post operative cognitive dysfunction

as the life expectancy has increased. more and more elderly patients are undergoing surgery. the burden of postoperative dysfunction has to be increased in future. There should be attempt to identify the risk factors and measures to prevent POCD.

1. Confused mind: Post operative cognitive dysfunction Dr. Priyanka Gupta Associate Professor, Deptt . Of Anaesthesia AIIMS Rishikesh

2. Cognition Invisible activities carried out by the brain P erceiving Analyzing R easoning Judging Generating ideas Remembering T hinking Insight

3. MR. A says that 6 month back his 70 year old father underwent hip replacement surgery. After the surgery he is not “The same” “He forgets things and will ask the same thing several times” He says, father was sharp as a tack before the operation. “He’s more like 80 % of him now” What went wrong with this patient?

4. Post operative cognitive dysfunction First described by Bedford in 1955 (The Lancet) as “ Adverse cerebral effects of Anaesthesia on old people” No universally accepted definition There is no International Statistical Classification of Disease code POCD is a neurodegenerative condition, acquired after surgery and anaesthesia , and is similar to Alzheimer’s disease (AD) in symptoms and risk factors . POCD- a form of cognitive dysfunction that begins between seven days to one year after surgery British Journal of Anaesthesia , 119 (S1): i115–i125 (2017)

5. Postoperative cognitive dysfunction Subtle condition, lack of clinical symptoms Memory & concentration domains affected Visuospatial perception, motor skills and executive function are affected Consciousness unaffected Last weeks to months Usually reversible

6. Incidence/ Prevalence ~ 40% of Patients of >60 year, hospitalized for major non cardiac surgery have POCD at discharge ~ 10% have POCD, three months later Anesthesiology. 2008 Jan;108(1):18-30 ~30-50% of patients, underwent cardiac surgery had POCD with first 6 weeks 10-50% of patients, had persisting dysfunction at 6 months Acta Anaesthesiol Scand. 2010 July ; 54(6): 663–677. ~25-30% patient developed POCD following CEA (no difference in regional/GA) Anesth Analg . 2008 Aug; 107(2): 636–642.

7. POCD following noncardiac surgery ISPOCD-1 (1998), 1218 elderly patients, 25% of patients developed POCD at 1 week, 10% at 3 months No correlation with intraoperative hypotension or episodes of low spo2 There is correlation of POCD with increasing age and longer duration of surgery ISPOCD-2 (2001) Postoperative cognitive dysfunction was detected in10—20% of patients at 1week and after 3months No significant difference between general and regional anaesthesia using the intention to treat approach (p=0.06 at 1week)

8. Risk factors for POCD Patient Surgery Anaesthesia Advanced age Extensive surgical procedure Extensive surgical procedure Pre-existing cerebral/cardiac/vascular disease Intra/post op complications Marked disturbance in homeostasis Preoperative cognitive impairment Secondary surgery Hypoxia/ hypoperfusion Low education level Intra/post op anaesthesia related complications Alcohol abuse Nutritional deficiency Apo lipoprotein E genotype

9. 6 minute walk test

10. Classification Acute POCD Develops with in a week of surgery (associated with higher mortality) Intermediate POCD Develops within 3 months following surgery (most common) Long term POCD/persistent POCD Develops 1-2 year following surgery 1% of patients have persistent POCD

11. Pathophysiology of POCD Peripheral initiation of inflammation Disruption of Blood-Brain-Barrier Microglial activation Oxidative stress Cholinergic anti inflammatory pathway

12. Peripheral initiation of inflammation Aseptic Surgical trauma, initiates inflammation at surgical site, which is amplified via peripheral pro-inflammatory cytokines

13. Disruption of Blood- Brain-Barrier and microglial activation Peripheral pro-inflammatory cytokines disrupt the blood brain barrier via COX-2 upregulation. This allows entry of inflammatory cytokines into the CNS. This setting activates microglial cells, which have proinflammatory and phagocytic property.

