Saving Lives Past the Emergency Room

For people who have suffered a massive traumatic injury--from a car crash, building collapse, or other life-threatening event--modern health care is paradoxical in nature. While the emergency room is successful in prolonging lives, it is the body's system failures that eventually kill trauma patients. "If you look at the successes that medicine has had in our ability to capture individuals immediately after trauma, to resuscitate them, get them to the emergency room, we've been remarkably successful," says Lyle Moldawer, a surgery professor at the University of Florida.1 "We keep them alive and move them into the [intensive care] unit. [But] our ability to have a positive impact on those patients who are going to develop multi-system organ failure and succumb is really very, very modest." Also known as multi-organ dysfunction syndrome, this gradual, then hasty, cessation of vital organs is a major cause of posttraumatic event death. The reasons are obscure. "We really don't have a clue," says J. Perren Cobb, a surgery professor at Washington University in St. Louis. An attempt to grasp the nature of the problem and improve the situation came this past October when a $25 million, five-year grant was awarded from the National Institute of General Medical Sciences. The research involves 500 patients and some 45 investigators at 20 centers. This so-called glue grant, because it brings together scientists from a large number of institutions, is focused on understanding inflammation by using the knowledge and techniques spawned by human genome research. The Problem of Inflammation Though the reason behind organ failure is obscure, it does follow a grim order, notes Cobb. The lungs are the first to shut down, and then the brain, heart, kidneys, intestines, and liver follow. Finally, blood loses its ability to coagulate. The lungs are the linchpin, says Ronald Tompkins, the John F. Burke professor of surgery at Harvard Medical School, chief of trauma and burn services at Massachusetts General Hospital, and the grant's principal investigator. "The entire blood supply goes through [it]," he says. Consequently, any blood-borne bacteria from infection or any inflammatory substances the body releases to fight infection also pass through this organ. "Any inflammatory reaction [in the lung] makes gas exchange very difficult, and so you immediately see difficulties with oxygenation and removal of waste gases," explains Tompkins. The lung's impairment signals a cascade of failure; in effect, the body's basic services go out on strike. Tompkins and other researchers point to inflammation as a central mystery in this whole process; understanding and bringing it to heel are vital in improving the survival rate of trauma patients. The body's inflammatory response, says Timothy Buchman, a surgery professor at Washington University, is designed to control pathogens and remove damaged tissue from wounds. "These inflammatory molecules were designed to act locally, not globally. As nearly as we can tell, the body has all sorts of mechanisms to contain the cells that produce these inflammatory molecules at the site where the problem occurs. Somehow large numbers of these molecules gain access to the bloodstream [and] render their effects at points distant from the site of the original inflammation." Inflammatory molecules, says Tompkins, don't make a distinction between cleaning up damaged and undamaged tissue once they are seeded throughout the bloodstream. A number of these molecules exist, including such cellular messenger proteins as tumor necrosis factor, interleukins, and cytokines. Numerous attempts to control them have been made in the past. The Promise of Genomics Courtesy of Robert Danner Robert Danner What these attempts led to, says Robert Danner, a senior investigator and head of the National Institutes of Health's Infectious Diseases section, was a focus on each individual inflammatory molecule or mediator. "Having been in this field for about 20 years, what I've seen is there has been a kind of mediator of the month or mediator of the year, where people have said, 'Now we have it. This is the central mediator and if we block this one mediator, we will change outcome.' That has led to a huge set of clinical trials, over 30 trials, and we're at a point [where] we haven't made the kind of progress I would have expected," he says. One drawback of this single-factor approach was that it ignored the body's complex interplay, according to Danner: "It was like taking a 5,000-piece jigsaw puzzle and reaching in one at a time and pulling out pieces and trying to fit things together one at a time, and hoping the next piece you pulled out would give you a view of what was going on." But the human genome project and the high throughput technology it spawned has changed that and should enable researchers to grasp the interaction among genes. "You get to take the entire puzzle box and dump it on the desk and look at it all at once," says Danner. Among the parts of the genome that will receive a good deal of attention are the promoters, the switches that turn the genes on and off. "Those promoters are very, very complex structures," says Danner. "They are often over 1,000 base pairs long. There are a large number of DNA-binding proteins that read signals which bind or detach from the promoter. So what you have is a lot of switches that interact with one another." Peter Eichacker, head of the critical section at NIH, adds, "Genomics allows us to look at signals which tell us whether regulators are being upregulated or downregulated. We can try to define patterns which may be associated with a good response or a bad response." One recent study took just that approach. Thilo Menges of Justus-Liebig University in Giessen, Germany, and his colleagues report that trauma patients who died had a particular promoter polymorphism in the gene for palsminogen-activator-inhibitor-1, whereas trauma patients who survived had a different polymorphism. The former polymorphism was associated with high levels of two inflammatory factors, tumor necrosis factor* and interleukin.2 Using a mouse model, Cobb and his colleagues found a number of genes that were upregulated and downregulated in response to antibiotics given for spleen injury.3 While many findings exist to explore and possibly exploit, Danner acknowledges that the technology and techniques to analyze and comprehend them all are not yet available. According to Buchman, "tools of complex systems research" are needed. He, Cobb, and others view what happens in the body as an interaction between a set of complex systems, the various organs, the bloodstream, and the genome. The tools they need are highly complex mathematical models and computers, which already exist for other disciplines but have yet to be modified for research purposes. "These are tools that have been applied to such diverse problems as weather prediction, economic forecasting, and baggage handling in the airline industry; problems where there are all sorts of directions a system might take," he says. The computer modeling, what Buchman describes as "simulations in silico" will help researchers determine the most promising techniques and experiments that could control inflammation. "That's the type of insight we need to take resources, which are limited, and apply them wisely in service of these patients," he says. Understanding Previous Failures While this new approach may pay dividends, new research could explain why the attempt to block individual inflammatory agents has proven so disappointing. Eichacker and his colleagues have found that the attempt to block these factors may not have been conducted in the most effective manner.4 The agents that blocked individual inflammatory factors "were most beneficial in the most lethal [conditions] and least beneficial in the least lethal," Eichacker says. "If you take an infection where the likelihood that the subject is going to die is small, so that inflammation is likely doing something good, and you interfere with that inflammatory response, you might disturb a beneficial response and create a harmful situation," he says. In reviewing clinical trials, Eichacker and colleagues searched for those that classified patients based on their risk of death. "We were able to assess what the effects of the agents were in patients that had high risks of death or low risks of death. We found the same pattern we had seen in our pre-clinical [animal] work," he says. The researchers discovered that an infection, prematurely blocked in the natural inflammatory process, can get out of hand and become life-threatening. Eichacker emphasizes these conclusions are based on retrospective analysis. What is needed, he says, is prospective research. But, he adds, in pre-clinical or animal work, researchers should evaluate the effectiveness of anti-inflammatory agents as a function of an infection's severity. Harvey Black (73773.2227@ compuserve.com) is a freelance writer in Madison, Wis. References 1. A. Oberholzer et al., "Sepsis syndromes: understanding the role of innate and acquired immunity," Shock, 16:83-96, 2001. 2. T. Menges et al., "Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients," Lancet, 357:1096-7, April 2001. 3. T.H. Chung et al., "Sepsis gene expression profiling: effects of antibiotics over time on murine splenocytes after cecal ligation and puncture," Shock, 26(Suppl. 1):496, 2001. 4. P. Eichacker et al., "Risk of death and the efficacy of inflammatory therapies in spesis: A metaregression analysis," The Journal of the American Medical Association, In Press.

Saving Lives Past the Emergency Room

Interested in reading more?

Become a Member of