Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.



Published on

  • Be the first to comment

  • Be the first to like this


  1. 1. Is Anesthesia Bad for the Newb orn 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 all contributed to improved survival rates of preterm and newborn infants receiving general anesthesia for a variety of surgical procedures and imaging studies. Recogni- tion of functional nociceptive pathways in these patients has led to the development of general anesthetic techniques designed to ameliorate the stress response associated with painful procedures and decreased perioperative mortality and morbidity.1,2 However, reports of anesthetic-induced neurotoxicity in immature animal models have raised questions about the overall safety of general anesthesia in human babies. Landmark reports have linked the administration of commonly used anesthetic and sedative drugs to neurodegeneration and behavioral deficits in neonatal rats.3,4 This phenomenon has subsequently been verified on other mammalian species. Subse- quently, these studies have fueled contentious debates on the clinical relevance of these 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 to help answer this question. In this article, the authors review the relevant preclinical and clinical 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 an essential part of normal development.10 Maturation of the central nervous system is influenced by external cues. As the immature central nervous system is extremely sensitive to its environment, various exposures and physiologic insults have the potential to amplify this neurodegenerative process. Establishment of synaptic connections 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, USA b 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: (M.E. McCann). Anesthesiology Clin 27 (2009) 269–284 doi:10.1016/j.anclin.2009.05.007 1932-2275/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
  2. 2. 270 McCann Soriano circuitry and survival. The neurologic development of all mammalian species is similar, although the duration of this development is different and loosely correlates with the lifespan of the organism. In humans, rapid brain growth begins in the intrauterine period and continues for the first 2 to 3 years of life. Disruption of this process leads to central nervous system (CNS) developmental abnormalities and, in many cases, fetal death.11 General anesthetics given to immature animals have been found to increase the level of apoptosis leading to ‘‘overpruning’’ and abnormally small number of neurons remaining. Many different types of general anesthetics, sedatives, and anti- convulsants have been implicated in animal models, but all are believed to be related to alterations of synaptic transmissions involving the g-amino butyric acid (GABA) or N-methyl-D-aspartate (NMDA) receptors. Programmed cell death or apoptosis differs from other forms of neuronal cell death in 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 intrinsic pathway is a mitochondrial-dependent pathway, in which anesthetic drugs cause an increase in mitochondrial membrane permeability and release in cytochrome c into the cytosol, which then recruits the caspase system. The intrinsic system is activated quickly (within 2 hours of exposure to anesthetic drugs), and in rat studies, melatonin has been found to decrease the release of cytochrome c into the cytosol and therefore decrease the degree of apoptosis.12,13 An extrinsic pathway has also been described that involves activation of a protein called Fas, a tumor necrosing factor, which also activates the caspase system. This pathway takes longer to get activated by anesthetics than the intrinsic pathway.12 Although neurotrophins such as nerve growth factor, brain-derived neurotrophic factor (BDNF), and neurotrophic factor are necessary for neuronal survival, they have also been implicated in causing increased neuroapoptosis.14 One recent study in rats suggested that a triple agent cocktail frequently used in pediatric anesthesia (midazolam, isoflurane, and nitrous oxide) significantly enhanced the BDNF-activated neuroapoptotic cascades in the cerebral cortex and thalamus.15 Prolonged exposure to ketamine also increases BDNF levels in the developing rat brain.16 The ‘‘triple agent cocktail’’ has also been found to negatively affect levels of synaptic proteins important in activity-induced synaptic plasticity (eg, synaptophysin, synaptobrevin, amphiphy- sin, SNAP-25, and CaM kinase H).17 This might explain the consistent finding that anesthetic agents appear to have the greatest neurodegenerative impact when expo- sure occurs during the period of rapid synaptogenesis. Experimental studies in animals have found that b-estradiol may provide some protection against anes- thetic-induced neurotoxicity by this pathway.18 PRECLINICAL DATA Type of Exposures NMDA antagonists: dose and duration The neurotoxic effect of ketamine has been extensively investigated in mice, rats, and rhesus monkeys. Rat pups, given doses of 20 to 25 mg/kg every 90 minutes for at least seven 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 with neuroapoptosis and impaired learning once the mice reach adulthood.22,23 Newer investigations on rhesus monkeys have revealed that there is increased neurodegen- eration in monkeys that were exposed prenatally to roughly twice the standard ketamine concentrations (20–50 mg/kg/h for 24 hours) used in humans.24 Neonatal
  3. 3. Is Anesthesia Bad for the Newborn Brain? 271 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 monkeys exposed on the 35th day of life did not exhibit any neurodegeneration, even though the plasma ketamine levels of these monkeys was 10 times that found in anesthetized humans.24 This same study also demonstrated that when the exposure time was reduced from 24 hours to 3 hours, there was no neurodegeneration found even in the 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 mM ketamine solution for 6 to 48 hours.25,26 Primary neuronal cell culture preparations show decrease in dendritic branches and length of dendrites in 2 mg/mL ketamine for 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 not demonstrate any neurodegeneration, but when the ketamine was combined with either 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 The administration 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 infant rat.