Domino Effects

Intensivists strive to understand the science of critical care and improve the survival rates of critically ill patients.



Washington University intensivists at Barnes-Jewish Hospital battle many challenges in critical care, among them multiple organ dysfunction syndrome, in which one organ’s failure can bring other organs tumbling down like dominoes.

Finding new ways to improve these patients’ chances for survival is my professional passion. It’s what I think about day in and day out.”

MANY PATHS LEAD TO THE INTENSIVE CARE UNIT. Nearly 5 million people are admitted to U.S. ICUs each year, and while trauma, violence and accidental injury are leading causes of those admissions, other maladies ranging from pneumonia to cancer to obstetrical disorders also can necessitate an ICU stay.

The variety of conditions that pass through the ICU and the transitory nature of most patients’ stays have orphaned these units and the physicians who work in them. No patient advocacy groups exist for ICU patients, and no federal agency is mandated to fund critical care research. Although other countries, notably Canada and Germany, have national research networks dedicated to systematically improving the care of critically ill patients, funding in the United States is fragmented among organ- or disease-specific institutes.

But change is coming. J. Perren Cobb, MD, associate professor of surgery and of genetics, is leading a growing movement to increase public awareness of the value of critical care medicine. He and his colleagues in the ICU at Barnes-Jewish Hospital are laying the groundwork for an integrated U.S. research network that will bring the latest methods in high-speed genetic analysis, systems biology and molecular biology to bear on the question of how to better help critically ill patients fight for their lives.

Decisions in the ICU J. Perren Cobb, MD, right, with fellow intensivist Walter A. Boyle III, MD.

The condition of being critically ill is a relatively new component of the human experience. “ Since the mid 20th-century or so, we’ve been able to put people on ventilators and keep them alive in states that never existed before,” Cobb says. “Nature has never had the opportunity to engineer a solution for these states, because, prior to that time, people simply died.”

According to Cobb, medicine’s ability to treat these patients still mostly amounts to a holding measure — an ability to keep patients alive temporarily while factors within the patient that doctors don’t yet completely understand determine who lives and who dies.

“ Basically, we don’t really provide anything that per se speeds the healing process,” he says. “What we do is provide intravenous fluids, nutrition and an environment that we think — we hope — is optimal for patient recovery, and patients are either going to recover or they aren’t.”

For example, when critical care physicians strive to maintain “normal” levels of factors like blood pressure, water or potassium in their patients, Cobb notes, they target levels based on studies of healthy persons at rest.

“ It’s often unclear how truly helpful our efforts are to maintain these normal levels in the critically ill,” he says. “We could be trying to alter an adaptive response that might actually help the patient recover.”

This relative lack of knowledge sometimes leaves Cobb and his colleagues — critical care physicians known as intensivists — acting as the arbiters of conflicting medical directives from other, more specialized physicians.

“ It’s very common for the lung expert to tell us we need to give a patient medicine to dry them out,” he notes. “But then a kidney expert may come in and look at the same patient and tell us to give them lots of fluids. And we have to decide what to do.”

An intensivist has to span the gamut of expertises, knowing a great deal about every organ and system while not necessarily specializing in any one of them, according to Cobb.

“ In a way, we’re experts in the process of how people die,” he says. “That’s what we study — the process of death and how we can prevent it.”

From a systematic perspective, one of the key challenges intensivists have to deal with is the inflammatory response.

“ Inflammatory mediators are released into the bloodstream, so when this process of inflammation gets out of control, it’s not just confined to the area of the injury, it involves the entire body, affecting every organ,” Cobb says.

This can lead to multiple organ dysfunction syndrome, a condition in which one or more organs fail, and the supportive links between organs bring them all tumbling down like dominoes.

Researchers have identified and detailed the properties of several different inflammatory mediators over the last 20 years. However, in all but one case, their strategies for controlling these factors have been uniformly unsuccessful when tested in human patients.

It’s this frustration — having so much new information but still being able to clinically apply so little of it — that motivated Cobb to give up his role as a trauma surgeon in favor of pursuing opportunities to advocate for and advance change in the field of critical care.

“ When a previously healthy person arrives at the hospital after an accidental injury, and we treat them using very advanced technology only to basically have them ebb away and die over a period of 24 to 48 hours, it’s very frustrating” says Cobb.

“ Finding new ways to improve these patients’ chances for survival is my professional passion. It’s what I think about day in and day out.”

Five years ago, Cobb and other physicians and scientists interested in building a nationally coordinated, high-tech approach to trauma care research received a large five-year, multicenter grant from the National Institute of General Medical Sciences.

Recently, as part of that research, the group published results of an important trial in Proceedings of the National Academy of Sciences. In the multicenter study, they assessed the activity levels of all human genes in blood samples from critically ill patients and healthy volunteers.

“ We had quite a few decisions to make,” says Cobb. “How much time should there be between process A and process B? Should the blood be kept cold as it is brought to the lab, or warm, or at room temperature?”

Scientists showed that the protocols they established produced consistent results. This benchmark was essential for future plans to establish large, long-term studies of genetic factors in critical care patients.

A second major concern was whether the analyses were sensitive enough to detect changes in gene expression triggered by trauma. In blood samples from 34 trauma patients and 23 healthy persons, scientists found significant changes in the activity levels of several key genes related to inflammation.

Cobb suspects the complex connections between various inflammatory factors, genes, organs and major systems in the body may be one of the biggest reasons why efforts to improve critical care treatment have so far met with relatively little success.

“ For example, as we try to get a fix on the optimal levels of minerals in the bloodstream of critical care patients, we have to keep in mind that changing the level of one mineral will affect the levels of other minerals,” he explains.

He hopes that the new technology for rapidly assessing gene activity levels and other advanced scientific techniques will finally provide scientists with the ability to identify and fully understand these connections.

“ We’ve been like a driver trying to fix a car without knowing the names of all the engine parts or how they’re interconnected,” Cobb says. “Now, we finally have the tools we need to begin to identify all the parts and their connections.”

Assembling that list of parts and connections will be a massively complex undertaking. To that end, Cobb, who chairs an annual NIH meeting on critical care and genomics, has been recruiting scientists nationwide with a range of expertises to collaborate with critical care experts. This includes intensivist researchers locally who formed the Washington University ICU (WICU) group.

He and other leaders of this movement have resolved to apply the guiding principles of the NIH’s Roadmap Initiative and Washington University’s own Biomed 21 initiative: to take new insights from the lab to the patient’s bedside as quickly as possible, bringing together experts from many different fields with the latest genomic assessment technology.

“ We’re very hopeful that in this decade and the next, the frustrations we experienced in the 1990s are going to give way to real advances in understanding the complexity of these systems,” he concludes. “And that will allow us to begin to metabolically engineer new solutions that can actively help patients fight their way back to recovery.”