Short, one-time exposures are probably fine, it continued, although more research is needed to assess risks. Until that time, labels would be affixed to certain drugs, repeating this warning.

Of the anesthesiologists and other pediatric clinicians reading the warning (further updated in April 2017), some were not expecting its language or timing, like Linda J. Mason, MD, FASA, the current president of the American Society of Anesthesiologists (ASA). “We were really surprised when the FDA warning came out in 2016,” Dr. Mason said.

“I was kind of wondering why it was taking so long, to be honest with you,” said Vesna D. Jevtovic-Todorovic, MD, PhD, MBA, the CU Medicine Endowed Professor and chair of the Department of Anesthesiology at the University of Colorado Anschutz Medical Campus School of Medicine, in Aurora.

Mounting Concerns Amid Increasing Research

In overviews of the preclinical and clinical data in the journal Anesthesiology, which dedicated a large part of its April 2018 issue in a response to the FDA warning, the data are filled with complexities and caveats (128[4]:832-839; 128[4]:840-853).

The bulk of the evidence for the warning is rooted in preclinical trials, and it does not look positive. Throughout many of the models, researchers observed changes to the development of brain cells after anesthesia exposure, as well as cognitive, emotional and behavioral impairments later in life. These studies are done without any surgical intervention, which can separate surgery as a confounder in human studies, although it leaves the chance it may worsen the effects of anesthesia, said Dr. Jevtovic-Todorovic, who was also the author of the preclinical review and a preclinical researcher herself. “They still have issues with their development, so you don’t even have these confounding factors that we have in human studies, which makes the exposure more likely even worse,” she said.

However, this work has been done in animal models, using rodents and nonhuman primates. Many critics point to how hard it is to monitor vital signs or detect hypoxia in rodents as possible confounding factors—although Dr. Jevtovic-Todorovic noted that it can be done in monkey models, and the results are similar—and some studies have relied on extremely long exposures to find toxicity, which is not the norm for many pediatric surgeries. But, “as far as having a controlled environment, this is as close as we are ever going to get,” Dr. Jevtovic-Todorovic said.

The current landscape of clinical studies shows many large retrospective cohort studies, usually reviewing academic performance or school readiness test scores; diagnoses of neurodevelopmental or behavioral disorders or learning disabilities; or neuropsychological or behavioral assessment tools. Partly because of this spread of measures and their retrospective nature, which cannot rule out many confounding factors, the overall results—a possible association between anesthesia exposure and later problems—have been mixed and sometimes contradictory.

Better clinical studies have been few thus far, but have found no association, like in the PANDA (Pediatric Anesthesia NeuroDevelopment Assessment) study, an ambidirectional look at siblings before and after inguinal hernia repair (JAMA 2016;315[21]:2312-2320) and the MASK (Mayo Anesthesia Safety in Kids) study, which followed children unexposed, singly exposed and multiply exposed to anesthesia until 3 years of age (Anesthesiology 2018;129[1]:89-105).

Also, in the GAS (General Anesthesia compared to Spinal anesthesia) trial, data are still in early stages of reporting, with the five-year results to be released this year. (The two-year report was published in the Lancet 2015;387[10015]:239-250.) But only more time will tell what effects anesthesia will have, “because they go to school. They’re expected to learn. They’re expected to compete, and the tasks are getting progressively more difficult,” Dr. Jevtovic-Todorovic said.

What has been increasingly clear to many experts is that certain subsets are most likely seeing worse effects of anesthesia. “But one thing that for sure is coming out of this is that longer exposures, repeated exposures, are not to be ignored,” Dr. Jevtovic-Todorovic said. “They are not trivial.”

Even with a bulk of pediatric surgeries not falling into the category, that still leaves some hundreds of thousands of children experiencing more anesthesia, she said. But, it’s for a good reason. Premature babies are often sedated for weeks while they progress, or newborns may require multiple complicated surgeries in succession.

Anesthesia Care Versus Concern

So what can be done? While urgent or emergent situations necessitate the use of anesthesia, there is wiggle room for scheduling anesthesia use for elective procedures, according to experts.

Within the consultation, the anesthesia and surgical team should discuss options with parents or guardians on this issue, said Cheryl K. Gooden, MD, FAAP, an associate professor of anesthesiology, Division of Pediatric Anesthesia, Yale University School of Medicine, in New Haven, Conn., and a member of the Anesthesiology News editorial advisory board.

Dr. Gooden has already had to field more questions about anesthesia risks on development when talking with families, although she does not credit those concerns solely to the FDA warning, noting the influence of continuing research and ongoing press reports.

“I think that it definitely moved us forward toward a larger discussion with families,” Dr. Gooden said.

There’s a concern that it could possibly dissuade parents from following through with surgery. “When surgery is necessary, we want to be sure that parents realize that anesthesia is safe,” said Dr. Mason, who is also the director and professor of pediatric anesthesiology at Loma Linda University, in California. “Even though it’s a warning, it makes people concerned. ‘Well, why did they come out with this kind of warning?’

“Limited exposure is safe, and we don’t want to delay a surgery that is necessary for the child’s well-being,” she added.

Although some experts say they have not witnessed this repercussion, Smart Tots, a joint program of the FDA, ASA and International Anesthesia Research Society, will be launching a clinician survey to gauge the results of the FDA warning. As the survey begins, so too will new and continued research.

“As of now, a short, single exposure has not shown any problem in development of the child’s brain, but we need more research, and we need our students to get involved in the research,” Dr. Mason said, “because we need to answer some of these questions, especially in longer surgeries and [in] children with other health care conditions that have to come for surgery. This is not a subject that doesn’t need to be explored; it’s what we know so far is good for children.”