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 exposed to isoflurane.29 These data demonstrate that neurodegeneration increases with increasing doses and duration of exposure to NMDA antagonists. These changes are amplified when ketamine is given in combination with other anesthetic agents. GABAnergic agonists: dose and duration The anesthetics and sedatives that are implicated in causing increased apoptosis in immature mammals by way of being GABA agonists include benzodiazepines, barbi- turates, ethanol, propofol, and volatile anesthetics. GABA is the principal fast-acting excitatory transmitter in the neonatal brain. In contrast to mature neurons, excessive stimulation of this receptor causes excitotoxicity of the neurons and results in cell death 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 than neonatal rats. Young mice given a dose of diazepam 5 mg/kg developed increased neu- rodegeneration, although these mice later did not develop neurocognitive behavioral deficits.31 However, neonatal rats required higher doses of diazepam (10–30 mg/kg) before they demonstrated increased neurodegeneration.32 In addition, neonatal mice were susceptible to the neurotoxic effects of midazolam at doses of 9 mg/kg but neonatal 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 increased neurotoxicity after a single dose given intraperitoneally or subcutaneously to neonatal rats.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 administration of estradiol prevented this neurotoxicity.32,33 Estradiol has been found to increase the levels of prosurvival proteins, such as extracellular signal-regulated kinase and protein kinase B, rather than to alter GABA or NMDA currents in hippocampal neuronal cultures.33 In addition, thiopental given to neonatal mice in a dose of 5 to 25 mg/kg did not lead to apoptosis.28
  4. 4. 272 McCann Soriano Although etomidate has been shown to be a potent GABAnergic transmitter inhibitor, there are no preclinical studies in juvenile animals that demonstrate increased apoptosis.34 Propofol has shown to have a dose-dependent neurotoxicity in neonatal mice. Doses of 200 mg/kg intraperitoneally are needed to induce a surgical plane of anesthesia in a neonatal mouse.35 Exposure to a single subclinical dose of 10 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 mice did lead to neurodegeneration and long-term functional impairments,28,35 even though this 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/kg subcutaneously) 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 associated with learning impairments in mice, and exposure to 2 hours prenatally of halothane 2.5% leads to learning disabilities in rats.36 Prolonged exposure to halothane in subclinical doses of 25 to 200 ppm in young rats leads to decrease in cerebral synaptic density and dendritic numbers.37–39 Isoflurane exposure in young rats and mice has been studied extensively and has been 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 demonstrate that the rats need to be exposed for at least 4 hours of 0.75% isoflurane for evidence of neurotoxicity4,12,29,40 to induce increased caspase 3 and 9 activation. The effects of isoflurane on neonatal rodent neurons are potentiated by midazolam and nitrous oxide and ameliorated by xenon and dexmedetomidine.4,12,15,29,41 Isoflurane in combination with midazolam and nitrous oxide has also been shown to increase neuroapoptosis in guinea 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 resulted in caspase 3 activation and neurodegeneration in 7-day-old mouse pups.31,43 Another group examined the effect of exposure to sevoflurane for 6 hours in 6-day-old mice and reported increased neuroapoptosis and abnormal social and learning behaviors.44 Timing of Exposure All animals studied thus far have shown that the timing of exposure is critical in inducing neurotoxicity. It is generally believed that the exposure needs to occur when the CNS is developing, especially during the period of rapid synaptogenesis. Early studies in rats with a potent NMDA receptor antagonist, MK-801, showed that rats were most vulnerable to neurodegeneration from birth to day 14 of life, with peak sensitivity occurring on day seven of life. Fetal rats had a minimal increase in MK-801–induced neurodegeneration during the late fetal period (days 19–21) but none before this period.19 The period of sensitivity in the rat appears to be correlated to some extent with the peak expression of the NR1 subunit of the NMDA receptor in the developing rat brain. These data suggest that the rat is most sensitive to NMDA receptor–mediated neurotoxicity during early neuronal pathway development, referred to as the ‘‘brain-growth spurt period’’ or period of synaptogenesis.45 Mice have been shown to have the same period of vulnerability. Other potential neurotoxic agents, such as isoflurane and ketamine, have also shown peak effects on rodent brains 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 days 10 to 14 and only exhibit neurotoxicity on postnatal days 1 to 3 when exposed to
  5. 5. Is Anesthesia Bad for the Newborn Brain? 273 1.5% isoflurane.4,12,29 In rhesus monkeys, the period of most susceptibility is from postconception 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 brain growth spurt begins in the third trimester of gestation and extends through the third year of life.46 So it would appear that the period of susceptibility to neuroapoptosis for humans would extend through this time period. However, the period of maximal susceptibility to neuron-apoptotic injury in humans is controversial. Efforts to deter- mine the point of maximum vulnerability for humans have also been addressed using neuroinformatics, an analysis that combines neuroscience, evolutionary science, statistical modeling, and computer science, and this analysis reveals that the maximal point of vulnerability for humans may be at 17 to 20 weeks postconception, which is before the third trimester of pregnancy.47,48 This analysis is bolstered by additional work examining the most ethanol-sensitive times for the human conceptus using data from seasonal alcohol consumption and determining lag times, which suggests that the human fetus is most sensitive to fetal alcohol syndrome during the 18th to 20th week postconception.49 Ethanol is a potent neurotoxin that has NMDA antago- nist and GABA mimetic properties, which are believed to be responsible for its apoptotic action. Single doses of ethanol intoxication given to rodents can activate a massive wave of apoptotic neurodegeneration.5 