A single anesthesia exposure of inhaled anesthetic agents in healthy children before 36 months of age is not associated with impaired neurocognitive development and abnormal behavior in later childhood, a sibling-matched cohort study has found (JAMA 2016;315:2312-2320).
The impetus for the study was an earlier paper by Mellon et al (Anesth Analg 2007;104:509-520), “which summarized the neurotoxicity effects of anesthetic agents in juvenile animal studies,” explained lead author Lena S. Sun, MD, chief of pediatric anesthesiology, NewYork-Presbyterian Hospital/Columbia University Medical Center, in New York City. NewYork-Presbyterian/Columbia was one of four university-based U.S. pediatric tertiary care hospitals where the current study was conducted between May 2009 and April 2015.
“We wanted to know whether this could be a problem in human infants and young children,” Dr. Sun said. “Because millions of children receive anesthesia for surgical and nonsurgical procedures, any potential effects would be a very significant public health issue.”
Prospective Sibling Study
The study consisted of 105 sibling pairs. The exposed siblings were 9.5% female with a mean age of 17.3 months at the time of inguinal hernia surgery, with a median anesthesia duration of 80 minutes (range, 20-240 minutes). Unexposed siblings were 44% female.
The mean age at cognitive testing was 10.6 years for exposed children and 10.9 years for unexposed children. Mean global cognitive function (IQ) scores were not significantly different between the two groups.
The study authors had no preconceived ideas about outcomes. “Our results indicate a single episode of anesthesia of relatively short duration in healthy children was not associated with any effects on IQ or other cognitive functions,” Dr. Sun said. “These results are reassuring to parents who have healthy children who might need an anesthetic for a short procedure.”
Because the study consisted mostly of boys, however, “further research in girls is needed,” Dr. Sun said. Research is also warranted “in vulnerable groups of children, and in cases of long exposure and in repeated exposures of anesthesia.”
Results Not Surprising
Roderic Eckenhoff, MD, professor and vice chair of the Department of Anesthesiology of the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia, and chief scientific advisor for the Brain Health Initiative of the American Society of Anesthesiologists, is not surprised by any of the study results. “All of the retrospective data coming from humans has indicated that a single exposure of anesthesia is not associated with any detectable cognitive or behavioral effects extending to adolescents or teen years,” he said.
Dr. Eckenhoff said the significance of the study is that it is prospective. As for why the results are different for children versus young animals, where “there is a very robust effect of anesthesia in the preclinical domain,” he said, one possibility is that almost none of the preclinical studies have been conducted in conjunction with surgery. “It is entirely possible, although perhaps unlikely, that surgery could in some way mitigate the effects of the anesthetic on what is happening in the brain,” Dr. Eckenhoff said.
A second plausible explanation for the difference is that the normal variation in children presenting for surgery is extremely large compared with purpose-bred laboratory animals. “Simply put, other factors, such as the need for surgery, may have a larger effect than the anesthetic,” Dr. Eckenhoff said. “Almost none of the animal studies have even included surgery in their designs.”
A third possibility for differences in children and animals is that few of the preclinical models have controlled for anesthetic physiology, according to Dr. Eckenhoff. “This is very difficult to do in a 1-g neonatal rodent,” he said. “Nevertheless, some effects due to anesthesia alone have been detected in nonhuman primate models, where physiology has been more carefully controlled.” Ultimately, the question of why there is a disconnect between preclinical and clinical research on the topic of developmental neurotoxicity “is not clear and thus remains a neuropharmacological question of considerable importance,” Dr. Eckenhoff said.
Dr. Eckenhoff said clinicians in the future will be looking for prospective studies of multiple anesthesia exposures in young children. Even here, however, he personally believes an adverse effect on IQ will be difficult to detect, and even more difficult to attribute to the anesthetic per se. “This is because it is unlikely that parents will agree to have their children randomized to treatments that have already been widely implicated as causing harm,” Dr. Eckenhoff said. “In the end, this may be a very difficult question to lay to rest.”