䉬 EDITORIAL VIEWS
Anesthesiology 2008; 109:757– 61 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
Anesthesia and Neurodevelopment in Children
Time for an Answer?
Editor’s Note: This is the first in a three-part series of Editorial Views regarding design of clinical trials to address the effect
of anesthesia on the developing brain. Animal studies have suggested that anesthetic exposure could affect neurocognitive
development, and there is an urgent need for clinical trials to determine whether this effect occurs in humans. This series
presents the opinions of three world thought leaders in the possible designs of such clinical trials.
James C. Eisenach, M.D., Editor-in-Chief
RECENT animal studies have suggested that anesthetics
may be toxic to the immature developing brain.1–3 In
rodents, ␥-aminobutyric acid receptor agonists and N-
methyl-D-aspartic acid receptor antagonists, including
ketamine, isoflurane, midazolam, and nitrous oxide, in-
duce dose- and age-dependent neuronal apoptosis and
neuronal cell death in vitro,1,2 with the most prominent
effects being observed at postnatal day 7, which inter-
estingly is also the peak period for synaptogenesis. Ket-
amine produces similar age- and dose-dependent neurotox-
icity in nonhuman primates.3 Alarmingly, these in vitro
findings were shown to have long-term functional con-
sequences resulting in deficits in memory, learning, at-
tention, and motor function in adult rats after neonatal
exposure to anesthetics.2 Comparable data are not yet
available in nonhuman primates. Although the dose and
duration of anesthetic exposure used in most laboratory
studies are substantially higher than those used in chil-
dren, these findings are nevertheless of serious con-
cern.4,5 Moreover, recent work indicates that neurotox-
icity could indeed occur with doses within the human
range.6
According to the 2004 National Hospital Discharge
Survey, close to three million children in the United
States receive anesthesia for surgical procedures, and
many more require anesthesia and sedation for dental
procedures and imaging studies. Given this large expo-
sure vulnerability for so many infants and children to
agents that seem to be neurotoxic to animals, it is critical
to understand whether such toxicity also occurs in chil-
dren exposed to anesthesia. This concern prompted the
US Food and Drug Administration to hold an Advisory
Committee meeting in March 2007 to review the data on
neurotoxicity and determine whether changes in anes-
thesia practice should be recommended.7 Although no
Accepted for publication July 31, 2008. This Editorial View solely represents
the views of the authors and the investigators of the PANDA Research Network
and does not necessarily reflect the views of all of the participants of the First
Columbia University-Morgan Stanley Children’s Hospital of New York Sympo-
sium on “Neurodevelopment and Anesthesia in Children.”
Anesthesiology, V 109, No 5, Nov 2008
changes in anesthetic practice were recommended, the
panel did recommend that studies to determine whether
anesthetics are developmental neurotoxins in children
should be urgently performed. The concerns raised by
both the animal studies and the Food and Drug Adminis-
tration’s response have generated media interest resulting
in sensational headlines and reports on the potential “brain
damage” children might sustain from exposure to anesthesia.
Because there has been no clinical study specifically
designed to examine the effect of anesthesia on neuro-
cognitive function in children, it is therefore reasonable
to look to other studies that may inform the debate.
Studies that can tangentially address this issue include
neurodevelopmental outcome after surgery in groups
such as premature infants and infants with congenital
cardiac defects.8 –21 In premature infants, neurodevelop-
mental outcome was worse in those who had surgery for
ligation of patent ductus arteriosus compared with those
who were treated medically.17 Similarly, very low-birth-
weight infants and premature infants who had surgery
for necrotizing enterocolitis fared worse neurodevelop-
mentally than those who did not have surgery.18 The
Boston Circulatory Arrest Trial examined neurodevelop-
ment in infants who had repair of congenital cardiac
defects and found that these children had normal or only
very modest decreases in full scale intelligence quotient
(IQ) but had specific deficits in memory, language skills,
attention, and visuospatial skills.8 –16,22,23 These studies,
however, contain many confounding variables that make
it impossible to separate the effects of anesthesia from
surgery and comorbid conditions. The comparison of
outcomes in a group of relatively healthy children who
had tympanostomy either before age 3 yr or up to 9
months later is therefore of particular interest. At follow-
up, the two groups did not differ in their neurodevelop-
mental or neurocognitive function at age 6 yr.24,25 There-
fore, although these studies provide some reassurance
that anesthesia exposure before age 3 yr does not ad-
versely affect neurodevelopment, they do not directly
address the issue of anesthetic neurotoxicity because
757
758
they were not designed to examine the effect of anes-
thesia per se, but were a comparison between children
who received anesthesia at two different ages. Indeed,
none of the aforementioned studies could specifically
address the potential effects of anesthesia on neurode-
velopmental outcome.