So, although the period of maximal vulnerability has been determined for several mammalian species, there are still great uncertainties about this period in humans. Exposure Effects or Outcomes The histopathologic brain findings in exposed animals include increased apoptotic neurodegeneration of the laterodorsal thalamus, hippocampus, cortex, and caudate putamen.23,31,50 A few studies have demonstrated neurodegeneration with pre- or postnatal exposure initially but then no functional neurocognitive deficits later when the animals reached maturity, perhaps indicating neurologic plasticity.22,31,51,52 Most of the studies that revealed widespread neurodegeneration on histopathology also revealed neurocognitive behavioral issues later in the life of the exposed animals. The functional deficits described include disruption of spontaneous activity, learning acquisition, and impaired memory retention in adult mice that were exposed to propo- fol, or a combination of propofol with thiopental, or ketamine during the neonatal period.31 There were also more errors in maze tasks and learning tasks found in adult rats exposed to halothane or a combination of isoflurane, midazolam, and nitrous oxide, exposed either prenatally or postnatally.4,53,54 CLINICAL HUMAN DATA There are several difficulties in extrapolating the results from rat and small mammal studies to the human population. There are uncertainties about the determination of the timing of potential vulnerability during human development. Other possible confounders 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 their ongoing nutritional needs. It is impossible to care for newborn infant rats with the same attention because of the limitations imposed on researchers by the extreme small size of these research subjects. In addition, there may be some genetic factors within humans that allow for greater brain plasticity after general anesthesia. Although not much data have been published yet specifically examining the possible effects of anesthesia, there are several published reports on the
  6. 6. 274 McCann Soriano neurodevelopmental outcomes of children who were born prematurely or who have had surgery at a young age. Because of the multiple confounders in most of these studies, it is difficult to conclusively determine whether general anesthetics are safe for young children. There are many known predictors of poor neurodevelopmental outcomes, such as low birth weight, prematurity, morbidity at birth, and low maternal socioeconomic status, which are not controlled for in some of these studies. In addi- tion, it is probable that the perioperative events surrounding surgery independent of the general anesthesia may impact on neurologic development of young children, such as perioperative fasting, transport, hypothermia, hemodynamic instability, and stress 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 the last stages of delivery, there was statistically significant increase in neurologic sequelae at postnatal day five compared with infants who were not exposed to anes- thesia.55 These sequelae included weaker habituation to sound, stronger muscular tension, fewer smiles, and resistance to cuddling. Exposure to either short duration of 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 visual pattern preference in the neonates and lower scores at age 4 on the Peabody Picture Vocabulary Test but no differences between cases and controls at age 4 on the Wechsler Preschool Primary Scales of Intelligence (WPPI) or the Stanford-Binet Intel- ligence Test. This study was limited by the small number of participants (39 total patients 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 who have had surgery at a very young age. Most of the studies have been cohort or case-control studies, and the primary exposure examined has not been anesthesia but surgery. The Victorian Infant Collaborative Study Group did a case-control study of infants born less than 27 weeks postconception who had patent ductus arteriosus (PDA) ligation, inguinal hernia repair, gastrointestinal surgery, neurosurgery, and tracheotomy, and compared them with age-matched controls who did not require surgery, for a total of 221 infants. They found that there was an increased incidence of cerebral palsy, blindness, deafness, and WPPI 3 standard deviation below the mean.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 smaller studies corroborated the findings that premature infants treated for NEC surgically have more neurocognitive deficits compared with those treated medically.60–64 However, infants with isolated tracheoesophageal fistula repair, when tested in late childhood, did not have statistically different intelligence quotient (IQ) measurements compared with the general population.65,66 These children were exposed to general anesthesia at a later postconceptual age than the age of the children in the NEC studies. A study that compared PDA ligation with indomethacin treatment revealed that 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 have had cardiac surgeries as neonates have demonstrated increased incidence of cere- bral palsy, lower IQs, speech and language impairment, and motor dysfunction.67–75
  7. 7. Is Anesthesia Bad for the Newborn Brain? 275 A prospective randomized trial that compared surgery for transposition of the great vessels 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 within normal limits, the neurodevelopmental status of the cohort as a whole was below expectation, 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 of infants exposed to prolonged sedation in the neonatal intensive care unit. In the Neonatal Outcome and Prolonged Analgesia in Neonates (NOPAIN) trial, Anand and colleagues76 noted that there was a poorer neurologic outcome and increased mortality in premature infants sedated for prolonged periods of time with midazolam compared with placebo or morphine. Poor neurologic outcomes (grade 3–4 intraven- tricular hemorrhages, periventricular malacia, and death) occurred in 24% of neonates in 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 of midazolam in the neonatal intensive care unit (NICU).77 With the exception of the NOPAIN trial, the exposure of interest in these studies was not general anesthesia or sedatives; therefore, it is difficult to draw conclusions about the poorer neurologic outcomes found in most studies of infants who had surgical treatment rather than medical treatment. Most of the studies done in these