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For other articles and previous issues click here. July 12, 2004 Curbing Sepsis:
The Campaign Against a Killer Striking swiftly and often without warning, sepsis continues to climb the list of the nation’s leading killers. Although it’s one of the nation’s leading killers, sepsis isn’t quite a household word. Not an infection, it’s a systemic inflammatory response syndrome (SIRS) to an infection—whether fungal, bacterial, viral, or parasitic—that poses a dire risk of irreversible organ dysfunction and death. Severe sepsis is most likely to occur in patients who have trauma, surgery, burns, pneumonia, cancer, or AIDS or in those who are otherwise immunocompromised. Worldwide, sepsis kills approximately 1,400 people each day. In the United States, approximately 900,000 people develop sepsis each year. According to the 1995 U.S. Census, 236,000 of those will die of the disorder. As if those statistics aren’t dire enough, the problem has been growing every year, says W. Michael Scheld, MD, professor of infectious diseases, University of Virginia Health System, Charlottesville. “The best data that I’ve seen looked at seven states over the last five years and saw an annual increase of about 7%. The largest increase, which was almost 40% per year, was in people over the age of 85,” he says. The nation’s number of severe sepsis cases is expected to rise by 1.5% each year, increasing to 1 million by the end of the decade. The mortality figures may be misleadingly low, however, because deaths from sepsis are frequently attributed to other conditions. It ranks with stroke and myocardial infarction as among the nation’s leading killers. The numbers are rising, experts suggest, not only because the population is aging and resistance to antibiotics is on the rise but also because more individuals than ever are affected by immunosuppression as a result of increases in transplant surgery, the HIV/AIDS epidemic, and the increased use of chemotherapy. According to Scheld, “In order for us to say that someone is septic, they need to display SIRS plus evidence of infection. The manifestations of sepsis are actually related to the body’s response to the invading organism.” If not aggressively treated, it can lead to multiorgan dysfunction syndrome, which is life-threatening. “The more organ systems that fail, the higher the mortality,” says Daniel Dea, MD, a board-certified doctor in pulmonary and critical care medicine at Providence Saint Joseph Medical Center, Burbank, Calif., who explains that when sepsis progresses to encompass four organ systems—which can happen in a matter of hours—the mortality rate is 80%. Although sepsis doesn’t always progress to this severe stage, it must always be recognized as potentially life-threatening and treated rapidly. Although interventions exist, the problem in controlling sepsis is recognizing the illness. Among the challenges of diagnosis and treatment are the facts that there is no universally accepted clinical definition of the condition and that because symptoms such as rapid pulse, fever, vomiting, chills, diarrhea, confusion, and respiratory distress are often attributable to other conditions, sepsis is frequently misdiagnosed or undiagnosed until it is too late for the patient to receive lifesaving treatment. “Some patients clearly have all the signs of sepsis or septic shock and have multisystem organ failure. In these patients, it’s very clear that they have a life-threatening infection,” says Scheld. The problem is recognizing it in the early stages before someone becomes critically ill. Patients’ symptoms may be very subtle, yet their condition can be highly serious. There are no tests with which to demonstrate whether or not someone is septic. It would be nice, Scheld notes, to have a test directly applicable to bacterial infection or some way of predicting which patients might become critically ill, but there are no such tools in current clinical practice. Sepsis, observes Scheld, can kill a perfectly healthy child or adult in no time. He points to the widely publicized cases of “flesh-eating bacteria” or meningococcal meningitis that often lead to fatal septic shock. In the latter case, he says, “the patients are often young and healthy. They’re college-age or in late adolescence, and they can literally go from the first symptom to death in less than a day.” Although there are some vaccines that reduce the incidence of infections that may lead to sepsis, there is little otherwise that can be done to reduce the rates of the potentially deadly condition. “There’s a pneumococcal vaccine that has largely eliminated blood-borne pneumococcal disease in children and which should probably be used more often in adults,” says Scheld, who points to a particular need among people aged 60 or older or who have chronic underlying diseases such as heart failure, renal failure, or chronic obstructive pulmonary disease. “It may not prevent every episode of pneumonia,” he says, “but it may prevent these people from dying of sepsis if they do get pneumonia.” Meningococcal meningitis can be prevented through vaccination, Scheld adds, noting that inoculation is recommended for young adults entering college. Parents of freshman should consider getting the vaccine for their children, he suggests, because although the risk is very low, the consequences can be grave. There are other vaccines being developed against bacterial pathogens that may help curb the rates of sepsis, Scheld says, but most of those are years away. Also standing in the way of the eradication of sepsis is a lack of full understanding of the pathogenesis. “Not knowing what actually kills the patient with sepsis hinders our progress,” says Scheld. “Unless we can figure that out, it’s very difficult to come up with a successful adjunctive therapy.” Treatment Sepsis, he says, is a malignant condition of excessive inflammation and coagulation that activates much more than one response. “There are literally scores of cytokines or chemokines that are turned on, perhaps almost simultaneously, and trying to interrupt,” he says. The cornerstones of treatment are fluids, antibiotics, and monitoring the patient, often in the intensive care unit. “If a patient is in flagrant septic shock,” Scheld explains, “the death rate is about 50%, and there’s only so much that antibiotics can do.” There’s some evidence that antibiotic therapy might actually make inflammation worse, so clinicians are counting on adjunctive treatment as well as antibiotics to try to reduce the death rate. In recent years, several approaches have been shown to improve survival, says Dea. The first is