postoperative cognitive dysfunction: u.s. population by ... · cerebral infarction fat or air...

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Postoperative Cognitive Dysfunction: Can we prevent it?

Michael Rieker, DNP, CRNA, FAANDirector, Nurse Anesthesia Program

Wake Forest School of Medicine

U.S. Population by Age:1900-2050

Postoperative Cognitive Dysfunction

Impairment of Memory Impairment of Attention Delayed functional recovery

(psychomotor function)

Symes E et al. Issues associated with the identification of cognitive change following coronary artery bypass grafting. Aust NZ J Psychiatry 2000;34(5):770-84.

Types of postoperative cognitive dysfunction

Emergence delirium- immediate postop confusion, restlessness. Affects all ages, but prominent in elderly, emergency surgery

Interval delirium- POD 2-7; fluctuating impairment of cognition, memory, emotional lability

Characteristic postoperative cognitive dysfunction- lasts 3 months to years

Spectrum of cognitive disorders

Emergence Delirium

Interval Delirium

Post-Op Cognitive Dysfunction

Dementia

Differential Diagnosis

Rundshagen I. Postoperative Cognitive Dysfunction. Deutsches Ärzteblatt International. 2014;111(8):119-125.

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Postoperative Delirium Brief, fluctuating Impaired cognition Fluctuating levels of consciousness Altered psychomotor activity (pulling out

IVs, etc.) Emotional lability (crying, anger)

Characteristics of POCD Temporal association with surgery Fluctuating symptoms Impairment of

Memory Learning Sensory and language processing Concentration Social integration Sleep-wake cycle

Characteristics of POCD Hallucinations Delusions Motor dysfunction- tremor Lability of mood, anger, depression

Diagnosis is difficult!

Standardized Understanding is Elusive

Memory Attention

Concentration

Function/ADLs

Cognitive Function

Standardized Understanding is Elusive

Mahanna et al. applied different criteria to same sample

Found rates of POCD to vary 20% - 70%

Mahanna EP et al. Defining neuropsychological dysfunction after coronary artery bypass grafting. Annals of Thoracic Surgery 1996 61(5):1342-7.

Synonyms of POCD Postoperative psychosis Mild neurocognitive disorder. Acute confusional state Mental dysfunction Acute brain syndrome

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History of POCD Postoperative psychosis

Historical term. Various forms of cognitive disorder recognized since 1819

Bedford- retrospective review of > 1,000 elderly patients. 10% POCD (Bedford PD Adverse cerebral effects of anaesthesia

on old people. Lancet 1955;2:259-63.)

History of POCD Shaw PJ et al. Early intellectual dysfunction

following coronary bypass surgery. Q J Medicine 1986;58(225):59-68.

Savageau JA et al. Neuropsychological dysfunction following elective cardiac operation I. Early Assessment. J Thoracic Cardiovascular Surgery 1982;84(4):585-94.

Sequelae of Postoperative Cognitive Dysfunction

Increased morbidity Prolonged hospitalization Necessitates long-term care Loss of functional ability Cost!

Sequelae of Postoperative Cognitive Dysfunction

Patients with POCD at hospital discharge were more likely to die in the first 3 months after surgery (P = 0.02).

Patients who had POCD at both hospital discharge and 3 months after surgery were more likely to die in the first year after surgery (P = 0.02).

Monk TG. Et. al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 108(1):18-30, 2008 Jan.

Sequelae


Independent Multivariate Predictorsof One-Year Mortality

Risk Factors Relative Risk P ValueBaseline Comorbidity 16.86 < 0.001Volatile vs. TIVA 2.97 0.022Intraoperative Beta Blocker 1.67 0.004Chronic Beta Blocker 1.53 0.019Cumulative Deep Anesthesia Time (BIS < 45, per hour) 1.34 0.007Systolic Blood Pressure < 80 mmHg (per minute) 1.04 0.008

Beta blocker use was not protective

intraoperative beta-blockers – hemodynamic stability

chronic beta-blockers – higher comorbidity

Weldon et al. Anesthesiology 2002; 97: A-1097

Multivariate c-statistic = 0.806 (p <0.001)

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Sequelae 720 patients enrolled in multicenter studies of POCD

1995-2000 Cognitive function assessed before, 1 week and 30

days after non-cardiac surgery patients with POCD at 3 months showed higher

rates of mortality and lower rates of return to function

Steinmetz, Jacob; Christensen, Karl Bang; Lund, Thomas; Lohse, Nicolai; Rasmussen, Lars S. the ISPOCD Group Anesthesiology 2009;110(3):548-555.

