MAA - The Bulletin - Spring 2009

Start with a Congressional mandate for a national trauma study center. Add a program that treats 2,000 brain injuries a year, more than any other facility in the country, and expand such an impact with the talents of basic and translational researchers in both trauma and anesthesiology—all driven by the same tenacity to study and ultimately minimize the impact of trauma.
Thomas M. Scalea, MD, professor of surgery, director of the program in trauma, and physician-in-chief at the R. Adams Cowley Shock Trauma Center reports, “This building houses the only trauma hospital that exists in the United States. It encompasses 200,000 square feet of space dedicated entirely to injury and critical illness, and provides a patient population base that furthers critical trauma studies undertaken by the center for trauma and anesthesiology Research."

Designated an organized research center (ORC) by the University of Maryland in 2007, the center originally was created by an act of congress and named the Charles “McC” Mathias Jr. National Study Center for Trauma and Emergency Medical Systems. Today, the center is funded in excess of $20 million by the National Institutes of Health (NIH), the U.S. Department of Defense, the State of Maryland, and all three branches of the military.

Scalea explains the two medical specialties of trauma and anesthesiology share a long history of collaborative research at Maryland. “We have an impressive roster of first-class investigators, working together on one campus in robust clinical, basic and translational research paired with epidemiologic studies conducted by the National Study Center,” he says. “We can move from bench to bedside to population—and work in the reverse as well. I don’t know of any other institution that has that advantage.”

The war in Iraq has led to a growing recognition of a neglected area of research, one that has defined a targeted area of study at the ORC. Numerous studies have focused on severe brain injury. Mild to moderate brain injury, however, has been largely overlooked until recently when military personnel, exposed to the constant blast from explosions, have returned home to face consequences that often can be disabling. While the seriousness of complications associated with mild brain injury is underscored by war casualties, the impact to civilians is no less threatening. The massive number of such injuries sustained in Baltimore alone in any given year confirms the importance of extensive research. Such injuries may present no long-term setbacks—or they may result in post concussive incidents, headaches, hearing problems, sleeplessness, dizziness and even an inability to function on the job or in school.

The medical school’s national study center conducts a crash investigation project that provides valuable statistical information on the effort to reduce injuries, including brain injuries, resulting from vehicular accidents.

Patricia Dischinger, PhD, an epidemiologist at the center, reports that the project known as CIREN (Crash Injury Research Engineering Network), which is funded by the National Highway Traffic Safety Administration (NHTSA), involves participation from trauma surgeons, bio-mechanical engineers, social workers, crash reconstructionists, data managers and police officers.

“Our team goes into action immediately following an injury,” Dischinger reports. “We reconstruct the entire crash, obtaining detailed data on injuries as well as crash circumstances, including the forces, contact points and intrusions involved. In addition, we obtain follow-up interviews to determine factors related to return to pre-injury functional status. An extensive report on every aspect of the crash and the trauma itself is compiled and becomes part of a national data base used to provide feedback to NHTSA and auto manufacturers to reduce morbidity and mortality due to crashes.”

Peter Rock MD, MBA, professor and chair of anesthesiology, explains, “Severe brain injury is a more obvious condition, but the subtle injuries during which a patient has lost consciousness for a short time, or not at all, those are the ones that demand a high level of expertise and a team approach, such as the one employed at this center.”

Rock believes that one of the reasons the ORC has focused on brain injury is that its team of investigators has considerable experience in an arena that isn’t applicable to just one medical discipline.

“The importance of this research center is its success in putting together a multi-disciplinary team that, in addition to trauma specialists and anesthesiologists, includes neurologists, neurosurgeons, psychiatrists, psychologists, radiologists, biochemists, and people exploring new
technologies.

“During this time of fiscal constraints, it’s important for an institution to leverage its strengths,” he adds. “We have very deliberately established the kind of program that does that.”

A significant difficulty in treating mild to moderate brain injury stems from the inability to predict whether or not a specific patient will become disabled as a result of the initial incident. There is no conclusive way to look at two soldiers who sustained similar brain injuries in Iraq and determine which one will be fine, and which one is at risk for post-concussive illness. CT scans determine structural injury, but so far there is no technology that detects whether a person is likely to incur blackouts, nausea or memory loss as a result of a brain injury.

The imperative then becomes to better predict in individual patients what the outcome of a brain injury might be. That effort is underway through numerous studies at the ORC, beginning with the creation of a data base unlike anything available elsewhere. While trauma statistics traditionally have been thrown together in large data bases for years, the numbers generally are flawed because they are not prospective or detailed, and don’t include follow-up. Instead of looking at charts after the fact, the ORC program focuses on prospective patient and nurse interviews, pre-hospitalization data plus periodic and thorough patient follow-up over the course of a year.

Richard Dutton MD, MBA, associate professor of anesthesiology, explains. “We call people back to review their symptoms, medical history, depression, and the incidence, duration and severity of migraines,” he says. “At this point, we are searching for markers in the blood that are associated with brain injury and can be identified in lab tests.”

All of this is being used along with new technology, specifically a device called a brain acoustic monitor (BAM) which was developed at the university and works as a kind of stethoscope for the brain. It all came about as the result of a connection Dutton made with a Baltimore company of acoustical engineers once contracted by the government during the Cold War to detect Russian submarines through a sonar device. When that market no longer existed, company executives began thinking about medical applications.

