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Anesthetic Neurotoxicity: Should We Be Concerned?

James E. Cottrell, M.D. Brooklyn, New York

The assumption that anesthetics and sedatives do not harm the central nervous system is probably true for most patients. However, for patients
less than one year old, or more than 65 years old, that assumption is under challenge from a substantial body of evidence. Fetuses and infants
appear to be at risk because systems that would enable them to fully recover from the effects of more than 2 hours of anesthesia are still in
development. In distinction, seniors may be at risk because systems that once enabled full recovery have ever-diminishing capacity. Even for
some patients between the age of 1 and 60 years, full neurologic recovery may require replacing apoptosed neurons and pruning dendritic spines,
leaving them not quite the same person that they were prior to surgery.

THE YOUNG BRAIN

After 28 weeks of gestation, fetal neurons develop an acute ability to die from boredom.1 Given 78-94 billion neurons in the adult human brain,2
and evidence that at least one proto-neuron, and more likely two, undergo apoptosis for each neuron that survives, 3 a midpoint estimate is that the
human brain averages more than 19,000 apoptotic proto-neuron deaths per second during the last 11 weeks in utero. Those cellular suicides are
selective, leaving the core material and sculpting the primary architecture for subsequent CNS development.4-6
The trigger for much of that avalanche of apoptosis is a lack of synaptic feedback. Apoptosis appears to be the default program of many
excitable cell types, with cell-typical activity promoting proteins like anti-apoptotic Bcl-2’s that prevent the default program from running its
course. Put differently, the old saying “Use it or lose it” is not only for the old … synaptic activity may be as crucial to the survival of fetal
neurons as are O2, ATP and CBF. So what happens to fetal and 0-1 year old neurons that would be receiving and sending signals were it not for
the presence of anesthesia?

In laboratory animals
One of the first animal models to test the effect of anesthesia on fetuses was developed by Chalon in 1981. He exposed pregnant mice to
halothane and found that their offspring, and the offspring of those offspring, learned significantly more slowly than first and second generation
controls.7 see also 8 Analogous findings for offspring exposed in utero have been extended to isoflurane,9,10 sevoflurane11 and propofol12 in rodents
and to ketamine13 and isoflurane14 in fetal rhesus macaques. Takaenoki et al also reported cross-generational effects: neonatal exposure of female
mice to sevoflurane causes subsequent deficits in maternal behavior that lead to decreased survival of their non-exposed offspring.15 That finding
comports well with Amrock et al’s finding that “even brief exposures [to sevoflurane] induce long-lasting alterations in neuronal circuitry and
sensitize surviving synapses to subsequent loss.”16 The possibility of epigenetic effects notwithstanding, early laboratory reports indicating a
problem did not receive the attention they deserved until 2003 when Jevtovic-Todorovic and colleagues published “Early exposure to common
anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits” — a title that says it all.17
Many subsequent studies have confirmed those findings for neonatal exposure to desflurane, isoflurane, sevoflurane, propofol, nitrous oxide and
ketamine in rodents.
Postnatal apoptosis consequent to a clinically relevant depth and duration of general anesthesia also occurs in mammals with periods of rapid
synaptogenesis more analogous to humans, including pigs18,19 and non-human primates.20-23 Potentially relevant for burn victims, twenty-four
hours of “a light surgical plane” of ketamine anesthesia also causes long term cognitive deficits in Rhesus macaque neonates.24 In addition to
apoptosis, Stratmann and colleagues found that exposing 7-day-old rats to four hours of isoflurane induced a decrease in neurogenesis that
contributed to a permanent deficit in hippocampal-dependent learning and memory.25 Using 16-day-old rats, Briner and coauthors found that
sevoflurane, desflurane, isoflurane26 see also 27 and propofol28 rapidly increase dendritic spine density, which “could interfere with physiologic
patterns of synaptogenesis and thus might impair appropriate circuit assembly in the developing cerebral cortex.” Jevtovic-Todorovic’s group
recently found that neonatal propofol exposure changes synaptic plasticity proteins and increases stereotypic and anxyolitic behavior in
adulthood,29 and Huang and Yang have added “reduction in synaptic structural plasticity” as a cause of impaired motor learning during adulthood
in mice exposed to ketamine-xylazine 3 times between post-natal days 14-18.30 Many of these mechanisms probably contribute to Raper and
colleagues finding that 4 hours of sevoflurane anesthesia during postnatal day 6 to 10 increases anxiety-related behavior at 6 months of age in
Rhesus macaques.31

In humans
Levy reported a significant association between near-term emotional sequelae and younger age at anesthetic exposure in 1945 (p<0.0004, data not
statistically analyzed in the original article).32 Subsequent reports support an association between impaired neuro-cognitive-behavioral
development and exposure to surgery and anesthesia33-64, 69 with several supporting the relationship between younger age and increased
detrimental effects,e.g. 46, 49 suggesting that the period of extraordinary vulnerability in humans is in utero to twelve months postpartum – similar to
that found at analogous developmental stages (as distinct from chronological ages) in non-humans.
If duration of general anesthesia is as critical in human fetuses and neonates as it is in nonhuman mammals,19 then 30-60 minutes of exposure
is not sufficient to affect currently measurable long-term learning capacity, even in the high-vulnerability age group. Accordingly, Hansen and
colleagues finding of no substantive impairment in children “exposed to a single, brief anesthetic procedure in infancy,” 65 and Davidson et al’s

