December 14, 2016, the US Food and Drug Administration (FDA) issued a “Drug Safety Communication” regarding the effect of various anesthetics on the developing infant brain.
“The U.S. Food and Drug Administration is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than three years or in pregnant women during their third trimester may affect the development of children’s brains.”
Although the collection of published data has increased concern regarding the deleterious effects of anesthesia in young children, the lack of definitive data makes the warning by the FDA against the administration of many common anesthetic agents in children younger than three years old surprising. While the evidence for these deficits in animal models is compelling, the translatability of these results to humans is unclear, particularly in light of the mixed results of retrospective population-based studies and the lack of differentiation between the effects of surgery and anesthesia.
Since the FDA warning, the General Anesthesia compared to Spinal Anesthesia (GAS) and the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) trials have been the first published results to fulfill the need for prospective randomized studies.
In an international randomized-controlled equivalence trial from 28 hospitals (GAS), infants <60 weeks post-menstrual age, born at >26 weeks gestation presenting for inguinal herniorrhaphy were randomized to receive regional only, or general anesthesia for the operation. The GAS trial reported the intermediate result that no differences exists on the Bayley Scales of Infant and Toddler Development III (Bayley-III) between infants randomized to receive awake-regional anesthesia (n=238) or general anesthesia with or without regional anesthesia (n=294) for inguinal herniorrhaphy.
While the results were encouraging with regard to a short anesthetic exposure, the average anesthesia time of 54 minutes may be below the expected threshold for the development of anesthesia-associated deficits, and their primary outcome, the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient at 5 years old, is still pending.
In a sibling-matched cohort study, the Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) trial, a set of 105 siblings, where one sibling was exposed to anesthesia at <36 months, while the other sibling was not, were prospectively studied at 8-15 years. Like the GAS trial, the PANDA trial was reassuring in that a short anesthetic exposure (84 min) did not yield any difference between sibling pairs in full-scale IQ or domain-specific neurocognitive function, but the short duration of anesthesia, and the relatively high socioeconomic and educational level of families in the study may bias the results towards no difference.
Thus, it is difficult to surmise an ideal anesthetic regimen, let alone determine the dose limitations needed to avoid anesthetic neurotoxicity in these young patients. Many questions still remain, including the nature of neurotoxicity after anesthesia during a critical early period in human development, the underlying mechanism of disease, brain region at risk, the clinical relevance, the age limits for its development, as well as drug regimens, doses, and behavioral therapies that may worsen or ameliorate this disease process.
To summarize, in light of the FDA warning, careful consideration must be given to delaying needed surgical procedures in light of mixed evidence for cognitive and behavioral deficits after multiple or prolonged anesthetic exposures at an early age, and further prospective studies to delineate the nature and limits of this disease process are needed.