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From the *Department of Anesthesia, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, and Institute of Pediatric Anesthesia, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio; and Department of Anesthesia, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts.
Address correspondence and reprint requests to Dr. Andreas Loepke, Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH. Address e-mail to Andreas.Loepke{at}cchmc.org.
Abstract
BACKGROUND: Neuronal cell death after general anesthesia has recently been documented in several immature animal models. Worldwide, volatile anesthetics are used in millions of young children every year during surgical procedures and imaging studies. The possibility of anesthesia-induced neurotoxicity during an uneventful anesthetic in neonates or infants has led to serious questions about the safety of pediatric anesthesia. However, the applicability of animal data to clinical anesthesia practice remains uncertain. In the present review, we assess the evidence for the effects of commonly used anesthetics on neuronal structure and neurocognitive function in newborn humans and animals.
METHODS: Medical databases, including Medline, Cinahl, and Pubmed, abstract listings of the American Society of Anesthesiologists, International Anesthesia Research Society, Society for Pediatric Anesthesia, and Society for Neuroscience Annual Meetings, and personal files were queried regarding anesthesia-induced neurotoxicity.
RESULTS: A growing number of studies in immature animal models demonstrate degenerative effects of several anesthetics on neuronal structure. A few studies reveal cognitive impairment in adult animals after neonatal anesthesia. There are no prospective studies evaluating neurocognitive function in children after neonatal exposure to anesthetics. However, several retrospective reviews demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identify long-term neurodevelopmental impairment after neonatal surgery and anesthesia.
CONCLUSIONS: The evidence for anesthesia-induced neurodegeneration in animal models is compelling. Although this phenomenon has not been prospectively studied in young children, anecdotal data point toward the possibility for neurological impairment after surgery and anesthesia early in life. Given the serious implications for public health, further investigations of this phenomenon are imperative, both in laboratory animals and in young children.
Primum non nocere, this central maxim of medicine, is even more paramount for pediatric medicine, which treats the most vulnerable of patient populations. Pediatric anesthesia, which plays a part in the rapid advancement of anesthesiology, prides itself in having rendered surgical procedures now routine and safe in the smallest of patients, which were unthinkable 20 or 30 yr ago. Although the risk of anesthetic complications due to physiological differences remains higher in neonates and infants compared with adults,1 millions of children every year undergo seemingly safe general anesthetics for surgical procedures and imaging studies. Moreover, the appreciation for the infants’ stress response during surgery and the identification of the deleterious effects of inadequate anesthesia and analgesia during painful procedures in the developing brain have resulted in the current use of balanced anesthesia techniques.2 However, recent data in laboratory animals have raised significant concerns among anesthesiologists, neuroscientists, parents, the lay press, and electronic media regarding the safety of general anesthetics in infancy and their effects on normal brain development.3–8 Although the neurodegenerative effects of ketamine in animal models have recently been reviewed in this journal,9 the current article aims to provide an overview of the available evidence of degenerative or toxic effects of all commonly used general anesthetics in the developing brain, animal or human, and to put the available laboratory data into clinical perspective. We thereby intend to give a balanced view of this currently predominant controversy in pediatric anesthesiology.
Growth and development of the mammalian central nervous system (CNS) involve complex cellular processes such as neurogenesis, differentiation into specialized cell subspecies, migration of cells to their final destination in the CNS, synaptogenesis with connection formation, and axonal myelination. These processes vary significantly in duration and timing, relative to gestational age, among different mammalian species, in accordance with their life expectancy.10 In humans, synaptogenesis starts during the third trimester of gestation and rapid brain growth continues for up to 2 to 3 yr after birth.11 In small rodents, such as mice and rats, the brain is relatively immature at birth and matures very rapidly during the first 2 wk of life.12 The brain developmental stage of the 7-day-old postnatal mouse or rat has historically been considered equivalent to the human neonate at approximately 32-36-wk gestation.10,13
During normal CNS development, neurons are produced in excess and the elimination of supernumerary neurons is critical for achieving normal brain morphology, brain size, and viability of the organism. Importantly, as part of normal brain development, as much as 50%-70% of neurons and progenitor cells undergo physiological cell death and elimination by an inherent cell death program, termed apoptosis, which is centered around the caspase enzyme family.14–19 Disruption of this massive, physiological cell death mechanism leads to intrauterine malformation of the brain and premature death of the embryo.20
The diverse group of clinically used general anesthetics spans from IV anesthetics, such as benzodiazepines, barbiturates, ketamine, propofol, and etomidate, to inhaled anesthetics, such as halothane, isoflurane, sevoflurane, desflurane, nitrous oxide, and xenon. Although these compounds are chemically very dissimilar, strikingly, their proposed mechanism of action to inhibit neuronal activity is very similar, entailing, to varying degrees, alterations of synaptic transmission involving 
-aminobutyrate (GABA) and/or N-methyl-d-aspartate (NMDA) receptors.21 Because GABA- and NMDA-mediated neuronal activity is essential for mammalian brain development, exposure to general anesthetics could potentially interfere with normal brain maturation.22,23
Supporting this possibility, several laboratory studies in neonatal animal models, such as the 7-day-old mouse and rat, demonstrate that administration of anesthetic drugs was associated with an increase in the normal apoptotic neuronal degeneration. This phenomenon has sparked controversy about the implications for pediatric anesthesia.4,6,7,24–27 It has repeatedly been argued that the laboratory findings in 7-day-old rodents provide evidence for human susceptibility to anesthesia-induced neurotoxicity from the third trimester of pregnancy up to the second year of life.4,25
Given the major impact of the possibility of anesthesia-induced neurotoxicity on public health, it appears appropriate to examine the current clinical and preclinical evidence for the effects of various injectable and volatile anesthetics on neuronal structure in the developing brain as well as on subsequent neurocognitive function.
