General anesthetics may act as neurotoxins when given early in mammalian development. Experiments in rodents have demonstrated long-term impairments in cognition and social behavior after administration of general anesthetics early in life. General anesthetics are also neurotoxic to infant nonhuman primates, but their long-term effects on cognition and social behavior are not known. Retrospective studies in humans have shown that children who received more than one general anesthetic before the age of 4 are at a greater risk of learning disability. Thus, early neurotoxic insults from general anesthesia may result in long-term impacts on human cognitive development, but it is not possible to address this question directly in humans because randomized prospective studies are not possible and retrospective (observational) studies are subject to serious confounds: for example, children who need multiple general anesthetics early in life may differ in many ways from children who do not. Whether general anesthesia is neurotoxic to infants and children, and may result in long-term cognitive impairments, is one of the most critical questions in anesthesiology today. A nonhuman primate model of cognitive development after early exposure to anesthesia will address two key issues in establishing whether neurotoxicity of general anesthesia given early in life is cause for concern. First, the closer correspondence between neuroanatomy and cognitive development in nonhuman primates and humans increases the extent to which findings in the animal model can be translated to humans. Second, a nonhuman primate model of cognitive effects of early anesthetic exposure would provide a means to compare different anesthetic regimens, or potential treatments that could be given during or after anesthetic exposure to mitigate or reverse neurotoxic effects and subsequent cognitive impairments. We will test rhesus monkeys that have received three general anesthetics with sevoflurane (an inhalation anesthetic commonly used in pediatric anesthesiology) before their 6th week of life on cognitive and socioemotional tasks throughout their first three years of life, to track the effects of repeated postnatal anesthesia on cognitive and socioemotional development. This will provide data both on the effect of anesthesia on neurocognitive development, and on cognition and socioemotional behavior in juvenile monkeys at an age roughly corresponding to the onset of formal schooling in children. This work will provide a critical translational model for studying long-term effects of postnatal anesthesia on cognition and social behavior in nonhuman primates, which will be vital for assessing potential risks of anesthesia in pediatric populations, as well as for testing potential agents that may mitigate or eliminate this risk.

Public Health Relevance

General anesthetics may cause brain damage when given early in development, resulting in long-term impairments that lead to learning disabilities and potentially other developmental disorders. Whether these effects of general anesthetics, which have been demonstrated mainly in laboratory rodents, are cause for concern in humans is not known. This project will test, using a nonhuman primate model with brain function much closer to that of humans, whether early exposure to general anesthesia is associated with long-term impairments in memory and socioemotional behavior, providing critical information about whether concern about anesthetic use in children is warranted.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Zajicek, Anne
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Baxter, Mark G; Alvarado, Maria C (2017) Monkey in the Middle: Translational Studies of Pediatric Anesthetic Exposure. Anesthesiology 126:6-8
Alvarado, M C; Murphy, K L; Baxter, M G (2017) Visual recognition memory is impaired in rhesus monkeys repeatedly exposed to sevoflurane in infancy. Br J Anaesth 119:517-523
Raper, Jessica; Bush, Angela; Murphy, Kathy L et al. (2016) Multiple sevoflurane exposures in infant monkeys do not impact the mother-infant bond. Neurotoxicol Teratol 54:46-51
Raper, Jessica; Alvarado, Maria C; Murphy, Kathy L et al. (2015) Multiple Anesthetic Exposure in Infant Monkeys Alters Emotional Reactivity to an Acute Stressor. Anesthesiology 123:1084-92