infants were case-control or cohort studies rather than randomized control trials. Thus, there were many possible confounding variables that may have affected the neurologic outcome measures. The degree of presurgical morbidity may be one of the reasons that some infants had surgery for PDA and NEC rather than medical therapy. In children undergoing inguinal herniorrhaphies, a possible confounder might be a complicated respiratory neonatal course, which has been linked to both a higher incidence of inguinal hernias and to poorer neurologic outcomes.78 The effects of surgery in these studies cannot be separated from the effects of general anesthesia. Neonates often receive increased inspired oxygen during transport to the operating rooms and during surgical procedures, which can be another source of neurotox- icity.79 In the elderly, the inflammatory response activated by the trauma of surgery can 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 for prolonged periods to children in intensive care for the purposes of sedation. There are several very small case series that report short-term neurologic abnormalities in children exposed to these agents.82–86 These findings are difficult to interpret because there 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 (total number of patients, 48), when pentobarbital was given as a sedation agent for at least 1 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,
  8. 8. 276 McCann Soriano there were no short-term neurologic sequelae found in a very small series of six patients who were sedated with pentobarbital from 4 to 28 days.88 No neurologic sequelae other than immediate sedation were found in a case series of 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 or propofol for radiation therapy for retinoblastoma, a trend toward learning deficits and seizure disorders was noted in the sedated group compared with the nonsedated group.90 In 3 case series involving a total of 25 patients aged 1 month to 19 years who received isoflurane in conjunction with benzodiazepines for 1 to 497 minimum alveolar concentration (MAC)-hours, temporary neurologic sequelae included agitation, non- purposeful movement, myoclonus, hallucinations, and confusion on cessation of the volatile gas.91–93 All symptoms resolved within a few days, and normal neurologic follow-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 occur after an anesthetic and surgery in young children. In a large meta-analysis at a medical center, more maladaptive behaviors postoperatively were noted in children who were younger and whose parents were more anxious on induction.94 Several studies have noted that the maladaptive behaviors determined by parental report occur more frequently in children less than 3 years of age compared with older children.95–97 The maladaptive behaviors most often reported are night terrors, oppositional behavior, bedwetting, and changes in feeding routines. Young children given a mida- zolam premedication in addition to their general anesthetic exhibit less maladaptive behaviors compared with those who do not get a premedication, although by 6 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 whether general anesthesia is associated with learning disabilities. In a large retrospective cohort study of 5357 children, 593 patients were identified as having one or more general anesthetics before age 4 years.99 This study found that there were significantly more reading, written language, and math learning disabilities in children who had been exposed to two or more general anesthetics but no increase in disabilities in those children who had been exposed to a single anesthetic. The risk for learning disabilities also increased with the cumulative duration of the general anesthesia. In another epidemiologic study, a birth cohort of 5000 patients was identified from the New York State Medicaid billing codes.100 Of this group, 625 patients underwent inguinal 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. In a pilot study to test the feasibility of using a validated child behavior checklist in 314 children who had urologic surgery, it was determined that there was more disturbed neurobehavioral development in children who underwent surgery before age 24 months compared with those who underwent surgery after age 24 months, although the differences between the two groups were not statistically significant.101 These studies are provocative, but the data do not reveal whether anesthesia itself may contribute to developmental issues or whether the need for anesthesia is a marker for 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 the setting 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
  9. 9. Is Anesthesia Bad for the Newborn Brain? 277 compared with 23-month-old rats.102 Although only hypothermic protection has been shown to improve clinical outcome in perinatal hypoxic-ischemic encephalopathy, additional benefit may require adjunctive agents.103 The entry of calcium into the neuron appears to be the key element in cell death, and it is known that during asphyxia, excessive glutamate is released, which stimulates the voltage-dependent NMDA 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 of cortical neuronal infarction after asphyxia in 7-day-old rat pups.105 The picture of the role of NMDA antagonist in cerebral protection is further clouded by the fact that perinatal hypoxic-ischemic injury is associated with more concomitant apoptotic cell death in infants than similar injury to the adult CNS.106 There is accumulating evidence that pain systems develop and function very early in the gestational period.107 It is believed that the nociceptive nervous system is mostly mature by 23 to 25 weeks postconceptual age in humans but that the antinociceptive system develops later in infancy leaving premature and term infants more sensitive to pain than adults.108 Animal models have shown that sensory nerve fibers involved in nociception 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 The larger-diameter A fibers migrate first from the dorsal root to the periphery to form a cutaneous nerve plexus, which is followed by migration of C fibers. The last elements to appear are descending fibers from the brainstem, which modulate excitation and inhibition.107,108 Several short-term and long-term consequences of tissue damage during this developmental period have been reported.108,109 In immature animal models, chronic painful 