METHODS
Medline (1996-2007), Cinahl (1982-2007), and PubMed searches were performed in June 2007 with the following keywords: brain (newborn or infant or child or neonate or neonatal or animals, newborn) and (neurodegeneration or apoptosis or toxicity or neurocognitive impairment or developmental impairment or developmental disabilities, or learning disorders) and (isoflurane or desflurane or sevoflurane or propofol or etomidate or ketamine or lorazepam or diazepam or midazolam or pentobarbital or phenobarbital or anesthesia, IV or anesthesia, inhalation or anesthesia). In addition, citations in the reference lists of relevant articles, abstracts presented at the 2004-2006 American Society of Anesthesiologists (ASA), 2004-2007 International Anesthesia Research Society (IARS), 2004-2006 Society for Pediatric Anesthesia (SPA), and 2004-2007 Society for Neuroscience (SfN) Annual Meetings as well as personal files were reviewed.
RESULTS
The literature search strategy identified 42 articles. Inspection of their abstracts isolated 17 articles as being relevant to the topic. The remaining articles originated from the reference lists of the originally identified articles, our personal files, and from abstract searches of the American Society of Anesthesiologists, International Anesthesia Research Society, Society for Pediatric Anesthesia, and SfN abstract databases.
No studies were identified describing structural brain abnormalities in children after anesthesia. However, a multitude of studies demonstrate behavioral and neurocognitive abnormalities after surgical anesthesia. Some manuscripts specified the anesthetic regimen (Table 1), whereas others did not detail the particular anesthetics used during surgery (Table 2). Animal studies investigating anesthesia-induced brain structural or behavioral abnormalities are summarized in Table 3.
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Anesthesia in Neonates and Young Children
Neurodevelopmental outcome, as evaluated with validated neurocognitive assessment tools, has not been studied in healthy neonates or infants undergoing anesthesia for elective surgery. Conversely, several studies have evaluated long-term neurodevelopment in critically ill neonates after surgical procedures involving general anesthesia, including ligation of patent ductus arteriosus, repair of esophageal atresia, inguinal hernia repair, neurosurgical operations, laparotomy, or tracheotomy.42–51 However, the anesthetic regimen was not specified in any of these studies. Long-term neurodevelopmental impairment, such as a reduction in IQ, increased incidence of cerebral palsy, deafness, or blindness, has frequently been observed.45-49,51 Greater severity of illness and coexisting, congenital abnormalities were associated with worsening neurological outcome.43,48 In an attempt to at least partially control for severity of illness, several case-control studies compared neurodevelopmental outcome in survivors of surgical therapy of necrotizing enterocolitis and patent ductus arteriosus with patients undergoing medical management for the same illness. When compared with age-matched controls or medically treated patients in the same cohort, several investigators noticed an impairment in neurocognitive function in surgically treated survivors of laparotomy or thoracotomy,45-47,49,51 whereas others were unable to find these differences.42,44,50 However, it is difficult to separate the effects of neonatal stress and surgery from the effects of the anesthetics. Moreover, study designs did not include randomized, controlled trials, but were rather designed as cohort studies or case-control studies. It is therefore possible that, due to selection bias, some of the extremely premature neonates who needed surgery had concomitant illnesses and were therefore sicker than their matched controls. This notion is underscored by the fact that some of the studies identified longer periods of hypotension, more common use of inotropic support, and longer periods of total parenteral nutrition in the postsurgical patients.45,47 Accordingly, a prospective randomized trial of 117 preterm infants with necrotizing enterocolitis who were either assigned to laparotomy or peritoneal drainage did not find any difference in patient survival and early outcomes.52
Another patient population that has been followed for evaluation of long-term neurocognitive development is neonates and infants undergoing open-heart surgery for congenital heart disease, such as hypoplastic left heart syndrome, transposition of the great arteries, or tetralogy of Fallot.53–63 Neurocognitive impairment has been documented in many of these studies, compared with the general population,53-61,63 or with "best friend" control subjects.62 However, anesthetic regimen was not specified for any of these studies and confounding factors include preoperative neurological lesions, preexisting or perioperative hypoxia and hypotension, and chronic postoperative hypoxia in many of these patients. Interestingly, in the largest trial, the Boston Circulatory Arrest Trial, with patient follow-up for 8 yr after arterial switch operation, many outcome measures in a battery of neurodevelopmental tests were within normal population limits, despite major corrective cardiac surgery as neonates.61
Several case-control studies address the neurocognitive implications of prenatal anesthetic exposure in utero.64–67 Abnormal neurological activity observed in neonates early after delivery included increased motor tone and decreased interaction,67 visual test abnormalities,65 and motor weakness.64 Interestingly, the incidence of early neurological abnormalities after cesarean delivery did not differ between neonates exposed to general anesthesia, including thiopental and nitrous oxide, or to maternal epidural analgesia using lidocaine.64 In a small, 4-year follow-up after prenatal exposure to anesthetics for dental procedures,65 children had decreased intelligence scores compared with unexposed controls, but demonstrated similar performance on tests of their vocabulary.66 However, anesthetic exposure was not quantified, spanned from the first to the third trimester of pregnancy, and consisted of such diverse anesthetics as methohexital, penthotal, lidocaine, or carbocaine.
