Is Anesthesia Bad forthe Newborn Brain?

Mary Ellen McCann, MD, MPH, FAAPa,b,*, Sulpicio G. Soriano, MD, FAAPa,b

KEYWORDS

� Neonate � Anesthesia � Neurotoxicity � Neuroapoptosis� Neurocognition

Advances in surgical techniques, pediatric anesthesia, and intensive care have allcontributed to improved survival rates of preterm and newborn infants receivinggeneral anesthesia for a variety of surgical procedures and imaging studies. Recogni-tion of functional nociceptive pathways in these patients has led to the development ofgeneral anesthetic techniques designed to ameliorate the stress response associatedwith painful procedures and decreased perioperative mortality and morbidity.1,2

However, reports of anesthetic-induced neurotoxicity in immature animal modelshave raised questions about the overall safety of general anesthesia in human babies.

Landmark reports have linked the administration of commonly used anesthetic andsedative drugs to neurodegeneration and behavioral deficits in neonatal rats.3,4 Thisphenomenon has subsequently been verified on other mammalian species. Subse-quently, these studies have fueled contentious debates on the clinical relevance ofthese findings in the perioperative care of pediatric patients.5–9 Because the neuro-toxic potential of general anesthesia in infants is a recent controversy within the pedi-atric anesthesia community, there are very few clinical studies available at present tohelp answer this question. In this article, the authors review the relevant preclinical andclinical data that are currently available on this topic.

The developing brain begins with an excess of neurons, which must be physiolog-ically pruned by cell death or apoptosis. This physiologic neurodegeneration is anessential part of normal development.10 Maturation of the central nervous system isinfluenced by external cues. As the immature central nervous system is extremelysensitive to its environment, various exposures and physiologic insults have thepotential to amplify this neurodegenerative process. Establishment of synapticconnections between neurons is an essential process in the formation of neuronal

This work was supported by the CHMC Anesthesia Foundation.a Department of Anesthesia (Pediatrics), Harvard Medical School, 25 Shattuck Street, Boston,MA, USAb Department of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital Boston,300 Longwood Avenue, Boston, MA 02115, USA* Corresponding author. Department of Anesthesiology, Perioperative and Pain Medicine,Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115.E-mail address: mary.mccann@childrens.harvard.edu (M.E. McCann).

Anesthesiology Clin 27 (2009) 269–284doi:10.1016/j.anclin.2009.05.007 anesthesiology.theclinics.com1932-2275/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.

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circuitry and survival. The neurologic development of all mammalian species is similar,although the duration of this development is different and loosely correlates with thelifespan of the organism. In humans, rapid brain growth begins in the intrauterineperiod and continues for the first 2 to 3 years of life. Disruption of this process leadsto central nervous system (CNS) developmental abnormalities and, in many cases,fetal death.11 General anesthetics given to immature animals have been found toincrease the level of apoptosis leading to ‘‘overpruning’’ and abnormally small numberof neurons remaining. Many different types of general anesthetics, sedatives, and anti-convulsants have been implicated in animal models, but all are believed to be relatedto alterations of synaptic transmissions involving the g-amino butyric acid (GABA) orN-methyl-D-aspartate (NMDA) receptors.

Programmed cell death or apoptosis differs from other forms of neuronal cell deathin that it is mediated by the caspase enzyme system within the cytosol. Several path-ways have been discovered that activate the effector caspase system. The intrinsicpathway is a mitochondrial-dependent pathway, in which anesthetic drugs cause anincrease in mitochondrial membrane permeability and release in cytochrome c intothe cytosol, which then recruits the caspase system. The intrinsic system is activatedquickly (within 2 hours of exposure to anesthetic drugs), and in rat studies, melatoninhas been found to decrease the release of cytochrome c into the cytosol and thereforedecrease the degree of apoptosis.12,13

An extrinsic pathway has also been described that involves activation of a proteincalled Fas, a tumor necrosing factor, which also activates the caspase system. Thispathway takes longer to get activated by anesthetics than the intrinsic pathway.12