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 lasting effect 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 infants who had undergone circumcision, circumcision with EMLA (eutectic mixture of local anesthetics) pretreatment, and no circumcision, those infants who underwent circum- cision without pretreatment had the highest pain scores on vaccination at age 4 to 6 months.111 There are changes in pain thresholds in children who are graduates of NICUs, which can persist until the children reach their teenage years.112 Several possible mechanisms exist to account for this, including alterations in synaptic connectivity 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 relationship between 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 be neurotoxic to immature animals, there are also data suggesting that these same anes- thetics may be neuroprotective against hypoxic-ischemic injury, and that inadequate analgesia during painful procedures may lead to increased neuronal cell death in animals and long-term behavioral changes in humans. The challenge for the pediatric anesthesia community is to design and implement studies in human infants to
  10. 10. 278 McCann Soriano ascertain the safety of general anesthesia. It is likely that the answer to whether general anesthetics are neurotoxic to young babies will require many different study approaches, including epidemiologic, case-control, and randomized control trials.114–116 The permanent neurocognitive damage caused by general anesthetics is likely to be subtle in nature, if it exists, and thus may be difficult to measure. It may take many years of following cohorts of youngsters until maturity before some of these possible neurocognitive abnormalities are manifest. In the meantime, it is important to continue the preclinical studies to elucidate the general anesthetics least likely to be neurotoxic in the setting of painful stimulation. REFERENCES 1. Hickey PR, Hansen DD. High-dose fentanyl reduces intraoperative ventricular fibrillation in neonates with hypoplastic left heart syndrome. J Clin Anesth 1991;3:295–300. 2. Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. Anesthesiology 1990;73:661–70. 3. Ikonomidou C, Bittigau P, Koch C, et al. Neurotransmitters and apoptosis in the developing brain. Biochem Pharmacol 2001;62:401–5. 4. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876–82. 5. Olney JW, Wozniak DF, Farber NB, et al. The enigma of fetal alcohol neurotox- icity. Ann Med 2002;34:109–19. 6. Soriano SG, Anand KJ, Rovnaghi CR, et al. Of mice and men: should we extrap- olate rodent experimental data to the care of human neonates? Anesthesiology 2005;102:866–8, author reply 8–9. 7. Todd MM. Anesthetic neurotoxicity: the collision between laboratory neurosci- ence and clinical medicine. Anesthesiology 2004;101:272–3. 8. Anand KJ. Anesthetic neurotoxicity in newborns: should we change clinical practice? Anesthesiology 2007;107:2–4. 9. Olney JW. New insights and new issues in developmental neurotoxicology. Neu- rotoxicology 2002;23:659–68. 10. Buss RR, Oppenheim RW. Role of programmed cell death in normal neuronal development and function. Anat Sci Int 2004;79:191–7. 11. Kuida K, Zheng TS, Na S, et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 1996;384:368–72. 12. Yon JH, Daniel-Johnson J, Carter LB, et al. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic path- ways. Neuroscience 2005;135:815–27. 13. Yon JH, Carter LB, Reiter RJ, et al. Melatonin reduces the severity of anesthesia- induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis 2006;21:522–30. 14. Head BP, Patel HH, Niesman IR, et al. Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology 2009;110:813–25. 15. Lu LX, Yon JH, Carter LB, et al. General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis 2006;11:1603–15. 16. Ibla JC, Hayashi H, Bajic D, et al. Prolonged exposure to ketamine increases brain derived neurotrophic factor levels in developing rat brains. Curr Drug Saf 2009;4:11–6.
  11. 11. Is Anesthesia Bad for the Newborn Brain? 279 17. Nikizad H, Yon JH, Carter LB, et al. Early exposure to general anesthesia causes significant neuronal deletion in the developing rat brain. Ann N Y Acad Sci 2007; 1122:69–82. 18. MacLusky NJ, Chalmers-Redman R, Kay G, et al. Ovarian steroids reduce apoptosis induced by trophic insufficiency in nerve growth factor-differentiated PC12 cells and axotomized rat facial motoneurons. Neuroscience 2003;118: 741–54. 19. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283: 70–4. 20. Hayashi H, Dikkes P, Soriano SG. Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain. Paediatr Anaesth 2002;12: 770–4. 21. Scallet AC, Schmued LC, Slikker W Jr, et al. Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol Sci 2004;81:364–70. 22. Rudin M, Ben-Abraham R, Gazit V, et al. Single-dose ketamine administration induces apoptosis in neonatal mouse brain. J Basic Clin Physiol Pharmacol 2005;16:231–43. 23. Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine and midazo- lam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005;146:189–97. 24. Slikker W Jr, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007;98:145–58. 25. Wang C, Sadovova N, Fu X, et al. The role of the N-methyl-D-aspartate receptor in ketamine-induced apoptosis in rat forebrain culture. Neuroscience 2005;132: 967–77. 26. Wang C, Sadovova N, Hotchkiss C, et al. Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture. Toxicol Sci 2006;91:192–201. 27. Vutskits L, Gascon E, Potter G, Tassonyi E, Kiss JZ. Low concentrations of ket- amine initiate dendritic atrophy of differentiated GABAergic neurons in culture. Toxicology 2007;234:216–26. 28. Fredriksson A, Ponten E, Gordh T, et al. Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 2007;107:427–36. 29. Ma D, Williamson P, Januszewski A, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology 2007;106: 746–53. 30. Nunez JL, Alt JJ, McCarthy MM. A new model for prenatal brain damage. I. GABAA receptor activation induces cell death in developing rat hippocampus. Exp Neurol 2003;181:258–69. 31. Fredriksson A, Archer T, Alm H, et al. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav Brain Res 2004;153:367–76. 32. Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurode- generation in the developing brain. Proc Natl Acad Sci U S A 2002;99:15089–94. 33. Asimiadou S, Bittigau P, Felderhoff-Mueser U, et al. Protection with estradiol in developmental models of apoptotic neurodegeneration. Ann Neurol 2005;58: 266–76.