14. Role of oxidative stress

15. Cholinergic anti-inflammatory pathway “ Vagal reflex arc” Limit the degree of inflammation and protect organ systems from further damage

16. Diagnosis of POCD No real consensus of what tests define POCD in the literature Battery of tests available to measure cognition MMSE- sub optimal for POCD Montreal cognitive assessment ( MoCA )- sensitive to POCD Cognistat Postoperative quality recovery scale (PQRS) Clock in the box (CIB)

17. Tests to assess cognitive function Test Description Cognitive domain Ray Auditory verbal learning test Word learning test Verbal learning, recall and recognition Digit span test Ability to remember a sequence of numbers Working memory Digit symbol substitution test Copying symbols according to a predefined order in an answer key Working memory and information processing speed Stroop test Reading a list of colour names printed in incongruous colours Attention, concentration and executive function Grooved peg board test Placing 25 keyed pegs in an array of 5X5 holes with randomly positioned slots as quickly as possible Manual dexterity and psychomotor coordination Trail making test Joining number and letters in alternate order as quickly as possible Attention, sequencing, mental flexibility, visual search, motor function

18. Digit span test ( ability to remember a sequence of numbers ) Stroop test

19. Trail making test Grooved peg board test

20. Montreal cognition assessment Clock drawing test

21. Baseline performance To assess an actual change in cognition following surgery Performance of patient will be affected, if done after admission or on the day of surgery due to anxiety. Ideally should be performed 1-2 week prior to surgery, when patient visits for preanesthetic assessment Test should be validated for the language in which they will be administered Assessment of cognition in postoperative period Pain, drugs, immobility, PONV and fatigue may affect test performance POCD is diagnosed ≥2 SD decline in at least two of the cognitive domains

22. Perioperative cognitive trajectory

23. Prevention of POCD Preoperative optimization/ Prehabilitation Preoperative physical exercise Inspiratory muscle training Control of cardiovascular risk factor Nutritional optimization Vitamin B12/Folic acid/Homocysteine Vitamin D Correcting Anaemia Correcting electrolyte imbalance (Mg +2 ) Cognitive prehabilitation

24. Intraoperative strategy to prevent POCD Avoidance of prolonged fasting Avoidance of sedative premedication Balanced anaesthesia technique Use of short acting opioid Optimal depth of anaesthesia (BIS 40-60) GA vs Regional- no difference Maintenance of adequate cerebral oxygenation Avoidance of benzodiazepines and anti-cholinergic drugs Dexmedetomidine/ketamine- reducing POCD Avoiding Hypoxia/hypotension/hypothermia

25. Drugs with potential neurological effect (inappropriate to use in older patients)

26. Postoperative strategy Multi component non pharmacological intervention Early mobilization & exercise Cognitive stimulation Support of circadian rhythms Sleep protocol Good hygiene Vision & hearing aid (if required) Avoidance of high risk drugs Avoidance of polypharmacy

27. Postoperative pain management Non opioid strategy (Gabapentin, paracetamol, NSAIDS) Regional anaesthesia/ nerve blocks Removal of Foley’s catheter as early as possible Maintenance of electrolytes

28. Novel therapies to treat/prevent POCD COX-2 inhibitor (Parecoxib) COX- 2 selective anti inflammatory drug Reduces microglial activation Thus reduces neuroinflammation (primary mechanism of POCD) Few studies have shown reduction in incidence and severity of POCD with perioperative use of parecoxib ( Zhu, Y.-Z., Yao, R., Zhang, Z., Xu, H., & Wang, L.-W. (2016). Parecoxib prevents early postoperative cognitive dysfunction in elderly patients undergoing total knee arthroplasty. Medicine, 95(28),

29. Statins HMG-CoA reductase (rate limiting enzyme) Inhibiting conversion of HMGCR into Mevalonic acid Downregulation of NADPH Production Reducing oxidative stress Shown beneficial effects in the patients undergoing carotid endarterectomy by minimizing POCD ( Heyer , Eric J., Mergeche , J. L., Wang, S., Gaudet, J. G., & Connolly, E. S. (2015). Impact of Cognitive Dysfunction on Survival in Patients With and Without Statin UseFollowing Carotid Endarterectomy. Neurosurgery, 77(6), 880–887 )

30. Pregabalin Anti-convulsant drug Binds to α 2 δ subunit of voltage gated calcium channel These channels are prominently expressed in hippocampus By binding to these channel, pregabalin alters the release of neurotransmitter Moderates microglial activation and downregulate cytokine production Promising result in preclinical data Conflicting role in improving cognition in humans Might itself affect cognition