In summary, although several cohort studies in premature and term neonates undergoing major surgical operations involving general anesthesia demonstrate neurodevelopmental impairment later in life, none of these studies specified the anesthetic technique used. Moreover, because of the study design limitations, the effects of concomitant disease and the impact of the surgical procedure cannot be separated from the effects of anesthesia.
Although anesthetic regimen was not systematically described in the studies cited above, several reports, in animals or humans, address the effects of specific anesthetics and doses on neuronal structure and/or neurodevelopmental outcome.
Benzodiazepines
No studies were identified demonstrating neuronal degeneration or abnormal neurocognitive function in young children after brief sedation with benzodiazepines. However, there are several reports related to transient neurological abnormalities after prolonged sedation with benzodiazepines in children, which were generally attributed to withdrawal symptoms or tachyphylaxis.68–73 In a retrospective chart review of 45 patients who had received prolonged midazolam sedation between 0.07 and 0.94 mg · kg–1 · h–1 and fentanyl for up to 38 days, five patients (11%) were identified, ranging from 3 to 15-mo-of-age, who demonstrated poor social interaction, decreased visual attentiveness, dystonic postures, and choreoathetosis upon discontinuation of the sedation, whereas 40 patients had no neurologic abnormalities.68 A repeat neurological examination up to 4 wk after discontinuation of sedation was normal in all children. In a prospective study in 53 critically ill neonates and children, Hughes et al. observed disorientation and hallucinations in 11% and prolonged sedation in 8% for up to 1 wk after midazolam discontinuation,69 whereas Franck et al. found sleeplessness, agitation, and movement disorder in up to 50% in a smaller and younger cohort.71 In a retrospective chart review of 40 patients ranging from 6 mo to 14 yr of age, Fonsmark et al.70 observed neurological abnormalities in 35% of children after discontinuation of prolonged sedation with midazolam, pentobarbital, or a combination of the two. Neurological abnormalities were described as agitation, anxiety, muscle twitching, sweating, and tremor and were attributed to withdrawal symptoms. Symptoms were positively correlated with midazolam doses of more than 60 mg. Interestingly, although the diagnoses were diverse, half of the children who demonstrated neurological symptoms after discontinuation of sedation had preexisting CNS abnormalities, with an admission diagnosis of meningitis. In a case series of six critically ill cancer patients ranging from 1 to 6-yr-of-age, which represented 8% of the comparable intensive care unit patient population, Khan et al.72 described multifocal myocloni, dystonia, chorea, facial grimacing, tongue thrusting, and conjugate gaze deviation in the absence of seizure activity on electroencephalogram (EEG). Because five of these patients were being sedated with midazolam and an opioid for more than 10 days, although in one patient sedation had been discontinued 1 day before the onset of symptoms, the authors identified midazolam sedation as the most likely reason for the development of the generalized movement disorder. However, they acknowledge that the etiology could have been multifactorial, because 67% of the affected patients had undergone a resection of a brain tumor, 83% received amphotericin, a known neurotoxicant, and all received chemotherapy. Moreover, tachyphylaxis to midazolam could have been a factor, because symptoms were abolished in 67% of patients by increasing midazolam and fentanyl doses. In another study, a prospective trial in 29 patients, Dominguez et al.73 observed withdrawal symptoms in 25% of patients on discontinuation of lorazepam, which had been administered for a median duration of 21 days.
Preclinical data on neurodegeneration after benzodiazepine administration in animal models are conflicting. Studies in neonatal rat pups that received injections of diazepam 10-30 mg/kg or clonazepam 0.5-4 mg/kg demonstrated increased neurodegeneration.74,75 In the same study, however, a lower dose of diazepam, 5 mg/kg, did not increase neuronal degeneration in rats,75 whereas an identical dose of diazepam increased neurodegeneration in another study of neonatal mice.76 However, this diazepam-induced neurodegeneration in neonatal mice did not lead to impaired behavior or neurocognitive performance deficits in adulthood.76 Using midazolam, another group of researchers did not note any increase in the rate of neurodegeneration in neonatal rats for doses up to 9 mg/kg.77 This finding was supported by in vitro experiments in rat GABAergic neuronal cultures, which demonstrated that midazolam did not impact neuronal development.78 When midazolam was administered to neonatal mice, however, it triggered a neuroapoptotic response with the identical dose that was found safe in neonatal rats.79
Therefore, no information on long-term neurocognitive outcome is available in young children, whereas transient neurological abnormalities, generally ascribed to withdrawal symptoms, have been reported. The currently available data in animals support a dose-dependent increase in neurodegeneration after administration in small rodents, with higher susceptibility in mice compared with rats. However, even after injurious doses, neurocognitive testing does not reveal long-term neurological sequelae.
