Advances in Anesthesia 36 (2018) 125–137

ADVANCES IN ANESTHESIA

Neurocognitive Impact of
Anesthesia in Children
Susan Lei, MDa, Riva Ko, MDa, Lena S. Sun, MDa,b,*
a
Division of Pediatric Anesthesiology, Department of Anesthesiology, Columbia University Medical
Center, New York, NY, USA; bDepartment of Pediatrics, Columbia University Medical Center, New
York, NY 01132, USA

Keywords

Neurotoxicity
Neurodevelopment
Children
GAS study
PANDA study

MASK study
Anesthesia
Key points

Review the evidence of anesthetic neurotoxicity in the developing brain from
preclinical studies.

Understand the study design and findings related to effects of anesthesia on
neurodevelopment in children.

How to discuss the risk of anesthesia with parents and clinicians.

RISK FACTORS
Millions of children undergo anesthesia annually and many of them are younger
than 3 years old. Clinicians and parents frequently ask the question: is anesthesia
safe for the developing child and is there an age range that is associated with a higher
risk of anesthesia? The human brain starts developing in the embryonic period and
continues into the adolescent period. Based on animal studies, should anesthetic
agents pose a risk for neurodevelopment, the most susceptible period is believed
to be the period of maximal synaptogenesis. During this vulnerable period, there
is evidence that exposure to anesthetic agents can lead to neurotoxicity at the
cellular level, as well as functional deficits [1,2]. Most large observational studies
have used age younger than 3 years as the vulnerable period, under the assumption
that peak synaptogenesis in most human brain regions is completed by age 3 years.

Disclosure Statement: Dr L.S. Sun is the Medical Director of SmartTots, a Public Private Partnership between
the Food and Drug Administration and the International Anesthesia Research Society.

*Corresponding author. Department of Pediatrics, Columbia University Medical Center,

New York, NY 01132. E-mail address: lss4@cumc.columbia.edu

https://doi.org/10.1016/j.aan.2018.07.010
0737-6146/18/ª 2018 Elsevier Inc. All rights reserved.
126 LEI, KO, & SUN

Neonates presenting for surgical intervention are a very vulnerable popula-

tion: they tend to be much sicker due to congenital disease and immaturity, and
delaying surgical procedures usually is not an option. Neonates undergoing
surgery incur a much higher mortality and morbidity risk, almost 10 times
as high when compared with older children. They experience more hemody-
namic disturbances and respiratory complications during surgery and anes-
thesia. Disturbances in the microcirculation of the immature central nervous
system in neonates during surgery and in response to anesthetic agents can
affect the developing brain [3].

ANESTHETIC AGENTS
N-methyl-D-aspartate (NMDA)-mediated and c-aminobutyric acid (GABA)-
mediated signal receptors play an important role in neurodevelopment and
neuroapoptosis and their effects on normal neurotransmission and regulation.
Not surprisingly, anesthetic agents that act on these receptors have been impli-
cated in many animal and epidemiologic studies to cause widespread neurode-
generation and long-term neurocognitive disturbances. GABA-binding agents
include volatile anesthetic agents, such as sevoflurane and isoflurane, propofol,
benzodiazepines, barbiturates, and etomidate. NMDA-binding agents include
nitrous oxide and ketamine.
In rodent and nonhuman primate studies, consistent and reproducible
anesthetic-related neurotoxicity and long-term neurobehavioral changes have
been shown (Table 1). Whereas animal studies consistently have demonstrated
brain injury and behavioral changes when exposed to anesthetic and sedative
agents during critical periods of brain development, translating these findings

Table 1
Effects of anesthetic agents on rodents and nonhuman primates
Agents Cellular effects Neurobehavioral findings
Rodents Ketamine Neuroapoptosis
Learning
Isoflurane/ Neurodegeneration
Spatial memory
Sevoflurane Neuroinflammation
Motor activity
Propofol Defects in:
Attention
Combined
neurogenesis
Social behavior
agents
growth cone polarization
Behavior

cytoarchitecture

dendritic density
Modifiers (þ) Noxious stim (þ) isoflurane Not available
Modifiers () Noxious stim () ketamine () Sevoflurane