to make sure the patient is being treated by critical care specialists. According to campaign literature, “Evidence suggests that leadership of critical-care teams by full-time, board-certified intensivists improves patient outcomes and reduces patient mortality.” Such staffing, it suggests, would save 53,850 lives each year in the United States. Among the strategies these specialists have found most effective in improving survival include controlling blood glucose, administering low-dose steroid medication, and, for those with severe sepsis, trying a new and somewhat controversial drug, Xigris. Approved in November 2001 to treat severe sepsis, Xigris, made by Eli Lilly and Co., is being touted as a powerful new weapon in the war against severe sepsis. It’s not widely used, however, for reasons ranging from lack of provider awareness and stringent hospital protocols for patient selection to disagreement over its efficacy and, perhaps, bottom-line economics that have led to drug rationing. Some physicians suggest that the drug has limited benefits while others hail it as a major advance. “It’s the newest kid on the block in sepsis treatment,” says Scheld, who refers to its benefits as modest. “It’s very expensive, and only a certain subset of patients has been shown to benefit.” Each treatment, according to the Wall Street Journal, costs $6,800. At the University of Virginia Health System where Scheld practices, it’s a restricted agent—its use requires approval from the critical care medicine staff or infectious disease faculty, and the patient must have at least two organ systems failing to be considered a candidate for this drug therapy. According to Dea (a consultant for Eli Lilly), however, the benefits are more clear-cut and the literature on the drug is strong in its endorsement. “This drug was shown to be more effective in patients at a higher risk of death as determined by something called the APACHE I [acute physiology and chronic health evaluation] score,” says Dea. “There are protocols in some hospitals, including mine, where this medication is not given if the Apache score is lower. And there are some physicians, including myself, who feel that it shouldn’t be such a hard and fast rule.” There are some inaccuracies as to how sick a patient is depending on the APACHE II score alone, so Dea would like to see the rules bent depending on the individual patient. “It’s clearly an efficacious drug,” agrees Mitchell Levy, MD, FCCM, head of the medical intensive care unit (ICU), Rhode Island Hospital, Providence, who points to data suggesting that in the right population of patients with severe sepsis, the drug improves mortality by a significant amount—“between 6% and 10%, depending on the population you look at.” Nevertheless, many of those who may benefit do not receive the drug as a result of rationing. “There’s no question in my mind that to a certain extent, there is cost-based rationing going on for Xigris,” says Levy. “Most people will admit to you that if Xigris were free, they’d be using a lot more of it.” Some of the newer interventions—such as steroids and glucose control—that have been shown in clinical trials to be effective have been adopted more readily, he suggests, because they’re the least expensive. Levy is quick to point out that cost-based rationing isn’t always a bad thing, noting that some institutions are dependent on very fine margins for their survival. His point, and that of a task force charged with exploring the issue of such drug restriction, is that “while cost-based rationing may ultimately be a necessity, then that rationing has to be based on an evidence-based review of the efficacy of different agents. If we’re going to withhold therapies based on cost, then we want to be withholding the right therapies—those that are costly yet least likely to bring benefits.” Looking at Xigris in that light, Levy says, it’s not a drug that should be rationed based on a cost-effectiveness analysis. “This is another tool in your toolbox, and if you’re going to commit the patient to all the tools that you have available to treat sepsis, this should be another tool you should use,” echoes Dea. At the University of Virginia Health System, Scheld and other researchers are hopeful about an experimental drug, ATL 146e, which, if successful, could be a new and powerful weapon against sepsis. “We have a lot of data in animal models of infection, including meningitis, peritonitis, and septic arthritis, as well as sepsis models in mice, to show that this compound is highly protective and prevents inflammation tissue injury itself,” says Scheld. Because the compound, an adenosine receptor agonist licensed to a major pharmaceutical company for coronary stress imaging, is nontoxic and has already been shown to be safe in phase 1 trials in humans, the researchers are hopeful that the drug will be available in the clinic for sepsis patients within two years. Banding Together for Change “Over the past 10 years, we’ve actually codified what sepsis is in a precise manner, and we just want to educate providers on the precise definition of severe sepsis and everything that goes along with it,” says Dea. “Advances in critical care have been among some of the most dramatic in medicine,” comments Levy, a member of the governing council of the SCCM, in a campaign press release, “but we are well aware that a comprehensive program of education and action by policy makers and the medical community could significantly reduce the number of deaths caused by sepsis each year.” The campaign’s goal is to reduce mortality associated with sepsis by 25% over the next five years through targeted initiatives that will increase awareness, change perceptions and the behavior of healthcare providers, influence public policy, and define standards of care in severe sepsis. As part of this international collaboration, the first clinical management guidelines to address the treatment of patients with severe sepsis were unveiled at the Critical Care Congress in February, published in April in Critical Care Medicine and Intensive Care Medicine, and posted on the ESICM’s Web site. The creators reviewed the literature and produced 45 recommendations for the management of this potential killer, highlighting new interventions that have been shown to boost survival. “It’s a global initiative. We’re in a lot of countries talking about building networks to increase the utilization of these new interventions and have providers monitor and report survival,” says Levy. Cautious Optimism — Kate Jackson is a staff writer at For the Record. For more information, visit: |
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