Barbiturates
Several small studies or case series in children have described transient neurological abnormalities on discontinuation of pentobarbital infusion,70,80 such as choreo-athetoid movements, ataxia, and confusion, whereas other studies have not.81 Many of these abnormalities were attributed to withdrawal symptoms. Long-term, prenatal phenobarbital and phenytoin exposure in utero led to an increase in learning abnormalities and mental retardation, but not cognitive impairment in adulthood, compared with a healthy cohort.82 Moreover, a short-term exposure to phenobarbital as neonates did not diminish the performance on follow-up at age 8-14 yr, using tests of intelligence and attention, compared with healthy friends.83
In animal studies, increases in neuronal degeneration have been observed in rat pups after injections of pentobarbital 5-10 mg/kg or phenobarbital 40-100 mg/kg.75,84 However, phenobarbital in lower doses, between 20 and 30 mg/kg, failed to increase neurodegeneration. The authors noted, though, that plasma levels for phenobarbital in rats, when given in doses sufficient to increase neurodegeneration in animals, were comparable to therapeutic plasma levels in children. Simultaneous estradiol administration prevented the neurodegenerative effects of phenobarbital.84 Neonatal exposure to thiopental in doses between 5 and 25 mg/kg did not lead to an increase in neurodegeneration or long-term behavioral or learning impairment in mice.85
Hence, current evidence for the adverse neurological effects of barbiturates in humans is limited to case reports, usually attributed to withdrawal symptoms, and long-term neurological follow-up is lacking. Although no increased neurodegeneration or long-term neurocognitive impairment was seen after a neonatal exposure to thiopental in mice, barbiturate-induced neurodegeneration was dose-dependent in newborn rats, similar to benzodiazepines. Conversely, evidence from studies in mature rat models documents the neuroprotective effects of barbiturates during focal brain ischemia.86 Neuroprotective effects of barbiturates have yet to be studied in immature animals.
Ketamine
There are no data regarding the effects of administration of clinical doses of ketamine in young children on brain structure or neurocognitive function. A case series of inadvertant ketamine overdoses in neonates and young children reported prolonged sedation for up to 24 h without neurological sequelae on follow-up examination, where available.87 However, long-term neurocognitive assessments were not reported in this patient cohort.
In animal studies, similar to diazepam and phenobarbital, ketamine’s ability to increase the rate of developmental neurodegeneration appears to be dose-dependent. When ketamine was administered to neonatal rats in a single dose of up to 75 mg/kg or in repeated doses of 10 mg/kg, no increased neuronal degeneration was detected.88,89 However, after repeated doses of 20 or 25 mg/kg ketamine, increases of normal neurodegeneration were observed.88–90 Plasma ketamine levels after the noninjurious, single doses of 10 mg/kg were comparable to anesthetizing doses in humans. However, plasma levels of ketamine after repeated doses of 20 mg/kg, which led to increased neurodegeneration in rats, were 7-times higher than measured during anesthesia in humans.89 Conversely, a sedative dose of ketamine (5 mg/kg) administered to rat pups subjected to repetitive inflammatory pain did not increase neurodegeneration, but rather ameliorated the neurotoxic effects of painful stimulation on brain structure and short- and long-term memory.91
Neonatal mice, as shown by another group of researchers, demonstrated no increases in neurodegeneration after ketamine injections of 2.5 mg/kg or less, whereas doses of 5 mg/kg or higher increased neurodegeneration.92 However, none of the animals, regardless of ketamine dose, demonstrated gross neurobehavioral abnormalities 1 wk after injection. In a different strain of neonatal mice, another group of investigators observed the neurodegenerative threshold of ketamine to be between 10 and 20 mg/kg. A single ketamine dose of 10 mg/kg did not increase neuroapoptosis, whereas single doses of 20 mg/kg or higher led to an increased rate of neuroapoptosis.79 In another strain of slightly older 10-day-old mice, increased neurodegeneration was observed after 50 mg/kg ketamine, which led to abnormal behavior, impaired learning acquisition, and memory retention in adulthood.76 The same group observed learning impairment in adult mice after a neonatal dose of 25 mg/kg and an increase in neurodegeneration and a disruption of spontaneous activity and learning in adulthood when combined with noninjurious doses of thiopental and propofol.85 In nonhuman primates, a dose-dependent phenomenon was also recently observed.93 In prenatal (gestational age 122 days) and neonatal (5-day-old) rhesus monkeys, a 24 h infusion of ketamine (20-50 mg · kg–1 · h–1) significantly increased neuronal cell death. However, a ketamine infusion for 3 h did not lead to increased neurodegeneration in neonatal monkeys, and even a 24-h infusion failed to cause neuronal degeneration in older, 35-day-old animals. Ketamine neurotoxicity has also been studied using in vitro preparations from neonatal rats or rhesus monkeys.94,95 The common finding of these studies was an exposure time-dependent increase in neuronal cell death. Ketamine exposure of cortical cultures for 6 h or longer led to an increase in neurodegeneration in both species, whereas shorter exposure times did not. The threshold for increased neurodegeneration in both studies was not exactly defined, but was between 2 and 6 h. Studies using a GABAergic neuronal cell culture model have confirmed ketamine’s dose and exposure-time effects on neuronal structure.96,97 Higher ketamine concentrations led to early neuronal cell loss, whereas lower concentrations had to be administered continuously for 48 h to have a deleterious effect.
Importantly, ketamine requirements, similar to other injectable anesthetics, are 20-50 times higher in animals than in typical clinical practice. However, in a case series of neonates and young children, no neurological complications were reported on follow-up examinations after an accidental ketamine overdose of up to 50 mg/kg.87
In conclusion, although no information is available regarding the effects of clinical doses of ketamine on neuronal structure or neurocognitive function in young children, data obtained in developing animals point to a dose-dependent and exposure time-dependent neurodegenerative effect. Long-term neurocognitive dysfunction has thus far only been demonstrated in neonatal animals after administration of ketamine doses that led to significantly higher plasma levels than those measured during human anesthesia. However, concomitant administration of noninjurious doses of ketamine and GABAergic anesthetics significantly increased neurodegeneration and led to learning impairment in adulthood. Conversely, ketamine provides neuroprotection in adult animal models of focal brain ischemia,98 although it has not been studied in this context in developing animals.