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GAS Study finding of no difference between general anesthesia and awake regional anesthesia during infancy for a single, brief exposure,66
suggest that measurable deleterious effects start taking effect beyond one hour of exposure. cf. 67 In an effort to partially control for genetic
variation, The Pediatric Anesthesia Neuro Development Assessment (PANDA) study compared children exposed to general anesthesia prior to 3
years of age during hernia repair versus siblings of similar age (within 3 years) who were not exposed to general anesthesia prior to age three.68
Unfortunately, like the Davidson66 and Hansen studies,65 this investigation probably tested for an effect of exposures that were too brief to have a
measurable effect in a study population that was substantially composed of children who were too old to be sufficiently susceptible – i.e., too
little too late. Long-term learning deficits generated by brief exposures notwithstanding, Whitaker and coauthor’s recent finding that “A brief
(approximately 60 min) exposure to isoflurane general anesthesia, without induced surgical stress, significantly increased serum IL-1ß, a selective
activation marker of systemic inflammation” suggests a mechanism for measurable damage from longer exposures. 69 In distinction to a single
brief exposure, Wilder et al44 and Yan et al54 found that repeated brief exposures to general anesthesia have a measurable deleterious effect on
neurodevelopment.
Block and colleagues analyzed achievement test scores of 7-17 year-old children who received general anesthesia for up to 3.75 hours during
infancy for procedures that are not associated with cognitive impairment. After excluding children with any of 14 pre-specified CNS problems or
medical conditions associated with learning disabilities, they found that a substantial proportion of children without such risk factors scored
below the 5th percentile of the normative population (p<0.01), with increased duration of anesthesia associating with reduced performance. 49
Bong et al also found increased learning disabilities at age 12 in healthy children exposed to 30-120 minutes of sevoflurane prior age 1.55 In
distinction to Block and Bong’s finding for children exposed to general anesthesia, Williams et al did not find a significant difference in the
percentage of children scoring below the 5th percentile, nor a correlation between achievement scores and duration of surgery, in children who
received spinal anesthesia during infancy.67
To date, perhaps the most intriguing evidence for separating surgically and/or genetically induced neurodevelopmental deficits from
anesthesia/sedative-induced deficits comes from children anesthetized for craniosynostosis51 and reconstructive heart surgery,52,57 or sedated for
procedures during neonatal care.58 Naumann et al found a stronger association between anesthesia duration and neurodevelopmental delays at 36
months of age than between surgical duration and neurodevelopmental delays in children who had non-saggital, single suture craniosynostosis
when they were about 6 months old.51 “After adjustment for multiple relevant covariates” Andropoulos et al found “an association between VAA
[volatile anesthetic agents] exposure ... and lower neurodevelopmental outcome” at 12 months of age after complex neonatal cardiac surgery.52
Diaz and coauthors found a similar result. They performed a retrospective dose-response study on 96 infants who underwent staged
reconstructive surgery for hypoplastic left heart syndrome. Initial surgery with cardio-pulmonary bypass was performed at less than two months
of age. All subsequent surgical interventions as well as ICU stays, up to neurodevelopment assessment at age 4 years, were included in a
cumulative anesthetic exposure analysis. After adjusting for multiple covariates previously demonstrated to influence neurodevelopmental
outcomes, they demonstrated that greater exposure to VAA is correlated with lower full-scale IQ.57 Particularly telling, Duerden et al also found
a dose-response curve between midazolam and lower cognitive scores with reduced hippocampal volumes at age 18-19 months in preterm
neonates sedated for stressful and painful procedures during neonatal intensive care. 58
Just as preterm infants appear to be more sensitive to harmful effects of anesthesia and sedation than full-term infants, effects in fetuses may
be even stronger than those in post-natal infants. In 1986 Hollenbeck and coauthors reported decreased cognitive capacity in four-year-olds
whose mothers had been anesthetized while they were in utero.59 Several subsequent studies found analogous associations between pre-natal
exposure to anesthetics and developmental problems including autism,60 hydrocephalus,61 diminished general intelligence,62 impaired spatial
ability,63 small head size and mental retardation.64

Upcoming Trial?
At the SmartTots Workshop on June 20, 2014, McCann and Davidson put forth the null hypothesis that “Infants who undergo the cleft lip/palate
repair with an average of >8 hours of general anesthesia in the first year of life exposed to conventional general anesthesia with sevoflurane and
nitrous oxide will have similar neurocognitive outcomes to infants exposed to an ‘apoptosis sparing’ general anesthetic.” The core of their
“apoptosis sparing” anesthetic is dexmedetomidine with remifentanil, the efficacy of which is being tested in the “T REX” trial.70 Presumably, if
T REX demonstrates feasibility, a trial comparing dex/remi maintenance to sevo-N2O maintenance on subsequent neurocognitive development
will follow. Prospective clinical trials that compare potentially less neurotoxic anesthetic regimens, perhaps dex/remi xenon, to conventional
alternatives in children who receive sufficient anesthesia at a young enough age to test the anesthesia-neurodevelopment hypothesis ... children
for whom delaying surgery is seldom an option ... will address the most important question: Is there a better way anesthetize children? Such trials
are long overdue.

