Abstract and Introduction
Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.
Questions regarding the safety of general anesthetic drugs in children emerged nearly 20 yr ago with the finding of neuronal apoptosis and functional deficits in rodents after exposure to these medications. Over the course of the subsequent two decades, exposure to anesthetic agents during brain maturation has been found to consistently disrupt neurodevelopment in animal models. In response, in December 2016, the U.S. Food and Drug Administration (Silver Spring, Maryland) issued a Drug Safety Communication regarding all commonly used anesthetics that bind to γ-aminobutyric acid and N-methyl-D-aspartate receptors. The Food and Drug Administration warning that "repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 yr old or in pregnant women during their third trimester may affect the development of children's brains" was largely based on preclinical animal models and the limited clinical data available at the time. While preclinical data are convincing, the interpretation of the human data has been more complex, with some studies reporting an increased incidence of neurodevelopmental deficits in young children exposed to anesthetics and other studies finding no such differences.
Given the mixed results of the studies in children, the fundamental questions of the safety of commonly used anesthetics and whether this line of research inquiry should continue remains a source of intense debate. The purpose of this report is to provide expert consensus opinion regarding the state of the current preclinical and clinical evidence, the remaining questions, suggestions for future research, and comparisons to the evolution of research of other suspected neurotoxins, with the ultimate goal of ensuring that the millions of children who undergo procedures requiring anesthetic agents do so safely.[5–7]
Anesthesiology. 2022;136(3):500-512. © 2022 American Society of Anesthesiologists | Lippincott Williams & Wilkins