Although neurotrophins such as nerve growth factor, brain-derived neurotrophicfactor (BDNF), and neurotrophic factor are necessary for neuronal survival, theyhave also been implicated in causing increased neuroapoptosis.14 One recent studyin rats suggested that a triple agent cocktail frequently used in pediatric anesthesia(midazolam, isoflurane, and nitrous oxide) significantly enhanced the BDNF-activatedneuroapoptotic cascades in the cerebral cortex and thalamus.15 Prolonged exposureto ketamine also increases BDNF levels in the developing rat brain.16 The ‘‘triple agentcocktail’’ has also been found to negatively affect levels of synaptic proteins importantin activity-induced synaptic plasticity (eg, synaptophysin, synaptobrevin, amphiphy-sin, SNAP-25, and CaM kinase H).17 This might explain the consistent finding thatanesthetic agents appear to have the greatest neurodegenerative impact when expo-sure occurs during the period of rapid synaptogenesis. Experimental studies inanimals have found that b-estradiol may provide some protection against anes-thetic-induced neurotoxicity by this pathway.18

PRECLINICAL DATAType of Exposures

NMDA antagonists: dose and durationThe neurotoxic effect of ketamine has been extensively investigated in mice, rats, andrhesus monkeys. Rat pups, given doses of 20 to 25 mg/kg every 90 minutes for at leastseven doses on postnatal day seven, show evidence of neurotoxicity, whereas juve-nile rats given the same doses for four or less times show no neurotoxicity.19–21

In mice, single doses of greater than 10 mg/kg intraperitoneally are associated withneuroapoptosis and impaired learning once the mice reach adulthood.22,23 Newerinvestigations on rhesus monkeys have revealed that there is increased neurodegen-eration in monkeys that were exposed prenatally to roughly twice the standardketamine concentrations (20–50 mg/kg/h for 24 hours) used in humans.24 Neonatal

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monkeys exposed to the same doses of ketamine on the fifth day of life also devel-oped increased neurodegeneration of the frontal cortex. However, older monkeysexposed on the 35th day of life did not exhibit any neurodegeneration, even thoughthe plasma ketamine levels of these monkeys was 10 times that found in anesthetizedhumans.24 This same study also demonstrated that when the exposure time wasreduced from 24 hours to 3 hours, there was no neurodegeneration found even inthe postnatal day 5 monkeys.24

Primary cell cultures derived from neonatal rat and rhesus monkey frontal cortex ex-hibited increased DNA fragmentation and apoptosis when incubated in 10 to 20 mMketamine solution for 6 to 48 hours.25,26 Primary neuronal cell culture preparationsshow decrease in dendritic branches and length of dendrites in 2 mg/mL ketaminefor 8 hours or 5 mg/mL for 4 hours.27

Mice given a single dose of ketamine 25 mg/kg subcutaneously on day 10 did notdemonstrate any neurodegeneration, but when the ketamine was combined witheither thiopental 5 mg/kg or propofol 10 mg/kg, there was increased neurodegenera-tion and impaired learning in adult mice.28 Juvenile mice develop accelerated neuro-apoptosis after a single dose of ketamine (20–40 mg/kg) subcutaneously.22,23 Theadministration of nitrous oxide, a mild NMDA receptor antagonist, for 6 hours is asso-ciated with increased caspase 3 expression in the infant mouse but not in the infantrat.4,12,29 Nitrous oxide was also found to significantly increase the degree of neuro-apoptosis in neonatal rat pups and neonatal mouse hippocampal cultures exposedto isoflurane.29 These data demonstrate that neurodegeneration increases withincreasing doses and duration of exposure to NMDA antagonists. These changesare amplified when ketamine is given in combination with other anesthetic agents.

GABAnergic agonists: dose and durationThe anesthetics and sedatives that are implicated in causing increased apoptosis inimmature mammals by way of being GABA agonists include benzodiazepines, barbi-turates, ethanol, propofol, and volatile anesthetics. GABA is the principal fast-actingexcitatory transmitter in the neonatal brain. In contrast to mature neurons, excessivestimulation of this receptor causes excitotoxicity of the neurons and results in celldeath in these immature neuronal populations.30

The preclinical data on benzodiazepine administration seems to be species specific,with neonatal mice being more susceptible to the effects of benzodiazepines thanneonatal rats. Young mice given a dose of diazepam 5 mg/kg developed increased neu-rodegeneration, although these mice later did not develop neurocognitive behavioraldeficits.31 However, neonatal rats required higher doses of diazepam (10–30 mg/kg)before they demonstrated increased neurodegeneration.32 In addition, neonatal micewere susceptible to the neurotoxic effects of midazolam at doses of 9 mg/kg butneonatal rats were not.4,23 The benzodiazepines, clonazepam (0.5–4 mg/kg intraperito-neally) and diazepam (10–30 mg/kg), but not midazolam, are associated with increasedneurotoxicity after a single dose given intraperitoneally or subcutaneously to neonatalrats.31,32 So a variety of different benzodiazepines in single doses can induce neuroa-poptosis in both rats and mice.

