Warner DO, Zaccariello MJ, Katusic SK, Schroeder DR, Hanson AC, Schulte PJ, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Hu D, Voigt RG, Paule MG, Chelonis JJ, Flick RP. Anesthesiology. 2018 Apr 19 [Epub ahead of print]
There is a concern that drugs producing sedation or general anesthesia can cause neuroapoptosis and long-term deficits in learning and behavior in children. While studies in animal models have consistently found a connection to adverse neural impact, the findings of studies in humans to date have been variable. For example, it is unclear whether single and multiple exposures to general anesthesia are associated with deficits in learning and behavior. The outcomes assessed have also been variable, with only two studies reporting a comprehensive assessment of neuropsychological function. Even these studies were limited by their design or a limited patient population (e.g. only patients undergoing herniorrhaphy).
The Mayo Anesthesia Safety in Kids (MASK) study aimed to address the question of how exposure of children to anesthesia may affect neurodevelopment by: 1) employing comprehensive neuropsychological assessments; 2) evaluating unexposed, singly exposed, and multiply exposed patients; and 3) evaluating a population of children who underwent a diverse range of procedures within a defined locale.
The authors identified patients exposed to general anesthesia before the age of three years during the period of 1994 to 2007, born in Olmsted County, Minnesota. There were 997 children (411 unexposed, 380 singly exposed, and 206 multiply exposed) tested for the primary outcome of intelligence quotient (IQ) and secondary outcomes of individual domains from a comprehensive neuropsychological assessment of parent reports. When comparing patients who were unexposed, singly exposed, and multiply exposed to general anesthesia, there was no difference in IQ based on exposure status. Multiply exposed children demonstrated decreased processing speed and fine motor abilities, but singly exposed children did not. Parents of multiply exposed children reported more problems related to executive function, behavior, and reading, whereas parents of singly exposed children reported more problems related to executive function and reading.
The findings of this study have been widely anticipated by the pediatric sedation community. Although this study specifically addresses exposure to general anesthetics rather than frequently administered (sole) sedatives such as propofol, there is still a concern that pure sedatives may cause neurodevelopmental deficits. The results of the study may provide some preliminary insight into the sequelae of sedative administration.
This study was the largest to employ detailed neuropsychological assessments, and like other smaller studies, did not show any difference in IQ between children exposed and not exposed to general anesthesia. However, they did identify differences in other domains in children exposed to anesthetics that may be clinically meaningful. Parents of both singly and multiply exposed children reported more problems than unexposed children related to executive function and reading. In addition, multiply exposed children also had more problems related to behaviour reported by parents, as well as modest decreases (effect sizes of <0.5 SD) in processing speed related to reading and fine motor coordination. Although these are secondary outcomes and it should be recognized that the study was not designed to identify differences in these domains, there were still modest differences identified in domains that one might consider as important as IQ.
How these findings pertain to the sedation provider who does not administer general anesthetics, but rather sedatives, is not yet clear. The findings of this study suggest that the frequency of exposure is likely an important factor, with there being less neurodevelopmental sequelae in children with single compared to multiple exposures. It also supports the prevailing postulate that anesthetics, and possibly sedatives, are not entirely benign from a neurodevelopmental standpoint; although IQ may be unaffected, other domains relevant to a child’s day to day functioning and their family may be vulnerable. The findings of this study do not mandate a complete cessation in the current sedation practices nationwide, as further study is necessary to determine whether these sequelae are also present in children who receive sedatives, rather than general anesthetics. As advised by the FDA, the benefits of performing a test or procedure must be weighed against the possible effects of sedation/anesthesia on the child. Strong consideration should be given to weighing the risk and benefits of providing sedation to children under three. In addition, concerted efforts should be made to minimize multiple exposures to sedatives in every child when possible.