Have the data already changed clinical practice?


How would you answer the following question?
A 27-year-old woman presents with an operable, slow-growing, benign, mildly symptomatic brain tumor. Her neurosurgeon has scheduled the
case and estimates an operation time of 4.5 hours. She is 25 weeks pregnant. Would you:
A. Proceed with the case using state-of-the-art equipment, procedures and a volatile anesthetic for maintenance?
B. Discuss evidence that has emerged or gained renewed recognition since 2003 that 4.5 hours of anesthesia may cause neuro-degeneration and
persistent learning deficits in the developing brain and leave the decision to the neurosurgeon?
C. Discuss the above evidence with the neurosurgeon and the parents and leave the decision in their hands?
D. Discuss the above evidence with the neurosurgeon and the parents and, barring development of substantive symptoms, advise postponing
surgery until after the patient has given birth?

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My guess is that prior to Jevtovic-Todorovic and coauthors’ 2003 shot-heard-round-the-anesthesia-world,17 most of us were on the A train.
In the absence of survey data, my hope is that most of us would now follow a suggestion from Rappaport et al: “parents and care providers
should be made aware of the potential risks that anesthetics pose to the developing brain ... surgeons, anesthesiologist, and parents should
consider carefully how urgently surgery is needed”71 ... and opt for C or D because, as put by Drasner, “If you aren’t concerned, you haven’t been
paying attention.”72 see also 73

How might we fix this problem?


Olney and his group proposed that anesthetic drug effects on fetal and neonatal gamma-aminobutyric acid and N-methyl-D-aspartic acid receptors
cause translocation of pro-apoptotic proteins to mitochondrial membranes, leading to an apoptotic cascade. 74 Perhaps this problem can be alleviated
through anesthetic management. Dexmedetomidine has been shown to be non-neurotoxic in a fetal non-human primate model75 and has been
shown to ameliorate the apoptosis caused by ketamine,76 isoflurane,77 and propofol78 in the developing rodent brain.
Several adjunct pharmaceuticals have also shown promise. L-carnitine, an l-lysine derivative that transports long-chain fatty acids into
mitochondria, appears to have a beneficial effect in N2O/isoflurane-damaged neonatal rats.79 Lithium reduces damage from ketamine and
propofol in neonatal mice80 and Brambrink’s group found that lithium protects against anesthesia neurotoxicity in the infant primate brain –
completely preventing isoflurane-induced neuroapoptosis and significantly reducing apoptosis of oligodendroglia.81 Clonidine reduces the
apoptotic and behavioral effects of ketamine in neonatal mice82 and Patel’s lab has shown that inhibition of p75 neurotrophin receptors attenuates
both isoflurane83,84 and propofol85 neurotoxicity in mice. Using the early post-natal rat model, Yon and coauthors found that melatonin reduced
anesthetic-induced damage in the most vulnerable brain regions: “Melatonin-induced neuroprotection was mediated, at least in part, via inhibition
of the mitochondria-dependent apoptotic pathway since melatonin caused an up-regulation of the anti-apoptotic protein, bcl-XL, reduction in
anesthesia-induced cytochrome C release into the cytoplasm and a decrease in anesthesia-induced activation of caspase-3 [precursor of
apoptosis].”86 More recently, Jevtovic-Todorovic’s lab found that both EUK-134, a synthetic reactive oxygen species scavenger, and R(+)
pramepexole, a synthetic aminobenzothiazol derivative that restores mitochondrial integrity, “completely prevented general anesthesia-induced
cognitive impairment” in rats that had been exposed to 6 hours of midazolam/isoflurane/N2O anesthesia on post-natal day 7.87 see also 88,89
Erythropoietin (EPO) is another promising adjunct. Pellegrini and colleagues have presented evidence that EPO substantially diminishes
neurotoxicity and later learning deficits in rat pups exposed to sevoflurane on post-natal day 7.90 O’Gorman et al found evidence of improved
white matter development at 12-18 and again at 36-42 hours after birth in preterm human infants given recombinant EPO within 3 hours of
birth,91 and the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study recently reported that newborns given EPO for hypoxic-
ischemic encephalopathy had improved 1-year motor scores,92 and lower volume of brain injury.93

THE OLDER BRAIN

The older brain has less cognitive reserve — less resilience subsequent to neurological challenges. Oxidative phosphorylation does not work as
well. We acquire genetic mutations that can alter outcomes. Genetic alleles that were silent when we were young manifest themselves as we age.
And then there is free radical build-up with reduced levels of scavengers like vitamin C, melatonin and vitamin E. All of these dreary realities
probably contribute to Kline and coauthors’ finding that “Elderly subjects after surgery experienced an increased rate of brain atrophy,” 94 and as
found by Silbert et al,95 “subjects with mild cognitive impairment suffered greater subsequent cognitive effects.”