  12. 12. 280 McCann Soriano 34. Cheng VY, Martin LJ, Elliott EM, et al. Alpha5GABAA receptors mediate the am- nestic but not sedative-hypnotic effects of the general anesthetic etomidate. J Neurosci 2006;26:3713–20. 35. Cattano D, Young C, Straiko MM, et al. Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 2008;106:1712–4. 36. Chalon J, Tang CK, Ramanathan S, et al. Exposure to halothane and enflurane affects learning function of murine progeny. Anesth Analg 1981;60:794–7. 37. Uemura E, Bowman RE. Effects of halothane on cerebral synaptic density. Exp Neurol 1980;69:135–42. 38. Uemura E, Ireland WP, Levin ED, et al. Effects of halothane on the development of rat brain: a golgi study of dendritic growth. Exp Neurol 1985;89:503–19. 39. Uemura E, Levin ED, Bowman RE. Effects of halothane on synaptogenesis and learning behavior in rats. Exp Neurol 1985;89:520–9. 40. Stratmann G, Sall JW, May LD, et al. Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats. Anes- thesiology 2009;110:834–48. 41. Sanders RD, Xu J, Shu Y, et al. Dexmedetomidine attenuates isoflurane- induced neurocognitive impairment in neonatal rats. Anesthesiology 2009; 110:1077–85. 42. Rizzi S, Carter LB, Ori C, et al. Clinical anesthesia causes permanent damage to the fetal guinea pig brain. Brain Pathol 2008;18:198–210. 43. Zhang X, Xue Z, Sun A. Subclinical concentration of sevoflurane potentiates neuronal apoptosis in the developing C57BL/6 mouse brain. Neurosci Lett 2008;447:109–14. 44. Satomoto M, Satoh Y, Terui K, et al. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesi- ology 2009;110:628–37. 45. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg 2007;104:509–20. 46. Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev 1979;3:79–83. 47. Clancy B, Finlay BL, Darlington RB, et al. Extrapolating brain development from experimental species to humans. Neurotoxicology 2007;28:931–7. 48. Clancy B, Kersh B, Hyde J, et al. Web-based method for translating neurodevel- opment from laboratory species to humans. Neuroinformatics 2007;5:79–94. 49. Renwick JH, Asker RL. Ethanol-sensitive times for the human conceptus. Early Hum Dev 1983;8:99–111. 50. Olney JW, Wang H, Qin Y, et al. Pilocarpine pretreatment reduces neuroapoptosis induced by midazolam or isoflurane in infant mouse brain. Program No 286.15, Neuroscience Meeting Planner, Society for Neuroscience. Atlanta (GA), 2006. 51. Loepke AW, Istaphanous GK, McAuliffe JJ 3rd, et al. The effects of neonatal iso- flurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 2009;108:90–104. 52. Li Y, Liang G, Wang S, et al. Effects of fetal exposure to isoflurane on postnatal memory and learning in rats. Neuropharmacology 2007;53:942–50. 53. Smith RF, Bowman RE, Katz J. Behavioral effects of exposure to halothane during early development in the rat: sensitive period during pregnancy. Anesthe- siology 1978;49:319–23. 54. Quimby KL, Aschkenase LJ, Bowman RE, et al. Enduring learning deficits and cerebral synaptic malformation from exposure to 10 parts of halothane per million. Science 1974;185:625–7.
