THE YOUNG BRAIN
After 28 weeks of gestation, fetal neurons develop an acute ability to die from boredom.1 Given estimates of 40–50 billion neurons at birth,2 and evidence that at least 1 fetal protoneuron, and more likely 2, undergo apoptosis for each neuron that survives,3 a midpoint estimate is that the human brain averages about 8000 apoptotic neuronal deaths per second during the last 11 weeks in utero. Those cellular suicides are highly selective, leaving the core material and sculpting the primary architecture for subsequent CNS development.4
The trigger for 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 antiapoptotic Bcl-2s 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 late-term fetal neurons as are oxygen, adenosine triphosphate, and cerebral blood flow. So what happens to fetal 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 et al. in 1981. He exposed pregnant mice to halothane and found that their offspring, and the offspring of those offspring, learned significantly more slowly than the first and second generation of control mice.5 Chalon's findings for first-generation offspring were recently substantiated and extended for in utero exposure to isoflurane,6,7 and Hogan has found first-generation effects of fetal exposure to nitrous oxide that may extend to those offsprings' offspring.8 Recent studies notwithstanding, early laboratory reports indicating a potential problem did not receive the attention that 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.9 Many subsequent studies have confirmed and augmented those findings,6–8,10–32 with Istaphanous et al. reporting that “developmental neurotoxicity is a common feature … of equipotent concentrations of desflurane, isoflurane, and sevoflurane in neonatal mice.”29(cf22,30)
Early laboratory reports indicating a potential problem did not receive the attention that 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.
Neonatal apoptosis subsequent to a clinically relevant depth and duration of general anesthesia also occurs in mammals with periods of rapid synaptogenesis more analogous to humans, including pigs23 and a nonhuman primate.24 Potentially relevant for burn victims, 24 hours of “a light surgical plane” of ketamine anesthesia also causes long-term cognitive deficits in Rhesus macaques.31 Apoptosis notwithstanding, Stratmann and colleagues found that exposing 7-day-old rats to 4 hours of isoflurane anesthesia induced a decrease in neurogenesis that contributed to a permanent deficit in hippocampal-dependent learning and memory.18,19 Neurogenesis, of course, requires neural stem cells, and Culley et al. have presented evidence that 1 minimum alveolar concentration (MAC) isoflurane reduces the production of neural stem cells by 20% in vitro 24 hours after exposure.32 Decreased neurogenesis and decreased neural stem cell proliferation notwithstanding, using 16-day-old rats, Briner and coauthors found that sevoflurane, desflurane, and isoflurane 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.”25,26
Since 1945, investigators have observed an association between impaired neuro-cognitive-behavioral development and postnatal exposure to surgery and anesthesia prior to 3 or 4 years of age,33–52 with Levy33 having found a statistically significant association between near-term emotional sequelae and younger age at anesthetic exposure (P < 0.0004, data not statistically analyzed in original article). However, the investigation of monozygous twins by Bartels and colleagues addressed the hypothesis that children who need to undergo surgery and anesthesia at an early age are inherently predisposed to impaired neuro-cognitive-behavioral development. They studied 110 pairs of identical twins; in each pair, one twin had been anesthetized prior to age 3 years and the other had not. They found, in a pair-by-pair analysis, that the anesthesia-exposed twins had virtually the same score as their nonexposed twins on a national measure of educational achievement administered near age 12.48 Unfortunately, the Bartels study is not known to have included children who were anesthetized prior to 6 months of age. That shortcoming, together with the finding of Kalkman and colleagues of a trend toward a greater detrimental effect of anesthesia on neurocognitive development with decreasing age at administration of anesthesia,47(see also42) suggests that if there is a period of extraordinary vulnerability in humans, it is similar to that found at analogous developmental stages in nonhumans: second trimester to 6 months postpartum.
Since 1945, investigators have observed an association between impaired neuro-cognitive behavioral development and postnatal exposure to surgery and anesthesia prior to 3 or 4 years of age, with Levy having found a statistically significant association between near-term emotional sequelae and younger age at anesthetic exposure (P < 0.0004, data not statistically analyzed in original article).
