University of Missouri
Department of Anesthesiology
Postoperative Cognitive Disorders
Does Anesthesia Harm the Brain?
Terri G. Monk, M.D. , M.S.
Professor
Department of Anesthesiology and Perioperative Medicine
University of Missouri
Columbia, MO 65212
MOANA
March21, 2015
Objectives
Brain Aging
Historical evidence for Postoperative Cognitive Disorders
Definitions of Postoperative Cognitive Disorders
Diagnostic criteria for delirium and postoperative cognitive dysfunction
Improved understanding of diagnostic criteria for POCD
Incidence of POCD
Risk factors for Postoperative Cognitive Disorders
Age and preoperative cognitive status
Depth of anesthesia?
Is Inhalation Anesthesia Detrimental in Elderly Patients?
The Brain Atrophies with Age
Fotenos. Neurology 2005;64:1032
Aging Decimates Dendritic Spines and Synapses
A = Young
B = Aged
Morrison. Nat Rev Neurosci 2012; 13:240
White Matter Degradation in Aging
Black = young adults
Gray = nondemented old adults
Buckner. Neuron 2004; 44:195
Adverse Cerebral Effects of Anesthesia on Old People
Review of records of 1193 patients:
Age 50 years or older
Operation under GA
Mental deterioration in 120 (10%) patients
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
Postoperative Cognitive Disorders
Delirium
POCD
Dementia
Delirium
10-15% of elderly patients after GA
Up to 60% of patients with hip fracture
Mild neurocognitive disorder – POCD
10-50% after cardiac and noncardiac surgery
Dementia (rare)
Multiple cognitive deficits
Impairment in occupational and social function
Diagnostic and Statistical Manual of Mental Disorders
Diagnostic Criteria for Delirium (DSM-V)
Recognized psychiatric diagnosis
All physicians can diagnose delirium
Disturbance of consciousness
Reduced clarity of awareness of environment
Reduced ability to focus, sustain or shift attention
Change in cognition
Memory deficit, disorientation, language disturbance
Disturbance develops over a short period of time
Evidence that disturbance is caused by a medical condition
Perioperative period is associated with many risk factors
i.e., Medications, inflammatory response, environment etc.
Postoperative Cognitive Dysfunction:
A mild neurocognitive disorder
Deterioration of intellectual function presenting as impaired memory or
concentration
Not a diagnosis in the Diagnostic and Statistical Manual of Mental Disorders
(DSM-V)
Some experts doubt its existence
Most researchers consider POCD to be a mild neurocognitive disorder (DSM-V
diagnosis)
Not detected until days or weeks after anesthesia
Does not meet criteria for delirium, dementia or amnestic disorder
Duration of several weeks to permanent
Diagnosis is only warranted if:
corroborated with neuropsychological testing
evidence of greater memory loss than one would expect due to normal
aging
Essential Design Elements for POCD Research
Prospective longitudinal study with perioperative cognitive
testing
Testing must occur prior to and at least 2 weeks after surgery
Parallel non-surgical group completing same testing as
surgery participants; ideally age and disease matched
Many methodological problems in early POCD research
No control group
POCD: Attention in Lay Media
Biphasic Pattern of POCD after CAB
Change in Cognitive Index
From Baseline
Not impaired at discharge
2
Impaired at discharge
1
0
-1
-2
Nearly 50% of patients
Discharge
6-Weeks
6-Months
5 Years
Newman et al. N Engl J Med 2001; 344
JAMA 2007; 297: 701-8
This cardiac surgery study used better methodology and a control group.
Do Management Strategies for CAD Influence 6-year Cognitive Outcomes?