  13. 13. Is Anesthesia Bad for the Newborn Brain? 281 55. Eishima K. The effects of obstetric conditions on neonatal behaviour in Japanese infants. Early Hum Dev 1992;28:253–63. 56. Blair VW, Hollenbeck AR, Smith RF, et al. Neonatal preference for visual patterns: modification by prenatal anesthetic exposure? Dev Med Child Neurol 1984;26: 476–83. 57. Hollenbeck AR, Grout LA, Smith RF, et al. Neonates prenatally exposed to anes- thetics: four-year follow-up. Child Psychiatry Hum Dev 1986;17:66–70. 58. Surgery and the tiny baby: sensorineural outcome at 5 years of age. The Victorian Infant Collaborative Study Group. J Paediatr Child Health 1996;32: 167–72. 59. Hintz SR, Kendrick DE, Stoll BJ, et al. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics 2005;115:696–703. 60. Blakely ML, Tyson JE, Lally KP, et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: outcomes through 18 months adjusted age. Pediatrics 2006; 117:e680–7. 61. Walsh MC, Kliegman RM, Hack M. Severity of necrotizing enterocolitis: influence on outcome at 2 years of age. Pediatrics 1989;84:808–14. 62. Tobiansky R, Lui K, Roberts S, et al. Neurodevelopmental outcome in very low birthweight infants with necrotizing enterocolitis requiring surgery. J Paediatr Child Health 1995;31:233–6. 63. Chacko J, Ford WD, Haslam R. Growth and neurodevelopmental outcome in extremely-low-birth-weight infants after laparotomy. Pediatr Surg Int 1999;15: 496–9. 64. Simon NP, Brady NR, Stafford RL, et al. The effect of abdominal incisions on early motor development of infants with necrotizing enterocolitis. Dev Med Child Neurol 1993;35:49–53. 65. Lindahl H. Long-term prognosis of successfully operated oesophageal atresia- with aspects on physical and psychological development. Z Kinderchir 1984;39: 6–10. 66. Bouman NH, Koot HM, Hazebroek FW. Long-term physical, psychological, and social functioning of children with esophageal atresia. J Pediatr Surg 1999;34: 399–404. 67. Bellinger DC, Rappaport LA, Wypij D, et al. Patterns of developmental dysfunc- tion after surgery during infancy to correct transposition of the great arteries. J Dev Behav Pediatr 1997;18:75–83. 68. Bellinger DC, Wypij D, duPlessis AJ, et al. Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: the Boston Circu- latory Arrest Trial. J Thorac Cardiovasc Surg 2003;126:1385–96. 69. Bellinger DC, Wypij D, Kuban KC, et al. Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999;100:526–32. 70. Miller G, Tesman JR, Ramer JC, et al. Outcome after open-heart surgery in infants and children. J Child Neurol 1996;11:49–53. 71. Hovels-Gurich HH, Seghaye MC, Dabritz S, et al. Cognitive and motor develop- ment in preschool and school-aged children after neonatal arterial switch oper- ation. J Thorac Cardiovasc Surg 1997;114:578–85. 72. Hovels-Gurich HH, Seghaye MC, Schnitker R, et al. Long-term neurodevelop- mental outcomes in school-aged children after neonatal arterial switch opera- tion. J Thorac Cardiovasc Surg 2002;124:448–58.
  14. 14. 282 McCann Soriano 73. Karl TR, Hall S, Ford G, et al. Arterial switch with full-flow cardiopulmonary bypass and limited circulatory arrest: neurodevelopmental outcome. J Thorac Cardiovasc Surg 2004;127:213–22. 74. Limperopoulos C, Majnemer A, Shevell MI, et al. Neurodevelopmental status of newborns and infants with congenital heart defects before and after open heart surgery. J Pediatr 2000;137:638–45. 75. Mahle WT, Clancy RR, Moss EM, et al. Neurodevelopmental outcome and life- style assessment in school-aged and adolescent children with hypoplastic left heart syndrome. Pediatrics 2000;105:1082–9. 76. Anand KJ, Barton BA, McIntosh N, et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal outcome and prolonged analgesia in neonates. Arch Pediatr Adolesc Med 1999;153:331–8. 77. Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Database Syst Rev 2000; 1:CD002052. 78. Brooker RW, Keenan WJ. Inguinal hernia: relationship to respiratory disease in prematurity. J Pediatr Surg 2006;41:1818–21. 79. van der Walt J. Oxygen–elixir of life or Trojan horse? Part 2: oxygen and neonatal anesthesia. Paediatr Anaesth 2006;16:1205–12. 80. Cunningham C, Campion S, Lunnon K, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 2009;65:304–12. 81. Palin K, Cunningham C, Forse P, et al. Systemic inflammation switches the inflammatory cytokine profile in CNS Wallerian degeneration. Neurobiol Dis 2008;30:19–29. 82. Bergman I, Steeves M, Burckart G, et al. Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration. J Pediatr 1991;119:644–9. 83. Fonsmark L, Rasmussen YH, Carl P. Occurrence of withdrawal in critically ill sedated children. Crit Care Med 1999;27:196–9. 84. Khan RB, Schmidt JE, Tamburro RF. A reversible generalized movement disorder in critically ill children with cancer. Neurocrit Care 2005;3:146–9. 85. Hughes J, Gill A, Leach HJ, et al. A prospective study of the adverse effects of midazolam on withdrawal in critically ill children. Acta Paediatr 1994;83: 1194–9. 86. Franck LS, Naughton I, Winter I. Opioid and benzodiazepine withdrawal symp- toms in paediatric intensive care patients. Intensive Crit Care Nurs 2004;20: 344–51. 87. Yanay O, Brogan TV, Martin LD. Continuous pentobarbital infusion in children is associated with high rates of complications. J Crit Care 2004;19:174–8. 88. Tobias JD, Deshpande JK, Pietsch JB, et al. Pentobarbital sedation for patients in the pediatric intensive care unit. South Med J 1995;88:290–4. 89. Green SM, Clark R, Hostetler MA, et al. Inadvertent ketamine overdose in chil- dren: clinical manifestations and outcome. Ann Emerg Med 1999;34:492–7. 90. McCann ME, Petersen RA, Marcus K, et al. Does repeated exposure to anesthetic drugs lead to neurodevelopmental disabilities? Anesthesiology 2006;105:A966. 91. Arnold JH, Truog RD, Rice SA. Prolonged administration of isoflurane to pedi- atric patients during mechanical ventilation. Anesth Analg 1993;76:520–6.