The methodology of Bartels et al. was also not able to provide an estimate of duration of anesthetic exposure. If duration of anesthesia is as important in human fetuses and neonates as it is in nonhumans,23 then a 30- to 60-minute exposure may not be sufficient to affect 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” leaves the question open for ≥2 hours of exposure.51 The same concerns apply to a recent report from DiMaggio and coauthors.52 They looked for developmental effects in children exposed to anesthesia and surgery prior to 3 years of age and replicated the Bartels et al. finding for twins on a smaller but more refined subsample. Nevertheless, only 6 or 7 of the 304 anesthesia-exposed children included in the DiMaggio and coauthors epidemiological investigation were aged <6 months at time of exposure, with the vast majority having been anesthetized for short procedures. Accordingly, they concluded “that a meaningful proportion of the association measured in the overall analysis of the … may not be causally attributable to surgery/anesthesia”—a conclusion that we agree with in reference to children exposed to anesthesia for <2 hours after they are 6 months old.
In distinction, a recent examination of children aged <1 year (average age, 101 days) exposed to anesthesia for procedures that lasted up to about 3.75 hours found an association with decreased academic performance after correcting for related CNS complications. Thomas and colleagues analyzed achievement test scores of 7- to 17-year-old children who received general anesthesia during infancy for procedures that are not independently associated with cognitive impairments: inguinal hernia repair/orchiopexy, pyloromyotomy, and circumcision. After excluding children with any of 14 prespecified CNS problems or medical conditions associated with learning disabilities, they found that a substantial proportion of children without such risk factors scored below the fifth percentile of the normative population (P < 0.01), with increased duration of anesthesia associating with reduced performance P < 0.01; (Figure 1).49
A recent examination of children aged <1 year (average age, 101 days) exposed to anesthesia for procedures that lasted up to about 3.75 hours found an association with decreased academic performance after correcting for related CNS complications.
Findings for fetuses may be stronger than those for postnatal humans. In 1986, Hollenbeck and coauthors reported decreased cognitive capacity in 4-year-olds whose mothers had been anesthetized while they were in utero.53 Several subsequent studies found analogous associations between prenatal exposure to anesthetics and developmental problems including autism,54 hydrocephalus,55 diminished general intelligence,56 impaired spatial ability,57 small head size, and mental retardation.58 Whether a component of those adversities can be attributed to anesthesia should be decipherable given studies with sufficient statistical power to correct for confounding variables without obscuring an effect of anesthesia.
With an anticipated completion date of December 2016 and a projected sample size of 660 children, the Multi-site Randomized Controlled Trial Comparing Regional and General Anesthesia for Effects on Neurodevelopmental Outcome and Apnea in Infants (GAS) study will test for a difference in preschool IQ between children who received sevoflurane or neuraxial bupivacaine for inguinal hernia repair when they were 26–60 weeks old.59 A recent laboratory experiment does not support the GAS study, because although it found substantially reduced neuronal apoptosis in postnatal rats that received spinal injection of bupivacaine compared with rats anesthetized with isoflurane, the spinal analgesia did not last long enough (40–60 minutes) to be expected to trigger apoptosis, whereas the apoptosis-inducing sevoflurane exposure lasted for 6 hours.60 A large retrospective study by Flick and coauthors found no difference in frequency of learning disabilities between (1) a group of children whose mothers received inhaled anesthesia (16%) or did not receive inhaled analgesia (84%) for vaginal delivery, and (2) a group of children delivered vaginally whose mothers received neuraxial block, with only 3.1% also receiving inhaled anesthesia.61 That study did not test for developmental differences between the children whose mothers received inhaled analgesia without neuraxial block versus the children whose mothers received neuraxial block without receiving inhaled anesthesia (the GAS study question), but even if those relevant subsamples are large enough to withstand such an analysis, one worries that fetal anesthetic exposure during birth in the Flick study was, and during hernia repair in the GAS study will be, too brief to test the anesthesia-development question (per Hansen et al51 and DiMaggio et al49). It may also be the case that the sample size of the GAS study will be effectively diminished because too high a proportion of participants will be too old at their age of exposure (per Bartels et al45 and DiMaggio et al49).