No difference in
cognitive outcomes in
subjects with CAD
despite different treatments
Subjects with CAD had
lower preoperative
cognitive tests scores at
baseline compared to the
heart healthy contro group
(HHC)
Selnes. Ann Thorsac Surg 2009; 88:445
Comparison of 3 studies evaluating POCD:
Coronary angiography under sedation
Total hip replacement under GA
Coronary artery bypass grafting (CAB ) under GA
POCD at 3 months after surgery was similar (16-21%)
Type of surgery and anesthesia does not influence POCD
Evered. Anesth Analg 2011; 112: 1179
POCD after Noncardiac Surgery
2 large prospective studies using recommended
methodology
Pre and postoperative testing
Age-matched control group
Identical neuropsychological tests and times of testing
Identical definitions of POCD
1282 subjects aged 60 years or older
Major noncardiac surgery with general anesthesia
This study followed diagnostic criteria for a mild neurocognitive disorder
Control group, pre and postop testing
Late testing > 2 weeks postop
Long-Term POCD in the Elderly
Hypotheses
Anesthesia and surgery in elderly patients (≥ 60
years) cause prolonged cognitive dysfunction
The incidence of prolonged POCD increases with
age
Potential mechanisms of POCD
Hypoxemia is a major cause of POCD
Hypotension is a major cause of POCD
Long-Term POCD in the Elderly
Physiologic Monitoring
O2 saturation by
continuous pulse oximetry
Noninvasive blood pressure
One night preop
Every 3 min in OR
Operating room
Every 15 min in PACU
24 hrs postop
Every 30 min for 24 hrs after
PACU discharge
Nights of POD 2-3
Incidence of POCD in Patients and Controls
30
*
Percentage (%)
25
20
15
*
10
Controls
Patients
5
0
Early
Late
* p < 0.004
Lancet 1998; 351:857
Long-Term POCD in the Elderly
Conclusions and More Questions
Anesthesia and surgery cause long-term POCD
Hypotension and/or hypoxemia not related to occurrence
of POCD
Variable incidence of early POCD at different centers
Differences in anesthetics, procedures, patients?
Are results generalizable to single institutions?
Lancet 1998; 351:857
● 1064 subjects aged 18 years or older
Young: 18-39 years
Middle-aged: 40-59 years
Elderly: 60 years or older
● Identical study design to ISPOCD 1 study
Same neuropsychological tests
Same test time points
Age-matched control groups
Incidence of POCD in Adult Patients:
Z Score Definition
80
70
% of Patients
60
50
Control
† † †
Young
Middle-Aged
Elderly
40
30
20
*†
10
0
Early
Late
*p < 0.05
†p < 0.05
Monk et al. Anesthesiology 2008;108: 18-30
Predictors of POCD
3 Months After Surgery
Risk Factors for POCD
Years of Education
Age
History of Stroke
No POCD at Discharge
Baseline Comorbidity
NYHA Status
History of MI
ASA Physical Status
Duration of Hospital Stay
Gender
Baseline MMSE
Anesthesia Time
Univariate P value
0.0002
<0.0001
0.0005
<0.0001
0.0639
0.0472
0.0195
0.0293
0.0173
NS
NS
NS
Multivariate Odds Ratio
0.84 (p=0.031)
1.02 (p=0.0109)
3.14 (p=0.0298)
0.32 (p<0.0001)
NS
NS
NS
NS
NS
NS
NS
NS
Monk et al. Anesthesiology 2008;108: 18-30
1 Year Mortality vs. POCD at 3 Months after Noncardiac Surgery
1 Y e a r M o r ta lity R a te (% )
12
*
*
10
8
6
4
2
0
None
Hospital
Discharge
Presence of POCD
3 months
Hospital
Discharge + 3
month
Monk et al. Anesthesiology 2008;108: 18-30
Potential Mechanisms for POCD
High-risk patients
High-risk surgical procedures
High-risk anesthetic techniques
Brain Reserve Capacity
Threshold Theory for Cognitive Decline
Lesion
Protective
Factor
Patient A
Lesion
Patient B
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.
Preoperative MRIs of 2 Patients Undergoing Orthopedic Surgery
Patient A 66 years old male
Patient B 86 year old male
PI=Terri Monk, M.D.; Study conducted at University of Florida
Potential Mechanisms for POCD
High-risk patients
High-risk surgical procedures
High-risk anesthetic techniques
Emboli
Intraoperative Emboli – measured by Transcranial
Doppler
Cardiac surgery
196 – 3395 “hits”
Jacobs et al., 1998
Non-cardiac surgery
1-200 “hits”per surgery
Edmonds et al., 2000
Courtesy of D Moody, MD
Potential Mechanisms for POCD
High-risk patients
High-risk surgical procedures
High-risk anesthetic techniques
Is There Evidence that Anesthesia
Damages the Brain?