Propofol
The effects of propofol administration on neuronal survival and neurocognitive performance have not been formally studied in young children. Neurological performance after propofol infusion, however, has been illustrated in several case reports. Propofol sedation for 48 h in a pregnant patient with intracerebral hemorrhage did not lead to any measurable adverse effects in the newborn after emergency cesarean delivery,99 as did propofol infusions of 2.7 mg · kg–1 · h–1 for more than 24 h in a case series of young children.100 However, convulsions have been observed after discontinuation of a prolonged infusion of propofol, which had been administered in doses of 6-18 mg · kg–1 · h–1 for 3-5 days.101,102 Another case report illustrated seizure, ataxia, and hallucinations in a 6-yr-old girl after prolonged propofol anesthesia for more than 6 h.103 However, the authors stated that this patient recovered without long-term sequelae.
A study of the effects of propofol on neuronal structure and neurocognitive performance in mice suggests that propofol increases neurodegeneration, leading to adult, behavioral, and learning impairment in a dose-dependent manner.85 Although neonatal exposure to propofol 10 mg/kg did not lead to neurological sequelae, increased neonatal neurodegeneration and disruption of spontaneous activity and learning in adult mice were observed after neonatal exposure to propofol 60 mg/kg or propofol 10 mg/kg plus ketamine 25 mg/kg. The higher propofol dose also led to alterations in the anxiolytic effect of diazepam in adult animals. Using in vitro preparations of neuronal cell cultures from immature chicks and rats, several investigators noted dose-dependent neuronal structural changes after propofol exposure.78,104–106 Supraclinical doses of propofol induced neuronal cell death in dissociated cell culture models, but failed to demonstrate neurotoxic effects in organotypic slice cultures,106 which more closely resemble the intact brain. Electrophysiological tests of neuronal function were not affected by propofol treatment in organotypic hippocampal slice cultures.106 Moreover, exposure of dissociated neurons to propofol in clinically relevant concentrations for up to 3 days failed to affect neuronal survival and arborization.106 Certain abnormalities, however, were associated with propofol administration, such as decreases in glutamic acid decarboxylase activity after 8 h of exposure105 and changes in dendritic development after 4 h of exposure.78
In conclusion, no prospective studies have examined the effects of propofol on neuronal structure and neurocognitive outcome in young children, whereas several case reports detail short-term neurological abnormalities without long-term neurocognitive impairment. However, detailed follow-up has not been conducted in this patient population. A study in neonatal mice points to propofol’s dose-dependent neurodegenerative properties, leading to behavioral and learning abnormalities, which are exacerbated by coadministration of ketamine. Animal studies using in vitro preparations demonstrate only subtle changes, whereas current evidence fails to reveal injurious effects of propofol on neuronal survival, arborization, and electrophysiological function. During brain ischemia, propofol has demonstrated neuroprotective properties in adult animal models,107 which has yet to be confirmed in immature animals.
Etomidate
No human or animal studies could be identified examining the effects of etomidate on neuronal structure or neurocognitive performance. Etomidate, however, has been shown in adult animals to possess neuroprotective effects during brain ischemia.108 This phenomenon has yet to be studied in newborn animals.
Halothane
No prospective studies have been conducted in children evaluating neuronal structure or neurocognitive outcome after halothane exposure early in life. Transient behavioral abnormalities, such as fear of strangers, temper tantrums, attention seeking, sleep disturbance, enuresis, and anxiety have been described after pediatric halothane anesthesia.30,31,33,35,37 Symptoms were most pronounced immediately postoperatively and significantly diminished over the first month after the operation. Laboratory experiments into halothane-induced neurotoxicity either used prolonged, subanesthetic exposure paradigms in utero until several weeks postnatally109–112 or brief prenatal exposure to anesthetic doses.113,114 Prenatal halothane exposure in clinical doses between gestational day 3 and 17 consistently led to learning impairment in adulthood, whereas subclinical doses decreased synaptic density, but lacked consistent neurocognitive dysfunction.112,113
Isoflurane
Prospective studies on neuronal structure or neurocognitive performance after isoflurane anesthesia in young children have not been published. However, several reports noted transient neurological abnormalities after prolonged sedation with isoflurane in the intensive care setting. In a case report, a 7-yr-old child exposed to 0.5%-1% isoflurane sedation for 4 days presented with disorientation, hallucinations, agitation, and seizure on discontinuation and resolution of symptoms within 5 days.115 Concomitant medications included midazolam and morphine. A small prospective study reported on 10 patients, ranging in age from 3 wk to 19 yr, who required isoflurane sedation for prolonged mechanical ventilation due to pulmonary pathologies.116 After discontinuation of isoflurane, transient agitation and nonpurposeful movements were noted in 50% of these patients, all of whom had received in excess of 70 MAC-h of isoflurane. Although all patients were simultaneously treated with a variety of benzodiazepines and opioids, the authors attributed the neurological symptoms to an "isoflurane abstinence syndrome" and recommended gradual weaning after prolonged administration. In a retrospective review of 6-mo to 10-yr-old children requiring sedation for mechanical ventilation, patients who had received isoflurane for more than 24 h experienced transient ataxia, agitation, hallucinations, and confusion on emergence, whereas patients who received benzodiazepines or isoflurane for <15 h did not.117 Four to six weeks after hospital discharge, neurological examinations were normal in all children. In a case report of a 3-yr-old patient requiring prolonged mechanical ventilation secondary to pneumonia and congenital myasthenia gravis with 81 MAC-h of isoflurane, a self-limiting, fine tremor of all four extremities was observed for 24 h after discontinuation of isoflurane.118 In another case series of three children requiring prolonged isoflurane sedation because of failed sedation with escalating doses of opioids and benzodiazepines, a 4-yr-old patient without prior CNS abnormalities developed temporary involuntary movements and ataxia after discontinuation of isoflurane, after 187 h of administration.119 However, the patient was simultaneously treated with several other medications, including morphine, midazolam, S-ketamine, clonidine, propofol, and droperidol. A 12-yr-old patient who was sedated with isoflurane for 6 days experienced transient myoclonus on discontinuation of isoflurane. A 9-yr-old child was sedated with 0.9% isoflurane for 8 days for an intractable seizure disorder. No overt neurological abnormalities were observed for any of the patients on follow-up, however, no long-term neurological assessments were described.119