“We started exploring the possibility of developing a brain monitor,” Dutton says. “Since scans tell us a lot about the anatomy of the brain, but nothing about how it is working, we were looking for a non-invasive method of getting real information about what is going on.”

The resulting BAM team came up with a device that can be attached to the patient in the ambulance or helicopter. Within a few seconds, it measures sound going through the brain, then emits a signal indicating whether or not the person has a brain injury. The ORC recently concluded a study for the Air Force that demonstrated how the monitor’s measurement can be compared to the severity of a brain injury and the occurrence of post-injury symptoms.

“This has taken a long time to develop,” Dutton says. “We’re now conducting the eighth trial of the device. First, we focused on determining the presence of a brain injury. Now the question is whether or not it can tell us when a patient’s condition has improved. We have data from 500 patients we are analyzing. It will take some time yet, but we hope one day to be able to prescribe therapy based on a patient’s BAM.”

As the busiest trauma program in the country, Maryland’s ORC treats more patients with life-threatening bleeding from trauma than any other. Questions have been raised about transfusion—when to administer blood, how much to administer, whether or not to give the patient both red blood cells and plasma.

“If it becomes a surgical problem, you can fix it,” Dutton says. “But we’ve learned there are important medical considerations as well.
His laboratory has a large grant to study specific components of clotting aimed at determining factors that may identify people at risk for bleeding, and trying to pinpoint when a patient becomes coagulapathic, as well as which injuries may be most closely related. In the last five years, investigators have been studying a drug called Factor VIIa, an artificial form of a natural protein in the body that stimulates clotting. ORC researchers have determined which patients it will help, and have been using it to replace the natural protein in the body when needed. In the meantime, Dutton is one of 10 investigators serving on a worldwide Factor VII steering committee, and has co-authored several papers on Maryland’s experience with the drug.

Deborah Stein MD, MPH, assistant professor of surgery, admits brain injury is a frustrating disease process. “Most of what we do is necessarily reactive,” she says “We see swelling, and so we treat that. But if we could say beforehand that a person is at risk because a specific cytokine in the blood is particularly dangerous, then we could come up with a drug to counteract the cytokine.”

Stein’s primary area of research is identifying substances associated with brain injury. “We know that these patients have severe respiratory failure and an elevation of cytokines,” she says. “Some of them become seriously ill with systemic disorders including lung and liver problems. What I want to know is what it is that increases the danger of this happening. Is it that the brain is releasing substances that lead to systemic illness?”

The laboratory is conducting a prospective study for the presence of systemic inflammatory response in selected patients within 24 hours of admission. The team does blood sampling and collects spinal fluid. Approximately 30 patients were enrolled in an unfunded study last year and results are now being analyzed. A new funded study is currently enrolling additional patients.

“We’re looking to see if levels of cytokines in the blood and spinal fluid correlate with intracranial pressure,” Stein reports. “Is the amount and specific type of cytokine related to death or other outcomes? We continue to perform functional follow-up studies on these patients to see if their conditions can be predicted by anything we see early on. Of course, our ultimate goal is to come up with therapy.”

Translational neuroprotection research is ongoing at the ORC under the leadership of Gary Fiskum PhD, professor of anesthesiology and vice chair for research. His team approaches brain injury from two perspectives—when it is a direct result of the injury, and when it is caused by brain- impaired blood flow that occurs when the brain swells following trauma, or when there is a severe drop in blood pressure.

“Much of our work focuses on energy metabolism in the brain,” Fiskum reports. “The brain consumes about 90 percent of the energy in the body. One of the strengths of our research is understanding how the change in the energy metabolism of the brain ultimately leads to brain cell death and neurological impairment. Then by knowing what appears to be important, we can come up with strategies to repair the damage.”

He adds that a vast majority of oxygen is used by the body in a safe way to fuel energy metabolism. There is a small percentage, however, that creates toxic byproducts called reactive oxygen species or free radicals. These have been generally accepted as contributing to many forms of traumatic and inflammatory tissue injury, and are even responsible for age-related memory loss.

One part of the cell especially sensitive to oxidated stress is the mitochondrion, and that’s the part of the cell that produces the vast majority of the energy necessary to sustain life. If it is injured, it can cause brain dysfunction or even death. Fourteen members of Fiskum’s research group, including seven faculty members, are involved in highly developed studies of the mitochondrion, in collaboration with investigators from several ther departments, including pediatrics, neurology, and biochemistry and molecular biology. They are examining how it works normally, how it is damaged following brain ischemia and head trauma, and how to inhibit that damage by optimizing critical care procedures after injury and by administration of experimental drugs. Fiskum and colleagues are at the forefront of the emerging field of mitochondrial medicine, applicable to the treatment of critically il patients who survive only when the energy metabolism of the brain and other vital organs is maintained.

Rock summarizes the ORC program by stressing its efficiency. “We do not over-extend ourselves,” he says. “We have focused on traumatic brain injury and have put together the strongest resources possible to address important problems—and that includes the enormous personal resources within our faculty.”

Scalea agrees and adds that the essence of the ORC is finding answers that can be put to use at the bedside of traumatized patients.

“For instance, there is a great deal of interest in post- traumatic stress disorder,” he says. “There is considerable incidence of this as well as brain injury in the military. Could they be the same disease? It’s possible. Certainly there is a close association between the two. There are many similarities here to unlock. Right now, we don’t have the answers. But we’re trying to find them. That’s what this center is all about.”