Incidence of Cognitive Dysfunction Age is a prominent risk factor.

Affects 10% overall elderly surgical patients Can occur in any age group; delirium (immediate

post-op) more common in young. Incidence highest in days-weeks postop. (50-80%) Declines to 5-60% at 3 months After six months may also be due to depression or

awareness of age related changes. Dighstra JB et al Br J Anaesth 1999;82(6))

Risk Factors The independent risk factors for POCD at 3

months after surgery were: increasing age lower educational level history of previous cerebral vascular accident with

no residual impairment POCD at hospital discharge.


Age as a major risk factor


Predictors of POCD:3 Months After Surgery

NS0.046History of MI

NS0.021Baseline ComorbidityNS0.009ASA Physical StatusNS0.003History of Stroke

2.51 (p=0.057)0.001Age0.86 (p=0.028)< 0.001Years of Education

NS0.028NYHA Status

NSNSAnesthesia TimeNSNSBaseline MMSENSNSGenderNSNSSurgery Type

Multivariate Odds RatioUnivariate P valueRisk Factors for POCD

Multivariate c-statistic = 0.671 (p = 0.003)

Monk et al. Anesthesiology 2001; 95: A-50

Age as a major risk factor

Advanced age is a consistent, independent predictor Decreased lean body mass Decrease total body water Increase in body fat Thus, increase in dose-response variability.

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Theory on Aging Incidence of Cognitive Dysfunction 25-50% following ortho procedures

Galanakis et al. Int J Geriatric Psych. 2001;16:349-355.

30% following cardiac surgery post-op, 7% after 5 days. Silber et al. J Cardiothoracic Vasc Anesth 2001;15(1):20-4.

Low incidence with minimally-invasive procedures (~1-3% with Cataract ext.)

Meta-analysis of 80 studies showed incidence as high as 75% Dyer. Ann Int Med. 1995;155:461-465.

Pathophysiology Hypotheses

1. Metabolic encephalopathy2. Neurological injury

Metabolic encephalopathy Hypoxia

Ach synthesis sensitive to hypoxia (would alter memory, alertness, motor function)

Hypoglycemia Hypothermia Surgical trauma (factors may alter amino acids and

neurotransmitters) Decreases thyroid hormone Increases cortisol Releases cytokines

Metabolic Encephalopathy Research recently is focusing on cytokines

and other humoral markers of the stress response.

-would suggest shorter and less-invasive surgery are beneficial

Wang W, Wang Y, Wu H, et al. Postoperative Cognitive Dysfunction: Current Developments in Mechanism and Prevention. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2014;20:1908-1912.

Neurological Injury Cerebral infarction

Fat or air embolism Thrombus

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International Study of POCD 1218 patients over 60 yoa Tested pre-op, 1 week, and 3 months after

major non-cardiac surgery

Moller, J et al Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998; 351:857-861.

1 week 3 monthsSurgery 25.8 % 9.9%Control 3.4 2.8

p value 0.0001 0.0037

International Study of POCD Risk factors:

Age Duration of anesthesia Lower education Second operation Postoperative infections Respiratory complications

Moller, J et al Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998; 351:857-861.

No relation of POCD to: ASA status, lung, heart, PVD, HTN, head inj.,

stroke, a-fib, delirium, cancer, anesthetic technique, smoking, ETOH, EBL, periop fluids, type of operation, gender, long-term ICU stay, hypoxemia, hypotension

International Study of POCD

Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness.

Retrospective cohort study of 575 participants tested annually at the Washington University Alzheimer’s Disease Research Center

Three cohorts: surgical, no surgery/no illness, no surgery/illness

Retrospective, matched-control group. Long-term annual testing.

