The potential risk to the brains of young children in relation to exposure to anesthesia remains undetermined and is a subject of contention. The answer may depend on how the question is posed—that is, the outcome measures used to define neurotoxicity. The issue is also important in that it determines how precious research dollars will be spent.
In a roundtable discussion, four pediatric anesthesiologists—Caleb Ing, MD, assistant professor of anesthesiology at Columbia University Medical Center in New York City; Mary Ellen McCann, MD, MPH, senior associate in perioperative anesthesia at Boston Children’s Hospital and associate professor of anesthesia at Harvard University; Randall Flick, MD, of Mayo Clinic in Rochester, Minn., who is president of the Society for Pediatric Anesthesia (SPA); and Per-Arne Lönnqvist, MD, professor of pediatric anesthesia and intensive care at the Karolinska Institutet in Stockholm—debated what conclusions can be drawn from conflicting neurotoxicity data from studies conducted in the United States and Europe.
The roundtable was held at the 2017 meeting of the SPA/American Academy of Pediatrics Section on Anesthesiology and Pain Medicine.
Outcome Measures Vary
Dr. Ing opened the discussion by pointing out that many clinical studies have been done in this area, but that the outcome measures used to define neurotoxicity vary greatly. He cited a study led by Dr. Flick in children exposed to anesthesia under 2 years of age, using the development of learning disabilities by age 19 as the primary outcome measure to determine neurotoxicity. The study found no difference between exposed and unexposed children from a single anesthesia exposure, but did find a difference in children with multiple exposures.
“The dose of anesthesia may have an impact on the results,” Dr. Ing said. “We currently don’t know what the minimum toxic dose is, and most studies involving short, single exposures have been found to be negative. There have, however, been a number of studies looking at longer and multiple exposures that have found a positive association between exposure and neurodevelopmental deficit. This may be due to the higher exposure dose, but could also be due to the fact that children getting longer exposures may be sicker and at higher risk for poor neurodevelopmental outcomes.”
Another study, in which Dr. Ing was involved, looked at children in Perth, Australia, who were exposed under 3 years of age, using neuropsychological tests as the primary outcome. By age 10, exposed children had lower scores on some neuropsychological tests and were more likely to have International Classification of Diseases, 9th Revision–coded clinical diagnoses of behavioral and developmental disorders, according to Dr. Ing. However, the same groups of children showed no differences in academic achievement.
He cited several other studies, from both the United States and Europe, that consistently found academic achievement to be unaffected or minimally affected by anesthesia administered at a young age, including a study of twins in the Netherlands. However, Dr. Ing advised caution in interpreting the results, because of varying doses and outcomes measures used in the different studies. He likened the landscape of available studies to a “Choose Your Own Adventure” book, with different studies leading to different possible conclusions depending on the variables and outcome measures used.
“Given the limitations in the published studies, we cannot yet conclude that anesthesia exposure in young children causes long-term cognitive deficits, but we also do not have enough evidence to rule out that possibility,” Dr. Ing said.
Neurocognitive outcomes can be affected by many factors, the most significant of which is underlying pathology, Dr. McCann said. “As anesthesiologists, we really can’t alter that too much.” Moreover, she added, surgery and pain are known to negatively affect neurocognitive and behavioral outcomes in neonates as well as adults, even in the absence of anesthesia.
“When we look at anesthesia, we really need to break it up into two parts—what’s the neurotoxic potential of the agents themselves and how are we managing these kids?” Dr. McCann said. Although animal studies have shown neurotoxicity from anesthetic agents over prolonged exposures, she argued that the difficulties involved in management may be responsible for those observations, given that the animals are much smaller than already difficult-to-manage children.
Dr. McCann cited a retrospective twin study from 2009, by Bartels et al (Twin Res Hum Genet 12:246-253) that looked at more than 1,000 monozygotic twin pairs. The study found similar cognitive decline in both twins in cases where only one twin was exposed to anesthesia before age 3, and concluded that an underlying genetic vulnerability—not anesthesia—was responsible for the observed neurocognitive deficits. She also described ongoing work with which she is involved, examining the role of blood pressure, but noted that no firm conclusions have been reached.