POCD After Non-Cardiac Surgery


In 1955 P.D. Bedford published "Adverse cerebral effects of anaesthesia on old people." 96 He reviewed 1,193 (presumably non-cardiac) patients
over 50 years old who had received general anesthesia. Mental deterioration in 10% of patients appeared to be long-term or permanent — a
figure that concurs with subsequent findings. Bedford concluded that cognitive decline is related to anesthetic agents and hypotension. He
recommended that “Operations on elderly people should be confined to unequivocally necessary cases” and that “postoperative medication
should not be a routine matter.” The next major study to report POCD skips ahead 43 years to 1998 — the first International Study of
Postoperative Cognitive Dysfunction (ISPOCD).97 In non-cardiac patients more than 59 years old, the incidence of cognitive dysfunction 1 week
after surgery was 22% higher than in age-matched controls and 7% higher 3 months after surgery (p<0.004 for both) with 10% of patients
evidencing POCD. So the ISPOCD results were identical to Bedford’s finding at a longer postoperative interval. Increasing age, duration of
anesthesia, lesser education, a second operation, postoperative infection, and respiratory complications were risk factors for early postoperative
cognitive dysfunction. However, under a circumstance of significantly reduced statistical power due to a 22% loss of follow-up at 3 months,
among the risk factors that were significant in the early postoperative period, only age remained statistically significant.
Monk and colleagues found that 12.7% of elderly (>59 y o) non-cardiac patients had POCD three months after surgery98 — again, within a
narrow confidence interval around Bedford’s 1955 report. Corroborating earlier work, 99 Monk’s study also found a substantial relationship
between POCD and death within one year of surgery.see also 100,101 Independent risk factors for sustained POCD included greater age, less
education, POCD at hospital discharge and a history of stroke without residual damage. Consistent with many investigations, more education
may indicate greater pre-surgical cognitive reserve, just as prior stroke may indicate pre-surgical reduction of cognitive reserve.101,102 Notably,
Monk’s ‘08 study did not find duration of anesthesia to be a risk factor. However, the risk of a false negative conclusion is high in that regard,
because the sample size of elderly patients at the 3-month measurement was even smaller (308 with 39 POCD patients99) than in the International
Study of POCD (901 with 91 POCD patients97). The longest follow-up study of POCD patients (median = 8.5 years) was published by the
ISPOCD group in 2009: "Cognitive dysfunction after noncardiac surgery was associated with increased mortality, risk of leaving the labor
market prematurely, and dependency on social transfer.103

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POCD After Cardiac Surgery


Most of us have heard friends or relatives say something like “since he had open-heart surgery, he’s not the same … he can’t think as well, he’s
not as happy.” The New York Times brought attention to this problem with an article entitled “Saving the Heart Can Sometimes Mean Losing
Your Memory.”104 In that article, Jauhar explained the basics of extracorporeal circulation and discussed reasons for memory loss, focusing on a
patient who had gone back to work and found that he had difficulty with his job … a patient who could not perform functions that he had
performed for many years. That article raised a great deal of concern, setting the stage for a paper published a year later in the New England
Journal of Medicine by Newman and colleagues.105 see also 106 They found POCD in 53% of Coronary Artery Bypass Graft (CABG) patients at
discharge and in 36% of patients six weeks later. That proportion went down to 24% six months after surgery, but came back up to 42% five
years after surgery — a pattern of early improvement followed by subsequent decline that was predicted by POCD at discharge. see also 107 Evered et
al subsequently found strong associations between POCD at 12 months after CABG surgery and death within 10 years, and dramatically
increased incidence of dementia 7.5 years after CABG surgery.108
The factors that cause decline in cognitive capacity among non-CABG patients also affect CABG patients. However, some of those risk
factors, like duration of exposure to anesthetics, may be masked by damage done to CABG patients from increased liability to cerebral emboli,
cerebral ischemia during re-perfusion, and over-warming after bypass.109

