Each year, hundreds of thousands of children 3 years of age and under are anesthetized during surgeries and other common medical procedures and tests. Doctors believed that the risk of using anesthetics in infants and toddlers was minimal. But recent scientific studies, both in animals and humans, suggest that there may be a relationship between the use of anesthesia in young children and later cognitive deficits.
Cell self-destruction in the developing brain
Since the 1990s, many scientists have studied the effect of different classes of drugs on the developing brain. Chrysanthy Ikonomidou, now head of the pediatric neurology department at the Dresden University of Technology in Germany, has led a great deal of research looking at what drugs might result in apoptosis, or programmed cell self-destruction, in neurons.
“We found that certain classes of drugs cause a lot of cells to die in the developing mouse and rat brain,” she says. “It would seem that drugs like barbiturates, alcohol and anti-seizure medications depress the activity of the brain by inhibiting excitatory signals or by enhancing inhibitory signals. This then causes neurons to die by self-destruction. And it seems that this apoptosis is age-dependent, roughly translated in humans, to the last three months of pregnancy and the first three years of life.”
Given these findings, Vesna Jevtovic-Todorovic, an anesthesiologist at the University of Virginia Health System, wondered if common anesthetic drugs might also result in apoptosis. She and colleagues exposed developing rats to six hours of anesthetic drugs that are commonly used on small children and then followed the rats for the next 8 months of life.
They found that the rats behaved normally on many basic behavioral tests, she says. “But on more difficult learning and memory tasks, they were significantly impaired. They showed a long-term impairment of executive function.”
These results, published in the February 1, 2003, issue of the Journal of Neuroscience, were the first to suggest that anesthesia might not be as harmless as previously thought. Since then, a variety of anesthetics have been studied; each has shown the same kinds of cell death in a variety of rodent and some primate models.
“With all kinds of different anesthetics, we see these same cognitive problems,” Jevtovic-Todorovic says. “And it’s got many concerned. We may not be quite as safe using anesthetics so early during human brain development as we once thought.”
Anesthesia and the human brain
But how well do these animal studies translate to the developing human brain? Critics have suggested that both the duration and the dosage of the anesthesia in rodent studies make them tricky to apply to children. To examine this question more closely, Robert Wilder, an anesthesiologist at the Mayo Clinic in Rochester, Minn., decided to use the hospital system’s unique health-care database of local residents.
“The question I posed was whether we had a way of looking at school outcomes for kids who had been treated here, and it turned out that epidemiologists were already looking at the prevalence of learning disabilities among school-aged children in Rochester,” says Wilder. “They had a cohort of 7 years’ worth of kids that we could examine.”
Wilder and colleagues looked at more than 5,000 children who had been treated with anesthesia for common surgeries like the insertion of ear tubes or orthopedic procedures. They then looked at whether those children were more likely to develop a learning disability, defined by the group as a normal intelligence quotient (IQ) but difficulty in reading, writing or mathematics performance, later in life.
“What we found was that nearly 20 percent of kids in Rochester schools had a learning disability, which to me was fairly staggering,” Wilder says. “So if you weren’t given any anesthetics, the chances of a learning disability were 1 in 5. If you had one anesthetic before the age of 4, the chance remained exactly the same. But if you had two or more anesthetics, the odds went up 1.6 times. And those with three or more anesthetics, 2.6 times.” Their research was reported in the April issue of Anesthesiology.
Despite a strong correlation, Wilder says that the results are too preliminary for panic. “We definitely see an association, and given some of the animal studies that show similar issues, it is worrisome. But the data don’t prove any sort of causality.” he says. Wilder argues that the higher incidence of learning disability could be due to the underlying condition that led to several surgeries or perhaps even something about the surgeries themselves. He is working on a follow-on study that compares the anesthetized children to children with similar medical conditions to try to remove some of the variables that may be confounding the results.
Jevtovic-Todorovic would like to see more focus on finding a “safe agent,” or anesthetic drug that doesn’t show these kinds of apoptotic effects in animals.
“If you look at the studies, pretty much all of the anesthetics we use clinically have been implicated,” she says. “And in the real world, we don’t use single anesthetics but combinations or cocktails of drugs. Perhaps there is one combination that is less problematic than another.”
She also argues that many of the studies suggest there is not a dosage or duration effect, per se, but rather one of timing in development. “What you see in these animal studies and what’s been hinted at in the clinical setting is that the timing of exposure is the important thing,” she says. “If a baby happens to be actively going through brain development during a surgery, that three to four hours of anesthesia can be devastating. But a 4-year-old, whose brain is pretty much developed, can go under for eight hours with no problem.” She hopes that more clinical studies of human children will provide more concrete answers.
No changes to practice patterns
Despite many studies now pointing to concerns about anesthesia in young children, Wilder argues that it’s still too soon to make any strong conclusions. “I’d argue that our data shouldn’t make doctors change their practice patterns at this point,” says Wilder. “And I would tell parents, if a doctor recommends a procedure with anesthetic, go ahead and do it.”
But Jevtovic-Todorovic’s work with animals has made her a bit more cautious. “We really do not have the concrete evidence we need to make a definitive conclusion,” she says. “But when I get calls from parents who are concerned, I always recommend that, in the cases of elective surgeries, they wait until the child is at least 6 months old. And if they can wait until after a year, maybe two, then so much the better.”