Anti-inflammatory agent

Environment enrichment
Nonhuman Ketamine Neuroapoptosis Learning, memory, motivation,
primates Neurodegeneration response speed, color
discrimination
Isoflurane Neuroapoptosis Not available
Propofol Apoptosis in neurons and Not available
oligodendrocytes
NEUROCOGNITIVE IMPACT OF ANESTHESIA IN CHILDREN 127

to humans and clinical medicine has been challenging. The rate of brain matu-
ration varies across species. The human brain is much more complex and un-
dergoes a longer period of development than rodents and nonhuman primates,
thus there may be more extended periods of vulnerability depending on the
brain region, and possibly a greater capacity for neuroplasticity and recovery
from any insult [4]. In addition, the dose and duration of anesthetic exposure
in animal studies often exceed what occurs clinically, further complicating
translation to relevant equivalents in humans. Moreover, in assessing long-
term cognitive and behavioral deficits in children, many other factors may
play an important role, such as social environment, diet, and level of parental
education and involvement. Indeed, the entire concept of anesthetic neurotox-
icity in children is controversial because this was not a clinically suspected issue
before the wealth of data derived from preclinical studies [5–7].
Translation of preclinical studies to humans also needs to consider that
almost all animal studies were conducted in the absence of a surgical stimulus
and associated stress and pain leading to inflammation. Children receiving
anesthesia during surgery also experience inflammatory stress response and tis-
sue damage of surgery and trauma. In addition, they also may have hemody-
namic derangements during surgery related to their underlying disease
conditions. When considering the clinical scenario, it is important to take
into account patient-related factors, including genetic anomalies, disease, under-
lying neurologic disease, prematurity, sepsis, vascular disease, and infection [8].
Dexmedetomidine is a potent a2-adrenoceptor agonist with sedative, anal-
gesic, sympatholytic, and anxiolytic properties, and possesses desirable proper-
ties in maintaining normal respiratory patterns. It has no known interactions
with either GABA or NMDA receptors. Preclinical and epidemiologic studies
have demonstrated that dexmedetomidine possesses significant neuroprotective
properties [9]. Dexmedetomidine, therefore, is a potential alternative as a safe
and effective anesthetic adjunct in the perioperative setting. Dexmedetomidine
has not been approved for use in the pediatric population by the Food and
Drug Administration (FDA), but it already is widely used in the clinical setting
by pediatric anesthesiologists and intensivists. Dexmedetomidine is commonly
used as an opioid sparing agent in tonsil surgery, as a premedication, for pro-
cedural sedation, for prevention of postoperative emergence delirium and as a
component of balanced general anesthetic regimens.

CLINICAL DATA
Because of the growing concern surrounding the potential neurotoxic effects of
anesthetic and sedative drugs, clinicians and researchers have necessarily begun
to explore the clinical relevance of anesthetic neurotoxicity by conducting obser-
vational epidemiologic studies. The early observational studies were almost
entirely retrospective in nature, with the inherent limitations and varying degrees
of confounding and reporting bias. Different studies used different outcome mea-
sures to assess neurocognitive and behavioral deficits. Some of the studies used
population-wide results of academic achievement testing and teacher evaluation,
128 LEI, KO, & SUN