Attempted to overcome methodological/statistical deficiencies of previous studies.

Avidan MS et al. Anesthesiology 2009;111:964-970.

Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness.

Failed to find correlation between surgery and long-term decline.

Suggests that accounting for pre-surgery cognitive trajectory removes association between surgery/illness and POCD.

Unclear how to account for inevitable crossover Unclear how many were lost to follow-up to arrive at the

final sample If incidence not different on annual testing, isn’t it still

important in shorter-term? Avidan MS et al. Anesthesiology 2009;111:964-970.

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Is there a connection we are missing?

“…thyroid hormones negatively regulate expression of the amyloid protein precursor (APP), which plays a key role in the development of AD.”

Mafrica F. Fodale V. Thyroid function, Alzheimer's disease and postoperative cognitive dysfunction: a tale of dangerous liaisons? Journal

of Alzheimer's Disease. 14(1):95-105, 2008 May.

Is there a connection we are missing?

Hypoxia, hypocapnia, and anesthetics trigger Alzhemier’s Disease.

Could this be a similar molecular trigger for POCD?

Zie, Z & Tanzi, RE. Alzheimer’s disease and post-operative cognitive dysfunction. Experimental Gerontology2006;41:346-359.

Is it all about beta-amyloid protein? Possible Etiologic Factors

Preoperative Intraoperative Postoperative

Preoperative Psychiatric disorder

Psychosis Dementia Depression Personality disorder

Ancelin, et al Exposure to anaesthetic agents, cognitive functioning and depressive symptomatology in the elderly. British journal of psychiatry 2001;178:360.

Preoperative- theories

Poor medical status Parkinson’s disease Cerebrovascular disease Hypoalbuminemia

Previous surgery Sensory impairment

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Pre-existing cognitive dysfunction Preexisting cognitive dysfunction was

identified in approximately one-third of the patients prior to surgery

Preexisting cognitive dysfunction was a predictor of cognitive dysfunction 3 months and 1 yr after surgery.

No evidence of anesthesia or surgery as direct causes

Silbert, B. et al. Preexisting Cognitive Impairment Is Associated with Postoperative Cognitive Dysfunction after Hip Joint Replacement Surgery Anesthesiology 2015;122(6):1224-1234

Preoperative

Nutritional deficiency Thiamine, etc.

Drug influences Alcohol abuse Benzodiazepine abuse or withdrawal Anticholinergic pre-med

Intraoperative Type of surgery (esp ortho, cardiac) Duration of surgery Hypoglycemia Electrolyte disturbance (esp. sodium) Temperature disturbance (hypo or hyperthermia have

been implicated) Drugs: anticholinergics, inhalational anesthetics,

polypharmacy Meperidine, long-acting BNZ, BNZ withdrawal

Intraoperative Hyperglycemia

hyperglycemic = POCD incidence of 40% vs 29% in the normoglycemic group (P = 0.01).

Hyperglycemia was the strongest factor associated with POCD

Puskas F, et al. Intraoperative hyperglycemia and cognitive decline after CABG. Ann Thorac Surg 2007; 84:1467–73.

Intraoperative CBF- found to be decreased after bypass Cerebral oximetry?

Hong SW. et al. Prediction of cognitive dysfunction and patients' outcome following valvular heart surgery and the role of cerebral oximetry. European Journal of Cardio-Thoracic Surgery. 2008;33(4):560-5

de Tournay-Jette, et. al. The relationship between cerebral oxygen saturation changes and postoperative cognitive dysfunction in elderly patients after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2011;25(1):95-104.

Zheng, R. et al. “Cerebral near-infrared spectroscopy monitoring and neurologic outcomes in adult cardiac surgery patients: a systematic review,” Anesthesia & Analgesia, 2013; 116(3):663–676

Hypotension Although these are good theoretical bases, nobody has been able to

show a direct correlation to POCD.

