Operative Cognitive Dysfunction is Independent of Type of Surgery and Anesthetic. Anesthesia & Analgesia 2011; 112( 5):

20 POCD Impact Un-noticed subjective complaints Length of Hospital Stay Prolonged No POCD 7.1 ± 3.4 days POCD 8.3 ± 4.1 days (p=0.02) Silbert B et al Anesthesiology 104(6): Quality of Life Reduced Steinmetz, J et al. (2009) Anesthesiology 110(3): Mortality Increased Monk, T. et al. (2008). Anesthesiology 108(1): Possibly of limited duration But 5 year association Newman N Engl J Med 2001;344:

21 Postoperative Cognitive Dysfunction (POCD) Subtle changes in neuropsychological (cognitive) function which follow surgery and anaesthesia Early POCD Acute Pharmacological & Physiological Response Late POCD Result of Prolonged stimulus in susceptible individuals Who is susceptible?

22 POCD Early temperature Stress microemboli Anaesthesia POCD perfusion age inflammation education genetic

23 POCD Late temperature Stress microemboli anaesthesia perfusion POCD age Inflammation education genetic

24 Stress

Cushing s syndrome Loss of diurnal variation associated with POCD Rasmussen, L. S., J. T. O'Brien, et al. (2005).

25 Stress Hippocampus has high levels of glucocorticoid receptors Stress responses Reducing excitability (pyramidal cells) Inhibiting neuronogenesis (dentate gyrus) Triggering dendritic atrophy (pyramidal cells) Hippocampal atrophy in PTSD, Cushing s syndrome Loss of diurnal variation associated with POCD Rasmussen, L. S., J. T. O'Brien, et al. (2005). "Is peri-operative cortisol secretion related to post-operative cognitive dysfunction?" Acta Anaesthesiol Scand 49(9):

26 Inflammation and Surgery Kragsbjerg et al Eur J Surg 1995; 161: IL-6, IL-8, Interleukin 1-b, TNF-a

27 Anaesthesia Drugs MIC Stress Psychological Physiological Inflammation

28 It s not just the drugs (our drugs ) Pharmacological neurotoxicity Physiological stress response Inflammatory responses Resilience Cognitive Reserve

29 The Ageing Brain Post-Operative Cognitive Dysfunction (POCD) Consistently associated with increased age Decreased Cognitive Reserve POCD inversely associated with IQ Pre-operative Cognitive Impairment (PreCI) and POCD Chronic Neurodegenerative Processes Vascular disease and vascular dementia Alzheimer s Disease

30 Why does this matter to anaesthesia? Australia (2010) 13% population are 65 years or older The elderly receive 37.5% of anaesthetics A growing proportion of our patients may be at risk

31 1,023,052 48% Australian Institute of Health and Welfare

32 Second International Perioperative Neurotoxicity Workshop Toronto, June 15 th, 2010 It is fair to say at this point that considerable experimental evidence provides plausibility for anaesthesia and surgery to independently cause durable cognitive decline after either neonatal or elderly exposure, and that molecular mechanisms may be operant Eckenhoff RG. Anesth Analg 2011; 112:

33 Jack et al. Lancet Neurology, 2010 vol:9 iss:1 pg:

34 Hippocampus (Olfaction) Memory encoding Long Term Potentiation Spatial coding Place Cells (rats) Navigation Cognitive map

35 Beta-Amyloid Peptide (Ab)

degeneration and neurofibrillar tangles (NFT) Protective

36 Tau Protein Tau intraneuronal microtubular transport proteins Tau phosphorylation eventually leads to microtubular degeneration and neurofibrillar tangles (NFT) Protective Protein Phosphatase 2A reduced in AD patients Tau-opathies in other diseases

37 Jack et al. Lancet Neurology, 2010 vol:9 iss:1 pg:

38 Preexisting Cognitive Impairment (PreCI) Mild Cognitive Impairment (MCI) MCI PreCI Subtle Subtle Non-Surgical* Surgical Transitional? Transitional 10-15% general population 19-35% surgical population Leads to Alzheimer s Disease May be PreCI May lead to POCD May be MCI Petersen, R et al. Arch Neurol, (12): p Silbert,B. Scott,D. Evered,L et al. Anesth Analg 2007; 104:

Dementia 250,000 Australians have dementia 1 million individuals are directly affected 10 15 % population

39 Dementia 250,000 Australians have dementia 1 million individuals are directly affected % population - Mild Cognitive Impairment (MCI) MCI leads to Dementia (10 x rate of progression) Access Economics (2008)

40 Why does this matter to anaesthesia? Australia (2010) 13% population are 65 years or older The elderly receive 37.5% of anaesthetics A growing proportion of our patients will be at risk We are not screening for cognition MCI / PreCI Anaesthesia is possibly implicated in the pathogenesis of Alzheimer s disease

Pre-existing Cognitive Impairment and Mild Cognitive Impairment in Subjects

41 Preexisting Cognitive Impairment (PreCI) Mild Cognitive Impairment (MCI) n = 162 Evered LA, Silbert BS, Scott DA, Maruff P, Ames D, Choong P. Pre-existing Cognitive Impairment and Mild Cognitive Impairment in Subjects Presenting for Total Hip Joint Replacement. Anesthesiology 2011 ; 114 (6):

