The U.S. Department of Defense has awarded $2 million to Children’s National Hospital to study how a family of protease enzymes known as caspases may contribute to brain cell degeneration when activated by prolonged anesthesia and cardiopulmonary bypass during cardiac surgery for congenital heart disease.
This U.S. Army Medical Research Acquisition Activity Award, Anesthesia Neurotoxicity in Congenital Heart Disease, is led by principal investigator Nobuyuki Ishibashi, M.D., with both clinical and basic science co-investigators including Kazue Hashimoto-Torii, Ph.D., (Neuroscience), Richard Jonas, M.D., (Cardiovascular Surgery) and Nina Deutsch, M.D., (Anesthesiology).
While the specific cellular and molecular mechanisms of how anesthesia and cardiac surgery impact cortical development are poorly understood, both seem to impact brain growth and development in young children. The most common neurologic deficit seen in children after CHD surgical repair is the impairment of fine and gross motor skills.
Both anesthetic agents and inflammation like that seen as a result of cardiopulmonary bypass have also been shown to contribute to the activation of a specific group of enzymes that play an essential role in the routine (programmed) death of cells: caspases. However, recent pre-clinical research shows that these enzymes may also contribute to other alterations to cells beyond cell death, including making changes to other cell structures. In pre-clinical models, these changes cause impairments to fine and gross motor skills – the same neurological deficits seen in children with CHD who have undergone procedures requiring prolonged anesthesia and cardiopulmonary bypass.
The research team hypothesizes that caspases are extensively activated as a result of cardiac surgery and while that activation is rarely causing reduced numbers of neurons, the changes that caspase enzymes trigger in neurons are contributing to neurological deficits seen in children with CHD after surgery.
While the study focuses specifically on the impacts of cardiac surgery for correction of a heart defect, the findings could have major implications for any pediatric surgical procedure requiring prolonged anesthesia and/or cardiopulmonary bypass.