1. Postoperative Cognitive Dysfunction: The Next Challenge in Geriatric Anesthesia Terri G. Monk, M.D. Professor Department of Anesthesiology University of Florida Gainesville, FL Emery A. Rovenstine Memorial Lecture October 13, 2003

2. E.A. Rovenstine, M.D. New York City Geriatrics 1946 vol. 1, no. 1.

3. Table of Contents - Geriatrics 1946;1(1) GERIATRIC ANESTHESIA E. A. Rovenstine, M.D. GERIATRIC ANESTHESIA E. A. Rovenstine, M.D. SPECIAL PROBLEMS OF POOR SURGICAL RISKS AMONG THE AGED William B. Kountz, M.D., and Louis H. Jorstad, M.D. SPECIAL PROBLEMS OF POOR SURGICAL RISKS AMONG THE AGED William B. Kountz, M.D., and Louis H. Jorstad, M.D. MENTAL DISORDERS OF OLD AGE Harold D. Palmer, M.D. MENTAL DISORDERS OF OLD AGE Harold D. Palmer, M.D.

4. Objectives Importance of Geriatric Anesthesia Importance of Geriatric Anesthesia Definition of Postoperative Cognitive Dysfunction (POCD) Definition of Postoperative Cognitive Dysfunction (POCD) Historical evidence for POCD Historical evidence for POCD Potential Mechanisms for POCD Potential Mechanisms for POCD Current evidence for POCD following Current evidence for POCD following  Coronary Artery Bypass Surgery  Non-Cardiac Surgery Long-Term Implications of POCD and Anesthetic Management Long-Term Implications of POCD and Anesthetic Management

5. Projection of the U.S. Population by Age: 1995-2050

6. Orthopedic Surgery in the Elderly In past, hesitancy to perform hip and knee replacement in elderly  80 years Prospective study comparing pain, functional outcome and quality of life outcomes in young (55-79 yrs) and elderly (  80 yrs):   No difference in outcomes between groups at 6 months after surgery   Age should not be a limiting factor for this type of surgery Jones et al. Arch Intern Med 2001; 161:454

7. Realities for the Practicing Anesthesiologist Half of all individuals  65 years will have at least 1 surgery in the remainder of their lifetime Half of all individuals  65 years will have at least 1 surgery in the remainder of their lifetime Over 7,000,000 inpatient surgeries per year in people over 65 years Over 7,000,000 inpatient surgeries per year in people over 65 years Most anesthesiologists will become geriatric anesthesiologists

8. Adverse Cerebral Effects of Anesthesia on Old People Review of records of 1193 patients: Review of records of 1193 patients:  Age 50 years or older  Operation under GA Mental deterioration in 120 (10%) patients Mental deterioration in 120 (10%) patients Conclusions Conclusions  Cognitive decline related to anesthetic agents and hypotension  “Operations on elderly people should be confined to unequivocally necessary cases” Bedford. The Lancet 1955; 2:259

9. Postoperative Cognitive Disorders DeliriumPOCDDementia Delirium Delirium  10-15% of elderly patients after GA Mild neurocognitive disorder - POCD Mild neurocognitive disorder - POCD Dementia (rare) Dementia (rare)  Multiple cognitive deficits  Impairment in occupational and social function

10. Postoperative Cognitive Dysfunction Deterioration of intellectual function presenting as impaired memory or concentration. Deterioration of intellectual function presenting as impaired memory or concentration. Not detected until days or weeks after anesthesia Not detected until days or weeks after anesthesia Duration of several weeks to permanent Duration of several weeks to permanent Diagnosis is only warranted if: Diagnosis is only warranted if:  corroborated with neuropsychological testing  evidence of greater memory loss than one would expect due to normal aging

12. Implications of Postoperative Neurocognitive Disorder Abrupt decline in cognitive function heralds: Abrupt decline in cognitive function heralds:  Loss of independence  Withdrawal from society  Death Seattle Longitudinal Study of Aging Berlin Aging Study

13. Potential Mechanisms for POCD High-risk patients High-risk patients High-risk surgical procedures High-risk surgical procedures High-risk anesthetic techniques High-risk anesthetic techniques

14. Threshold Theory for Cognitive Decline Lesion Lesion Protective Factor Case A Case B Brain Reserve Capacity A: Protective factor (greater brain reserve capacity), lower test sensitivity, no impairment B: Vulnerability factor (less brain reserve capacity), higher test sensitivity, impairment Satz Neuropsychology 1993:(7);273.

