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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 changes in anesthetic practice were recommended, the
may be toxic to the immature developing brain.1–3 In panel did recommend that studies to determine whether
rodents, ␥-aminobutyric acid receptor agonists and N- anesthetics are developmental neurotoxins in children
methyl-D-aspartic acid receptor antagonists, including should be urgently performed. The concerns raised by
ketamine, isoflurane, midazolam, and nitrous oxide, in- both the animal studies and the Food and Drug Adminis-
duce dose- and age-dependent neuronal apoptosis and tration’s response have generated media interest resulting
neuronal cell death in vitro,1,2 with the most prominent in sensational headlines and reports on the potential “brain
effects being observed at postnatal day 7, which inter- damage” children might sustain from exposure to anesthesia.
estingly is also the peak period for synaptogenesis. Ket- Because there has been no clinical study specifically
amine produces similar age- and dose-dependent neurotox- designed to examine the effect of anesthesia on neuro-
icity in nonhuman primates.3 Alarmingly, these in vitro cognitive function in children, it is therefore reasonable
findings were shown to have long-term functional con- to look to other studies that may inform the debate.
sequences resulting in deficits in memory, learning, at- Studies that can tangentially address this issue include
tention, and motor function in adult rats after neonatal neurodevelopmental outcome after surgery in groups
exposure to anesthetics.2 Comparable data are not yet such as premature infants and infants with congenital
available in nonhuman primates. Although the dose and cardiac defects.8 –21 In premature infants, neurodevelop-
duration of anesthetic exposure used in most laboratory mental outcome was worse in those who had surgery for
studies are substantially higher than those used in chil- ligation of patent ductus arteriosus compared with those
dren, these findings are nevertheless of serious con- who were treated medically.17 Similarly, very low-birth-
cern.4,5 Moreover, recent work indicates that neurotox- weight infants and premature infants who had surgery
icity could indeed occur with doses within the human for necrotizing enterocolitis fared worse neurodevelop-
range.6 mentally than those who did not have surgery.18 The
According to the 2004 National Hospital Discharge Boston Circulatory Arrest Trial examined neurodevelop-
Survey, close to three million children in the United ment in infants who had repair of congenital cardiac
States receive anesthesia for surgical procedures, and defects and found that these children had normal or only
many more require anesthesia and sedation for dental very modest decreases in full scale intelligence quotient
procedures and imaging studies. Given this large expo- (IQ) but had specific deficits in memory, language skills,
sure vulnerability for so many infants and children to attention, and visuospatial skills.8 –16,22,23 These studies,
agents that seem to be neurotoxic to animals, it is critical however, contain many confounding variables that make
to understand whether such toxicity also occurs in chil- it impossible to separate the effects of anesthesia from
dren exposed to anesthesia. This concern prompted the surgery and comorbid conditions. The comparison of
US Food and Drug Administration to hold an Advisory outcomes in a group of relatively healthy children who
Committee meeting in March 2007 to review the data on had tympanostomy either before age 3 yr or up to 9
neurotoxicity and determine whether changes in anes- months later is therefore of particular interest. At follow-
thesia practice should be recommended.7 Although no up, the two groups did not differ in their neurodevelop-
mental or neurocognitive function at age 6 yr.24,25 There-
Accepted for publication July 31, 2008. This Editorial View solely represents
fore, although these studies provide some reassurance
the views of the authors and the investigators of the PANDA Research Network that anesthesia exposure before age 3 yr does not ad-
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-
versely affect neurodevelopment, they do not directly
sium on “Neurodevelopment and Anesthesia in Children.” address the issue of anesthetic neurotoxicity because

Anesthesiology, V 109, No 5, Nov 2008 757


they were not designed to examine the effect of anes- In addition, we might also apply the lessons learned
thesia per se, but were a comparison between children from a variety of clinical neurodevelopmental studies in
who received anesthesia at two different ages. Indeed, considering which endpoint measures might be relevant
none of the aforementioned studies could specifically in studying the neurotoxic effects of anesthetic agents in
address the potential effects of anesthesia on neurode- children. Studies of developmental outcomes related to
velopmental outcome. environmental neurotoxins have used a wide range of
The absence of clinical data to address this critically endpoint measures, including mental and motor devel-
important public health issue underscores the need for opment, intelligence quotients, behavioral deviations,
more rigorous and definitive studies to examine whether and quality of home environments.29 Both large-scale
anesthetic agents cause neurotoxicity in children. Such national studies of brain development in normal children