Abundant evidence
Cell cultures
Animal models
Controversial or negative evidence
Human studies
Hypothetical pathway by which isoflurane induces a vicious cycle of apoptosis and
A{beta} generation and aggregation
Xie et al. J Neurosci 2007; 27:1247
Tg2576 Mouse Model of Alzheimer’s Disease
Tg2576 mice:
•Overexpress human APP695
•Develop memory deficits and plaques
with age
•Show age-dependent AD-type
neuropathology
•Suitable for examining the relationship
Between Aβ and memory
Anesthesia with Isoflurane Increases Aβ Pathology
51 male mice in study
26 exposed to anesthesia
11 Wild type (controls) and 15 Tg2576 mice
25 without anesthesia
12 Wild type (controls) and 13 Tg2576 mice
Anesthetic technique
Isoflurane – 4% for induction and 2% for maintenance with O2
Time of exposure 20-30 minutes (4 Tg2576 mice died at 30 min)
Anesthetic exposures repeated twice a week for 3 months
Investigated the effects of repetitive exposure to
isoflurane on:
survival, behavior, cell death, Aβ deposition
J Alz Disease 2010; 19:1245
Effect of Isoflurane Treatment on Survival
p = 0.017
J Alz Disease 2010; 19:1245
Anesthesia with Isoflurane Increases
Aβ Pathology - Conclusions
Isoflurane treatment of Tg2576 mice (↑ risk for AD)
↑ mortality
↓ responsiveness after anesthesia
↓ exploratory behavior
↑ ratio of pro-apoptotic proteins in hippocampus
↓ astroglial and ↑ microglial responses
↑ Aβ aggregates and high molecular weight peptides
Conclusions:
Isoflurane is probably not a general risk factor for
AD
Inhaled anesthetics may be a risk in patients with
special genetic or environmental risk factors for AD
J Alz Disease 2010; 19:1245
Preoperative Cognition not Type of General Anesthesia
is Associated with Postoperative Delirium
200 adult patients age 65 years or older undergoing major orthopedic
surgery randomized to either:
TIVA
Isoflurane
Remainder of anesthetic technique standardized
BIS in normal range (40-60)
Incidence of postoperative delirium:
Isoflurane – 12.6%
TIVA – 13.6%, p = 0.84
Preop ↓ executive function and memory → POD
No difference in the incidence of cognitive decline at 3 months or 1 year
after surgery
Monk 2011 and 2012: ASA abstracts
Does Anesthetic Technique Matter?
Regional vs. GA
10 RCTs comparing cognitive outcomes after GA vs. Regional
Epidural vs. GA for TKA
(JAMA 1995; 274:44-50)
262 patients – median age of 69 yrs
No difference in cognitive function change from baseline at 1 week or 6 months
5% incidence of POCD at 6 months
Type of anesthesia did not affect magnitude or pattern of POCD
Regional vs. GA for major surgery
(Acta Anaesthesiol Scand 2003; 47:260-6)
364 patients 60 years or older
No difference in cognitive function between groups at 3 months after surgery –
14.3% vs. 13.9%
921 patients undergoing elective major surgery
Age ≥ 60 years
Surgery ≥ 2 hours
Hospital stay ≥ 4 days
MMSE ≥ 24
Randomized to either
BIS guided care (40 to 60)
Routine care
J Neurosurg Anaesth 2013; 25:33
BIS-guided Anesthesia:
Conclusions
Postoperative delirium
BIS-guided
Routine care
15.6%
24.1%
p = 0.01
Cognitive performance similar at 1 week postop
Postoperative cognitive dysfunction at 3 months
BIS-guided
Routine care
10.2%
14.7%
p = 0.025
BIS-guided anesthesia reduced anesthetic exposure and ↓ risk
of POD and POCD at 3 months after surgery
J Neurosurg Anaesth 2013; 25:33
1277 patients undergoing elective surgery with GA
Age ≥ 60 years
Surgery ≥ 60 minutes
MMSE ≥ 24
Excluded patients with neurological deficits
Randomized to
BIS use during surgery
Routine care – BIS data blinded
Br J Anaesth 2013; 110:198
Monitoring Depth of Anaesthesia
Conclusions
Postoperative delirium
BIS use
Routine care
16.7%
21.4%
p = 0.036
Mean BIS values
BIS use
39 ± 7
Routine care
39 ± 7
↓ extreme low BIS values (<20) with BIS use
No difference in
POCD at 7 days or 3 months after surgery
Mortality at 3 months after surgery
Br J Anaesth 2013; 110:198
Conclusions
Anesthesia, per se, is not neurotoxic in most patients
Some patients may be predisposed to postoperative
cognitive problems
Preoperative cognitive impairment
Metabolic syndrome
Others??
The effect of excessive amounts of anesthesia on the brain
needs to be investigated.
WHAT DO WE STILL NEED TO
LEARNZ
• Etiology of postoperative cognitive disorders
• Easy techniques to identify high-risk patients
• Prevention/Treatment
Superman in his later years