15. Continuum from Normal Aging through Mild Cognitive Impairment to Dementia Mild cognitive impairment Dementia Age Function Normal Aging

16. Potential Mechanisms for POCD High-risk patients - “Functional Cliff” High-risk patients - “Functional Cliff” High-risk surgical procedures High-risk surgical procedures  Cardiac Surgery  Orthopedic Surgery High-risk anesthetic techniques High-risk anesthetic techniques

18. Anesthetic Risk Factors for POCD Cholinergic neurons in the basal forebrain regulate normal memory Cholinergic neurons in the basal forebrain regulate normal memory Choline reserves  with aging Choline reserves  with aging Anesthetic agents affect release of CNS neurotransmitter Anesthetic agents affect release of CNS neurotransmitter  acetylcholine, dopamine, norepinephrine Difficult to postulate effects of anesthesia on memory, since mechanisms of general anesthesia are poorly understood. Difficult to postulate effects of anesthesia on memory, since mechanisms of general anesthesia are poorly understood.

19. POCD: Attention in Lay Media

20. POCD after CAB: Longitudinal Assessment

21. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study JT Moller P Cluitmans LS Rasmussen P Houx H Rasmussen J Canet P Rabbitt J Jolles K Larsen CD Hanning O Langeron T Johnson PM Lauven PA Kristensen A Biedler H van Beem O Fraidakis, JH Silverstein JEW Beneken JS Gravenstein for the ISPOCD investigators THE LANCET Saturday 21 March 1998 Vol. 351 No. 9106 Pages 857-861 Collaborative research effort: Collaborative research effort:  Members from 8 European countries and USA  13 hospitals Research conducted from 1994 - 1996 Research conducted from 1994 - 1996 International Study of Postoperative Cognitive Dysfunction

22. Long-Term POCD in the Elderly Hypotheses Anesthesia and surgery in elderly patients cause prolonged cognitive dysfunction Anesthesia and surgery in elderly patients cause prolonged cognitive dysfunction The incidence of prolonged POCD increases with age The incidence of prolonged POCD increases with age Potential mechanisms of POCD Potential mechanisms of POCD  Hypoxemia is a major cause of POCD  Hypotension is a major cause of POCD

23. Long-Term POCD in the Elderly Physiologic Monitoring O 2 saturation by continuous pulse oximetry O 2 saturation by continuous pulse oximetry  One night preop  Operating room  24 hrs postop  Nights of POD 2-3 Noninvasive blood pressure Noninvasive blood pressure  Every 3 min in OR  Every 15 min in PACU  Every 30 min for 24 hrs after PACU discharge

24. Incidence of POCD in Patients and Controls * * * p < 0.004 Lancet 1998; 351:857

25. Long-Term POCD in the Elderly Conclusions and Questions Anesthesia and surgery cause long-term POCD Anesthesia and surgery cause long-term POCD Hypotension and/or hypoxemia not related to occurrence of POCD Hypotension and/or hypoxemia not related to occurrence of POCD Variable incidence of early POCD at different centers Variable incidence of early POCD at different centers  Differences in anesthetics, procedures, patients?  Are results generalizable to single institutions? Lancet 1998; 351:857

26. A Prospective Study Evaluating The Relationship Between Age and POCD Single site - University of Florida: 1999 - 2002 Single site - University of Florida: 1999 - 2002 1200 patients undergoing elective surgery 1200 patients undergoing elective surgery  Young - 18 to 39 years of age  Middle-aged - 40 to 59 years of age  Elderly - 60 years and older Controls - primary family members Controls - primary family members Study design identical to ISPOCD study Study design identical to ISPOCD study  Same psychometric test battery  Outcome Endpoints:  POCD (primary) and mortality (secondary)

27. The Relationship Between Age and POCD : Inclusion/Exclusion Criteria Inclusion criteria Inclusion criteria  Aged 18 years or older  General anesthesia > 2 hrs  Major abdominal/thoracic or orthopedic surgery  Mini-Mental State Exam (MMSE) ≥ 24 Exclusion criteria Exclusion criteria  Cardiac or neurosurgical procedures  CNS disease  Alcoholism or drug dependence  Major depression  Patients not expected to live 3 months or longer

28. Evaluation of Factors Affecting Outcome Effect of patient, procedure and anesthetic variables on outcome was evaluated using multivariate modeling  Co-morbidity Scores, Demographics, Patient History  Medications, Anesthetic Agents / Duration, Surgery Type  Cumulative Deep Anesthesia Time (BIS < 45)  Intraoperative Hemodynamics

29. POCD After Major Surgery: Baseline Characteristics Young (18-39 yrs) Middle Aged (40-59 yrs) Elderly (  60 yrs) Baseline Characteristics of the Patients Number of Patients Age (yrs) † Gender (M/F) Years of Education † Baseline MMSE † Baseline Charlson Comorbidity Index † 331 (31%) 30.7 (6.0) 30/70% 13.4 (2.2) 29.3 (1.1) 1.0 (1.5) 379 (36%) 49.9 (5.6) 35%/65% 13.7 (2.8) 29.2 (1.2) 1.4 (1.8) 354 (33%) 69.5 (6.5) 43%/57% 13.5 (2.8) 28.8 (1.4) 1.9 (2.1)* † Numbers are expressed as Mean (standard deviation) * Elderly group significantly different from younger groups