There is evidence in neonatal rats that both pentobarbital 5 to 10 mg/kg and pheno-barbital 40 to 100 mg/kg lead to increased apoptosis, but simultaneous administrationof estradiol prevented this neurotoxicity.32,33 Estradiol has been found to increase thelevels of prosurvival proteins, such as extracellular signal-regulated kinase and proteinkinase B, rather than to alter GABA or NMDA currents in hippocampal neuronalcultures.33 In addition, thiopental given to neonatal mice in a dose of 5 to 25 mg/kgdid not lead to apoptosis.28

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Although etomidate has been shown to be a potent GABAnergic transmitterinhibitor, there are no preclinical studies in juvenile animals that demonstrateincreased apoptosis.34 Propofol has shown to have a dose-dependent neurotoxicityin neonatal mice. Doses of 200 mg/kg intraperitoneally are needed to induce a surgicalplane of anesthesia in a neonatal mouse.35 Exposure to a single subclinical dose of10 mg/kg did not lead to either increased neurologic degeneration or functional neuro-logic impairments, but exposure to a higher dose of 50 to 60 mg/kg in neonatal micedid lead to neurodegeneration and long-term functional impairments,28,35 even thoughthis dose is only one-fourth the total dose needed for surgical anesthesia in a mouse.Similar findings were also found in rats with a single high dose of propofol (60 mg/kgsubcutaneously) but not with a small dose (10 mg/kg subcutaneously).28

Exposure to halothane or enflurane for as little as 0.5 hour prenatally is associatedwith learning impairments in mice, and exposure to 2 hours prenatally of halothane2.5% leads to learning disabilities in rats.36 Prolonged exposure to halothane insubclinical doses of 25 to 200 ppm in young rats leads to decrease in cerebral synapticdensity and dendritic numbers.37–39

Isoflurane exposure in young rats and mice has been studied extensively and hasbeen found to lead to increased apoptosis in a manner dependent on the dose dura-tion of exposure. Studies of isoflurane exposure in young rats or mice demonstratethat the rats need to be exposed for at least 4 hours of 0.75% isoflurane for evidenceof neurotoxicity4,12,29,40 to induce increased caspase 3 and 9 activation. The effects ofisoflurane on neonatal rodent neurons are potentiated by midazolam and nitrous oxideand ameliorated by xenon and dexmedetomidine.4,12,15,29,41 Isoflurane in combinationwith midazolam and nitrous oxide has also been shown to increase neuroapoptosis inguinea pigs.42

Sevoflurane has also been shown to increase neuroapoptosis in neonatal mice.Exposure to a subanesthetic concentration of sevoflurane (1.7%) for 2 hours resultedin caspase 3 activation and neurodegeneration in 7-day-old mouse pups.31,43 Anothergroup examined the effect of exposure to sevoflurane for 6 hours in 6-day-old miceand reported increased neuroapoptosis and abnormal social and learningbehaviors.44

Timing of Exposure

All animals studied thus far have shown that the timing of exposure is critical ininducing neurotoxicity. It is generally believed that the exposure needs to occurwhen the CNS is developing, especially during the period of rapid synaptogenesis.Early studies in rats with a potent NMDA receptor antagonist, MK-801, showed thatrats were most vulnerable to neurodegeneration from birth to day 14 of life, withpeak sensitivity occurring on day seven of life. Fetal rats had a minimal increase inMK-801–induced neurodegeneration during the late fetal period (days 19–21) butnone before this period.19 The period of sensitivity in the rat appears to be correlatedto some extent with the peak expression of the NR1 subunit of the NMDA receptor inthe developing rat brain. These data suggest that the rat is most sensitive to NMDAreceptor–mediated neurotoxicity during early neuronal pathway development,referred to as the ‘‘brain-growth spurt period’’ or period of synaptogenesis.45 Micehave been shown to have the same period of vulnerability. Other potential neurotoxicagents, such as isoflurane and ketamine, have also shown peak effects on rodentbrains during this period of synaptogenesis. Rats exposed to 0.75% to 1.5% isoflur-ane for 6 hours demonstrate evidence of neurotoxicity if the exposure occurs on post-natal day seven but do not exhibit any evidence of neurotoxicity if exposed on days10 to 14 and only exhibit neurotoxicity on postnatal days 1 to 3 when exposed to