The absence of clinical data to address this critically
important public health issue underscores the need for
more rigorous and definitive studies to examine whether
anesthetic agents cause neurotoxicity in children. Such
studies may have many different possible approaches:
experimental, observational, prospective, or retrospec-
tive. Perhaps not one single study could provide the
answer to the question, and data may need to be gener-
ated from various sources that converge to answer the
research question. To be more precise, the research
question should be directed to address the effects of
anesthetic exposure on neurodevelopment in children
with and without surgery. The two most important de-
sign considerations for such a study are the identification
of the appropriate endpoints to use to determine
whether neurotoxicity exists and the choice of the epi-
demiologic design. In addition, the successful implemen-
tation of such a study must consider feasibility issues and
the cost and duration for the study.
Taking all of these considerations into account, we pro-
pose a study with a mixed epidemiologic design using a
retrospective historical cohort that had anesthesia expo-
sure during early childhood before age 3 yr, but a prospec-
tive follow-up for direct assessment of outcome. The neu-
rodevelopmental outcome measures will include global IQ
and targeted areas of neurocognitive function, including
attention, memory, behavior, and motor function. The
comparison group will be developmental age–matched sib-
lings without history of anesthesia exposure. The assess-
ment will be performed within a specified age range in late
childhood for both the index and the comparison group
using validated age-specific instruments.
With respect to identifying the appropriate endpoints,
the existing findings from animal studies, mostly on rat
pups, cannot be directly extrapolated to children who
receive anesthesia because of interspecies differences in
brain development and in the brain’s age- and dose-
dependent vulnerability to injury26,27 In addition, anes-
thetic neurotoxicity may be modulated by noxious stim-
uli such as occurs during surgery.28 Nevertheless, the
preclinical data do provide consistent and irrefutable
evidence that anesthetic exposure can produce negative
neurodevelopmental consequences. The specific areas
in which deficits were identified in rodents could be
translated to corresponding neuropsychological func-
tional domains in humans and could be readily measured
in children by trained professionals using a wide range of
available and well-established developmental neuropsy-
chological tests.
Anesthesiology, V 109, No 5, Nov 2008
EDITORIAL VIEWS
In addition, we might also apply the lessons learned
from a variety of clinical neurodevelopmental studies in
considering which endpoint measures might be relevant
in studying the neurotoxic effects of anesthetic agents in
children. Studies of developmental outcomes related to
environmental neurotoxins have used a wide range of
endpoint measures, including mental and motor devel-
opment, intelligence quotients, behavioral deviations,
and quality of home environments.29 Both large-scale
national studies of brain development in normal children
and studies of neurodevelopment outcomes after sur-
gery have also used similar ranges of endpoint measures,
including intelligence, verbal and nonverbal abilities,
memory, attention, multidomain development, and be-
havioral pathologies.12,18,20 –22,30,31 It is important to
note that these defined endpoints involve specific devel-
opmental domains and are not the same as a global
measure of intelligence. In the Boston Circulatory Arrest
Trial, even in situations of significant physiologic inju-
ries, decrements in general IQ scores were extremely
modest, and deficits were only detected using a targeted
examination that assessed specific areas such as execu-
tive function, memory, and attention.9,11,16 In human
studies, although it would be informative to have an IQ
measure, more specific information can only be obtained
by evaluating defined developmental domains. Assess-
ment could be selective for the specific domains of
interest and does not necessarily require a complete
battery of neuropsychological testing. Although these
studies did not specifically address the question of anes-
thesia neurotoxicity, they do demonstrate the value of
examining global as well as domain-specific outcome
measures. The need to perform long-term follow-up as-
sessment is illustrated by the results from neurobehav-
ioral outcome studies in children after surgery and anes-
thesia. The overwhelming majority of these clinical studies
have consistently identified minor behavioral regressions
followed by recovery within a month. Therefore, they have
been limited to assessment of short-term rather than long-
term neurodevelopmental consequences.32–36
Therefore, based on the findings in the preclinical
anesthetic neurotoxicity studies and other developmen-
tal neurotoxicity studies in children, we propose to as-
sess the neurodevelopmental endpoints by direct assess-
ments of both global intelligence measures and specific
domain measures in executive functioning, attention,
memory, and motor development. Because human de-
velopment is impacted by complex interactions, inter-
pretation will also require the appraisal of social, behav-