The other major prospective study scheduled for completion in 2016, the Infant Anesthesia Exposure and Neuro-Outcome study (formerly PANDA) is aiming to enroll 1000 participants to compare “global and domain-specific neurocognitive function” between children exposed to general anesthesia prior to 3 years of age during hernia repair versus siblings of nearly the same age (within 3 years) who were not exposed to general anesthesia prior to age 3. Unfortunately, like the GAS study, this investigation will test for an effect of exposures that are probably too brief to have an effect in a study population that may be substantially composed of children who are also too old to be sufficiently susceptible.62
So Where Do We Stand?
The data in laboratory rodents are conclusive: Clinically relevant doses and durations of anesthesia during the period of rapid synaptogenesis cause neuronal apoptosis and long-term learning deficits. The same has been established in pigs and a nonhuman primate with regard to apoptosis. In distinction, the effect of anesthesia in human neonates remains a concern that is confounded by genetics, by age at anesthetic exposure, by the effects of surgery independent of anesthesia, and by the duration of anesthesia exposure. Data from human fetuses may be a cause for even more concern because they associate anesthesia with adverse outcomes that are probably less confounded by genetics (the mother's genetic predispositions would be the primary association with a need for surgery, but half of her fetus' genes are not derived from her), by age at exposure (second and third trimester have now been implicated as high-risk periods in rodents, perhaps translating back to late first trimester and beyond in humans), by the effects of surgery independent of anesthesia (although the fetus and mother are equally anesthetized, the effects of surgery on the mother are likely to be diminished in the fetus), and by duration of anesthesia (if mid third trimester is the period of peak vulnerability, with a plateau of vulnerability extending roughly equally in both temporal directions).
What Might Be Done?
Olney and his group have proposed that anesthetic drug effects on fetal and neonatal γ-aminobutyric acid and N-methyl-D-aspartic acid receptors (NMDAR) cause translocation of the Bcl-2–associated protein to mitochondrial membranes, leading to an apoptotic cascade.63 Perhaps this problem can be alleviated by anesthetic choice in pregnant females. Maze and his group have presented evidence that “xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain,”64 as does dexmedetomidine,65 and xenon is currently in clinical trials for perinatal hypoxic-ischemic brain injury.66 Analogously, Laing and coauthors found that sevoflurane causes less apoptosis than isoflurane, but this difference was not manifest in behavioral tests.22(cf29,30) 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 nitrous oxide/isoflurane-damaged neonatal rats,67 and lithium reduces damage from ketamine and propofol in neonatal mice.68 Using the early postnatal 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 antiapoptotic 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].”69 Melatonin has also been shown to protect against learning disorders in hypoxic-ischemic injured neonatal rats70 and excitotoxic brain-lesioned newborn mice.71
Augmentation of another endogenously generated substance with neuroprotective potential, erythropoietin (EPO),72,73 has shown promise against NMDAR-antagonist neurotoxicity in rat74 and mouse75 neonates, in human newborns with hypoxic-ischemic encephalopathy,76 and in extremely preterm human infants.77 What about hypothermia and neonatal brain damage? Creeley and Olney have reported laboratory evidence that hypothermia (30°C) attenuates anesthesia-induced apoptosis in neonatal mice,78 and human trials looking at whole-body hypothermia79 and selective head cooling80 in neonates with hypoxic-ischemic encephalopathy have found a decrease in death and/or moderate-to-severe disability. And magnesium sulfate? Systematic reviews have found a significant reduction in the rate of cerebral palsy in children born to magnesium-treated women at risk of preterm delivery,81,82 and a clinical trial found that postnatal magnesium sulfate treatment improves neurologic outcome for term neonates with severe perinatal asphyxia.83
Have the Data Already Changed Clinical Practice?
How would you answer the following question? A 27-year-old female presents with an operable, benign, slow-growing, barely 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.Use state-of-the-art equipment, procedures, and drugs to proceed with the case?
- B.Discuss with the neurosurgeon evidence that has emerged or gained renewed recognition since 2003 that 4.5 hours of anesthesia may cause neurodegeneration and persistent learning deficits in the developing brain and leave the decision in his or her hands?
- 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 or undergone a caesarean section?
Our guess is that prior to Jevtovic-Todorovic and coauthors' 2003 shot-heard-round-the-anesthesia-world,9 most of us were on the A train. In the absence of survey data, our best guess is that most of us would now opt for B, C, or D.