whereas others used birth cohort registries and used diagnostic codes for learning
disabilities or behavioral disorders such as attention-deficit/hyperactivity disorder
(ADHD). In some of the studies, neuropsychological testing results were used to
assess IQ scores and other specific cognitive functions. Cohorts usually consisted
of a group of children who had undergone surgery and anesthesia compared with
an unexposed group of controls. In attempting to assess the possible risks inherent
in exposure to anesthetic agents, areas of interest include single versus multiple ex-
posures, ages of exposure, and the types of surgical procedures (Boxes 1–3).
To date, an association between anesthesia exposure early in life and the
development of adverse neurodevelopmental outcomes has been inconsistent,
and very much dependent on the outcome measures examined [10]. Data from
3 studies (General Anesthesia compared to Spinal Anesthesia [GAS], Pediatric
Anesthesia NeuroDevelopment Assessment [PANDA], and Mayo Anesthesia
Safety in Kids [MASK]) have made and will make important contributions
to our understanding of the clinical effects of anesthesia exposure on neurode-
velopment in children.
The GAS study is an ongoing international, multicenter, prospective ran-
domized controlled equivalence trial randomizing premature and full-term in-
fants undergoing inguinal hernia surgery to 2 different anesthetic techniques,
either general anesthesia with inhaled sevoflurane or a regional anesthetic
[11]. Because not anesthetizing patients is not an option, randomizing to general
versus regional anesthesia is one of the only ways to conduct a randomized
prospective clinical trial in these patients. The study was conducted at 28 study
sites, including hospitals in the United States, Australia, Italy, United Kingdom,
Canada, Netherlands, and New Zealand. Infants with previous exposure to
general anesthesia or with any risk factors for adverse neurodevelopmental out-
comes were excluded. The study aims to determine whether regional and gen-
eral anesthesia resulted in equivalent neurodevelopmental outcomes. The
primary outcome measure is IQ at age 5 (results should be available sometime
in 2018). Secondary outcomes include assessment of neurodevelopmental
outcome at age 2 using the Bayley III scale, and the frequency and character-
istics of postoperative apnea. Reports of the interim analysis at age 2 years did
not show any difference in the composite cognitive score between the 2 groups
of children who received regional anesthesia versus general anesthesia. Howev-
er, age 2 years still may be too early to detect any cognitive deficits or behav-
ioral changes, as the brain is still developing. It is well known that the Bayley
performed at age 2 years is a poor predictor of neurodevelopmental outcome
later in life. Therefore, although the interim results of the GAS study are reas-
suring, they are not the primary outcome of the study, nor are they necessarily
predictive of long-term cognitive functions. The median duration of sevoflur-
ane anesthesia exposure was just less than 1 hour (54 minutes), so the effects
of a longer duration of anesthesia still need to be investigated. Nonetheless,
the GAS study provides evidence that general anesthesia in infancy does not
cause any major injury, particularly with exposure to sevoflurane-based anes-
thesia for short durations.
NEUROCOGNITIVE IMPACT OF ANESTHESIA IN CHILDREN 129

Box 1: Summary of clincial studies & risks of adverse

neurodevelopment
Increased Risk

Wilder and colleagues (multiple exposures) [24].

Flick and colleagues (multiple exposures) [25].

Sprung and colleagues (multiple exposures) [26].

Hu and colleagues (multiple exposures) [27].

Warner and colleagues (multiple exposures) [15].

DiMaggio and colleagues. (2009) [28].

DiMaggio and colleagues. (2011) [29].

Andropoulos and colleagues [30].

Ing and colleagues (Raine, 2011) [31].

Block and colleagues (multiple exposures) [32].

Naumann and colleagues [33].

Garcia Guerra and colleagues (2013) [34].

Bong and colleagues [35].

Stratmann and colleagues (multiple exposures) [36].

Backeljauw and colleagues (multiple exposures) [37].
No Increased Risk

Wilder and colleagues (single exposure) [24].

Flick and colleagues (single exposure) [25].

Sprung and colleagues (single exposure) [26].

Hu and colleagues (single exposure) [27].

Warner and colleagues (single exposure) [15].

Hansen and colleagues [38].

Bartels and colleagues [39].

Guerra and colleagues (2011) [40].

Bong and colleagues (achievement scores) [35].

Fan and colleagues [41].

Williams and colleagues [42].

Ing and colleagues (Raine, 2014) [43].

Davidson and colleagues (GAS Trial) [11].

Sun and colleagues (PANDA) [5].

O’Leary and colleagues [17].

Graham and colleagues [18].

Glatz and colleagues (Sweden, 2017) [16].

Ko and colleagues [44,45].
130 LEI, KO, & SUN

Box 2: Single anesthetic exposure & risks of adverse

neurodevelopment
Increased Risk

Ing and colleagues (Raine) [31].

Block and colleagues (Iowa) [32].
No Increased Risk

Graham and colleagues [18].

O’Leary and colleagues [17].

Sun and colleagues (PANDA) [5].

Davidson and colleagues (GAS) [11].

Wilder and colleagues (Mayo) [24].

Flick and colleagues (Mayo) [25].

Sprung and colleagues (Mayo) [26].

Hu and colleagues (Mayo) [27].

Warner and colleagues (Mayo, 2018) [15].

Hansen and colleagues [38].

Bartels and colleagues [39].

Ko and colleagues [44,45].