  15. 15. Is Anesthesia Bad for the Newborn Brain? 283 92. Kelsall AW, Ross-Russell R, Herrick MJ. Reversible neurologic dysfunction following isoflurane sedation in pediatric intensive care. Crit Care Med 1994; 22:1032–4. 93. Sackey PV, Martling CR, Radell PJ. Three cases of PICU sedation with isoflurane delivered by the ‘AnaConDa’. Paediatr Anaesth 2005;15:879–85. 94. Kain ZN, Caldwell-Andrews AA, Maranets I, et al. Preoperative anxiety and emergence delirium and postoperative maladaptive behaviors. Anesth Analg 2004;99:1648–54. 95. Kain ZN, Caldwell-Andrews AA, Weinberg ME, et al. Sevoflurane versus halo- thane: postoperative maladaptive behavioral changes: a randomized, controlled trial. Anesthesiology 2005;102:720–6. 96. Eckenhoff JE. Relationship of anesthesia to postoperative personality changes in children. AMA Am J Dis Child 1953;86:587–91. 97. Keaney A, Diviney D, Harte S, et al. Postoperative behavioral changes following anesthesia with sevoflurane. Paediatr Anaesth 2004;14:866–70. 98. Kain ZN, Mayes LC, Wang SM, et al. Postoperative behavioral outcomes in chil- dren: effects of sedative premedication. Anesthesiology 1999;90:758–65. 99. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009;110: 796–804. 100. DiMaggio CJ, Sun L, Kakavouli A, et al. Exposure to anesthesia and the risk of developmental and behavioral disorders in young children. Anesthesiology 2008;109:A1415. 101. Kalkman CJ, Peelen L, Moons KG, et al. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology 2009;110: 805–12. 102. Zhan X, Fahlman CS, Bickler PE. Isoflurane neuroprotection in rat hippocampal slices decreases with aging: changes in intracellular Ca21 regulation and N-methyl-D-aspartate receptor-mediated Ca21 influx. Anesthesiology 2006; 104:995–1003. 103. Sanders RD, Ma D, Brooks P, et al. Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity. Br J Anaesth 2008;101:597–609. 104. Levene M. Role of excitatory amino acid antagonists in the management of birth asphyxia. Biol Neonate 1992;62:248–51. 105. Ford LM, Sanberg PR, Norman AB, et al. MK-801 prevents hippocampal neuro- degeneration in neonatal hypoxic-ischemic rats. Arch Neurol 1989;46:1090–6. 106. Nakajima W, Ishida A, Lange MS, et al. Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci 2000;20:7994–8004. 107. Walco GA. Needle pain in children: contextual factors. Pediatrics 2008; 122(Suppl 3):S125–9. 108. Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci 2005; 6:507–20. 109. Fitzgerald M, Howard F. The neurologic basis of pediatric pain. In: Schecter NL, Berde CB, Yaster M, editors. Pain in infants, children and adolescents. Philadel- phia: Lippincott, Williams and Wilkins; 2003. p. 19–42. 110. Anand KJ, Garg S, Rovnaghi CR, et al. Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res 2007;62: 283–90.
  16. 16. 284 McCann Soriano 111. Taddio A, Katz J, Ilersich AL, et al. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 1997;349: 599–603. 112. Hermann C, Hohmeister J, Demirakca S, et al. Long-term alteration of pain sensitivity in school-aged children with early pain experiences. Pain 2006;125: 278–85. 113. Page GG, Blakely WP, Kim M. The impact of early repeated pain experiences on stress responsiveness and emotionality at maturity in rats. Brain Behav Immun 2005;19:78–87. 114. Sun LS, Li G, Dimaggio C, et al. Anesthesia and neurodevelopment in children: time for an answer? Anesthesiology 2008;109:757–61. 115. Davidson AJ, McCann ME, Morton NS, et al. Anesthesia and outcome after neonatal surgery: the role for randomized trials. Anesthesiology 2008;109: 941–4. 116. Hansen TG, Flick R. Anesthetic effects on the developing brain: insights from epidemiology. Anesthesiology 2009;110:1–3.