ioral, and family function. The rationale for using direct
assessment for these outcome measures is that the data
will be specific, consistent, and complete with respect
to the research question. Unlike using a clinical diagno-
sis, which not only may lack standardization and uniform
criteria but may only point to significant and serious
conditions, direct assessment allows for detection of
EDITORIAL VIEWS
more subtle, though important, functional deficits. For
example, a diagnostic endpoint of attention deficit hy-
peractivity disorder would exclude more subtle atten-
tion dysfunctions that are, nevertheless, suboptimal for
age and impact on learning, such as poor selective and
sustained attention abilities, self-regulation, and monitor-
ing. We further propose that the assessment be per-
formed in a single session later in childhood, at least 3 yr
after exposure, to determine the long-term outcome. To
perform the assessment in a single session would mean
that the comparison of these outcome measures be-
tween the exposed and unexposed groups could be
performed using the same age-specific instruments dur-
ing a defined developmental period. This would elimi-
nate the methodologic challenge of interpreting data
obtained using different age-specific instruments across
sequential developmental periods in childhood. Poor
predictability over time of widely used and respected
instruments for infants and young children, e.g., the
Bayley Scales of Infant Development,37 is well docu-
mented and would constitute a significant limitation.
The second important consideration in study design is
the choice of the epidemiologic approach. Direct and
prospective neuropsychological evaluation would pro-
vide the most valid information. However, useful data
derived from direct but nonprospective neuropsycho-
logical evaluation may be available in certain life-course
birth cohorts constructed over the past 50 yr in the
United States and elsewhere.38 – 43 Because almost all
birth cohort studies have some information on child
health and development and are likely to have surgical
histories, this has the appeal of providing answers rela-
tively quickly. Several of the more recent birth cohort
studies, including the MoBa-Norway cohort constructed
in 1999 and the National Child Study initiated in 2006,43
are particularly attractive because they would not in-
volve any significant changes in anesthesia practice in
children and therefore exposure history to obsolete
agents, as would be the case with some of the older birth
cohorts. However, these birth cohorts have not com-
pleted their enrollment, and any data from these studies
may not be available for some time to come.
Direct and prospective neuropsychological evaluation
could be performed as a randomized controlled trial or as
an observational study. Because surgery without anesthesia
is not an ethical or acceptable option, a placebo-controlled
randomized clinical trial is precluded. Observational stud-
ies could be performed with either a prospective cohort or
a retrospectively assembled exposed and unexposed co-
hort, which is then followed and assessed, in a prospective
fashion. The approach of prospective assessment of a ret-
rospective cohort has been successfully used in studies of
childhood cancer survivors44 and on the effect of tympa-
nostomy on childhood development.24,25 Creating a cohort
with anesthesia exposure having occurred in the past has a
number of distinct advantages. First, there would be a large
Anesthesiology, V 109, No 5, Nov 2008
759
number of potential subjects. Second, if only subjects who
have sufficient quality of documentation are enrolled, the
actual dose and duration of anesthetic exposure could be
examined. Third, one could use age-specific, validated as-
sessment tools for the direct assessment of outcomes.
Fourth, the comparison is within a well-defined develop-
mental period and not across ages of different developmen-
tal periods. It is difficult to make comparison across ages
representing different periods of physiologic and psycho-
logical development, because the predictive value from
one age group to another is relatively weak with the cur-
rently available age-specific neuropsychological assessment
tools.37 Finally, this approach offers economy in the time
required to obtain initial results, and in the potential cost of
the study because there will be no need to budget for
extensive follow-up.
All of the preclinical data have consistently demonstrated
that neuronal apoptosis and degeneration in response to
anesthetic exposure were developmental age dependent,
with the greatest vulnerability occurring during the period
of synaptogenesis. We therefore propose to assemble a
retrospective cohort that had anesthetic exposure before
age 3 yr, a period for synaptogenesis in humans.
The choice of comparison group is perhaps the most
important consideration in this study design. In our pro-
posed design, the comparison group consists of siblings
who had no anesthesia exposure. Parental education and
socioeconomic status are two of the most important
confounding factors to control for in any study involving
evaluation of neurocognitive function. For this reason,
the adoption of siblings as the comparison group has
been widely used in psychiatric research.45,46 In using the
sibling as the comparison group, one important consider-
ation is the intersibling differences in IQ that may exist.