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1.5% isoflurane.4,12,29 In rhesus monkeys, the period of most susceptibility is frompostconception day 122 to postnatal day five. At postnatal day 35, there was no neu-roapoptosis seen in monkeys exposed to ketamine infusions. In humans, the braingrowth spurt begins in the third trimester of gestation and extends through the thirdyear of life.46 So it would appear that the period of susceptibility to neuroapoptosisfor humans would extend through this time period. However, the period of maximalsusceptibility to neuron-apoptotic injury in humans is controversial. Efforts to deter-mine the point of maximum vulnerability for humans have also been addressed usingneuroinformatics, an analysis that combines neuroscience, evolutionary science,statistical modeling, and computer science, and this analysis reveals that the maximalpoint of vulnerability for humans may be at 17 to 20 weeks postconception, which isbefore the third trimester of pregnancy.47,48 This analysis is bolstered by additionalwork examining the most ethanol-sensitive times for the human conceptus usingdata from seasonal alcohol consumption and determining lag times, which suggeststhat the human fetus is most sensitive to fetal alcohol syndrome during the 18th to20th week postconception.49 Ethanol is a potent neurotoxin that has NMDA antago-nist and GABA mimetic properties, which are believed to be responsible for itsapoptotic action. Single doses of ethanol intoxication given to rodents can activatea massive wave of apoptotic neurodegeneration.5 So, although the period of maximalvulnerability has been determined for several mammalian species, there are still greatuncertainties about this period in humans.

Exposure Effects or Outcomes

The histopathologic brain findings in exposed animals include increased apoptoticneurodegeneration of the laterodorsal thalamus, hippocampus, cortex, and caudateputamen.23,31,50 A few studies have demonstrated neurodegeneration with pre- orpostnatal exposure initially but then no functional neurocognitive deficits later whenthe animals reached maturity, perhaps indicating neurologic plasticity.22,31,51,52

Most of the studies that revealed widespread neurodegeneration on histopathologyalso revealed neurocognitive behavioral issues later in the life of the exposed animals.The functional deficits described include disruption of spontaneous activity, learningacquisition, and impaired memory retention in adult mice that were exposed to propo-fol, or a combination of propofol with thiopental, or ketamine during the neonatalperiod.31 There were also more errors in maze tasks and learning tasks found in adultrats exposed to halothane or a combination of isoflurane, midazolam, and nitrousoxide, exposed either prenatally or postnatally.4,53,54

CLINICAL HUMAN DATA

There are several difficulties in extrapolating the results from rat and small mammalstudies to the human population. There are uncertainties about the determination ofthe timing of potential vulnerability during human development. Other possibleconfounders exist. Human infants are very carefully monitored during anesthesia,with great care taken to ensure that they are hemodynamically and electrophysiolog-ically stable throughout the perioperative period, with additional attention paid to theirongoing nutritional needs. It is impossible to care for newborn infant rats with the sameattention because of the limitations imposed on researchers by the extreme small sizeof these research subjects. In addition, there may be some genetic factors withinhumans that allow for greater brain plasticity after general anesthesia.

Although not much data have been published yet specifically examining thepossible effects of anesthesia, there are several published reports on the

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neurodevelopmental outcomes of children who were born prematurely or who havehad surgery at a young age. Because of the multiple confounders in most of thesestudies, it is difficult to conclusively determine whether general anesthetics are safefor young children. There are many known predictors of poor neurodevelopmentaloutcomes, such as low birth weight, prematurity, morbidity at birth, and low maternalsocioeconomic status, which are not controlled for in some of these studies. In addi-tion, it is probable that the perioperative events surrounding surgery independent ofthe general anesthesia may impact on neurologic development of young children,such as perioperative fasting, transport, hypothermia, hemodynamic instability, andstress response secondary to surgical stimulus.