31. Dexmedetomidine Selective α2 receptor agonist Selectively binds at locus coeruleus at brain stem Suppresses release of spinal adrenaline and noradrenaline Intraoperative use of dexmedetomidine has shown to reduce incidence and severity of POCD Reduces inflammatory markers and s100 β protein level ( Ge, Y.-L., Li, X., Gao, J. U., Zhang, X., Fang, X., Zhou, L., … Lin, S. (2016). Beneficial effects of intravenous dexmedetomidine on cognitive function and cerebral injury following a carotid endarterectomy. Experimental and Therapeutic Medicine, 11(3),1128–1134)

32. Ketamine Anaesthetic agent with hypnotic/analgesic/amnesiac property NMDA receptor antagonist Moderate inflammatory macrophages activation Reduces production of inflammatory cytokines Synaptogenesis effect Has shown significant protective cognitive effect in few studies ( Hudetz , J. A., Iqbal, Z., Gandhi, S. D., Patterson, K. M. (2009). Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiologica Scandinavica , 53(7), 864–872)

33. Lignocaine Binds to voltage gated sodium channels Significant reduction in levels of IL-8 and CRP in humans ( The in vitro mechanisms and in vivo efficacy of intravenous lidocaine on the neuroinflammatory response in acute and chronic pain. European Journal of Pain, 20(5), 655–674. May improve cognitive function in post operative period ( Neuroprotective effects of intravenous lidocaine on early postoperative cognitive dysfunction in elderly patients following spine surgery. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 21, 1402–1407 .

34. Minocycline Tetracycline group of antibiotic, commonly used to treat acne Highly fat soluble, easily cross BBB Has anti-inflammatory and microglial inhibitory properties Reduces excitotoxicity Minocycline may have potential for prevention and treatment of POCD

35. N-acetyl cysteine Bioavailable precursor for glutathione Reduce systemic markers of inflammation and suppress mitochondrial dysfunction downregulate pro-inflammatory cytokine production increases the production of anti-inflammatory cytokines Modulation of oxidative stress efficacy in the setting of mild traumatic brain injury ( Amelioration of Acute Sequelae of Blast Induced Mild Traumatic Brain Injury by N-Acetyl Cysteine:A Double-Blind, Placebo Controlled Study. PLoS ONE, 8(1), e54163)

36. Photo-biomodulation “nonthermal process involving endogenous chromophores that elicit photophysical and photochemical events, resulting in beneficial photobiological responses” most often used low-level laser therapy (LLLT) LLLT leads to ischemic preconditioig Has cerebro vasodilatory effect Anti inflammatory/anti-apoptotic/antioxidant Neurogenesis/synaptogenesis

37. Photo-biomodulation

38. Vagal nerve stimulation Cholinergic anti-inflammatory pathway

39. Vagal nerve stimulation Promising preclinical data Direct vagal nerve stimulation Transcutaneous vagal nerve stimulation Auricular vagus nerve stimulation

40. Why so much discussion and research going on about POCD?

41. Consequences of POCD Life expectancy has increased By 2050 it is estimated that about 16% of the world’s population will be aged > 65 years, Concomitant increase in the need for surgical intervention for a variety of diseases for this group of patients Burden of cognitive impairment increased POCD - considerable impact on quality of life Withdrawal from society Economic burden Increased dependency

42. 701patients were followed up for median of 8.5 years POCD at 3 months was associated with increased mortality (hazard ratio, 1.63; p<0.01) Risk of leaving work because of disability or voluntary early retirement was higher among patients with patients who developed POCD at 1 week (hazard ratio, 2.26; p<0.01) Conclusions: cognitive dysfunction after non cardiac surgery as associated with increased mortality, risk of leaving work prematurely and dependency on social transfer payments

43. Summary

44. Post operative cognitive improvement(POCI) New evidence suggests that there is potential for cognitive improvement after surgery POCI could occur when surgery improves health, enhances quality-of-life, decreases inflammation, or alleviates pain Even with older patients, the brain retains neuroplastic potential t

45. Postoperative cognitive improvement