Though a recent study has documented a difference in IQ
based on the birth order of siblings when they were tested
as adults,45 other sibling studies have shown little intersib-
ling differences in intelligence when testings were per-
formed at ages 4, 7, and 11 yr.46,47 Although intersibling
differences in more subtle aspects of brain functioning
related to learning and behavior are less known, these data
do strongly suggest that the choice of age for testing is
important in the study design when sibling comparison
groups are used for studies examining neurocognitive func-
tion as an outcome.
It is clear that a study to determine whether anesthet-
ics are neurotoxic in children is urgently needed. The
proposed epidemiologic design would be efficient and
feasible and would yield reliable and valid outcome data.
The neurodevelopmental endpoint measures for the pro-
posed study, including tests of memory, attention, motor
function, and behavior, are chosen based on extrapolat-
ing the deficits identified in the available though limited
animal data, while incorporating the experiences from
other developmental neurotoxicity studies. The assess-
ment will be performed within a specified age range in
760
late childhood for both the index and the comparison
group using validated age-specific instruments. Finally,
the study is designed to detect modest effects of anes-
thetic agents on the neurodevelopmental outcome in the
context of surgery. Therefore, a relatively large sample
size for such a study would be anticipated, which could
be more effectively achieved with a multisite design.
Irrespective of the epidemiologic design, distinguishing
the effects of anesthesia from the effects of surgery repre-
sents a daunting challenge to clinical researchers. Our pro-
posed study design may be the most appropriate and im-
mediate approach to perform an observational study to
address the research question of anesthetics as potential
developmental neurotoxins. With the proposed study de-
sign, if there is no difference in any neurodevelopmental
outcome between groups, then that is strong evidence that
anesthesia does not produce neurotoxicity, but if the re-
sults show any evidence for any difference between ex-
posed and unexposed groups in any neurodevelopmental
outcome, then no definite conclusion can be made that this
effect is due to the surgery or the anesthesia.
In the context of history of anesthesiology as a specialty,
once before, the anesthesia scientific community had an-
swered a pressing question of anesthetic toxicity and
safety. Forty years ago, the National Halothane Study was
the largest epidemiologic study ever performed up to that
time. It was a multisite study that used a retrospective
cohort design, similar to the study proposed here. The
results of The National Halothane Study significantly influ-
enced anesthetic practice and assured the public of the
safety of the anesthetic agent halothane.48 We believe, 40
yr later, it is once more time for a major anesthesia-related
epidemiologic study. It is both a responsibility and an
opportunity for the specialty of anesthesiology. It is our
responsibility to address this critical public health issue
related to pediatric anesthesia. It is also an opportunity for
us to lead the way in translational research from develop-
mental neuroscience to population child health.
Lena S. Sun, M.D.,* Guohua Li, M.D., Dr.P.H.,† Charles DiMaggio,
Ph.D., M.P.H.,† Mary Byrne, Ph.D., M.P.H.,‡ Virginia
Rauh, Sc.D., M.S.W.,§ Jeanne Brooks-Gunn, Ph.D., Ed.M.,㥋
Athina Kakavouli, M.D.,# Alastair Wood, M.D.,** Coinvesti-
gators of the Pediatric Anesthesia Neurodevelopment Assessment
(PANDA) Research Network†† *Departments of Anesthesiology and Pedi-
atrics, Columbia University, New York, New York. lss4@columbia.edu. †De-
partments of Anesthesiology and Epidemiology, ‡School of Nursing, §Depart-
ment of Population and Family Health, School of Public Health, 㛳Teachers’
College and Department of Pediatrics, #Department of Anesthesiology, Co-
lumbia University. **Departments of Internal Medicine and Pharmacology,
Vanderbilt University, Nashville, Tennessee; Department of Internal Medicine
and Department of Pharmacology, Weil Cornell Medical College, New York,
New York. ††See appendix.
The authors acknowledge the contribution of all of the guest participants of
the First Columbia University–Morgan Stanley Children’s Hospital of New York
Symposium on “Neurodevelopment and Anesthesia in Children,” held on May 3,
2008: Cynthia Salorio, Ph.D. (Assistant Professor, Department of Physical Medi-
cine and Rehabilitation, Johns Hopkins School of Medicine, and Pediatric Neu-
ropsychologist, Department of Rehabilitation and Department of Neuropsychol-
ogy, Kennedy Krieger Institute, Baltimore, Maryland); Gregory Crosby, M.D.
