An unlikely team of heart surgeons and brain chemistry experts at Johns Hopkins has experimental evidence that some common drugs including anti-seizure medications may reduce or eliminate the most feared risk to people facing heart bypass surgery -- inevitable, if often subtle, brain damage.
Five years into an eight-year National Institutes of Health grant, the Hopkins team has conducted laboratory tests with chemicals that dramatically protect animal brains from the kind of damage that occurs during heart surgery. Patient trials are expected to start in early 1998.
"The truth is that surgeons have gone about as far as they can go to indirectly protect the brain from injury by both decreasing operating time and refining cardiopulmonary bypass (the heart-lung machine)," says William A. Baumgartner, M.D., chief of cardiac surgery. "Since satisfactory methods have been developed to protect the heart during open-heart operations, the next challenge is to protect the brain.
"Our goal has been two-fold. We want to define the cellular and biochemical mechanism of nerve cell injury and then develop pharmacologic strategies to reduce the injury."
Baumgartner likened the neuroprotective strategy to newer tactics in the battle to reduce death and injuries from auto accidents. "The first approach years ago was driver education -- getting people to avoid accidents and reduce their frequency. But accidents persisted, so the next phase was to build a more protective car, with better brakes, air bags and seat belts. If you know that every time people get behind the wheel some accidents are inevitable, then the goal becomes making those accidents less harmful, regardless of the cause."
The apparently protective drugs tested at Hopkins inhibit overproduction of the neurotransmitter glutamate (an excitatory amino acid), glutamate receptors like N-methyl-D-aspartase, and nitric oxide. The team has shown in several published studies that, when administered, these medications result in far less brain cell damage and document better neurologic outcomes after undergoing bypass surgery.
In a paper to be presented 8 a.m., Nov. 8 at the Southern Thoracic Surgical Association annual meeting in Naples, Fla., the researchers report that 17477AR, an inhibitor of the enzyme nitric oxide synthase, significantly reduced brain cell death in a model of open-heart surgery, where brain damage is known to occur. The particular areas of the brain affected are those that involve memory and learning.
One of the documented causes of brain damage has been an excessive accumulation of glutamate, the major neurotransmitter in the brain. This can cause over activation of brain nerve cell receptors, triggering a cascade of cellular events that lead ultimately to cell death. Nitric oxide, a chemical normally involved in many body functions, also has been implicated as a mediator of glutamate neurotoxicity. The medications being tested aim to interrupt this cascade and preserve cognitive function.
In the current study, researchers measured brain levels of nitric oxide, comparing the drug 17477AR with controls. They found that the medication reduced production of citrulline (a marker of nitric oxide) by 58 percent. Superior neurologic function also was demonstrated compared with controls.
"These results provide the first evidence that nitric oxide mediates brain cell death in a model of open-heart surgery and that nitric oxide synthase plays a significant role in this neurotoxicity," says Elaine E. Tseng, M.D., lead author of the study and a cardiac surgery fellow. "Pharmacologic strategies to inhibit nitric oxide synthase may be clinically beneficial."
The study was supported by the National Institutes of Health and the Nina Braunwald Research Fellowship from the Thoracic Surgery Foundation for Research and Education. The co-authors were Malcolm V. Brock, M.D.; Mary S. Lange, M.A.; Jorge D. Salazar, M.D.; John R. Doty, M.D.; Charles J. Lowenstein, M.D.; Juan C. Troncoso, M.D.; Mary E. Blue, Ph.D.; Michael V. Johnston, M.D.; and Baumgartner.
For the more than 400,000 Americans a year undergoing coronary artery bypass surgery, refined surgical techniques have improved outcomes almost to the limits of "driver ed," with mortality overall at less than 3 percent at the best medical centers, even among a rapidly aging patient population. At Hopkins, for example, in 1996, the mortality rate was just 2.8 percent overall, despite a patient population that has aged rapidly. Thirty-five percent of patients that year were more than 70 years old.
With the increasing age of patients undergoing cardiac surgery, cerebral complications represent one of the leading causes of morbidity and mortality in this group of patients. Neurological disturbances also are associated with increased length of stay and costs.
--JHMI--
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