42 Perioperative Neurotoxicity - Elderly Sevoflurane Induces apoptosis, Amyloid PP processing and increases Ab protein (mice) Xie Z. et al Anesthesiology 2006;104: Increased neurotoxicity and neuroinflammation (tnf-a) Lu Y et al Anesthesiol 2010; 112: 1404 Isoflurane Behavioural changes (rats / mice) medium-term learning deficits Culley DJ, Crosby G et al. Anesthesiology 2004;100: Tau hyperphosphorylation Planel E et al J Neurosci 2007;27:3090 7

43 Inflammation - Activated Microglia Nature Medicine - 12, (2006)

44 Does anaesthesia exacerbate conversion to dementia? Avidan et al Methods Analysis of Dementia Clinic Database 575 patients: 214 initially non-demented; 361 very mild/mild dementia Coded for: surgery / illness / nil Outcomes Demented patients progressed faster 23% conversion for nondemented No association with procedure Limitations Retrospective Non-standard POCD definition Heterogenous timing Group analysis Avidan, M. et al. (2009). Anesthesiology 111(5):

45 Does Anaesthesia or Surgery Exacerbate Progression to Dementia? 9% patients 1y following Non-cardiac surgery Expectation 1-2% 10% patients 1y following Sedation Expectation 1-2% 22% patients 5y 7y following Cardiac surgery Expectation 5-10% Data from preliminary analysis CACF data set

46 Inflammation and Cognition Eckenhoff et al, Prog Neuro-Psychopharm Biol Psychiatry (2012), epub

47 Anaesthesia Drugs MIC Improve! Early POCD Delirium Dementia Risk Stress Psychological Physiological Late POCD Inflammation

48 Anaesthesia may be good Cognitive Improvement General anesthesia with isoflurane and nitrous oxide improves spatial memory in young rats (not aged rats) Culley, D. J., M. Baxter, et al. (2003) Anesth Analg 96(4): Isoflurane anaesthetised mice showed better cognitive performance 1 day later than controls Increased hippocampal NMDA expression and LTP Effect blocked by NMDA antagonist Rammes, G., L. K. Starker, et al. (2009) Neuropharmacology 56(3): Isoflurane Preconditioning is protective Wei H, Liang G, Yang H. Isoflurane preconditioning inhibited isoflurane-induced neurotoxicity. Neurosci Lett 2007;425:59 62 No difference in CEA GA versus LA trial in UK The Lancet, 372, (9656)p , 20 December 2008 Middle aged is good Young adult (60 d) rats improved performance cf infant rats after isoflurane anaesthesia Stratmann, G., J. W. Sall, et al. (2009) Anesthesiology 110(4):

1%] Ab oligomerisation; apoptois; long term memory Sevoflurane Harmful: [6h 3%] Ab increased;

49 Type of anaesthetic agent Limited for POCD Differences in laboratory indices for AD Isoflurane Protective: Low concentration / short duration Harmful: [6h or > 2.1%] Ab oligomerisation; apoptois; long term memory Sevoflurane Harmful: [6h 3%] Ab increased; neurotoxicity increased Desflurane No harm with 12% for 6h Nitrous Oxide No harm 70% for 6h Propofol No APP processing effects May protect against Isoflurane

50 Perioperative Cognitive Screening Aim: To flag concern not to make a bedside diagnosis What tools are appropriate? Effective Reliable Convenient

51 Cardiac evaluation and care algorithm for noncardiac surgery Fleisher L A et al. Circulation 2007;116:e418-e500 Copyright American Heart Association

graded severity 20 45 mins Computerised tests Camcog / Cantab Cogstate

52 Screening Tools for Cognition Cognition PreCI / MCI / Dementia GP-Cog Primary care 4 to 5 mins MMSE (or AMTS) Widely used 5 minutes ADAS-Cog graded severity mins Computerised tests Camcog / Cantab Cogstate 15 to 20 mins Future Cognitive Reserve Evaluation Tool Rapid Assay Biomarkers

53 The value of screening Advise on expectations Informed Consent Reconsider elective procedures Critically evaluate non-elective procedures Modify surgery Modify anaesthesia Follow-up Clinical Referral Diagnostic opportunities Protective strategies

54 Anti-Inflammatory Drugs Complex TNF-a antagonists etanercept, infliximab Simple NSAIDs Non-specifc Known risk profile Steroids Lignocaine

55 Anaesthesia and the Adult Brain Early POCD Largely reversible Significant impact on some patients Late POCD - Long-term effects Targets vulnerable individuals Dementia Preoperative assessment of cognitive reserve Collaborative research Improve outcomes

56 Executive Members: Lis Evered (Chair) David Scott Rod Eckenhoff Greg Crosby Zhong-Cong Xie

57 Research imperative for this decade

Preventing Postoperative Cognitive Decline in the Elderly

Preventing Postoperative Cognitive Decline in the Elderly Alex Bekker, M.D., Ph.D Professor and Chair Department of Anesthesiology Rutgers New Jersey Medical School "My brain, that's my second favorite