Aggravating Factors

- On-pump vs. Off-pump


Does on-pump versus off-pump make a neurocognitive difference? Several trials failed to detect a neurocognitive advantage for off-pump
patients.110-112 Although Shroyer et al did not find a statistically significant difference across their composite test battery, they did find a
significant difference on one important test in favor of off-pump, suggesting the possibility of a false negative conclusion. 110 cf. 113 Both the 1-year
follow-up from the CORONARY investigators111 and the GOPCABE study group112 failed to find a statistically significant advantage of off-
pump bypass. Statistical significance aside, both investigations found a lower incidence of stroke in off-pump patients and Kowalewski et al’s
recent meta-analysis of 100 investigations covering 19,192 patients found a 28% reduction in stroke for off-pump bypass (p<0.009).114 So we are
left wondering how patients who experience more strokes (on-pump patients) did not evidence statistically significantly worse neurocognitive
outcome. One reason is that in the CORONARY study some surgeons took the liberty of performing off-pump surgery on 102 patients who had
been randomly assigned to on-pump surgery because those patients had calcification of their aortas. In the intention-to-treat analysis, those
patients’ results were analyzed as if they had on-pump surgery.115 These profound protocol violations were accompanied by patient-selected, as
distinct from randomly selected, inclusion in neurocognitive testing.111 Dr. Hartung and I have argued that intention-to-treat analysis should
always be accompanied by on-treatment analysis,116 and calculating a ‘p’ value for non-random samples makes no sense. In this case “absence of
evidence is not evidence of absence,”117 and unless strokes do not have neuro-cognitive consequences, my best-guess is that the CORONARY
study should be disregarded.
Puskas and colleagues found that “After a mean of 7.5 years of follow-up, patients undergoing off-pump coronary artery bypass performed
better than those undergoing [on-pump] cardiopulmonary bypass in several neuropsychological domains,” 118 and in what amounts to a
serendipitous positive-control study, Li et al found that preconditioning with hyperbaric oxygen reduced markers of cerebral injury in patients
undergoing on-pump bypass but not in patients having off-pump bypass, reasoning that “the protective effects of HBO preconditioning may only
manifest when there is a relatively severe injury, such as an on-pump procedure and not in off-pump CABG surgery patients.”119 Subsequently,
Brewer and coauthors found more postoperative complications, including permanent strokes, in 3,898 on-pump patients who were baseline-
matched to 3,898 off-pump patients.120 More recently, Kok et al’s prospective study found substantially less POCD 3 months after CABG
surgery in patients randomized to off-pump.121
Less direct evidence came from a study of over 16,000 patients in whom a greater incidence of delirium occurred after on-pump
cardiopulmonary bypass, with duration of surgery (and so anesthesia) as a significant risk factor. 122 Although these patients were not followed up
for POCD, Girard and coauthors found that in “mechanically ventilated medical intensive care unit patients, duration of delirium (which is
potentially modifiable) was independently associated with long-term [12 month] cognitive impairment123 and Morandi et al found that “delirium
duration in the intensive care unit was associated with white matter disruption at both discharge and 3 months later with worse cognitive scores
up to 12 months after discharge.”124 In a prospective study of 225 CABG patients, Saczynski and and coauthors found that “Delirium is
associated with a significant decline in cognitive ability during the first year after cardiac surgery” 125 and in 263 Alzheimer’s disease patients,
Gross and colleagues concluded that “Delirium is highly prevalent among persons with Alzheimer’s disease who are hospitalized and is
associated with an increased rate of cognitive deterioration that is maintained for up to 5 years.” 126 Neufeld et al found that post-op delirium in
the PACU “is associated with subsequent delirium on the ward, and ... with a decline in cognitive function and increased institutionalization at
hospital discharge.”127 More recently, Mangusan et al also found that: “Patients with postoperative delirium had significantly longer stays and
greater prevalence of falls than did patients without delirium. Patients with delirium also had a significantly greater likelihood for discharge to a
nursing facility, greater need for home health services if discharged to home, and a significantly higher need for inpatient physical therapy (all p
< .001).”128 Most recently, Royse et al found that patients who experienced delirium after cardiac surgery were less likely to recover cognitive
capacity 6 months post-op.129 Clearly, a relationship between depression, sedation, delirium, poor neurological outcome and POCD should not be
discounted,122-135 such that off-pump patients may be at lesser risk for POCD.

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- Inflammation
Inflammation caused by surgical trauma may also aggravate POCD and is associated with the pathogenesis of Alzheimers’ Disease (AD) in a
mouse model.136 Evidence that the association is causal comes from Vom Berg and coauthors’ finding that intracerebroventricular delivery of
anit-p40, and inhibitor of inflammatory signaling, significantly reduces the concentration of amyloid  (A) and reverses cognitive deficits in
aged Alzheimer’s mice.137 We know about the up-regulation of IL-1, and this in turn can affect anesthetic receptors.138 The ensuing cascade of
events ultimately affects the anesthetic gamma-aminobutyric acid and N-methyl-D-aspartic acid receptors and increases production of A … and
we know that soluble oligomers of A, even in non-demented patients, associate with cognitive problems. Genetic predispositions are another
aggravating factor. For example, Matthew and coauthors have shown the contribution of P-selectin and C-reactive protein alleles in modulating
susceptibility to cognitive decline caused by inflammation after cardiac surgery,139 and Cai et al found an association between APOE4 and early
POCD in elderly patients undergoing inhalation anesthesia.140

- General Anesthetics
Are anesthetics aggravating factors? If so, are some more toxic than others? Xie’s group found greater cognitive decline in patients 1 week after
surgery who received spinal anesthesia with desflurane versus spinal anesthesia with isoflurane or spinal anesthesia alone. 141, cf. 142 Examining
autopsy brain tissue, Crary and coauthors found that PKMzeta, an atypical protein kinase C isoform, accumulates in the neurofibrillary tangles of
Alzheimer’s patients, but not in control patients.143 One wonders whether anesthetics might increase this tangling in both AD and non-AD
patients. My lab is currently investigating the effect of anesthetics on PKMzeta in the adult mouse hippocampus. 144,145