The PANDA study is a multicenter, ambidirectional, observational study

examining the effect of a single brief anesthetic on performance in a sibling
cohort discordant for exposure to general anesthesia for inguinal hernia repair
[5]. The exposure is retrospective but assessment is prospective. Sibling pairs
within 36 months in age were assessed for neurocognitive and behavior out-
comes prospectively and the data from the documented anesthesia records of
the exposed siblings were reviewed retrospectively. At the time of the surgery
and anesthesia exposure, the exposed siblings were healthy and younger than
3 years, a period of peak synaptogenesis activity in various regions of the human
brain. The study aimed to examine whether the exposure was associated with
impaired neurocognitive development and abnormal behavior in later child-
hood. The sibling pairs were evaluated at age 8 to 15 years using the PANDA
neuropsychological battery, a questionnaire developed by a team of experts in
neuropsychology and neurodevelopment. This age range was chosen because re-
sults from that age group would be reliable and valid, and enough time would
have passed by for impairments and deficits to emerge. The primary outcome
was global cognitive function (IQ), while the secondary outcomes included
domain-specific neurocognitive functions and behaviors. The results from the
PANDA study showed a statistically insignificant mean difference of 0.2 IQ
points between exposed and unexposed siblings. This degree of difference is
deemed clinically undetectable, especially when compared with mean IQ losses
of up to 6 points in population studies of lead exposure in children [12]. The
NEUROCOGNITIVE IMPACT OF ANESTHESIA IN CHILDREN 131

Box 3: Age of exposure & risks of adverse neurodevelopment

Increased Risk

Wilder and colleagues (multiple exposures, Mayo) [24].

Hu and colleagues (multiple exposures, Mayo) [27].

Warner (multiple exposures, Mayo) [15].

DiMaggio and colleagues (2009) [28].

DiMaggio and colleagues (2011) [29].

Naumann and colleagues [33].

Ing and colleagues (Raine) [31].

Block and colleagues (Iowa) [32].

Bong and colleagues [35].

Garcia Guerra and colleagues (at 4 years) [34].

Andropoulos and colleagues [30].

Backeljauw and colleagues [37].

Flick and colleagues (multiple exposures at 0–2 years, Mayo) [25].

Sprung and colleagues (multiple exposures at 0–2 years, Mayo) [26].
No Increased Risk

Wilder and colleagues (single exposure) [24].

Hu and colleagues (single exposure) [27].

Warner and colleagues (single exposure) [15].

Hansen and colleagues [38].

Bartels and colleagues [39].

Bong and colleagues [35].

Garcia Guerra and colleagues (at 18–24 months) [34].

Davidson and colleagues [11].

Sun and colleagues [5].

Flick and colleagues (0–2 years and single exposure) [25].

Sprung and colleagues (0–2 years and single exposure) [26].

O’Leary and colleagues (0–2 years) [17].

Graham and colleagues (0–2 years) [18].

Glatz and colleagues (0–3 years) [16].

Ko and colleagues [44,45].

secondary outcomes also showed no statistically significant differences in mean

scores of memory, attention, visuospatial function, executive function, language,
motor and processing speed, or behavior between sibling pairs. The PANDA
study used sibling matched comparison groups to control for confounding fac-
tors such as genetics, familial environment, parental education, and socioeco-
nomic influences on neurodevelopment. However, the study has several
132 LEI, KO, & SUN

limitations. First, there are no data on neurocognitive risks of repeated or pro-

longed exposure, or risk in premature infants. Second, some of the anesthesia
records from many years ago that were retrospectively reviewed were hand-
written, so data may not be complete or accurate.
The MASK study, similar to the PANDA study, is an ambidirectional observa-
tional study with a retrospective arm that involves analysis of anesthesia records
and school records, and a prospective testing arm that requires children to un-
dergo the Operant Test Battery, a neurodevelopment test [13,14]. The study com-
pares children exposed to anesthesia before age 3 with a reference sample of
propensity-matched unexposed children to determine whether anesthetic expo-
sure was associated with neurodevelopmental abnormalities. The study uses a
population-based birth cohort born to mothers residing in Olmsted County, Min-
nesota. From data gathered from birth and medical records, the birth cohort was
divided into 3 propensity-stratified groups consisting of: no anesthesia exposure,
single exposure before 3 years of age, and multiple exposures before age 3. The
Mayo group recently examined an Olmsted County birth cohort from 1996 to
2000, and reported that there was an increased risk for learning disability and
ADHD associated with multiple exposures but not single exposure, mainly
with sevoflurane anesthetic. These results essentially validated the investigators’
previous study using a birth cohort from Olmsted County from 1976 to 1982, in
which the anesthetic agents used were primarily halothane, ketamine, and nitrous
oxide. Therefore, the results from both the older cohort and the more recent
cohort had the same findings, showing an increased risk of learning disabilities
with multiple anesthetic exposures but not with a single anesthetic exposure;
this occurred in spite of the differences in the anesthetic medications and intrao-
perative monitoring used in the 1970s, 1980s, and 1990s. The ambidirectional
MASK study includes children born between 1994 and 2007 who still reside in
the area who undergo prospective testing with the Operant Test Battery, which
was also used to study anesthetic-related neurotoxicity in nonhuman primates,
and offers a direct comparison of the effects of anesthetic exposure in children
and nonhuman primates performing identical behavioral tasks. The domains
tested include cognition, memory, language, executive function, motor and visual
spatial tasks, attention, and processing speed. MASK study results indicate that
anesthesia exposure before age 3 years was not associated with deficits in general
intelligence [15]. The MASK study also found that single exposures were not asso-
ciated with deficits in other neuropsychological domains, but multiple exposures
were associated with modest decreases in processing speed and fine motor coor-
dination. In addition, in multiple exposed children, parents reported more behav-
ioral problems [15].
Recent population-based cohort studies from Canada and Sweden have pro-
vided evidence that exposure to anesthesia before age 2 years did not increase
the risk of adverse child development [16–18]. For their outcome measures,
both the O’Leary and Graham studies from Canada used the Early Develop-
ment Instrument (EDI), which is a 103-item questionnaire completed by
kindergarten teachers in the second half of the school year that measures
NEUROCOGNITIVE IMPACT OF ANESTHESIA IN CHILDREN 133

