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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.
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.
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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
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.”
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Aggravating Factors
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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
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.
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!
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References: (For references given as 7 or 8 digit numbers, put just the number in the PubMed search box.)
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