In neonatal animal models, isoflurane has been linked to apoptotic neurodegeneration in newborn rats, mice, guinea pigs, and piglets,120–126 with most data being available in 7-day-old mice or rats. In rats, a 6-h exposure to an anesthetic combination of isoflurane, midazolam, and nitrous oxide has been demonstrated to induce widespread apoptotic neurodegeneration in newborn animals, followed by impairment in learning and memory retention tests later in adulthood.77 The neonatal anesthetic combination, however, did not affect overall growth, sensory motor ability, attention, and spontaneous locomotion. Preliminary data in neonatal rats from another research group indicate that isoflurane, when administered for 4 h as a single anesthetic drug, alters fear conditioning and spatial learning in adulthood.125 However, preliminary data obtained in mice demonstrate intact spatial learning, memory retention, and behavior in adult mice after a 6-h, 1.5% isoflurane exposure as neonates.127 Both in vitro and in vivo experiments in neonatal rodent models point to a narrow time window for isoflurane-induced neurotoxicity. In an in vitro model of the newborn rat brain, organotypic hippocampal slices from 7-day-old pups were susceptible to isoflurane-induced neurodegeneration, whereas slices from 4 or 14-day-old pups were not.128 Moreover, preliminary data in rats indicate that a 6 h isoflurane anesthetic in pregnant dams at the third trimester of gestation did not increase, but rather decreased neuronal cell death in rat embryos and pups and improved their spatial memory as adolescents.129 However, preliminary data corroborate isoflurane-induced neurodegeneration in two other species. Guinea pig embryos demonstrated a dramatic increase in neurons expressing the cell suicide marker caspase 3 after a 4 h anesthetic with isoflurane, nitrous oxide, and midazolam in utero at 35-40 days gestation.124 Interestingly, compared with this triple combination, neuronal suicide was dramatically decreased in guinea pig embryos whose mothers were exposed only to fentanyl for the same period of time. Similar preliminary data were presented for neonatal piglets.123 The cell suicide marker caspase 3 was significantly increased in 5-day-old piglets, which were anesthetized with isoflurane, nitrous oxide, and midazolam and mechanically ventilated for 4 h. Animals, however, which received only fentanyl for the same time period, demonstrated a dramatic decrease in caspase 3 activity, compared with the triple combination. Several studies have addressed how to mitigate isoflurane-induced neurodegeneration. Melatonin, when given to neonatal rats during an anesthetic of isoflurane, nitrous oxide, and midazolam, caused a dose-dependent reduction in the severity of anesthesia-induced neurodegeneration.130
The coadministration of the noble gas xenon prevented isoflurane-induced neurodegeneration during a 6 h exposure to 0.75% isoflurane in neonatal rats.121 There are preliminary data for the 
2-agonist dexmedetomidine to inhibit isoflurane-induced neuroapoptosis in neonatal rats exposed to 0.75% isoflurane for 6 h.131 In neonatal mice, preliminary data show that pretreatment with the muscarinic agonist pilocarpine reduced neuroapoptosis induced by an isoflurane exposure of 0.75% for 4 h.122 However, pilocarpine’s therapeutic margin might be limited by its ability to induce status epilepticus with concomitant neuronal degeneration.132–134
Contrary to the neurodegenerative effects, isoflurane was found to be neuroprotective during hypoxia-ischemia using in vivo and in vitro animal models of the developing brain.135–137
Thus, isoflurane has been shown in multiple developing animal models to increase baseline apoptotic neuronal degeneration. Strategies are being developed in the laboratory to mitigate the neurodegeneration. The long-term effects of neonatal isoflurane anesthesia remain controversial. Abnormal effects seem to be specific to the particular test used and to the species studied. In humans, although anecdotal data suggest at least transient neurological sequelae after prolonged exposure, no human studies have been completed examining the long-term effects of isoflurane on the developing brain. During ischemic periods, however, isoflurane administration protects neurons in the developing brain.
Desflurane
No human or animal studies could be identified that examined neuronal structure or neurocognitive performance after administration of desflurane. However, desflurane has been shown to protect the developing brain during episodes of hypoxia-ischemia in a hypothermic cardiopulmonary bypass brain ischemia model in piglets.138,139
Sevoflurane
Sevoflurane’s effects on neuronal structure and neurocognitive performance have not been studied in humans or animals. However, numerous case reports (reviewed in Ref.140) and several studies141,142 have reported epileptiform EEG and seizure activity during induction of anesthesia with sevoflurane, whereas other studies have failed to document this phenomenon.143,144 Moreover, sevoflurane anesthesia during surgery in young children has been associated with postoperative behavioral changes, such as increased temper tantrums, sleep disturbance, and loss of appetite.35–37,38 whereas these symptoms were described as transient, no long-term neurocognitive assessment has been conducted for these patients. Contrasting these deleterious effects of sevoflurane, preliminary data in neonatal mice suggest that sevoflurane protects developing neurons during brain ischemia.145
Thus, although sevoflurane is the most prevalent volatile anesthetic in pediatric anesthesia, there are no data regarding neuronal structure or neurocognitive function after sevoflurane administration in newborn humans or animals. However, sevoflurane can lead to EEG abnormalities and seizures, especially when administered without preoperative sedation and with controlled ventilation, rather than spontaneous breathing.
