Multiple exposures to anesthesia may increase risk of ADHD, learning disabilities in young children

Infants and very young children who are exposed to anesthesia may experience higher rates of learning disabilities and cognitive difficulties than children who are not exposed to anesthesia, according to research and emerging data presented during the SmartTots: Pediatric Anesthesia Neurotoxicity panel at the International Anesthesia Research Society annual meeting in Vancouver, B.C.

"We want to impress upon people that there is a very reliable link between the animal and human data that is rapidly emerging," said panel moderator Dr. Vesna Jevtovic-Todorovic, M.D., Ph.D., M.B.A., Professor of Anesthesiology and Neuroscience at the University of Virginia Health System and SmartTots Scientific Advisory Board member.

Studies in nonhuman primates, including rhesus monkeys, have raised serious concerns about the effects of anesthesia on the developing nonhuman primate brain. Merle Paule, Ph.D., Director of the Division of Neurotoxicology at the National Center for Toxicological Research and SmartTots Scientific Advisory Board member, discussed his recent findings that a single 24-hour episode of ketamine anesthesia results in very long-lasting deficits in brain function in nonhuman primates. According to Dr. Paule, these findings provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits.

"Very clearly, the studies done by the folks at the National Center for Toxicological Research are extremely important. They can't be overrated because they show in a species similar to humans that there is an effect not only on the pathology in the brain, but also in behavior. And that effect is a lasting effect," said Randall Flick, M.D., M.P.H., Associate Professor of Anesthesiology and Pediatrics at the Mayo Clinic. Dr. Flick is also the Society for Pediatric Anesthesia representative on the SmartTots Affiliate Advisory Council.

Dr. Flick presented his findings from a recent study at the Mayo Clinic, which concluded that multiple exposures to anesthesia before the age of 2 years are a "significant risk factor" for the development of Attention Deficit Hyperactivity Disorder. A single exposure to anesthesia did not appear to have an effect, Dr. Flick said.

"[Our] most recent work suggests that even when you adjust for illness within the population, there appears to be an effect with multiple exposures to anesthesia," said Dr. Flick. Interestingly, the age of exposure, the cumulative length of exposure, and the number of anesthetics are critically important considerations. Children younger than 4 years who were exposed to anesthesia for 120 min and longer for at least two times are at high risk.

Greg Stratmann, M.D., Ph.D., Associate Professor of Clinical Anesthesia and Perioperative Care at the University of California, San Francisco, discussed whether anesthesia-induced cognitive decline is treatable. His group at the University of California, San Francisco found that in the rat model the ill effects of anesthesia on brain function, which are apparent later in life, can be overcome through environmental enrichment even when instituted 3 weeks after exposure to sevoflurane anesthesia.

According to Stratmann, "These findings support the concept that harnessing the brain's natural ability to adapt to functional demands can modify the course of anesthesia-induced cognitive decline in rats."

The current work builds on groundbreaking rodent studies by Dr. Jevtovic-Todorovic. Dr. Jevtovic-Todorovic authored a 2003 paper that demonstrated that common anesthetics, alone and in combination, caused massive damage in the brain of young rodents, manifested as a widespread nerve cell death. Importantly, the rodents suffered long-lasting cognitive impairment in learning and memory, which worsened as they aged.

The growing evidence that multiple exposures to anesthesia may have deleterious effects on developing human brains presents doctors and parents with a difficult and even frightening dilemma. Rarely is surgery optional for the youngest patients. Dr. Flick cautions that, absent more definitive data about the effects of anesthesia, deferring necessary surgery could cause children more harm.

"We need to understand if and how anesthesia changes brain function both in animals and in humans so that we can study the outcome we are most worried about -- cognitive function -- using clinically relevant models of anesthesia and possibly even surgery. We should not be tempted to change clinical practice unless we are certain that we need to and know exactly how to," said Stratmann.

At minimum, however, physicians should strive to minimize the length of time a child is sedated, as well as the number of trips to the operating room, suggests Dr. Jevtovic-Todorovic. If a surgery can be deferred until after the child is 4 years old, without causing serious harm to the child, the deferral may be warranted.

"The momentum of the data suggests that the concern is a potentially real one and the only way for us to reassure parents is to fund a substantial amount of research over the next several years," said Jevtovic-Todorovic.