Over one million young children are exposed to drugs used to induce and maintain general anesthesia each year in the United States. Mounting evidence shows that exposure of the developing brains of animals to alcohol, anesthetic and sedative medications may cause neurodegenerative changes with adverse effects on learning and behavior. These changes are associated with long-term changes in behavior, both in rodents and in non-human primates. The clinical significance of these observations is a topic of intense debate and concern, as there are very few human studies of how anesthetic exposure may affect neurodevelopment. Existing studies show that exposure to multiple, but not single, anesthetics at a young age is associated with an increased frequency of learning disabilities, but there are significant limitations of all existing human studies. The long term goal of this researc is to improve the safety of drugs that produce general anesthesia in young children. The overall objective of this application is to determine whether exposure of children to anesthesia is associated with neurodevelopmental abnormalities. The central hypothesis is that exposure to multiple anesthetics at a young age will impair later performance of children on detailed tests of neurodevelopmental performance. To achieve the objective, the Specific Aim of this proposal is to determine if exposure to anesthesia prior to age three is associated with neurodevelopmental abnormalities in children. Using a unique population-based resource, the Rochester Epidemiology Project, a cohort of children born in Olmsted County, MN between 1994 and 2007 and still currently resident in the area will be identified. From this cohort children exposed to anesthesia prior to age 3 will be propensity matched to children not exposed to anesthesia. Subjects (those exposed to anesthesia and those not exposed) will undergo detailed neuropsychological testing in the domains of intellectual ability, memory function, executive function, motor integrity, language and speech development, and academic achievement to test the hypothesis that multiple, but not single, exposures to anesthesia are associated with impaired performance in these domains. Children will also receive the Operant Test Battery from the National Toxicological Research Center. This will allow for comparison of results in children with published studies of how anesthetic exposure affects infant rhesus monkeys. Testing will be performed at ages 7-11 and 15-19 (in separate groups of children) to explore the persistence of any observed effects. The expected product of this research will be the first detailed phenotype of anesthetic- induced neurotoxicity in humans (if indeed evidence of neurotoxicity is found). More than one million children under the age of 3 years undergo anesthesia annually in the US so that the potential impact of this finding cannot be overstated. This phenotype would assist in interpreting the pre-clinical data, potentially devising strategies to mitigate anesthesia-induced injury, and assist patients and clinicians in making informed decisions.

Public Health Relevance

Studies suggest that exposure of infant animals to general anesthesia causes the death of some types of nerve cells and may be associated with learning deficits. It is not known if these studies are relevant to children undergoing anesthesia. This project will determine whether exposure to anesthesia prior to the age of 3 is associated with impaired brain function later in life. Children born and residing in a defined geographical area will be tested for their functioning at ages 7-11 and 15-19 years, comparing those children exposed to anesthesia to those not exposed to anesthesia.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Giacoia, George
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Mayo Clinic, Rochester
United States
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Warner, David O; Zaccariello, Michael J; Katusic, Slavica K et al. (2018) Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology 129:89-105
Shi, Yu; Hu, Danqing; Rodgers, Erin L et al. (2018) Epidemiology of general anesthesia prior to age 3 in a population-based birth cohort. Paediatr Anaesth 28:513-519
Warner, David O; Shi, Yu; Flick, Randall P (2018) Anesthesia and Neurodevelopment in Children: Perhaps the End of the Beginning. Anesthesiology 128:700-703
Hu, Danqing; Flick, Randall P; Zaccariello, Michael J et al. (2017) Association between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort. Anesthesiology 127:227-240
Bjur, Kara A; Payne, Eric T; Nemergut, Michael E et al. (2017) Anesthetic-Related Neurotoxicity and Neuroimaging in Children: A Call for Conversation. J Child Neurol 32:594-602
Hu, Danqing; Flick, Randall P; Gleich, Stephen J et al. (2016) Construction and Characterization of a Population-Based Cohort to Study the Association of Anesthesia Exposure with Neurodevelopmental Outcomes. PLoS One 11:e0155288
Warner, David O; Flick, Randall P (2015) Effects of anesthesia and surgery on the developing brain: problem solved? Paediatr Anaesth 25:435-6
Gleich, Stephen J; Flick, Randall; Hu, Danqing et al. (2015) Neurodevelopment of children exposed to anesthesia: design of the Mayo Anesthesia Safety in Kids (MASK) study. Contemp Clin Trials 41:45-54
Flick, Randall P; Nemergut, Michael E; Christensen, Kaare et al. (2014) Anesthetic-related neurotoxicity in the young and outcome measures: the devil is in the details. Anesthesiology 120:1303-5
Nemergut, Michael E; Crow, Sheri; Flick, Randall P (2014) Cognitive outcomes after infant spinal anesthesia: the other side of the coin. Anesth Analg 119:514-5

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