An international multicenter trial has concluded that just under an hour of sevoflurane anesthesia during infancy does not increase the risk for adverse neurodevelopmental outcome at 2 years of age, relative to awake regional anesthesia. The finding is in contrast to some previous cohort studies.
According to Andrew J. Davidson, MD, senior anesthesiologist and director of the Melbourne Children’s Trials Centre at The Royal Children’s Hospital, in Melbourne, Australia, as well as principal investigator on behalf of the “General Anesthesia compared to Spinal anesthesia” (GAS) Consortium, although preclinical data suggest that general anesthetics affect brain development, previous research in young children exposed to anesthesia have produced conflicting results as to their effect on neurodevelopmental outcome. As such, Dr. Davidson and his colleagues from 28 institutions in Australia, New Zealand, the United States, Canada, the United Kingdom, Italy and the Netherlands aimed to shed some more light on this sometimes contentious subject.
To that end, the investigators recruited 722 infants into the trial, all of whom were undergoing inguinal herniorrhaphy at less than 60 weeks postmenstrual age (meaning the time at which the mother had her last menstrual period). The infants—all of whom were born at greater than 26 weeks gestation—were randomly assigned to receive either awake regional anesthesia (n=363) or sevoflurane-based general anesthesia (n=359). Infants were excluded if they had existing risk factors for neurologic injury.
“The primary outcome of the trial will be the WPPSI-III [Wechsler Preschool and Primary Scale of Intelligence–Third Edition Full Scale IQ] score at 5 years of age,” said Dr. Davidson. The current analysis comprised the trial’s secondary end point: the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, which was assessed at 2 years of age.
As Dr. Davidson reported at the 2015 annual meeting of the American Society of Anesthesiologists, outcome data were available for the 238 children who received awake regional anesthesia and 294 who received general anesthesia between Feb. 9, 2007, and Jan. 31, 2013. Duration of surgery was comparable between groups; the median duration of anesthesia in the general anesthesia group was 54 minutes.
“At 2 years, the children were reasonably well matched in terms of other things that may have affected their development,” Dr. Davidson said. “Interestingly, about 14% of them had had a subsequent anesthetic, though this was also well matched between the two groups.”
It was found that the mean cognitive composite score was 98.6 in the awake regional group and 98.2 in the general anesthesia group. “The difference was less than half a point, and the 95% confidence intervals around that difference were within three points, which fell well within our predefined margins of equivalence,” Dr. Davidson commented.
“Importantly, the results are almost identical in the as-per-protocol and the intention-to-treat analysis, implying that the regional failure rate we observed [approximately 19%] had no influence on the veracity of the results.”
When the researchers examined all the domains for individual Bayley Scales scores, they found that the differences between groups were all within one or two points. “The confidence intervals for those were also within or very close to our predefined measures of equivalence,” he said. The incidence of children with hearing or vision problems, or who developed cerebral palsy or autism, were all as low as predicted, and too low to make any meaningful comparison between the two groups.
“We also performed a post hoc analysis where we looked at children who scored one or two standard deviations below the mean, to see if there was a tail of children who fared really poorly,” Dr. Davidson added. “And once again, there was very little difference between the groups, with risk ratios close to 1.00.”
Despite the strength of its results, the trial was not without its potential shortcomings, including the fact that its participants received less than an hour of general anesthesia. “There is some evidence to suggest the injuries or changes that we see in animals are much greater with much longer anesthesia exposures,” Dr. Davidson explained.
“The other important limitation is this is a two-year outcome measure,” he continued. “Assessment at 2 years is a fairly imperfect predictor of future outcome, in part because children develop at different rates, and because some measures of our executive function have not yet developed and are not yet assessable. That’s why the study’s primary outcome analysis was set at the age of 5.
“In summary,” he added, “while not conclusive, this is still the strongest evidence yet that just under an hour of anesthesia in infancy does not cause any significant adverse neurodevelopmental outcomes compared to awake regional as measured at 2 years of age.”
Session moderator James C. Eisenach, MD, editor-in-chief of Anesthesiology, which sponsored the session, told Anesthesiology News that if the results of the interim analysis are confirmed after five years, they “will go a long way to reassure parents and practitioners that general anesthesia for procedures like this with relatively short duration may not have negative effects on development,” Dr. Eisenach said. “It’s estimated that nearly half of surgical procedures performed during infancy are of this duration or shorter. Whether longer exposures have an effect deserves further study.”