- Anesthesia and Neurodegenerative Diseases


Do anesthetics aggravate neurodegenerative diseases? Hydrophobic cavities keep sticky proteins from becoming irreversibly glued together.
Unfortunately, molecules of inhalational anesthetics can fill those cavities and reduce the amount of energy required to maintain protein
assembly.146 This anesthesia-facilitated disinhibition of protein binding helps monomers aggregate into oligomers, and if those monomers are
A, the resulting oligomerization can lead to protofibrils that are small enough to diffuse into neurons and large enough to be neurotoxic. Soluble
A oligomers147 and alpha-Synuclein148 appear to contribute to the neurodegeneration characterized by Alzheimer in the early 20 th Century.
Thirteen million Americans are projected to have AD by the middle of the 21 st Century. Many of them will need to be anesthetized, and many of
those will have been anesthetized before they became demented.
The role of inhalational anesthetics in the above scenario has been verified in vitro by a decade of work from Eckenhoff and coauthors,149
and is also supported by in vivo mouse models.150,151 In addition to the A-anesthesia connection, Xie's group has utilized human neuroglioma
cell cultures to add anesthesia-induced apoptosis as a factor contributing to AD150, 152,153 and they have found that isoflurane, but not desflurane,
degrades mitochondrial function and impairs learning and memory in mice. 154 Do the rodent and cell culture findings apply to humans?
Eckenhoff’s group reported that the total-tau/A(1-42) ratio in CSF, the only biomarker validated for use in the diagnosis of AD by the
Alzheimer’s Disease Neuroimaging Initiative (ADNI), elevates during surgery and anesthesia in healthy patients and rises above ADNI’s
threshold for mild cognitive impairment within 48 hours.155 In an article entitled “Coronary artery bypass surgery provokes Alzheimer’s disease-
like changes in the cerebrospinal fluid,” Palotas and colleagues found an increased tau/A ratio in patients 6 months after surgery.156
Early results from retrospective studies on a possible association between anesthetic exposure and AD were unsettling but inconclusive. 157-
159
Now two large studies have found substantial evidence. Matching for age and gender, Pin-Liang Chen and coauthors compared 1,539
patients who had never been anesthetized to 661 patients who had been anesthetized after age 50. Even after adjustment for comorbidities, the
patients exposed to anesthesia had a nearly 2-fold greater incidence of dementia (p<0.001).160 Comparing 5,345 patients recently diagnosed with
dementia to 21,380 age and gender matched individuals without dementia, Chia-Wen Chen and colleagues found a substantially higher incidence
of anesthesia exposure, in a dose-response relationship, among the demented patients (p<0.0001).161 Benzodiazepine use may also be a
substantive risk factor, with a “stronger association observed for long term exposures.” 162-166 cf. 167, 168 With regard to anesthesia and
neurodegenerative diseases, Shoair et al hit the trifecta, finding significant associations between POCD and APOE4 (p<0.037), use of highly
anticholinergic or sedative-hypnotic drugs at home prior to surgery (p<0.014), and anesthesia with sevoflurane (p<0.01). 169
If the association between anesthetic exposure and AD is causal, as evidence indicates for the association between anesthesia and
developmental delay in children,32-64,69 Bedford’s admonition from 1953 still holds: “Operations on elderly people should be confined to
unequivocally necessary cases”96 ... and BIS should be kept on the high side, with intravenous anesthesia substituted for inhalational anesthesia
when practicable, and with regional anesthesia substituted for general anesthesia when feasible (see below).

Potential Alleviating Factors

- Deeper vs. Lighter & Regional vs. General Anesthesia


Neuman et al found higher mortality and more pulmonary complications in general anesthesia patients compared to regional anesthesia patients
undergoing hip fracture surgery,170 and Brown and colleagues found that elderly patients with serious comorbidities receiving light sedation
(BIS>80) during spinal anesthesia for hip surgery had reduced 1-year mortality compared to patients who received deep sedation (BIS≈50). 171
Examining results from 980 patients who underwent intra-arterial therapy for acute ischemic stroke under conscious (light) sedation versus (light)
general anesthesia, in addition to finding higher mortality in the general anesthesia patients, Abou-Chebl and coauthors also found poorer
neurological outcome.172 Ancelin found that “Adding sedation to peridural anesthesia led to a decline in verbal secondary memory”173 and Sieber
et al found that lighter sedation during spine surgery led to less delirium.174 Again, there are empirical and neuropathological reasons to suspect a
link between delirium, deep sedation, poor neurological outcome, and POCD. 122-135
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Indeed, presaged by results from a pilot study by Ballard et al, 175 an investigation by the CODA Trial Group of 921 elderly patients
undergoing major non-cardiac surgery found that patients with a median BIS of 53 experienced less delirium and had less POCD 3 months after
surgery than a control group maintained at a median BIS of 36.176, see also 177 cf. 178 As put by Green et al, “The important point about this trial is that
the investigators were able to maintain an average BIS of 53 in the intervention group vs 36 in the control group. This not only resulted in a
significant decrease in POCD but also in postoperative delirium, which we acknowledge is a cause of significant postoperative morbidity ... As
our population ages, we can no longer be complacent about how our intraoperative management may affect postoperative outcome.”179
It may be the case that regional anesthesia with deep sedation is equivalent to general anesthesia when it comes to POCD.180 Be that as it
may, whether the effect is on mortality, morbidity or POCD, a substantial and growing body of evidence indicates that, ceteris paribus, lighter is
better than deeper and regional is better than general.