Cardiopulmonary Bypass Temporary depression of CBF Microembolization of vessels

(arterial filtration reduces incidence) Fall below limits of autoregulation Prolonged focal changes on EEG correlate with

POCD; while increasing perfusion pressure reduced it. Bekker AY. Cognitive dysfunction after anaesthesia in the

elderly. Best Prac Research in Clin Anaes. 2003;17(2):259-272.

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Cardiopulmonary Bypass In the end, difference between cardiac and non-

cardiac may likely be only related to differences in diagnostic criteria used.

Keizer AM, Hijman R, Kalkman CJ, Kahn RS, Van DD. The incidence of cognitive decline after (not) undergoing coronary artery bypass grafting: the impact of a controlled definition. Acta Anaesthesiol Scand 2005; 49: 1232–5.

Cardiac Surgery as a Protectiveevent meta-analysis- cardiac surgery results in

postoperative cognitive improvement Reducing myocardial ischemia improves

cognitive dysfunction?

Cormack F, et al. A meta-analysis of cognitive outcome following coronary artery bypass graft surgery. NeurosciBiobehav Rev 2012;36: 2118-2129.

Cardiac Surgery as a Protectiveevent Transient myocardial ischemia caused

cognitive dysfunction evidenced by impaired long term potentiation and increased expression of inflammatory biomarkers.

Effect attenuated by preconditioning with sevoflurane.

LTP impairment did not occur after a sham procedure.

Zhu J, et al.Sevoflurane preconditioning reverses impairment of hippocampal long-term potentiation induced by myocardial ischemia-reperfusion injury Eur J Anaesthesiology 2009;26:961–968

Is it a lingering effect of the anesthetic drugs?

Down-regulation of nerve growth factor (NGF) and protein expression in the cortex and thalamus after propofol.

Extrinsic apoptotic pathway induced by over-expression of TNF which led to the activation of caspase-3.

Neurodegeneration was confirmed by Fluoro-Jade B staining. Concluded that anesthetic dose (25 mg/kg) of propofol induces

complex changes that are accompanied by cell death in the cortex and thalamus of the developing rat brain.

Pesić, Vesna V. Potential mechanism of cell death in the developing rat brain induced by propofol anesthesia. International journal of developmental neuroscience, 2009;27 (3): 279.

Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23: 876–82.

Addressed also in Hudson, A E. Hemmings, H C Jr. Are anaesthetics toxic to the brain. Br J Anaesth.


Tau phosphorylation and cognitive dysfunction found to be linked to sevoflurane administration and dependent upon duration of exposure.

Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Le Freche H. Brouillette J. Fernandez-Gomez FJ. Patin P. Caillierez R. Zommer N. Sergeant N. Buee-Scherrer V. Lebuffe G. Blum D. Buee L. Anesthesiology. 116(4):779-87, 2012


Isoflurane impaired spacial learning capacity, independent of tau phosphorylation or beta amyloid protein.

Isoflurane-induced spatial memory impairment by a mechanism independent of amyloid-beta levels and tau protein phosphorylation changes in aged rats. Liu W. Xu J. Wang H. Xu C. Ji C. Wang Y. Feng C. Zhang X. Xu Z. Wu A. Xie Z. Yue Y. Neurological Research. 34(1):3-10, 2012

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Related to NMDA activation?

Within hours of exposure to NMDA blocker, developing rat brains show: Cellular injury Reduced ability to regenerate new cells Impaired cell-to-cell communication Auditory deficits

(Rat model at developmental stage equivalent to 0-2 year-old human brain)

Related to NMDA activation?

Spacial learning found to be impaired in rats after 4-hr isoflurane exposure.

NMDA activation found present, and NMDA inhibitor helped reduce POCD.

Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain. Mawhinney LJ. de Rivero Vaccari JP. Alonso OF. Jimenez CA. Furones C. Moreno WJ. Lewis MC. Dietrich WD. Bramlett HM. Brain Research. 1431:23-34, 2012

Could some drugs be protective?

Occurrence of POCD in rats after isofluraneexposure was demonstrated to be prevented with co-administration of lidocaine.

Lidocaine attenuates cognitive impairment after isofluraneanesthesia in old rats. Lin D. Cao L. Wang Z. Li J. Washington JM. Zuo Z. Behavioural Brain Research.228(2):319-27, 2012

Does minimizing anesthetic help?

