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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.
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?
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.
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)
Pediatric Anesthesia NeuroDevelopment Assessment (PANDA Study)
- Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood
- Feasibility and pilot study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project
- Pediatric anesthesia and neurodevelopmental impairments: a Bayesian meta-analysis
- Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia
Mayo Clinic Research: MASK (Mayo Safety in Kids) Study
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.
SmartTots responds to the release of the secondary outcomes of the GAS Trial
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
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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