Abstract
This chapter, provides an overview on the concerns centered on neurotoxicity from anesthetics in children following the FDA warning from 2016 and 2017. The authors provide a background for both clinical and basic science evidence on the effects of commonly used anesthetics on neural development. After review of the landmark studies in both animals and humans, the chapter provides suggestions for reducing exposure as well as addressing parental concerns.
A nine-month-old, 7 kg male arrived for primary repair of hypospadias. He was born at 32 weeks and required ligation of a patent ductus arteriosus at 35 weeks of age via a thoracotomy. At three months, he underwent a brain MRI after a seizure, with no critical findings. During the routine preoperative evaluation, the parents ask about the possible harmful effects of anesthesia on their child and are concerned because this is his third exposure to general anesthesia.
How Many Children Undergo Procedures with Anesthesia Annually?
In the United States, about 1.5–2 million infants under one year of age undergo anesthesia each year for a variety of surgical procedures or diagnostic tests.
What Is the 2017 Concern/Warning About General Anesthesia from the Food and Drug Administration?
In 2016, with a revision in 2017, the US Food and Drug Administration (FDA) issued a warning regarding the administration of anesthetics in children. Specifically, the warning states:
The U.S. Food and Drug Administration (FDA) is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.
Table 3.1 What drugs are included in the 2017 concern/warning from the US Food and Drug Administration (FDA)?
| • Desflurane | • Propofol | • Ketamine |
| • Halothane | • Pentobarbital | • Etomidate |
| • Sevoflurane | • Midazolam | • Methohexital |
| • Isoflurane | • Lorazepam |
What Studies Led to the FDA-Issued Warning?
The initial studies concerning for neurotoxic effects of anesthetics in young children date back to 1999. Ikonomidou et al. (1999) demonstrated that administration of dizocilpine (a ketamine analog) in pregnant rats and rat pups resulted in significant neuronal cell death compared to unexposed controls.
Following this study, other groups were able to demonstrate similar neurotoxic effects using halogenated agents as well as propofol in rat and rhesus macaque brains for both neonatal and fetal animal groups.
Based on the Animal Studies, Are the Effects of Neural Toxicity Dose Dependent?
Early studies using ketamine by Ikonomidou et al. (1999) demonstrated a significant dose-dependent effect on neuroapoptosis.
Summarize the Human Studies Evaluating Neurologic Effects of Anesthetics in Children
Several studies have been presented evaluating the long-term effects of early anesthesia exposure on neurological development.
An early study by Flick et al. (2011) compared 350 children with anesthesia exposures before age two. These patients were compared with 700 propensity-matched controls evaluating for the incidence of learning disabilities and school specialized educational programs. They concluded that repeated (not a single) exposure to anesthesia prior to age two was associated with a risk for development of learning disabilities.
In 2016, Sun et al. published the Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study which reported the findings of a longitudinal sibling-matched multicenter study.
They compared unexposed siblings to siblings exposed to a single anesthetic for inguinal hernia repair prior to age two. The patients underwent neuropsychological testing for IQ and neurocognitive functions at a mean age of ten years. They concluded that a single exposure to anesthesia prior to thirty-six months in age did not result in any statistically significant differences in IQ scores in childhood.
In 2016, Davidson et al. presented the findings of the General Anesthesia compared to Spinal anesthesia (GAS) trial. This multi-institutional, prospective, randomized-controlled equivalent trial compared Bayley Scales of Infant and Toddler Development III, assessed at two years in children undergoing inguinal hernia repair younger than sixty weeks postconceptual age. Patients were randomly assigned to either awake-regional anesthesia (spinal) or sevoflurane-based general anesthesia. They found no difference in Bayley III scores in children having one hour or less of anesthesia compared with unexposed children (regional group). The primary outcome of the study released in 2019 concluded that less than 1 h of general anaesthesia in early infancy did not alter neurodevelopmental outcomes at five years of age compared with awake-regional anaesthesia
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