Nitrous Oxide
There are no human trials examining the effects of nitrous oxide in young children on neuronal structure and neurocognitive performance. Case studies in neonates after exposure to nitrous oxide in utero during the third trimester of pregnancy67 or during cesarean delivery64 indicated at least transient neurological sequelae, such as increased muscle tone, habituation to sound, resistance to cuddle, and fewer smiles,67 without long-term follow-up.
In animal studies, no significant increase in apoptotic neurodegeneration was found in neonatal rats treated with 50%, 75%, or 150% (in a hyperbaric chamber) nitrous oxide for 6 h.77 Another group of researchers also observed no increase in the apoptotic marker caspase 3 in neonatal rats exposed to 75% nitrous oxide for 6 h.121 However, nitrous oxide at a dose of 75% exacerbated neuroapoptosis caused by 0.75% isoflurane.
Interestingly, similarly to some of the volatile anesthetics, nitrous oxide has been shown to protect from excitotoxic neurodegeneration.146
Xenon
Xenon’s effects on neuronal structure and neurocognitive performance have not been studied in young children.
In animals, one study observed that a 6 h exposure to 0.5 MAC xenon did not increase apoptotic neuronal death in neonatal rats, but rather attenuated the neurotoxic effects of isoflurane and nitrous oxide.121 Moreover, in the same study, xenon did not increase neuronal degeneration in organotypic hippocampal slices obtained from neonatal mice. No data on long-term neurocognitive function after neonatal exposure are available for xenon.
Withholding Anesthesia
Several studies in neonatal animals have documented the deleterious effects of painful stimuli or stress on increasing stress hormone levels, neuronal cell death, pain thresholds, and abnormal behavior.147–149 A recent study in neonatal rats has shown that ketamine anesthesia during painful injections ameliorated the deleterious effects of painful stimulation, without causing neurodegenerative effects.91 It seems therefore conceivable that the deleterious effects of painful stimulation, such as during surgery, are abolished by anesthetics, whereas the painful stimulus, in turn, prevents the toxic effects of the anesthetics.
Mechanism of Anesthesia-Induced Neurotoxicity
Mechanism and selectivity of anesthesia-induced neurodegeneration are actively being investigated. It has been suggested that anesthesia-induced GABAA-receptor activation and NMDA-receptor blockade during a critical stage in brain development lead to depression of neuronal activity, which initiates the apoptotic cell death cascade in immature neurons.25 This hypothesis, however, has yet to be tested. Interestingly, contrary to this hypothesis, GABAA receptor stimulation leads to neuronal depolarization and not to decreased activity in immature neurons.150
Animal studies have demonstrated that anesthetic exposure is associated with a decrease in brain-derived neurotrophic factor,120 a nonspecific protein supporting neuronal survival, growth, and differentiation, which is decreased during stressful states. The involvement of the intrinsic and the extrinsic pathways of the apoptotic cell death cascade have been demonstrated during anesthesia-induced neurodegeneration in rats.126 However, the cellular mechanism for activation of the apoptotic cascade and the cellular selectivity remain unresolved. Apoptosis and neuronal cell death are integral parts of normal mammalian brain development. During normal fetal and neonatal brain development, neurons are produced in excess and as much as 50%-70% of neurons and progenitor cells undergo apoptotic cell death.14–19 Apoptotic cell death is imperative to establish the normal structure of the CNS, and experimental disruption of the physiological apoptotic cell death mechanism will lead to intrauterine brain malformation and premature demise of the embryo.20 Because the mechanism of anesthesia-induced neuronal cell death in not entirely understood, it remains unclear whether anesthesia induces apoptosis of cells not otherwise destined to die (i.e., pathological apoptosis), or whether it accelerates apoptosis of cells destined to die at a later time (i.e., premature physiological apoptosis).
Protective Adjuvants and Alternative Anesthetics
Several adjuvants, such as estradiol, pilocarpine, melatonin, and dexmedetomidine, have been identified in animal studies to ameliorate anesthesia-induced neurodegeneration.83,122,130 However, their use in neonatal anesthesia has not been studied. The rarely used NMDA-antagonist xenon has been shown to be devoid of neurodegenerative properties in neonatal rats during a 6 h administration of 0.5 MAC and also to ameliorate isoflurane-induced neurodegeneration.121 However, xenon is not widely available for clinical anesthesia practice. Preliminary data in guinea pigs and piglets have illustrated a significantly lower number of dying neurons after a fentanyl-based anesthetic, compared with isoflurane anesthesia.123,124 While this regimen is similar to anesthetic management in critically ill premature neonates and during cardiac surgery, during "routine" pediatric practice, fentanyl is usually combined with a "neurotoxic" anesthetic, such as isoflurane, midazolam, or propofol.