The use of volatile anesthetics that are rapidly eliminated with minimal metabolic breakdown may reduce postoperative cognitive dysfunction and postoperative delirium by facilitating a faster recovery

Chen X et al. Anesth Analg 2001;93:1489-94.

Does minimizing anesthetic help? Deep (BIS <45) Anesthesia Time: Significant

Independent Predictor Of Mortality Increased Relative Risk: 19.7% / Hr

Lennmarken et al, Anesthesiology 2003; 99:A-303

Does minimizing anesthetic help? 220 patients, mean 70 years THA or TKA 90% under spinal Opioid-sparing in all cases 1.5 days in hospital No incidence of post-op delirium

Delirium after fast-track hip and knee arthroplasty. Krenk L. Rasmussen LS. Hansen TB. Bogo S. Soballe K. Kehlet H. Br. J Anaes. 108(4):607-11, 2012 Apr.

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General vs. Regional Rasmussen, Moller et. al. as part of

International Study of POCD repeated earlier study in 2003. Included researchers in US, UK, Europe, and Netherlands.

Looked at 438 elderly (>60) patients. Rasmussen LS, Johnson T, Kuipers M, et. al. Does

anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaes Scand 2003;47:260-266.

ISPOCD follow-up Findings:

Mostly ortho procedures POCD occurred in 10-20% of all patients at 1 week and 3

months. No difference based on anesthesia type.

Limitations: High refusal/drop-out rate Regional group received propofol sedation GA group- didn’t specify technique

Comparison of rates of POCD in patients having CEA with regional are similar to those of patients having CEA under general, in comparison to controls.

Heyer, Eric J EJ (08/2008). "A study of cognitive dysfunction in patients having carotid endarterectomy performed with regional anesthesia". Anesthesia and analgesia. 107 (2), p. 636.

Does anesthetic type make a difference?

Extracorporeal Shockwave Lithotripsy under GA or spinal without sedation.

POCD was almost three times as high after spinal anesthesia.

At 1 week, POCD was 11.9% after spinal vs. 4.1% after GA; at 3 months the incidence was 19.6% and 6.8% for spinal and GA, respectively

B. S. Silbert, et al. Incidence of postoperative cognitive dysfunction after general or spinal anaesthesia for extracorporeal shock wave lithotripsy Br. J. Anaesth. (2014) 113 (5): 784-791.


Comparison of propofol and sevo. Very weak differences noted. Sevo caused faster initial emergence and less early

delirium. No difference in POCD.

Nishikawa et. al. Recovery characteristics and post-operative delirium after long-duration laparoscope-assisted surgery in elderly… Acta Anaes Scand. 2004;48:162-168.


Recent studies show slightly better performance from volatiles vs. propofol

Schoen J. Husemann L. Tiemeyer C. Lueloh A. Sedemund-Adib B. Berger KU. Hueppe M. Heringlake M. Br J Anaesth. 106(6):840-50, 2011 Jun.

Royse CF. Andrews DT. Newman SN. Stygall J. Williams Z. Pang J. Royse AG. Anaesthesia. 66(6):455-64, 2011 Jun.


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100 patients ASA status I-III; age 65-83, undergoing elective abdominal or urologic surgery > 2 hours

Percentage with POCD at X interval

1 Day 6 Days 30 Days

Propofol 50% 18% 12%Xenon 44% 12% 6%

Höcker, Jan J Postoperative neurocognitive dysfunction in elderly patients after xenon versus propofol anesthesia for major noncardiac surgery: a double-blinded randomized controlled pilot study. Anesthesiology 2009;110(5):1068.

No difference in POCD according to type of anesthetic.

Overall 5% long-term POCD. Williams-Russo, et. al. Cognitive effects after

epidural versus general anesthesia in older adults. JAMA. 1995;274:44-50.


130 ortho patients 64-87 years old POCD duration General anes > regional +

sedation > regional without sedation

Ancelin, et al Exposure to anaesthetic agents, cognitive functioning and depressive symptomatology in the elderly. British journal of psychiatry 2001;178:360.


