Sepsis
from WebMD Scientific American® Medicine
Posted 10/14/2003
Steven M. Opal, M.D., Christian E. Huber, M.D.
What is Sepsis?
Sepsis, septic shock, systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS) were defined at the American College of Chest Physicians/Society for Critical Care Medicine (ACCP/SCCM) Consensus Conference on Definition. The definitions take into account the finding that sepsis may result from a multitude of infectious agents and microbial mediators and may or may not be associated with actual bloodstream infection. Despite the clinical logic, intrinsic simplicity, and widespread acceptance of these consensus definitions, their clinical applicability has been justifiably criticized. The SIRS definition is so broad and nonspecific that it lacks discriminatory power; many patients admitted to general medical services and most ICU patients have conditions that meet the definition of SIRS. The current definition of sepsis fits virtually every person within the first 24 hours of an episode of influenza, because in these patients, the SIRS criteria are met and an infectious agent (an orthomyxovirus) causes the syndrome; however, clinicians do not generally regard the flu as sepsis. Nevertheless, a consensus conference held in 2001 to address some of these concerns concluded that apart from a need to expand the list of signs and symptoms of sepsis to reflect clinical bedside experience, no evidence existed to support a change in the definitions.[1]
One of the tenets on which these definitions are based is that the inflammatory response itself, not the infectious organism, drives the septic process. This hypothesis may be largely correct, but the nature of the microbial pathogen responsible for sepsis clearly contributes to the ultimate fate of the patient. Microbial pathogens differ in their susceptibility to host defenses, their potential for developing antimicrobial resistance, and their ability to generate toxins -- all of which affect their pathogenicity. Failure to account for these intrinsic differences in microbial virulence limits the utility of current sepsis definitions.
A Diagnostic Marker for Severe Sepsis
Procalcitonin, the propeptide of calcitonin, is normally produced by C cells in the thyroid. In septic patients, procalcitonin is generated by numerous extrathyroidal tissues; its precise origin in this situation is unclear. Procalcitonin has attributes that make it a potential marker for sepsis. It has a long half-life (approximately 24 hours), and measured levels will increase from undetectable to over 100 ng/ml during the course of septic shock. Procalcitonin levels do not become elevated as rapidly as interleukin-6 or interleukin-8 levels; elevated levels of procalcitonin are seen 4 to 6 hours after a systemic challenge with endotoxin or other septic stimuli.
Of interest is that procalcitonin levels are elevated in severe sepsis but not in localized infections, severe viral infections, or inflammatory conditions of noninfectious origin. In organ transplant recipients, procalcitonin levels may allow differentiation between the fever associated with rejection and that associated with sepsis. Although the precise physiologic role of procalcitonin in sepsis has yet to be defined, procalcitonin elevation appears to be the most sensitive and reasonably specific indicator of severe sepsis currently available.
New Therapies for Sepsis
Over the past 15 years, more than 30 double-blind, placebo-controlled, multicenter, phase 2 or phase 3 trials have been conducted to study the efficacy of new experimental agents in the treatment of septic shock.[2] After a long list of disappointments, two recent studies have now shown convincing positive results. A phase 3 clinical trial in which 1,690 patients were treated with recombinant human activated protein C (drotrecogin alfa [activated]) was stopped when an interim analysis revealed a survival benefit for patients receiving activated protein C; mortality was 24.7% in treated patients versus 30.8% in placebo recipients (P < 0.005)[3]. This study -- the first successful phase 3 international trial in severe sepsis -- resulted in Food and Drug Administration approval of drotrecogin alfa (activated) (Xigris) for the treatment of adult patients with severe sepsis who have an especially high risk of dying of sepsis. Carefully selected patients benefit from this treatment regardless of the type of infecting microorganism that caused their sepsis. The drug is given as a continuous infusion at 24 µg/kg/hr for 4 days. Because protein C is an endogenous anticoagulant, the major side effect of treatment is bleeding.
The second successful trial was a multicenter clinical study of low-dose corticosteroids. Annane and coworkers reported a significant improvement in survival in patients with vasopressor-dependent septic shock through the use of hydrocortisone (50 mg every 6 hours for 7 days) and fludrocortisone (50 µg/day for 7 days).[4] This treatment strategy is based on the frequent occurrence of relative adrenal insufficiency in patients with septic shock. In fact, low-dose corticosteroid therapy was effective only in those patients who showed evidence of inadequate adrenal response when given a short corticotropin test. A large clinical trial is under way in Europe and Israel to confirm and extend these exciting results; meanwhile, a German study in 40 patients with septic shock has provided supporting evidence.[5] A follow-up study with a larger number of patients would be worthwhile (the Annane study involved 299 patients), but to date, low-dose corticosteroids appear to be a cost-effective, readily available, and relatively safe treatment option for patients with refractory septic shock.
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