One hour of general anesthesia in early infancy did not result in measurable neurodevelopment problems for children up to the age of 5, the randomized controlled GAS trial found.
Infants who had general anesthesia for a median of 54 minutes showed equivalent full-scale intelligence quotient scores at age 5 as children who had regional anesthesia, reported Andrew Davidson, MD, of Murdoch Children’s Research Institute in Parkville, Australia, and colleagues in The Lancet.
“Nearly half the general anesthetics given to infants are used for less than one hour; therefore our findings should reassure health professionals and the millions of parents whose young children undergo surgical or diagnostic procedures with anesthetic drugs worldwide every year,” Davidson said in a statement.
“These findings mean children no longer need to be subjected to the potential medical and developmental risks of delaying surgery, and anesthetists do not have to avoid general anesthetics in favor of less well established anesthetic techniques,” he added.
The GAS (General Anesthesia compared to Spinal anesthesia) study is the first randomized trial to investigate whether exposure to general anesthesia in infancy negatively affects the developing brain at age 5. In 2016, an interim analysis found that Bayley Scales of Infant and Toddler Development III scores at age 2 did not differ between children who received general or regional anesthesia.
In 2017, however, the FDA issued a safety communication that exposure to general anesthetic drugs for “lengthy periods of time or over multiple surgeries or procedures may negatively affect brain development in children younger than 3 years,” based on animal and human research. While studies in infant rhesus monkeys and other animals have raised concerns that general anesthesia may lead to long-term cognitive deficits, cohort studies of human children have yielded mixed and conflicting evidence.
In the GAS trial, researchers enrolled 722 infants who had surgical repair of inguinal hernia at 28 hospitals in Australia, Italy, the U.S., the U.K., Canada, the Netherlands, and New Zealand from 2007 to 2013. Children were randomly assigned to sevoflurane-based general anesthesia (n=363) or awake-regional anesthesia (n=359). They had no previous exposure to general anesthesia or risk factors for neurological injury.
In both groups, infants were about 70 days old at surgery and more than 80% were boys. Infants in the general anesthesia group received sevoflurane for induction and maintenance in a mix of air and oxygen for a median duration of 54 minutes.
The primary outcome measure was the full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at age 5. The researchers performed the primary analysis on a per-protocol basis, adjusting for gestational age at birth and country, and also conducted an intention-to-treat analysis, predefining a difference in means of 5 points as the clinical equivalence margin.
Because of deviations from the treatment protocol — some children in the awake-regional group had to be given a general anesthetic — and losses to follow-up, only 205 children in the awake-regional group and 242 children in the general anesthesia group were included in the final analysis.
In the per-protocol analysis, FSIQ was 99.08 in the awake-regional anesthesia group and 98.97 in the general anesthesia group (mean difference 0.23, 95% CI –2.59 to 3.06). Intention-to-treat results were similar (mean difference 0.16, 95% CI –2.45 to 2.78).
Verbal, performance, and processing speed composite scores of the WPPSI-III also appeared equivalent, and there was no significance in other neurocognitive or behavioral outcomes.
GAS provides the “strongest evidence to date” that a single, brief exposure to general anesthesia during infancy is not harmful to gross neurodevelopment, noted James O’Leary, MD, and Beverly Orser, MD, PhD, both of the University of Toronto, Canada, in an accompanying editorial.
But preclinical studies “provide a clear signal that neurological injury can occur after lengthy or repeated exposures,” they wrote. “Whether anesthesia causes neurological injury in patients under these conditions remains to be established.”
The GAS researchers noted several limitations to the study. The population was predominantly male and children were exposed in a narrow period of early development. The study evaluated sevoflurane only, but other agents including isoflurane, desflurane, and propofol, also are used in pediatric surgery.
Children who performed poorly in the interim analysis (at age 2) were more likely to be lost to follow-up at age 5, for unknown reasons. However, the 2-year outcomes were included in the multiple imputations model, the researchers noted.
This study was funded by the U.S. National Institutes of Health, the U.S. Food and Drug Administration, the Thrasher Research Fund, the Australian National Health and Medical Research Council, the Health Technologies Assessment–National Institute for Health Research (U.K.), the Australian and New Zealand College of Anaesthetists, the Murdoch Children’s Research Institute, Canadian Institutes of Health Research, the Canadian Anesthesiologists Society, Pfizer Canada, the Italian Ministry of Health, Fonds NutsOhra, the UK Clinical Research Network, the Perth Children’s Hospital Foundation, the Stan Perron Charitable Trust, and the Callahan Estate.
The researchers reported no conflicting interests. Editorialist Orser serves on the Scientific Advisory Board and Steering Committee of SmartTots.