studies may have many different possible approaches: and studies of neurodevelopment outcomes after sur-
experimental, observational, prospective, or retrospec- gery have also used similar ranges of endpoint measures,
tive. Perhaps not one single study could provide the including intelligence, verbal and nonverbal abilities,
answer to the question, and data may need to be gener- memory, attention, multidomain development, and be-
ated from various sources that converge to answer the havioral pathologies.12,18,20 –22,30,31 It is important to
research question. To be more precise, the research note that these defined endpoints involve specific devel-
question should be directed to address the effects of opmental domains and are not the same as a global
anesthetic exposure on neurodevelopment in children measure of intelligence. In the Boston Circulatory Arrest
with and without surgery. The two most important de- Trial, even in situations of significant physiologic inju-
sign considerations for such a study are the identification ries, decrements in general IQ scores were extremely
of the appropriate endpoints to use to determine modest, and deficits were only detected using a targeted
whether neurotoxicity exists and the choice of the epi- examination that assessed specific areas such as execu-
demiologic design. In addition, the successful implemen- tive function, memory, and attention.9,11,16 In human
studies, although it would be informative to have an IQ
tation of such a study must consider feasibility issues and
measure, more specific information can only be obtained
the cost and duration for the study.
by evaluating defined developmental domains. Assess-
Taking all of these considerations into account, we pro-
ment could be selective for the specific domains of
pose a study with a mixed epidemiologic design using a
interest and does not necessarily require a complete
retrospective historical cohort that had anesthesia expo-
battery of neuropsychological testing. Although these
sure during early childhood before age 3 yr, but a prospec-
studies did not specifically address the question of anes-
tive follow-up for direct assessment of outcome. The neu-
thesia neurotoxicity, they do demonstrate the value of
rodevelopmental outcome measures will include global IQ
examining global as well as domain-specific outcome
and targeted areas of neurocognitive function, including measures. The need to perform long-term follow-up as-
attention, memory, behavior, and motor function. The sessment is illustrated by the results from neurobehav-
comparison group will be developmental age–matched sib- ioral outcome studies in children after surgery and anes-
lings without history of anesthesia exposure. The assess- thesia. The overwhelming majority of these clinical studies
ment will be performed within a specified age range in late have consistently identified minor behavioral regressions
childhood for both the index and the comparison group followed by recovery within a month. Therefore, they have
using validated age-specific instruments. been limited to assessment of short-term rather than long-
With respect to identifying the appropriate endpoints, term neurodevelopmental consequences.32–36
the existing findings from animal studies, mostly on rat Therefore, based on the findings in the preclinical
pups, cannot be directly extrapolated to children who anesthetic neurotoxicity studies and other developmen-
receive anesthesia because of interspecies differences in tal neurotoxicity studies in children, we propose to as-
brain development and in the brain’s age- and dose- sess the neurodevelopmental endpoints by direct assess-
dependent vulnerability to injury26,27 In addition, anes- ments of both global intelligence measures and specific
thetic neurotoxicity may be modulated by noxious stim- domain measures in executive functioning, attention,
uli such as occurs during surgery.28 Nevertheless, the memory, and motor development. Because human de-
preclinical data do provide consistent and irrefutable velopment is impacted by complex interactions, inter-
evidence that anesthetic exposure can produce negative pretation will also require the appraisal of social, behav-
neurodevelopmental consequences. The specific areas ioral, and family function. The rationale for using direct
in which deficits were identified in rodents could be assessment for these outcome measures is that the data
translated to corresponding neuropsychological func- will be specific, consistent, and complete with respect
tional domains in humans and could be readily measured to the research question. Unlike using a clinical diagno-
in children by trained professionals using a wide range of sis, which not only may lack standardization and uniform
available and well-established developmental neuropsy- criteria but may only point to significant and serious
chological tests. conditions, direct assessment allows for detection of

Anesthesiology, V 109, No 5, Nov 2008


more subtle, though important, functional deficits. For number of potential subjects. Second, if only subjects who
example, a diagnostic endpoint of attention deficit hy- have sufficient quality of documentation are enrolled, the
peractivity disorder would exclude more subtle atten- actual dose and duration of anesthetic exposure could be
tion dysfunctions that are, nevertheless, suboptimal for examined. Third, one could use age-specific, validated as-
age and impact on learning, such as poor selective and sessment tools for the direct assessment of outcomes.