Europe vs. United States
The controversy intensified when Dr. Flick took the podium. “I think it’s always good, if you want to have a debate with somebody, to use their own words,” he said, referring to an editorial coauthored by Dr. Lönnqvist about the “rise and fall” of anesthetic-related neurotoxicity, which compared, unfavorably, epidemiological studies between the United States and Europe.
“If you go through that very nice editorial, they tell us exactly why the European studies are negative and American studies are positive, and you can see it’s because the American health care system is poor, and the school system is poor, and the anesthesiologists aren’t particularly good, and we only care about [National Institutes of Health] funding, which is, of course, true,” Dr. Flick said, to laughter from the audience. “So we know why the studies are different in Europe—their education is better, their health care is better, our anesthesia care stinks and we want funding. Nowthis may be true, or maybe not, but if you think about this, the comparison isn’t between the U.S. and Europe—it’s between Sweden and Rochester, Minnesota.”
Dr. Flick cited a study from Harvard comparing scores on the Programme for International Student Assessment, pointing out that students in Minnesota scored higher on reading proficiency than in Sweden, although the United States overall was below Sweden; similarly, Minnesota placed at No. 2 on math proficiency in this country, and considerably higher internationally than Sweden.
In terms of health care, Dr. Flick merely pointed out that 95% of the health care in Rochester is provided by Mayo Clinic, eliciting more laughter from the crowd.
Noting that blood pressure management often comes up in discussions of European versus U.S. anesthesia management, Dr. Flick cited an international trial that found no difference in management between the two regions.
“The transatlantic rift is really not about geography; it’s about methodology,” he said. “The animal data are compelling—including in big primates, nonhumanprimates, so it’s not just about providing care for tiny little rats,” he added, in a rejoinder to Dr. McCann’s remarks about animal studies. “In fact, new data is coming out showing that even shorter durations of anesthetic have an impact on the nonhuman primate brain.”
In concluding, Dr. Flick said negative studies are consistently brief, single-exposure studies with a nonspecific outcomes measure, whereas positive studies consistently feature multiple, prolonged exposures with specific outcomes measures. “Research funding for this problem is clearly not wasted—we don’t have nearly enough information to establish a causal relationship between anesthetic exposure and adverse developmental outcome.”
Dr. Lönnqvist rose to Dr. Flick’s challenge. “U.S. epidemiologic studies suck. I mean, they really, really suck,” Dr. Lönnqvist half-joked, to uproarious laughter. “And why is that? They use different outcome parameters compared to other studies. I referenced this with true experts—I mean, true experts—and at best, it can be said that there’s alternative effects.”
Dr. Lönnqvist said in contrast to U.S. studies, European studies—and Scandinavian studies in particular—are large-scale epidemiological studies conducted using national registries, which drastically reduces loss to follow-up. He added that the European studies also use “solid, clearly defined outcomes,” such as IQ, Intensive Behavioural Intervention (IBI) scores, national school tests and academic performance. “If this was really a problem, we would have noticed this decades ago. So this is all a storm in a teacup.”
The discussion was a helpful presentation of the evidence, but not strongly persuasive in one direction or the other, said Dudley Hammon, MD, assistant professor of anesthesiology at Wake Forest Baptist Medical Center, in Winston-Salem, N.C. “I think it’s probably the hottest topic going on in pediatric anesthesiology, and the conclusions are not yet out. There’s something there, but we don’t know what. Is it blood pressure, SPO2, … or is it anesthetic toxicity? Animal models seem to suggest it’s the neurotoxicity, but I don’t think the evidence is there yet in humans.”
Brian Johnson, DO, an anesthesiologist in private practice in Grand Junction, Colo., agreed with Dr. Hammon’s assessment. “I think it was great to hear from four experts in the field from North America and Europe. No conclusions were really cleared up in my mind, which I think speaks to the need for continuing study on the topic, so we can better inform parents about the risks of anesthesia.”