Research and Grants

Research Priorities | Grants | SmartTots Funded Studies | Related Research Projects

Anesthesia Use in Children: Concerns and the Need for Research

For several years the FDA’s National Center for Toxicological Research (NCTR), as well as investigators at several universities, have been conducting research to study the effects of anesthetics on the nervous systems of developing animals. This research continues to demonstrate that exposure to some anesthetics and sedatives cause memory and learning difficulties and other harmful changes in the central nervous systems of some laboratory animals. Currently, inadequate data exist to prove or disprove whether similar effects occur in children. SmartTots was launched to facilitate and support studies of existing anesthetic drugs and their effects on childhood development, as well as the impact of drug type, dosage amounts and number of exposures. Information from these research studies will help to determine if particular anesthetic drugs pose hazards to young children, to design the safest anesthetic regimens (dose and duration), and potentially foster the development of new anesthetic drugs. The early research in animals has raised concerns about some anesthetic drugs. Further investigation is needed to determine if there is a risk to infants and children, particularly those younger than four years of age. To date, although research is ongoing, the results are not yet conclusive. Dangers to infants and children from anesthesia are still unproven at this point. More research is needed and SmartTots seeks to facilitate the funding of well controlled clinical studies that will ultimately yield definitive answers.

Research Priorities

Insufficient human data currently exist to determine whether anesthetics induce neurotoxicity in the developing brain. Current research is focused on determining whether volatile anesthetics administered during periods of rapid brain growth are neurotoxic to the developing human brain, and whether they cause long-term difficulties in learning and behavior. Thus far, implicated anesthetic agents include NMDA receptor antagonists, such as ketamine, and GABA agonists, such as sevoflurane.

Key Research Questions

As determined by our Scientific Advisory Board, SmartTots will fund research focused primarily on three fundamental areas:

  1. What is the spectrum of general anesthetic agents, sedatives, surgical procedures, and/or opiates that cause developmental neurotoxicity? What are the doses, durations, and frequencies of exposure? What are the most vulnerable periods of development?
  2. Are there short- and long-term neurocognitive, emotional, behavioral, and/or social outcomes resulting from exposure to anesthetic agents?
  3. What approaches can be taken to prevent or mitigate developmental anesthetic neurotoxicity?
Oregon Health & Science University: Ansgar Brambrink, MD, PhD


Project: Long-Term Outcome of Single vs. Triple Anesthesia Exposure of Infant Monkeys Dr. Brambrink proposes using their newly established infant non-human primate (NHP) model to simulate the human condition of general anesthesia in a highly controlled environment and, supported by a team of expert neuroscientists at the Oregon National Primate Research Center, will investigate long-term functional and morphologic consequences of single vs. triple anesthesia exposure of infant NHPs. Dr. Brambrink’s study is supported by the IARS Frontiers in Anesthesia Research Award. Related Publications:

National Center for Toxicological Research (NCTR)
FDA’s National Center for Toxicological Research (NCTR) is conducting non-clinical studies in both rodents and nonhuman primates to assess: 1) the mechanisms underlying the neurotoxicity associated with clinically-relevant general anesthetics such as ketamine, nitrous oxide, and isoflurane; 2) long-term cognitive deficits related to developmental exposure to these agents; 3) strategies to prevent or ameliorate the adverse effects of anesthesia; and 4) the utility of PET imaging approaches to assist in the non-invasive monitoring of the location, severity, and time course of neurotoxic events associated with general anesthesia; it is hoped that such approaches will translate to use in humans. Related Publications

Pediatric Anesthesia NeuroDevelopment Assessment (PANDA Study)
The Pediatric Anesthesia & Neurodevelopment Assessment (PANDA) project is a large, multi-center study based at the Morgan Stanley Children’s Hospital of New York (Columbia University). The project aims to examine two groups of children – those who have been exposed to a single episode of general anesthesia during inguinal hernia surgery before age three years and those who are siblings of the first group who have not – and assess their neurodevelopment and cognitive functions between ages 8 to 15 years. The goal of the PANDA project is to add to the body of knowledge surrounding the important topic of the long-term neurodevelopmental effects of anesthesia and surgery in infants and young children. Currently, participating study sites include Boston Children’s (Harvard University), Children’s Hospital of Philadelphia (University of Pennsylvania), Chicago Children’s Memorial (Northwestern University), Cincinnati Children’s Hospital (University of Cincinnati College of Medicine), Pittsburgh Children’s Hospital (University of Pittsburgh), Mott Children’s Hospital (University of Michigan) and Vanderbilt Children’s Hospital (Vanderbilt University). Learn more about the PANDA Study. Related Publications

Mayo Clinic Research: MASK (Mayo Safety in Kids) Study
Researchers at the Mayo Clinic in collaboration with the National Center for Toxicological Research (NCTR) are conducting a population-based study of long-term cognitive development in a large cohort of Rochester, MN children. The study compares performance of children with no anesthetic exposure to those with single or multiple exposures prior to age three years on an extensive battery of neurocognitive tests including the operant test battery (OTB). Researchers at NCTR and Arkansas Children’s Hospital are using the OTB to evaluate cognitive performance in both children and non-human primates.