children’s ability to meet age-appropriate developmental expectations in 5 gen-

eral domains. Both of these Canadian studies showed that EDI scores were un-
affected after either single or multiple anesthetic exposures before the age of
2 years. The Swedish study by Glatz and colleagues [16] compared Swedish
children born between 1973 and 1993 with 1 anesthesia and surgery exposure
before age 4 and no subsequent hospitalization to unexposed controls, with a
primary outcome measure of mean school grades at age 16, and a secondary
outcome measure of IQ scores at age 18. No difference was seen in school
grades with 1 exposure from ages 0 to 36 months. Exposure to surgery with
anesthesia before age 4 was associated with clinically insignificant lower IQ
test scores; the overall difference was markedly less than the differences asso-
ciated with sex, maternal educational level, or month of birth during the same
year. Interestingly, in both the Canadian and Swedish studies, a small but insig-
nificant difference in academic performance was detected in children exposed
at ages 2 to 4 years.
The available data thus far from the interim results of the GAS study and
those from the ambidirectional observational PANDA, the recently published
MASK study, as well as from several large Canadian and Swedish cohort
studies, suggest that a single brief anesthetic exposure does not appear to
be associated with any neurodevelopmental deficits and behavioral changes,
but the case is less clear with repeated exposures and exposures of long dura-
tion [11,15,19].

FOOD AND DRUG ADMINISTRATION WARNING/

INFORMATION FOR PARENTS REGARDING RISKS OF
ANESTHESIA IN YOUNG CHILDREN
In December 2016, the FDA issued the warning that ‘‘repeated or lengthy use
of general anesthetic and sedation drugs during surgeries or procedures in chil-
dren younger than 3 years or in pregnant women during their third trimester
may affect the development of children’s brains’’ [20]. The FDA recommended
that health care providers discuss with pregnant patients and parents of young
children the benefits, risks, and appropriate timing of surgery requiring anes-
thesia that will take longer than 3 hours. This warning was issued based almost
entirely on evidence from preclinical studies. The objective of the labeling
change was to raise awareness and to ensure that the information needed about
the risks and benefits of anesthesia in young children is widely available to cli-
nicians and parents. However, the association between anesthetic drugs and
their potential neurotoxic effects and the degree of risk remains unclear. There
were no recommendations for an alternative anesthetic strategy from the FDA
when they issued the warning, and although clinicians are looking into alterna-
tive drugs, such as dexmedetomidine and opioids, the research has been limited
and very likely will not represent a feasible option alone when compared with
conventional general anesthetic agents for most surgical procedures [21].
In response to the FDA warning, the American Society of Anesthesiologists,
the Society for Pediatric Anesthesia, and the Executive Committee of the
134 LEI, KO, & SUN

