Each year millions of infants and toddlers undergo surgery that involves exposure to general anesthesia. Whether such exposure increases a child's neurodevelopmental risk has never been established. Studies in animal models provide compelling evidence that commonly used agents (e.g., sevoflurane, isoflurane, propofol, midazolam, nitrous oxide) enhance neuronal cell death in the immature brain, in some studies at doses lower than those required to achieve a surgical plane of anesthesia. Some retrospective cohort studies in children have shown that early exposure to general anesthesia, even a single short exposure, is associated with later learning difficulties. The clinical implications of these data are controversial, however, because none of the studies used the gold standard design of a randomized trial to evaluate neurodevelopment in children after exposure to anesthetic agents in infancy, thus limiting the inferences that can be drawn about causality. This application seeks funding for USA sites to complete the GAS study, an ongoing international, prospective, multi-site, randomized, controlled, equivalence trial comparing children's neurodevelopment following receipt of general or regional awake anesthesia. A total of 149 infants who underwent inguinal herniorrhaphy, a common surgery that can be performed using either form of anesthesia, were enrolled at 10 sites in the USA. An additional 573 infants were enrolled at sites in Australia/New Zealand, the United Kingdom, Canada, Italy and the Netherlands, for a total enrollment of 722. Enrollment was completed in January 2013. The primary hypothesis is that neurodevelopmental outcomes at 5 years of age are equivalent in children who received general anesthesia or regional awake anesthesia. The primary endpoint is the Full Scale IQ on the Wechsler Preschool and Primary Scale of Intelligence. Secondary endpoints include test scores that assess specific domains, including attention/executive function, verbal/language skills, memory and learning, social perception, visuomotor integration, sensorimotor skills, academic achievement, behavior, and adaptive skills. The primary hypothesis of equivalence in Full Scale IQ at 5-years of age will be accepted if the 2-sided 95% confidence interval of the adjusted treatment group difference in means lies within -5 and +5 points. In light of the widespread use of general anesthesia in infant surgery, the results will have substantial public health implications, either supporting the safety of general anesthesia or indicating the need to consider alternative sedation strategies in this patient population.
If general anesthesia is neurotoxic to infants under conditions of clinical use, the public health implications would be substantial given the frequency with which such agents are used in infant surgery. This would lead to the development of less toxic general anesthetics, delay in surgical repairs and increased use of regional anesthesia. If general and regional awake anesthesias result in neurodevelopmental outcomes that are equivalent, this would support the safety of general anesthetics as currently used.