sustained attention abilities, self-regulation, and monitor- Fourth, the comparison is within a well-defined develop-
ing. We further propose that the assessment be per- mental period and not across ages of different developmen-
formed in a single session later in childhood, at least 3 yr tal periods. It is difficult to make comparison across ages
after exposure, to determine the long-term outcome. To representing different periods of physiologic and psycho-
perform the assessment in a single session would mean logical development, because the predictive value from
that the comparison of these outcome measures be- one age group to another is relatively weak with the cur-
tween the exposed and unexposed groups could be rently available age-specific neuropsychological assessment
performed using the same age-specific instruments dur- tools.37 Finally, this approach offers economy in the time
ing a defined developmental period. This would elimi- required to obtain initial results, and in the potential cost of
nate the methodologic challenge of interpreting data the study because there will be no need to budget for
obtained using different age-specific instruments across extensive follow-up.
sequential developmental periods in childhood. Poor All of the preclinical data have consistently demonstrated
predictability over time of widely used and respected that neuronal apoptosis and degeneration in response to
instruments for infants and young children, e.g., the anesthetic exposure were developmental age dependent,
Bayley Scales of Infant Development,37 is well docu- with the greatest vulnerability occurring during the period
mented and would constitute a significant limitation. of synaptogenesis. We therefore propose to assemble a
The second important consideration in study design is retrospective cohort that had anesthetic exposure before
the choice of the epidemiologic approach. Direct and age 3 yr, a period for synaptogenesis in humans.
prospective neuropsychological evaluation would pro- The choice of comparison group is perhaps the most
vide the most valid information. However, useful data important consideration in this study design. In our pro-
derived from direct but nonprospective neuropsycho- posed design, the comparison group consists of siblings
logical evaluation may be available in certain life-course who had no anesthesia exposure. Parental education and
birth cohorts constructed over the past 50 yr in the socioeconomic status are two of the most important
United States and elsewhere.38 – 43 Because almost all confounding factors to control for in any study involving
birth cohort studies have some information on child evaluation of neurocognitive function. For this reason,
health and development and are likely to have surgical the adoption of siblings as the comparison group has
histories, this has the appeal of providing answers rela- been widely used in psychiatric research.45,46 In using the
tively quickly. Several of the more recent birth cohort sibling as the comparison group, one important consider-
studies, including the MoBa-Norway cohort constructed ation is the intersibling differences in IQ that may exist.
in 1999 and the National Child Study initiated in 2006,43 Though a recent study has documented a difference in IQ
are particularly attractive because they would not in- based on the birth order of siblings when they were tested
volve any significant changes in anesthesia practice in as adults,45 other sibling studies have shown little intersib-
children and therefore exposure history to obsolete ling differences in intelligence when testings were per-
agents, as would be the case with some of the older birth formed at ages 4, 7, and 11 yr.46,47 Although intersibling
cohorts. However, these birth cohorts have not com- differences in more subtle aspects of brain functioning
pleted their enrollment, and any data from these studies related to learning and behavior are less known, these data
may not be available for some time to come. do strongly suggest that the choice of age for testing is
Direct and prospective neuropsychological evaluation important in the study design when sibling comparison
could be performed as a randomized controlled trial or as groups are used for studies examining neurocognitive func-
an observational study. Because surgery without anesthesia tion as an outcome.