Prenatal Human Exposure to General Anesthesia

In a study of Japanese full-term infants who were exposed to nitrous oxide during thelast stages of delivery, there was statistically significant increase in neurologicsequelae at postnatal day five compared with infants who were not exposed to anes-thesia.55 These sequelae included weaker habituation to sound, stronger musculartension, fewer smiles, and resistance to cuddling. Exposure to either short durationof general anesthesia or a small amount of local anesthesia for maternal dental proce-dures during pregnancy was found to be associated with a prolongation of visualpattern preference in the neonates and lower scores at age 4 on the Peabody PictureVocabulary Test but no differences between cases and controls at age 4 on theWechsler Preschool Primary Scales of Intelligence (WPPI) or the Stanford-Binet Intel-ligence Test. This study was limited by the small number of participants (39 totalpatients with nine patients prenatally exposed to anesthesia) and possibility of con-founding by indication (maternal stress and morbidity).56,57

Neonatal or Early Infantile Human Exposure to General Anesthesia

Several studies have reported the neurodevelopmental outcomes of neonates whohave had surgery at a very young age. Most of the studies have been cohort orcase-control studies, and the primary exposure examined has not been anesthesiabut surgery. The Victorian Infant Collaborative Study Group did a case-control studyof infants born less than 27 weeks postconception who had patent ductus arteriosus(PDA) ligation, inguinal hernia repair, gastrointestinal surgery, neurosurgery, andtracheotomy, and compared them with age-matched controls who did not requiresurgery, for a total of 221 infants. They found that there was an increased incidenceof cerebral palsy, blindness, deafness, and WPPI <3 standard deviation below themean.58 In another study involving almost 4000 extremely low-birth-weight infants,there was a higher incidence of cerebral palsy and lower Bayley Scales of Infant Devel-opment 2 scores in patients who had been treated surgically for necrotizing enteroco-litis (NEC) compared with those treated with peritoneal drainage.59 Five other smallerstudies corroborated the findings that premature infants treated for NEC surgicallyhave more neurocognitive deficits compared with those treated medically.60–64

However, infants with isolated tracheoesophageal fistula repair, when tested in latechildhood, did not have statistically different intelligence quotient (IQ) measurementscompared with the general population.65,66 These children were exposed to generalanesthesia at a later postconceptual age than the age of the children in the NECstudies. A study that compared PDA ligation with indomethacin treatment revealedthat there was an increase in cerebral palsy, cognitive delay, hearing loss, and blind-ness in the surgically treated group. Multiple outcome studies in children who havehad cardiac surgeries as neonates have demonstrated increased incidence of cere-bral palsy, lower IQs, speech and language impairment, and motor dysfunction.67–75

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A prospective randomized trial that compared surgery for transposition of the greatvessels followed 155 patients and did neurologic assessments at ages 1, 2.5, 4,and 8 years found that although the mean scores for most outcomes were withinnormal limits, the neurodevelopmental status of the cohort as a whole was belowexpectation, including academic achievement, fine motor function, visual spatial skills,working memory, hypothesis generating and testing, sustained attention, and higher-order language skills.67–69

There have also been some studies examining the neurocognitive outcomes ofinfants exposed to prolonged sedation in the neonatal intensive care unit. In theNeonatal Outcome and Prolonged Analgesia in Neonates (NOPAIN) trial, Anand andcolleagues76 noted that there was a poorer neurologic outcome and increasedmortality in premature infants sedated for prolonged periods of time with midazolamcompared with placebo or morphine. Poor neurologic outcomes (grade 3–4 intraven-tricular hemorrhages, periventricular malacia, and death) occurred in 24% of neonatesin the placebo group, 32% in the midazolam group, and 4% in the morphine group,leading a Cochrane review to find that there was no evidence to support the use ofmidazolam in the neonatal intensive care unit (NICU).77

With the exception of the NOPAIN trial, the exposure of interest in these studies wasnot general anesthesia or sedatives; therefore, it is difficult to draw conclusions aboutthe poorer neurologic outcomes found in most studies of infants who had surgicaltreatment rather than medical treatment. Most of the studies done in these infantswere case-control or cohort studies rather than randomized control trials. Thus, therewere many possible confounding variables that may have affected the neurologicoutcome measures. The degree of presurgical morbidity may be one of the reasonsthat some infants had surgery for PDA and NEC rather than medical therapy. Inchildren undergoing inguinal herniorrhaphies, a possible confounder might bea complicated respiratory neonatal course, which has been linked to both a higherincidence of inguinal hernias and to poorer neurologic outcomes.78 The effects ofsurgery in these studies cannot be separated from the effects of general anesthesia.Neonates often receive increased inspired oxygen during transport to the operatingrooms and during surgical procedures, which can be another source of neurotox-icity.79 In the elderly, the inflammatory response activated by the trauma of surgerycan accelerate neurodegenerative disease.80,81 It is not known if the surgical inflam-matory response leads to long-term neurologic development issues in children.