- Anesthetics & Sedatives


Are some general anesthetics less deleterious than others? Crosby’s group presented data indicating that “In aged rats, propofol anesthesia is
devoid of the persistent memory effects observed with other general anesthetic agents in this model. Thus, it appears that general anesthesia-
induced memory impairment may be a function of the agent rather than the anesthetic state itself.” 181 That surmise is complimented by Ishii et
al’s recent finding that propofol is associated with less post-op delirium compared to sevoflurane in elderly patients,182 and Geng et al’s finding
that propofol associated with less short-term POCD than sevoflurane and isoflurane following laparoscopic cholesystectomy in elderly patients.183
Newman's group at Duke reported a significant reduction in POCD at 6 weeks and 1 year among non-diabetic cardiac patients who received
i.v. lidocaine. This effect was most pronounced in patients who received less than 43 mg/kg (total dose), while lidocaine appears to have had a
deleterious effect in diabetic patients and in patients who received higher total doses. 184 Analysis of a follow-up study is pending.185 Meanwhile,
Chen et al reported that low dose lidocaine reduced early POCD and serum levels of IL-6, TNF-, S100 and neuron-specific enolase in elderly
non-diabetic spine surgery patients.186
Dexmedetomidine has been reported to reduce delirium compared to placebo, 187 midazolam or propofol sedation,188-190 increase survival rate
in patients undergoing cardiac surgery,191 reduce delirium, ventilator time, tachycardia and hypertension compared to midazolam in critically ill
ICU patients,192 reduce focal neurologic dysfunction during mild sedation in patients with supratentorial mass lesions compared to midazolam
and propofol,193 and to reduce early POCD and serum levels of A and Tau protein in orthotopic liver transplant patients.194

- Adjuvants, Diet & Exercise


What about erythropoietin, melatonin, vitamin E, memantine, insulin, statins, edaravone and exercise?
Lauretani and colleagues found that EPO levels are lower in 60-to-98-year-olds with impaired peripheral nerve function and/or clinical
diagnosis of polyneuropathy.195 Haljan et al found a trend toward improved neurocognitive recovery with erythropoietin use in CABG patients, 196
and in post-hoc analyses Tseng et all found EPO to be protective in SAH patients who are younger, non-septic, and on statin therapy.197 More
recently, a double-blind trial by Abrishamkar and colleagues found improved Glasgow Outcome Scores in patients with diffuse axonal injury
who received subcutaneous injections of EPO every other day for two weeks. 198
Cheng and colleagues’ review of the beneficial effects of melatonin in experimental models of AD is encouraging,199 as is Ni and coauthors’
finding that melatonin premedication attenuates isoflurane-induced A in the hippocampus of aged rats.200 A clinical trial by Furio et al201 found
that melatonin improved cognitive function in elderly outpatients who suffered from mild cognitive impairment and Wade et al202 found the same
in mild to moderate Alzheimer’s patients. More recently, Hatta et al found that a stronger melatonergic sleep agent, ramelteon, prevented
delirium in hospitalized older patients.203
Several studies indicate that memantine,204, 205 and insulin therapy,206, 207 improve cognitive function or delay clinical worsening in AD
patients, and vitamin E with other dietary supplements have shown similar promise. 208-210 Perhaps most promising is the human monoclonal
antibody aducanumab, which has been shown to reduce brain A and slow decline in AD patients.211
The jury has looked hard for evidence that statin therapy prevents or ameliorates AD, but a definitive verdict is still pending.212 In
distinction, Blanco et al found that statin withdrawal increased the incidence of poor outcome in ischemic stroke patients 213 and retrospective
reviews by Flint and colleagues found that statin use during ischemic stroke hospitalization214 and after intracerebral hemorrhage215 is strongly
associated with improved survival and discharge disposition,”216 even for patients without prior statin use. Tsivogoulis et al found that statin
pretreatment in patients diagnosed with acute large artery atherosclerosis associates with neurologic improvement and reduced stroke
recurrence.217 Using a prospective design, Al- Khaled et al found that statin treatment reduced mortality 3 months after acute ischemic stroke, 218
Zhang et al found enhanced recovery with increased brain-derived neurotrophic factor 2 months after ischemic stroke in patients who received
atorvastatin219 and Zheng et al found that adding the free radical scavenger edaravone to atorvastatin increased recovery 2 weeks post-stroke.220
Pharmacological and mechanical approaches notwithstanding, perhaps age-appropriate exercise remains the best all-round regimen for both
prevention and treatment of POCD.221-230