Does anesthetic type make a difference? Other factors are likely to contribute to the

pathogenesis of POCD: inflammatory processes triggered by the surgical

procedure. Animal studies demonstrate a correlation

between the inflammatory response in the hippocampus and the development of POCD in rodents.

Caza N. Taha R. Qi Y. Blaise G. The effects of surgery and anesthesia on memory and cognition. Progress in Brain Research. 169:409-22, 2008.

So where are we now? There is currently minimal clinical evidence

linking surgery or anesthesia to incident dementia. Rigorous clinical research is needed to resolve the controversy whether anesthesia or surgery is likely to cause persistent neurological decline or to precipitate dementia.

Avidan, Michael S. Evers, Alex S. Review of clinical evidence for persistent cognitive decline or incident dementia attributable to surgery or general anesthesia. J Alzheimers Dis. 2011;24(2):217-20;

Prevention Preoperative assessment

Detailed history of drugs Detection of sensory or perceptual deficits Mental preparation prior to surgery Neuropsychologic testing

Preoperative depression is a risk factor for postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus. Kadoi Y. et. al. A. Journal of Anesthesia. 25(1):10-7, 2011

Thrombus prophylaxis Optimize medical condition Tailor anesthetic plan… Postoperative cognitive disorders. Monk TG. Price CC. Current Opinion in Critical Care. 17(4):376-81, 2011.

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Intraoperative precautions Minimally invasive surgery Adjust drug dose (BIS to minimize doses) Effect of auditory evoked potential-guided anaesthesia on

consumption of anaesthetics and early postoperative cognitive dysfunction: a randomised controlled trial. Jildenstal PK. Hallen JL. Rawal N. Gupta A. Berggren L. European Journal of Anaesthesiology. 28(3):213-9, 2011

Prevention Intraoperative precautions

Minimize the variety of drugs Avoid atropine, diazepam, scopolamine Minocycline hypothesized to be possibly

helpful. Fan, L. Wang, Tian-Long. Xu, Y C. Ma, Y H. Ye, W G. Minocycline may be useful to prevent/treat postoperative cognitive decline in elderly patients. Medical Hypotheses. 2011;76(5):733-6.

Prevention

Cerebral oxygenation may be more important than peripheral saturation.

Duration of cerebral desaturation time during single-lung ventilation correlates with mini mental state examination score. Suehiro K. Okutai R. Journal of Anesthesia.25(3):345-9, 2011

The relationship between cerebral oxygen saturation changes and postoperative cognitive dysfunction in elderly patients after coronary artery bypass graft surgery. de Tournay-Jette E. Dupuis G. Bherer L. Deschamps A. Cartier R. Denault A. Journal of Cardiothoracic & Vascular Anesthesia. 25(1):95-104, 2011

Prevention Postoperative care

Frequent orientation Early mobilization Environmental support (noise reduction,

glasses/hearing aids used, promote sleep pattern)

Multi-modal non-opioid pain treatment Identify risk-associated drugs Reassure patient and family

Prevention

Geriatric-Anesthesiologic Intervention Program

Preop and postop assessment Early surgery Thrombus prophylaxis Tight BP control Oxygen therapy

Parikh SS & Chung F. Postoperative delirium in the elderly Anesthesia & Analgesia, 1995;80:1223-1232

Treatment of POCD Recognize and prevent causes Rule out organic cause

Hypo/hyperglycemia Hypoxemia Electrolytes Anemia Sepsis Dehydration Malnutrition

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Treatment of POCD Remove contributing factors

Encourage patterned rest Opioids/BNZ/DA antagonists Pain Polypharmacy

Control with drugs only if necessary Narcoleptics (buterophenones/chlorpromazine) better

than BNZ, unless BNZ withdrawal Physostigmine

Summary POCD is variable in definition, but affects a

significant number of patients May be associated with increased cost and

functional decline Awareness of risk factors and measures to

avoid those that are preventable may benefit the patient.

postoperative cognitive dysfunction: u.s. population by ... · cerebral infarction fat or air...

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