Early Childhood Human Exposure to General Anesthesia

Many of the agents suspected of causing neurotoxicity have been administered forprolonged periods to children in intensive care for the purposes of sedation. Thereare several very small case series that report short-term neurologic abnormalities inchildren exposed to these agents.82–86 These findings are difficult to interpret becausethere are many reasons, in addition to the actions of the sedatives, that may be caus-ative of the neurologic sequelae, including concomitant hypoxia, hypotension, infec-tion, and antecedent neurologic trauma.

Midazolam, when given in conjunction with opioids, is associated with agitation,muscle twitching, myoclonus, chorea, facial grimacing, hallucinations, and disorienta-tion in 11% to 50% of patients when it is discontinued after an infusion in children.82–86

Symptoms usually resolve completely within 7 days. In two small case series (totalnumber of patients, 48), when pentobarbital was given as a sedation agent for at least1 day in conjunction with benzodiazepines, it was associated with agitation, anxiety,sweating, and muscle twitching in up to 35% of patients on cessation.83,87 However,

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there were no short-term neurologic sequelae found in a very small series of sixpatients who were sedated with pentobarbital from 4 to 28 days.88

No neurologic sequelae other than immediate sedation were found in a case seriesof 18 children aged 1 month to 7 years given an inadvertent overdose of ketamine (13–56 mg/kg).89 In a pilot study of children sedated with repetitive doses of ketamine orpropofol for radiation therapy for retinoblastoma, a trend toward learning deficits andseizure disorders was noted in the sedated group compared with the nonsedatedgroup.90

In 3 case series involving a total of 25 patients aged 1 month to 19 years whoreceived isoflurane in conjunction with benzodiazepines for 1 to 497 minimum alveolarconcentration (MAC)-hours, temporary neurologic sequelae included agitation, non-purposeful movement, myoclonus, hallucinations, and confusion on cessation of thevolatile gas.91–93 All symptoms resolved within a few days, and normal neurologicfollow-up 4 to 6 weeks later was reported for all 12 patients in one of the case series.

Several studies have attempted to quantify the psychologic changes that may occurafter an anesthetic and surgery in young children. In a large meta-analysis at a medicalcenter, more maladaptive behaviors postoperatively were noted in children who wereyounger and whose parents were more anxious on induction.94 Several studies havenoted that the maladaptive behaviors determined by parental report occur morefrequently in children less than 3 years of age compared with older children.95–97

The maladaptive behaviors most often reported are night terrors, oppositionalbehavior, bedwetting, and changes in feeding routines. Young children given a mida-zolam premedication in addition to their general anesthetic exhibit less maladaptivebehaviors compared with those who do not get a premedication, although by6 months, 20% of children will still exhibit some behavioral problems that parents attri-bute to the surgical experience.98

There has been interest in doing epidemiologic studies to determine whethergeneral anesthesia is associated with learning disabilities. In a large retrospectivecohort study of 5357 children, 593 patients were identified as having one or moregeneral anesthetics before age 4 years.99 This study found that there were significantlymore reading, written language, and math learning disabilities in children who hadbeen exposed to two or more general anesthetics but no increase in disabilities inthose children who had been exposed to a single anesthetic. The risk for learningdisabilities also increased with the cumulative duration of the general anesthesia. Inanother epidemiologic study, a birth cohort of 5000 patients was identified from theNew York State Medicaid billing codes.100 Of this group, 625 patients underwentinguinal herniorraphy at a young age. After controlling for gender and low birth weight,the authors found nearly a twofold increase in developmental and behavioral issues. Ina pilot study to test the feasibility of using a validated child behavior checklist in 314children who had urologic surgery, it was determined that there was more disturbedneurobehavioral development in children who underwent surgery before age 24months compared with those who underwent surgery after age 24 months, althoughthe differences between the two groups were not statistically significant.101 Thesestudies are provocative, but the data do not reveal whether anesthesia itself maycontribute to developmental issues or whether the need for anesthesia is a markerfor other unidentified factors that contribute to these.