(Associate Professor, Department of Anesthesiology, Perioperative and Pain Med-
Anesthesiology, V 109, No 5, Nov 2008
EDITORIAL VIEWS
icine, Harvard Medical School, Boston, Massachusetts); Randall Flick, M.D.,
M.P.H. (Assistant Professor, Department of Anesthesiology, Mayo Clinic, Roch-
ester, Minnesota); Michael M. Todd, M.D. (Professor and Head, Department of
Anesthesia, University of Iowa Carver College of Medicine, Iowa City, Iowa);
David Bellinger, Ph.D. (Professor, Department of Neurology, Harvard Medical
School, Boston Children’s Hospital, Boston, Massachusetts); Alan J. Moskowitz,
M.D. (Professor, Department of Medicine and Department of Health Policy and
Management, and Co-Director, InCHOIR, Columbia University, New York, New
York); and Ezra Susser, M.D., Dr.P.H. (Anna Cheskis Gelman and Murray Charles
Gelman Professor and Chair, Department of Epidemiology, Mailman School of
Public Health, Professor, Department of Psychiatry, Columbia University).
The authors also acknowledge other significant contributors to the design and
development of the PANDA Study Research Network: Charles Dean Kurth, M.D.
(Professor, Departments of Anesthesia and Pediatrics, University of Cincinnati
College of Medicine, and Anesthesiologist-in-Chief and Director, Department of
Anesthesia, Cincinnati Children’s Hospital, Cincinnati, Ohio); Annetine Gelijns,
Ph.D. (Professor, Department of Health Policy and Management and Surgical
Science, and Co-Director, InCHOIR, Columbia University); William J. Greeley,
M.D., M.B.A. (Professor, Departments of Anesthesia and Pediatrics, University of
Pennsylvania School of Medicine, and Anesthesiologist-in-Chief and Chair, De-
partment of Anesthesiology and Critical Care Medicine, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania); Charles Schleien, M.D. (Professor, De-
partments of Pediatrics and Anesthesiology, Columbia University, and Director,
Pediatric Intensive Care Unit, Morgan Stanley Children’s Hospital of New York–
Presbyterian, New York, New York); Charles J. Stolar, M.D. (Rudolph N. Schul-
linger Professor, Departments of Surgery and Pediatrics, Columbia University,
and Surgeon-in-Chief, Morgan Stanley Children’s Hospital of NewYork–Presbyte-
rian); Joseph R. Tobin, M.D. (Professor and Chair, Department of Anesthesiology,
Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina);
and Margaret Wood, M.D. (E.M. Papper Professor and Chairman, Department of
Anesthesiology, Columbia University).
The authors thank Barbara Lang, B.S. (Administrative Assistant, Department of
Anesthesiology, College of Physicians and Surgeons, Columbia University, New
York, New York), for her excellent editorial assistance.
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Appendix: Coinvestigators of the PANDA
Research Network
Robert I. Block, Ph.D. (Associate Professor, Department of Anesthe-
siology, University of Iowa Roy J. and Lucille A. Carver College of
Medicine, Iowa City, Iowa); Jayant K. Deshpande, M.D., M.P.H. (Pro-
fessor, Departments of Anesthesiology and Pediatrics, Vanderbilt Uni-
versity Medical Center, Nashville, Tennessee); Steven C. Hall, M.D.
(Arthur C. King Professor of Pediatric Anesthesia, Department of An-
esthesiology, Northwestern University, Feinberg School of Medicine,
Chicago, Illinois); Andreas Loepke, M.D., Ph.D., F.A.A.P. (Associate
Professor, Departments of Anesthesia and Pediatrics, University of
Cincinnati College of Medicine, Cincinnati, Ohio); Lynne Maxwell,
M.D. (Associate Professor, Department of Anesthesiology and Critical
Care, University of Pennsylvania, Philadelphia, Pennsylvania); Francis
X. McGowan, Jr., M.D. (Professor, Department of Anesthesia, Chil-
dren’s Hospital Boston, Boston, Massachusetts); Tonya Miller, M.D.
(Instructor, Department of Anesthesia, Children’s Hospital Boston);
Santhanam Suresh, M.D. (Professor, Department of Anesthesia, North-
western University, Feinberg School of Medicine); Ronald S. Litman,
D.O., F.A.A.P. (Associate Professor, Departments of Anesthesiology
and Pediatrics, University of Pennsylvania).