Treatments to reduce anesthesia-induced injury in children show promise in animal studies

As detailed in a study published in the March 23 online edition of the journal Neuroscience, Wake Forest Baptist scientists explored a number of strategies designed to prevent anesthesia-induced damage to the brain in infants.

Using an animal model, the researchers tested the effectiveness of a fragment of a neuroprotective protein called ADNP, as well as vitamin D3, a low-level dose of anesthetic and aspirin. They found that three of the four strategies tested protected the brain from injury induced by 20 mg ketamine, a commonly used general anesthetic.
“What didn't work was aspirin, which was a surprise because aspirin is known to protect the brain from injury,” said Christopher P. Turner, Ph.D., assistant professor of neurobiology and anatomy at Wake Forest Baptist and lead author of the study. “In fact, in our study aspirin actually increased the severity of injury from the anesthesia, possibly because it prevents the generation of substances that may be neuroprotective.”

Turner and his team studied rats at ages equivalent to children from birth to age 4.

In separate tests, the rodents were injected with: NAP, a peptide fragment of activity-dependent neuroprotective protein (ADNP), 15 minutes before ketamine was administered; two 20-mg doses of vitamin D3, at 24 hours and at 15 minutes before 20 mg ketamine; a non-toxic (5 mg) doses of ketamine 24 hours before a toxic dose of 20 mg ketamine was administered; and a 30-mg dose of aspirin 15 minutes before exposure to ketamine.

The Turner lab found that NAP, vitamin D3 and prior exposure to low (non-toxic) ketamine could all prevent injury from exposure to a toxic (20 mg) level of ketamine. However, aspirin appeared to enhance ketamine-induced injury.

“We designed our studies to give doctors several possible treatment options because not all of these strategies may work in clinical applications,” Turner said. “However, because vitamin D3 is already in clinical use, our findings show that it is quite promising with few risks. Further, NAP is currently in clinical trials to diminish the severity of other types of brain injury, so we feel this discovery represents a breakthrough for anesthesia-induced neurotoxicity. However, there may be a critical window of efficacy for NAP, which we need to explore further.

“Of all the approaches that our team studied, using a low dose of ketamine may be both the simplest and most cost-effective, as it suggests children can be pre-treated with the same anesthesia that will be used when they undergo general surgery,” Turner added. “In essence, a low-level dose of ketamine primes the child's brain so that the second, higher dose is not as lethal, much like an inoculation.”

The study was funded by the National Institutes of Health, Wake Forest Baptist Intramural Research Fundand the Tab Williams Family Neuroscience Endowment Fund.

Co-authors of the study are: Silvia Gutierrez, Ph.D., Chun Liu, Lance Miller, Ph.D., Jeff Chou, Ph.D., Beth Finucane, Ansley Carnes, James Kim, Elaine Shing, Tyler Haddad and Angela Phillips, all of Wake Forest Baptist.
Media contacts: Marguerite Beck, marbeck@wakehealth.edu, 336-716-2415; Media office main number, 336-716-4587.

Wake Forest Baptist Medical Center (www.wakehealth.edu) is a fully integrated academic medical center located in Winston-Salem, N.C. Wake Forest School of Medicine directs the education and research components, with the medical school ranked among the nation's best and recognized as a leading research center in regenerative medicine, cancer, the neurosciences, aging, addiction and public health sciences. Piedmont Triad Research Park, a division of Wake Forest Baptist, fosters biotechnology innovation in an urban park community. Wake Forest Baptist Health, the clinical enterprise, includes a flagship tertiary care hospital for adults, Brenner Children's Hospital, a network of affiliated community-based hospitals, physician practices and outpatient services. The institution's clinical programs and the medical school are consistently recognized as among the best in the country by U.S.News & World Report.