Beneficial Effects of Anesthesia for Newborns

Isoflurane and other NMDA antagonists, such as ketamine, in preclinical studies in thesetting of hypoxia decrease the total amount of neuronal loss. At least in in vivo exper-iments, this protection is greater in hippocampal slides derived from 5-day-old rats

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compared with 23-month-old rats.102 Although only hypothermic protection has beenshown to improve clinical outcome in perinatal hypoxic-ischemic encephalopathy,additional benefit may require adjunctive agents.103 The entry of calcium into theneuron appears to be the key element in cell death, and it is known that duringasphyxia, excessive glutamate is released, which stimulates the voltage-dependentNMDA receptor to open with an accumulation of excess intracellular calcium.104

MK-801, a potent NMDA receptor antagonist, has been shown to limit the extent ofcortical neuronal infarction after asphyxia in 7-day-old rat pups.105 The picture ofthe role of NMDA antagonist in cerebral protection is further clouded by the factthat perinatal hypoxic-ischemic injury is associated with more concomitant apoptoticcell death in infants than similar injury to the adult CNS.106

There is accumulating evidence that pain systems develop and function very early inthe gestational period.107 It is believed that the nociceptive nervous system is mostlymature by 23 to 25 weeks postconceptual age in humans but that the antinociceptivesystem develops later in infancy leaving premature and term infants more sensitive topain than adults.108 Animal models have shown that sensory nerve fibers involved innociception grow out of the dorsal root ganglia during the prenatal period and even-tually innervate the skin starting with the trunk and ending with the limbs.109 Thelarger-diameter A fibers migrate first from the dorsal root to the periphery to forma cutaneous nerve plexus, which is followed by migration of C fibers. The last elementsto appear are descending fibers from the brainstem, which modulate excitation andinhibition.107,108

Several short-term and long-term consequences of tissue damage during thisdevelopmental period have been reported.108,109 In immature animal models, chronicpainful stimuli can provoke cell death in the cortical, thalamic, hypothalamic, amyda-loid, and hippocampal areas of the neonatal rat brain.110

Although many nervous system responses may resolve after an injury has healed,tissue damage during certain critical periods of development may have a more lastingeffect even into adulthood.108,109 There are several clinical correlates in which expo-sure to painful stimulation has altered human behavior. In a cohort study of 87 infantswho had undergone circumcision, circumcision with EMLA (eutectic mixture of localanesthetics) pretreatment, and no circumcision, those infants who underwent circum-cision without pretreatment had the highest pain scores on vaccination at age 4 to6 months.111 There are changes in pain thresholds in children who are graduates ofNICUs, which can persist until the children reach their teenage years.112 Severalpossible mechanisms exist to account for this, including alterations in synapticconnectivity and signaling, changes in the balance of inhibition versus excitation,and increased terminal density in the injured area resulting from increased concentra-tion of nerve growth factor.108,109 Early postnatal pain may also affect neurodevelop-ment through stress responses. In a study designed to evaluate the relationshipbetween early pain and stress, repeated painful experiences seemed to affect subse-quent responses to open field habituation, an index of emotionality.113

SUMMARY

Although certain emerging data suggest that common general anesthetics may beneurotoxic to immature animals, there are also data suggesting that these same anes-thetics may be neuroprotective against hypoxic-ischemic injury, and that inadequateanalgesia during painful procedures may lead to increased neuronal cell death inanimals and long-term behavioral changes in humans. The challenge for the pediatricanesthesia community is to design and implement studies in human infants to

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ascertain the safety of general anesthesia. It is likely that the answer to whethergeneral anesthetics are neurotoxic to young babies will require many different studyapproaches, including epidemiologic, case-control, and randomized controltrials.114–116 The permanent neurocognitive damage caused by general anestheticsis likely to be subtle in nature, if it exists, and thus may be difficult to measure. Itmay take many years of following cohorts of youngsters until maturity before someof these possible neurocognitive abnormalities are manifest. In the meantime, it isimportant to continue the preclinical studies to elucidate the general anesthetics leastlikely to be neurotoxic in the setting of painful stimulation.

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