GAS Study
The primary purpose of the GAS study, an international, multi-site, randomized controlled trial, is to investigate the long-term effects of two commonly used modes of anesthesia—spinal and general—and determine whether they result in equivalent neurodevelopment outcomes. Newborns undergoing hernia surgery are randomly assigned to receive general or spinal anesthesia. They then undergo developmental testing at age 2 and neurodevelopmental and intelligence testing at age 5 to determine whether there are neurocognitive differences between the groups. The study also aims to describe the incidence of apnea in the post-operative period after both regional and general anesthesia for inguinal hernia repair in infants. This study is important because inguinal hernia surgery is one of the most common surgeries done in infants and it will provide evidence for the safety or toxicity of general anesthesia for this group of patients. Researchers from Children’s Hospital Boston are collaborating with researchers from nine other centers in the United States, as well as centers in Canada, Australia, Europe, and the United Kingdom, to collect data from 720 infants.

Additional grant opportunities will be announced as funding becomes available.

Grants and Funded Studies

2013 Research Grants Recipients

Lena Sun, MD - $200,000 Grant

lenaSun_photograph-200x300 Columbia University Medical Center Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) Study Dr. Lena S. Sun, E.M. Papper Professor of Pediatric Anesthesiology, Professor of Anesthesiology & Pediatrics and Chief of Division of Pediatric Anesthesiology at Columbia University Medical Center, leads the effort as the Principal Investigator of the multi-site PANDA (Pediatric Anesthesia and Neuro-Development Assessment) study to pursue the important research question of whether anesthetic exposure has detrimental effects in the developing human brain. SmartTots funding is supporting the completion of this ongoing study on the effects of a single episode of early childhood anesthesia exposure before age 3 years on long-term neurocognitive function and behavior in healthy children. The PANDA study will provide the first set of neurocognitive and behavior data in healthy children that are prospectively collected and directly assessed. The study is expected to provide the needed evidence for informed discussions with providers and parents as well as guidance for clinical decision-making. Update: In early 2015 Dr. Sun reported having successfully recruited 117 sibling pairs to participate in the study. She also obtained 23 completed anesthesia records in the exposed cohort to analyze whether low-flow versus high-flow sevoflurane anesthesia (based on fresh gas flow relative to minute ventilation) is associated with differences in results of neurocognitive testing. It is anticipated that the study will be complete and results reported by June 2016.

Jeffrey Sall, PhD, MD - $200,000 Grant



Jeffrey Sall, PhD, MD – $200,000 Grant

University of California San Francisco Recognition Memory Following Early Childhood Anesthesia Dr. Jeffrey Sall, Hamilton Associate Professor at UCSF School of Medicine, Department of Anesthesia and Perioperative Care, is utilizing the SmartTots grant funding to conduct a research study which is examining the limits or boundary conditions of early childhood anesthesia exposure that lead to cognitive deficits. This project will determine how the duration of anesthesia exposure and the age of the child at the time of exposure affect recognition memory deficits.

Update: During 2015, the study was more than 50% complete and continuing to make progress, actively partnering with academic centers around the country to recruit and test subjects. Once complete, the results will provide guidance to clinicians and parents when deciding to perform certain procedures and will give future researchers an important outcome measure that is easily testable.

Robert Block, PhD - $100,000 Grant


Prior Funded Studies

2012 Research Grants Recipients






Robert Block, PhD – $100,000 Grant

University of Iowa, Iowa City, Iowa General Anesthesia During Human Infancy and Brain Development Dr. Block aimed to evaluate the hypothesis that exposure to general anesthesia and surgery during infancy affects brain and cognitive development as reflected in measures of brain tissue volume and composition and white matter integrity, memory-related regional brain activation, and cognitive test performance. Adolescents who were exposed to anesthesia during infancy are compared to unexposed, but otherwise matched, control subjects. Patients will have been exposed to anesthesia during operations that would not normally, in themselves, be associated with subsequent central nervous system problems or risk factors; and both patients and controls will be individuals in whom no such problems or risk factors during infancy can be identified. Update: By the middle of 2014, Dr. Block’s study analysis found that there were lower white matter volumes and diminished white matter integrity in patients, relative to controls. He also reported finding trends toward differences in brain activity associated with long-term memory and working memory processes in patients, relative to controls. Dr. Block intends to complete the analyses of the present study, publish the results, and seek funding from NIH for a substantially larger-scale study to replicate and extend the results. His new research would involve studying more patients with a broader age range of exposure to anesthesia and comparing patients who were exposed for more vs. less invasive procedures, in addition to unexposed controls.

Caleb Ing, MD - $100,000 Grant

Caleb-200x300 Caleb Ing, MD – $100,000 Grant

Columbia University Medical Center, New York, New York Anesthetic Exposure Duration and Effects on Cognitive and Language Ability Dr. Ing and colleagues are conducting research to determine the relationship between anesthetic exposure before the age of three and long-term neurocognitive deficits using a battery of directly administered neuropsychological assessments. The results of this study will help determine the association between anesthetic exposure and long-term deficits. This will be a critical piece of information that will help parents and physicians weigh the risks and benefits of exposure to anesthesia and whether to delay certain types of elective surgery. Update: As of March 2015, Dr. Ing and team reported two important research findings, they determined that in their cohort, specific neuropsychological outcome measures related to language and abstract reasoning were able to determine differences in children exposed to anesthesia, while academic achievement tests could not. His team was also able to determine that initial exposure to anesthesia after age 3 had no measurable effects on language and abstract reasoning, suggesting that there may be distinct windows of vulnerability for different neurodevelopmental domains in children.

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