Period of Susceptibility to Anesthesia-Induced Neurotoxicity
Preclinical studies strongly suggest a narrow window of susceptibility to anesthesia-induced neurodegeneration. The developing animal brain is particularly vulnerable to neuronal cell death after anesthetic exposure at 7-days-of-age in rodents and before 5-days-of-age in rhesus monkeys. However, vulnerability quickly diminishes with increasing age. It is therefore critical to understand the equivalent brain maturational state during human brain development. Estimates for the equivalent time period in humans have ranged from the third trimester of gestation to 3-yr-of-age, potentially rendering neonates, infants, and toddlers vulnerable to anesthesia-induced neurotoxicity. However, recent work suggests the equivalent period during human brain development to be closer to 17-20 wk of gestation, which would render the most commonly used animal models irrelevant for common pediatric anesthesia practice.151,152
In conclusion, apoptotic neuronal degeneration occurs naturally in up to 70% of neurons and progenitor cells during normal mammalian brain development, which extends over weeks in small rodents and over years in humans. This cell death process is critical to achieve normal brain morphology. A dramatic, brief increase in this natural apoptotic cell death has been observed in developing animal brains after exposure to every commonly used anesthetic studied thus far. However, at least for injectable anesthetics, doses administered in animal models are several times higher than comparable doses in pediatric anesthesia. Therefore, in order for the animal models to be applicable for clinical anesthesia practice, both the neurodegenerative effects and the anesthetic effects need to act by similar mechanisms, which have yet to be established. Volatile anesthetic doses, on the other hand, are comparable to clinical anesthesia practice. Thus, repeated evidence for clinical doses of isoflurane leading to a dramatic increase in neuronal apoptotic cell death in animal models raises serious concerns for pediatric anesthesia practice. The neurodegenerative effects of etomidate, desflurane, and sevoflurane have yet to be closely studied, whereas there is evidence from one study that the rarely used anesthetic, xenon, in clinical doses does not have neurodegenerative effects and may be neuroprotective.
Even though neurodevelopmental outcome after anesthetic exposure during elective surgery in the neonatal period or infancy has not been studied in humans, anecdotal data suggest at least transient neurological impairment after prolonged exposure to several anesthetics. Moreover, several studies documenting long-term cognitive impairment after surgery and anesthesia in critically ill premature neonates and patients with congenital heart disease do not exclude a possible association of anesthetics with the observed dysfunction. Conversely, several anesthetics have demonstrated protective properties during ischemic insults to the developing brain. Therefore, given its dramatic implications for public health, anesthesia-induced neurotoxicity remains under intense study in animal models. Several animal studies have demonstrated anesthesia-induced neurodegeneration to be dose-dependent and exposure time-dependent. Moreover, animal data suggest neuronal cell death to be less severe after the administration of a single anesthetic versus a combination of several anesthetics. Laboratory studies indicate that a combination of a GABA-mimetic drug, such as a volatile anesthetic or propofol, and a NMDA antagonist, such as nitrous oxide or ketamine, might render the developing brain particularly susceptible to apoptotic neurodegeneration.
It remains unclear, however, whether anesthetics accelerate cell death in neurons destined to die due to natural apoptosis or if they trigger cell suicide in healthy neurons, which would have otherwise survived. If neurons are actively eliminated during anesthesia, it will be critical to demonstrate whether the developing brain is able to replace these neurons to maintain functional integrity. To answer these questions, it is imperative to study long-term neurocognitive function after neonatal anesthesia. However, long-term neurocognitive impairment has only been demonstrated in laboratory studies after neonatal administration of supraclinical doses of ketamine or propofol in mice or after prolonged isoflurane exposure in rats.76,77,85 However, preliminary data in mice suggest that even a prolonged exposure to isoflurane as the single anesthetic does not alter behavior and neurocognitive function in adulthood.153 These differential effects of anesthetics in two small rodent models mandate the examination of potential anesthetic neurotoxicants in several species, not only for their ability to trigger neuroapoptosis immediately after anesthetic exposure, but also in regards to long-term neurocognitive performance. Moreover, large animal and nonhuman primate studies should close the evolutionary gap between small rodents and humans.
Primum non nocere —Although prospective studies of neurodevelopment after elective surgery and anesthesia in infants are lacking, anecdotal data point to at least temporary neurological dysfunction after early life exposure to anesthetics. The implications of the possibility for neurotoxic effects of general anesthetics, as demonstrated in several animal models, mandate the vigilance of every anesthesiologist caring for young children. Because there are no commonly used anesthetics with proven safety records in animal studies, and because surgical procedures in neonates and infants are usually limited to those preserving life or quality of life, pediatric anesthesiologists should be vigilant to minimize the possibility of anesthesia-induced neurotoxicity in their youngest patients. Accordingly, meticulous care needs to be taken to prevent anesthetic overdoses and consideration should be given to formulate anesthetic plans involving regional anesthesia, where applicable, as well as avoiding the combined administration of multiple GABA-agonists and NMDA-antagonist anesthetics. However, hemodynamic stability and avoidance of hypoxia should still remain the principal objectives to prevent postoperative neurocognitive impairment. Moreover, pediatric anesthesiologists are encouraged to actively investigate this phenomenon in preclinical as well as clinical studies. The entire anesthesia community, the pharmaceutical industry, and government agencies are called upon to support research into the mechanism and prevention of anesthesia-induced neurodegeneration. The Food and Drug Administration has started this process by convening the Anesthesia and Life-Support Advisory Committee in March of 2007 (the transcript can be obtained at http://www.fda.gov/ohrms/dockets/ac/07/transcripts/2007-4285t1.pdf). At this point, the committee unanimously agreed, "there are not adequate data to extrapolate the animal findings to humans." The committee concluded, "the existing and well-understood risks of anesthesia" (hemodynamic and respiratory) "continue to be the overwhelming considerations in designing an anesthetic, and the understood risks of delaying surgery are the primary reasons to determine the timing."
Footnotes
Accepted for publication December 17, 2007.
REFERENCES
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