- Preconditioning & Perconditioning


Although fetuses and the elderly are particularly sensitive to ischemia, hypo-perfusion and hypoxia, “Nietzsche’s Toxicology: whatever doesn’t
kill you might make you stronger”231 could lead to improved clinical management of patients with fragile brains.
In 1964 Dahl and Balfour published evidence of “prolonged anoxic survival due to anoxia pre-exposure.”232 This phenomenon was
eventually replicated in a model of cerebral ischemia,233 and induction of endogenous proteins of repair and the genes that code for them are now
well documented. Our laboratory has added sevoflurane as a potential preconditioner, 234 and Maze's group reported that in comparison to
sevoflurane,235 nitrous oxide and hypoxia,236 xenon preconditions in a manner that "might mimic the intrinsic mechanism of ischemic
Refresher Course Lectures Anesthesiology 2017 © American Society of Anesthesiologists. All rights reserved. Note: This
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124
Page 7

preconditioning most closely."235 But if a limited dose of anesthesia triggers the same protective mechanisms as a limited bout of hypoxia, how
much anesthesia can we give before what would have been a protective effect becomes a deleterious effect on balance? 180
Clinically acceptable means of accomplishing cerebral preconditioning are being sought. Volatile anesthetics notwithstanding,
pharmacological cerebral preconditioning may be eclipsed by mechanical Remote Ischemic Preconditioning (RIPC). Clinical studies have
established that three 5-minute inflations of a blood pressure cuff to 200 mmHg around a patient's upper arm, followed by 5-minute intervals of
reperfusion, improves outcome,237, 238 including near-term POCD,239 after several cardiovascular procedures and evidence from laboratory
investigations indicates that the same technique initiated prior to neurosurgery may improve outcome. 240-243 Investigations of RIPC in
neurosurgical patients are underway or have recently been completed, 244 and a study by Hu and colleagues reported reduced biochemical markers
of neuronal ischemia and improved rate of recovery after cervical decompression in patients who received RIPC. 245 More recently, Meng and
coauthors reported that daily bilateral arm ischemia reduced recurrent stroke and time to recovery over a 300 day period in patients with
atherosclerotic intracranial arterial stenosis,246 and Hougaard et al found that “perconditioning” ischemic stroke patients in the ambulance on their
way to thrombolysis therapy reduced tissue risk of infarction at one month post-stroke.247

- Neurogenesis
The old adage that neurogenesis is only for the young was shown to be wrong for rodents in 1965, 248 is known to be wrong for non-human
primates,249 and has been reported in humans.250, 251 This raises the possibility that negative effects of surgery and anesthesia on the elderly, as
well as the very young, can be compensated by therapies that strengthen the neurogenic response. Results in rats encourage the conclusion that
"neural precursors resident in the brain initiate a compensatory response that results in the production of new neurons. Moreover, administration
of growth factors can enhance this compensatory response … [and] we may eventually be able to manipulate these precursors to improve
recovery of function."252, 253 In addition to ischemic preconditioning,254 granulocyte-colony stimulating factor255 and erythropoietin256, 257 appear to
be such manipulators, and neurogenesis may be the therapeutic mechanism of electroconvulsive therapy in patients with depression.258, 259

CONCLUSION

Reports of possible adverse cognitive effects of anesthetics on young patients appeared in our literature during the 1940’s, on elderly patients in
the 1950’s, and on fetuses in the 1980’s ... so these problems and some of their potential solutions are not new, but our awareness of them has
experienced a renaissance since 2003.17 Fortunately, in the vast majority of pediatric cases, anesthesia lasts for less than 1 hour. For that
majority, I agree that the “evidence is most consistent with the premise that ‘anesthesia per se,’ given to an otherwise healthy child who needs
only a ‘routine’ surgical procedure, is not neurotoxic”260 … or is not toxic enough to cause a currently measurable adverse effect. However, for
children less than 12 months old, fetuses of any age and patients over 60 exposed to anesthesia for more than 2 hours, until and unless we are able
to classify substantive anesthetic neurotoxicity as a rare complication, the conservative first-do-no-harm approach should: 1) add anesthesia to
surgery to the cost side of the cost/benefit equation when making decisions about whether and when to proceed with surgery; 2) avoid nitrous
oxide, isoflurane and ketamine in the young because multiple studies indicate that they are particularly toxic; 3) use non-ketamine intravenous
anesthesia instead of inhalational anesthesia when doing so is a reasonable option; 4) keep BIS on the high side; 5) limit the duration of
continuous anesthesia to less than 2 hours whenever possible; 6) consider the possibility that regional anesthesia with deep sedation may trigger
as much neuronal apoptosis as general anesthesia; and 7) when feasible, use regional anesthesia with light or no sedation.
At the very least, newfound concerns generated by available data should inspire a great deal of translational research. If that research is
funded, my guess is that we will soon have anesthetic, sedative and adjuvant drugs ranked according to their safety profile … and augmentation
of endogenous processes of regeneration will deliver brain protection and recovery to the very young, the old, and everyone in between … before
the younger among us are too far gone to benefit!

Refresher Course Lectures Anesthesiology 2017 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with permission.
Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission from the
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Page 8

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Refresher Course Lectures Anesthesiology 2017 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with permission.
Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission from the
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