Research and Grants

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

Pediatric Anesthesia Neurotoxicity related Abstract/Poster Sessions at the 2018 IARS/AUA/SOCCA Annual Meeting

Neonatal Disruption of PSD-95 PDZ Domain-mediated Protein-protein Interactions Alters Dendritic Spine Morphology, Long-term Potentiation, and Causes Deficits in Learning and Memory in Mice
Abstract #621
IARS: Moderated Poster Discussion Session-05*
Sunday, April 29: 7:30am – 9:00am

Adolescent rats display long-lasting abnormalities in REM sleep quantity and structure after postnatal anesthesia
Abstract #1039
IARS: Moderated Poster Discussion Session-05*
Sunday, April 29: 7:30am – 9:00am

Follow-up on the EGAIN Study: a Prospective Cohort Study on Impact of Exposure to General Anaesthesia during Infancy on Neurocognitive Development
Abstract #1098
IARS: Moderated Poster Discussion Session-08*
Sunday, April 29: 4:00pm – 5:30pm

Ketamine regulates cell cycle in rat fetal neural stem progenitor cells mediated by the p27/cyclin E-CDK2 pathway
Abstract #1392
IARS: Moderated Poster Discussion Session-11*
Monday, April 30: 11:30am – 1:00pm

Academic achievement after multiple exposures to early childhood surgery and anesthesia
Abstract #655
IARS: Moderated Poster Discussion Session-07*
Sunday, April 29: 2:00pm – 3:30pm

Relationship of Multiple Single Service Anesthesia Exposures and Rate of Quality Events
Abstract #1056
IARS: Moderated Poster Discussion Session-07*
Sunday, April 29: 2:00pm – 3:30pm

High-throughput Screen for Inhibitors of Anesthetic-Induced Neurotoxicity in C. elegans
Abstract #1172
AUA: Moderated Poster Discussion Session I*
Thursday, April 26: 12:45pm – 2:15pm

* All Moderated Poster Discussion Sessions are located in the Riverside Exhibit Hall West, East Tower

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:

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?
Are there short- and long-term neurocognitive, emotional, behavioral, and/or social outcomes resulting from exposure to anesthetic agents?
What approaches can be taken to prevent or mitigate developmental anesthetic neurotoxicity?

Related Research Projects

Ansgar Brambrink, MD, PhD New York Presbyterian/Columbia University Medical Center

Project: Long-Term Outcome of Single vs. Triple Anesthesia Exposure of Infant Monkeys. At the outset of this study, Dr. Brambrink utilized a newly established infant non-human primate (NHP) model to simulate the human condition of general anesthesia in a highly controlled environment. This project, initially begun by a team of expert neuroscientists at the Oregon National Primate Research Center, relocated in 2016 to the Department of Anesthesiology at Columbia University College of Physicians & Surgeons. The new team of investigators continue to study the 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.

Related Publications:

Dexmedetomidine + Sevoflurane in Neonatal Rats

Ansgar Brambrink, MD, PhD – Columbia University Medical Center
Andreas W. Loepke, MD, PhD – Cincinnati Children’s Hospital
Laszlo Vutskits, MD, PhD – University of Geneva

Dexmedetomidine + Sevoflurane in Neonatal Rats

This dose-finding study is being conducted in three laboratories and the combined results will be presented together to produce high quality data for subsequent studies in higher species. Dexmedetoimidine (DEX), an adrenoreceptor agonist, has been shown to have sedative and analgetic properties at all ages, but especially in neonates. This series of experiments will determine the most effective neuroprotective dose of DEX when provided in combination with 1 MAC SEVO (‘mitigation strategy’), in an established model of anesthetic neurotoxicity in neonatal rats. Additional experiments designed to specifically identify the optimal DEX dose will likely follow to (1) provide adequate anesthesia depth, and (2) allow for the reduction of the SEVO dosage (‘anesthesia sparing’), thereby reducing its neurotoxic effects in the developing brain (‘substitution strategy’).

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
5^th PANDA Symposium
4^th PANDA Symposium
3^rd PANDA Symposium

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.

Secondary Outcomes are In!

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

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SmartTots responds to the release of the secondary outcomes of the GAS Trial

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Additional grant opportunities will be announced as funding becomes available.

Grants and Funded Studies

2013 Research Grants Recipients

Lena Sun, MD - $200,000 Grant

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 study. PANDA was designed to exam 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 study is providing the first set of neurocognitive and behavior data in healthy children prospectively collected and directly assessed. The aim is to provide the needed evidence for informed discussions with providers and parents as well as guidance for clinical decision-making.

Update: By mid-2016 the study was complete. The study ultimately included 105 healthy children who underwent surgical repair of inguinal hernia—one of the most common operations of early childhood. IQ scores and secondary neurodevelopmental outcomes, including memory, learning, processing speed, visuospatial function, attention, executive function, language, and behavior, were assessed when the children were between the ages of 8 and 15, allowing enough time after exposure to anesthesia for any impairments to emerge. Outcomes for each child were compared with those of a healthy, biologically related sibling of a similar age who was not exposed to anesthesia. Dr. Sun and her team found that there was no statistically significant difference in IQ scores between the children who were exposed to anesthesia and siblings who were not. However, Dr. Sun stated that while this is good news, there are still important questions unanswered. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.

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, 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 faced a few logistical hurdles but still managed to complete more than 50% of its stated goals, actively partnering with academic centers around the state to recruit and test subjects. During 2016, with the delays behind them, the project was up and running well again and continuing to accrue subjects. Ultimately 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 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 April 2016, 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. An article published in the Journal of Neurosurgical Anesthesiology highlights their most recent findings. The article also discusses a potential neurodevelopmental phenotype that should be examined in children exposed to anesthesia and also describes the utility of a statistical technique called latent class analysis in analyzing neuropsychological outcomes.

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