American Academy of Pediatrics Section on Anesthesiology and Pain Medicine

all issued statements. In their statements, they emphasized that the FDA warn-
ing was based on animal studies that need to be verified further in human clin-
ical studies. Although the potential risk of negative cognitive or behavioral
effects of anesthetic agents remains uncertain, they cautioned clinicians and
parents regarding the need to weigh the possible risk of delaying needed surgi-
cal or diagnostic procedures against the unknown potential neurotoxic effects.
Nevertheless, when parents present to the doctor’s office for initial consultation
about a possible procedure, concerns about anesthesia and the FDA warning
about its potential neurotoxic effects may well need to be addressed [10].
As an example, Ear, Nose, and Throat procedures, such as myringotomy
tubes and tonsillectomy and adenoidectomy, are commonly performed on chil-
dren younger than 3 years, and normally are fairly short procedures lasting less
than 2 hours. However, these procedures may need to be repeated on multiple
occasions for recurrent symptoms, leading to multiple exposures to anesthetic
agents for short durations [22]. Nevertheless, the critical importance of these
procedures, in and of themselves, for appropriate development in hearing, lan-
guage development, and good health probably cannot be overstated. Thus, it is
not appropriate to postpone these procedures due to the potential effects of
anesthesia exposure on neurobehavioral development.
Physicians outside of anesthesiology should remain up to date with the most
recent literature and recommendations pertaining to issues relating to anes-
thesia in young children, and appreciate the importance of combining proced-
ures and diagnostic imaging under the same anesthetic event. Careful
consideration and discussion about possible changes or alterations made to
treatment protocols within members of the field may also help reduce the anes-
thetic exposure in young children. Further workup for surgical planning that
involves radiologic imaging, such as MRI or computed tomography scan,
should be combined with other surgical procedures when possible, and a child
life specialist may be recruited to help keep the child calm and preoccupied,
possibly alleviating the need for anesthesia for noninvasive diagnostic proced-
ures. When a procedure with anesthesia is deemed necessary, the physician
responsible for prescribing or performing the procedure should engage the fam-
ily in open discussion about timing and necessity of the procedure, which will
provide needed reassurance to families when considering potential anesthetic
risks, particularly because the pediatric anesthesiologist usually will not meet
the family until the day of the procedure.

SUMMARY
Although clinical research is ongoing and more results are emerging, because
young children usually do not undergo totally elective surgery or diagnostic
testing, postponing surgery or imaging studies may not be an option for young
children, and delaying the procedures may have negative consequences. As per
the recommendation in the FDA statement from 2016: ‘‘Parents should talk to
their doctors if they have any questions or concerns about general anesthesia
NEUROCOGNITIVE IMPACT OF ANESTHESIA IN CHILDREN 135

and sedation drugs.’’ Moreover, the FDA warning was modified in April 2017
to specifically state that ‘‘surgeries or procedures in children younger than
3 years should not be delayed or avoided when medically necessary. Consid-
eration should be given to delaying potentially elective surgery in young chil-
dren where medically appropriate.’’ [23].
Perhaps because of the assumption that peak synaptogenesis in most human
brain regions is complete by age 3 years, most large observational studies use
age younger than 3 years as the presumptive vulnerable period. Thus, the most
recent FDA labeling change has also used this as the age of ‘‘cutoff,’’ although
there is no evidence to support such an approach.
The minimum dose of anesthetic and sedative drugs that potentially can lead
to neurotoxic effects also is largely unknown. All published data on human
studies to date have involved volatile agents with or without additional use
of one or more intravenous sedative agents. None of these studies have any in-
formation regarding specific drugs administered or the exact doses of drugs
used. Therefore, it can only be inferred that a lower dose is used with a single
episode of exposure and that multiple exposures would be associated with
higher doses from the aggregate of multiple doses.
Brief, single exposures have not been associated with detectable neurodeve-
lopmental effects, but the precise nature of ‘‘brief’’ has not been defined. In the
case of whether to proceed with elective surgical procedures, the risks and ben-
efits in each case must be weighed carefully. Finally, whenever possible, pro-
cedures should be scheduled concurrently to minimize the number of
exposures to anesthesia, and the procedures should be performed by the
most skilled surgeons available to decrease the duration of the exposure.
In conclusion, anesthesia is an integral part of the millions of pediatric sur-
geries and diagnostic studies that take place annually. Despite the abundance
of preclinical data in young animals suggesting a relationship between anes-
thetic agents and neurotoxicity, translation of these findings to human children
is complex. Evidence from several recent large clinical studies has been reassur-
ing, but many questions remain. Hopefully future research endeavors will yield
further insights into this challenging and critical topic.

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