is not an ethical or acceptable option, a placebo-controlled It is clear that a study to determine whether anesthet-
randomized clinical trial is precluded. Observational stud- ics are neurotoxic in children is urgently needed. The
ies could be performed with either a prospective cohort or proposed epidemiologic design would be efficient and
a retrospectively assembled exposed and unexposed co- feasible and would yield reliable and valid outcome data.
hort, which is then followed and assessed, in a prospective The neurodevelopmental endpoint measures for the pro-
fashion. The approach of prospective assessment of a ret- posed study, including tests of memory, attention, motor
rospective cohort has been successfully used in studies of function, and behavior, are chosen based on extrapolat-
childhood cancer survivors44 and on the effect of tympa- ing the deficits identified in the available though limited
nostomy on childhood development.24,25 Creating a cohort animal data, while incorporating the experiences from
with anesthesia exposure having occurred in the past has a other developmental neurotoxicity studies. The assess-
number of distinct advantages. First, there would be a large ment will be performed within a specified age range in

Anesthesiology, V 109, No 5, Nov 2008


late childhood for both the index and the comparison icine, Harvard Medical School, Boston, Massachusetts); Randall Flick, M.D.,
M.P.H. (Assistant Professor, Department of Anesthesiology, Mayo Clinic, Roch-
group using validated age-specific instruments. Finally, ester, Minnesota); Michael M. Todd, M.D. (Professor and Head, Department of
the study is designed to detect modest effects of anes- Anesthesia, University of Iowa Carver College of Medicine, Iowa City, Iowa);
David Bellinger, Ph.D. (Professor, Department of Neurology, Harvard Medical
thetic agents on the neurodevelopmental outcome in the School, Boston Children’s Hospital, Boston, Massachusetts); Alan J. Moskowitz,
context of surgery. Therefore, a relatively large sample M.D. (Professor, Department of Medicine and Department of Health Policy and
Management, and Co-Director, InCHOIR, Columbia University, New York, New
size for such a study would be anticipated, which could York); and Ezra Susser, M.D., Dr.P.H. (Anna Cheskis Gelman and Murray Charles
be more effectively achieved with a multisite design. Gelman Professor and Chair, Department of Epidemiology, Mailman School of
Public Health, Professor, Department of Psychiatry, Columbia University).
Irrespective of the epidemiologic design, distinguishing The authors also acknowledge other significant contributors to the design and
the effects of anesthesia from the effects of surgery repre- development of the PANDA Study Research Network: Charles Dean Kurth, M.D.
(Professor, Departments of Anesthesia and Pediatrics, University of Cincinnati
sents a daunting challenge to clinical researchers. Our pro- College of Medicine, and Anesthesiologist-in-Chief and Director, Department of
posed study design may be the most appropriate and im- Anesthesia, Cincinnati Children’s Hospital, Cincinnati, Ohio); Annetine Gelijns,
Ph.D. (Professor, Department of Health Policy and Management and Surgical
mediate approach to perform an observational study to Science, and Co-Director, InCHOIR, Columbia University); William J. Greeley,
address the research question of anesthetics as potential M.D., M.B.A. (Professor, Departments of Anesthesia and Pediatrics, University of
Pennsylvania School of Medicine, and Anesthesiologist-in-Chief and Chair, De-
developmental neurotoxins. With the proposed study de- partment of Anesthesiology and Critical Care Medicine, Children’s Hospital of
sign, if there is no difference in any neurodevelopmental Philadelphia, Philadelphia, Pennsylvania); Charles Schleien, M.D. (Professor, De-
partments of Pediatrics and Anesthesiology, Columbia University, and Director,
outcome between groups, then that is strong evidence that Pediatric Intensive Care Unit, Morgan Stanley Children’s Hospital of New York–
anesthesia does not produce neurotoxicity, but if the re- Presbyterian, New York, New York); Charles J. Stolar, M.D. (Rudolph N. Schul-
linger Professor, Departments of Surgery and Pediatrics, Columbia University,
sults show any evidence for any difference between ex- and Surgeon-in-Chief, Morgan Stanley Children’s Hospital of NewYork–Presbyte-
posed and unexposed groups in any neurodevelopmental rian); Joseph R. Tobin, M.D. (Professor and Chair, Department of Anesthesiology,
Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina);
outcome, then no definite conclusion can be made that this and Margaret Wood, M.D. (E.M. Papper Professor and Chairman, Department of
effect is due to the surgery or the anesthesia. Anesthesiology, Columbia University).