30. * *p < 0.05 Incidence of POCD in Adult Patients: Z Score Definition % of Patients Monk et al. Anesthesiology 2001; 95: A-50

31. Predictors of POCD: 3 Months After Surgery NS0.046 History of MI History of MI NS0.021 Baseline Comorbidity Baseline Comorbidity NS0.009 ASA Physical Status ASA Physical Status NS0.003 History of Stroke History of Stroke 2.51 (p=0.057) 0.001 Age Age 0.86 (p=0.028) < 0.001 < 0.001 Years of Education Years of Education NS0.028 NYHA Status NYHA Status NSNS Anesthesia Time Anesthesia Time NSNS Baseline MMSE Baseline MMSE NSNS Gender Gender NSNS Surgery Type Surgery Type Multivariate Odds Ratio Univariate P value Risk Factors for POCD Multivariate c-statistic = 0.671 (p = 0.003) Monk et al. Anesthesiology 2001; 95: A-50

32. One-Year Mortality Rate by Cognitive Status * ** * P = 0.027 vs. No Decline; ** P = 0.014 vs. No Decline

33. Independent Multivariate Predictors of One-Year Mortality Risk Factors Relative Risk P Value Baseline Comorbidity Baseline Comorbidity16.86 < 0.001 Volatile vs. TIVA Volatile vs. TIVA2.970.022 Intraoperative Beta Blocker Intraoperative Beta Blocker1.670.004 Chronic Beta Blocker Chronic Beta Blocker1.530.019 Cumulative Deep Anesthesia Time (BIS < 45, per hour) Cumulative Deep Anesthesia Time (BIS < 45, per hour)1.340.007 Systolic Blood Pressure < 80 mmHg (per minute) Systolic Blood Pressure < 80 mmHg (per minute)1.040.008 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)

34. Outcomes Following Major Surgery: Conclusions POCD POCD  Common in all age groups at hospital discharge  3 months after surgery, POCD is more common in adults age 60 years or older, with lower educational achievement  Associated with increased one-year mortality Mortality Mortality  Increased by comorbidity  Anesthetic management has a significant effect  volatile agent use  cumulative deep anesthesia time  systolic hypotension

35. Is Anesthesia Associated with One-Year Mortality? Multi-center Prospective Trial (Sweden) Multi-center Prospective Trial (Sweden)  5,057 General Anesthetics, Non-cardiac Surgery 1 Year Mortality Rate = 5.6% 1 Year Mortality Rate = 5.6%  vs. 5.4% in our POCD/Mortality Study Deep Anesthesia Time: Significant Independent Predictor Of Mortality Deep Anesthesia Time: Significant Independent Predictor Of Mortality  Increased Relative Risk: 19.7% / Hr  vs. 34.1% in our POCD/Mortality Study Lennmarken et al, Anesthesiology 2003; 99:A-303

36. Additional Investigation Medicare Data Analysis  2001 MEDPAR Inpatient File (1.6 Million Surgeries)  Prediction of Risk-Adjusted Post-Surgical Mortality Rate  Cox Proportional Hazards Model:  Cox Proportional Hazards Model: c-statistic=0.848 (p < 0.001)  Rank-ordered decrease in risk-adjusted mortality with increasing use of intraoperative BIS monitoring. * P < 0.001 for Trend Monk, et al. Anesthesiology 2003; 99:A-1361 BIS Utilization Rate (% Procedures Monitored) # of Sites# of Cases Risk-Adjusted Mortality Rate None3,7741,087,0619.33% 1-25%350262,1808.89%* 26-75%308191,4628.95%* > 75% 10180,8048.69%* Total1,621,507

37. Summary “Anesthetic management, directly or indirectly, may contribute to the biology of remote adverse events” “Anesthetic management, directly or indirectly, may contribute to the biology of remote adverse events” “Practicing anesthesiologists may be able to influence long-term outcomes by adjusting anesthetic and adjuvant regimens” “Practicing anesthesiologists may be able to influence long-term outcomes by adjusting anesthetic and adjuvant regimens” “Reducing one-year mortality in the elderly by just 5% would translate to 40,000 - 50,000 lives saved each year” “Reducing one-year mortality in the elderly by just 5% would translate to 40,000 - 50,000 lives saved each year” Meiler, Monk et al. APSF Newsletter 2003; 18(3):33.

38. Research Support  Anesthesia Patient Safety Foundation (APSF)  I Heermann Anesthesia Foundation  NIA K01 award  Aspect Medical Systems

39. The POCO Group: Post-Operative Cognitive Outcomes Group

40. Mentors Make the Difference Paul White, MD Washington University 1988 - 1992 Joachim S. Gravenstein, MD University of Florida 1998-2003

41. Superman in his later years

42. Society for the Advancement of Geriatric Anesthesia www.sagahq.org