In the context of history of anesthesiology as a specialty, The authors thank Barbara Lang, B.S. (Administrative Assistant, Department of
Anesthesiology, College of Physicians and Surgeons, Columbia University, New
once before, the anesthesia scientific community had an- York, New York), for her excellent editorial assistance.
swered a pressing question of anesthetic toxicity and
safety. Forty years ago, the National Halothane Study was
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Robert I. Block, Ph.D. (Associate Professor, Department of Anesthe-
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neurodevelopment in the first 3 years of life among inner-city children. Pediatrics versity Medical Center, Nashville, Tennessee); Steven C. Hall, M.D.
2006; 118:e1845–59 (Arthur C. King Professor of Pediatric Anesthesia, Department of An-
30. Forbess JM, Visconti KJ, Bellinger DC, Jonas RA: Neurodevelopmental esthesiology, Northwestern University, Feinberg School of Medicine,
outcomes in children after the Fontan operation. Circulation 2001; 104:I127–32 Chicago, Illinois); Andreas Loepke, M.D., Ph.D., F.A.A.P. (Associate
31. Waber DP, De Moor C, Forbes PW, Almli CR, Botteron KN, Leonard G,
Milovan D, Paus T, Rumsey J: The NIH MRI study of normal brain development: Professor, Departments of Anesthesia and Pediatrics, University of
Performance of a population based sample of healthy children aged 6 to 18 years Cincinnati College of Medicine, Cincinnati, Ohio); Lynne Maxwell,
on a neuropsychological battery. J Int Neuropsychol Soc 2007; 13:729–46 M.D. (Associate Professor, Department of Anesthesiology and Critical
32. Kain ZN: Postoperative maladaptive behavioral changes in children: Inci- Care, University of Pennsylvania, Philadelphia, Pennsylvania); Francis
dence, risks factors and interventions. Acta Anaesthesiol Belg 2000; 51:217–26
33. Kain ZN, Caldwell-Andrews AA, Maranets I, McClain B, Gaal D, Mayes LC,
X. McGowan, Jr., M.D. (Professor, Department of Anesthesia, Chil-
Feng R, Zhang H: Preoperative anxiety and emergence delirium and postopera- dren’s Hospital Boston, Boston, Massachusetts); Tonya Miller, M.D.
tive maladaptive behaviors. Anesth Analg 2004; 99:1648–54 (Instructor, Department of Anesthesia, Children’s Hospital Boston);
34. Kain ZN, Caldwell-Andrews AA, Weinberg ME, Mayes LC, Wang SM, Gaal Santhanam Suresh, M.D. (Professor, Department of Anesthesia, North-
D, Saadat H, Maranets I: Sevoflurane versus halothane: Postoperative maladaptive
behavioral changes—A randomized, controlled trial. ANESTHESIOLOGY 2005; 102:
western University, Feinberg School of Medicine); Ronald S. Litman,
720–6 D.O., F.A.A.P. (Associate Professor, Departments of Anesthesiology
35. Kain ZN, Mayes LC, Wang SM, Hofstadter MB: Postoperative behavioral and Pediatrics, University of Pennsylvania).

Anesthesiology, V 109, No 5, Nov 2008