Editorial

Abstract

Sepsis with acute organ dysfunction (severe sepsis) is a serious clinical problem that is associated with significant morbidity and mortality. In addition, the projected incidence of severe sepsis is expected to increase steadily well into this century. The health economic burden of sepsis is staggering, causing an increase in drug use, hospital length of stay, and overall cost for patients who develop the disease. In the last 50 years, surgeons have appreciated the importance of source control and recognized that therapy must include appropriate antibiotics and organ support. Despite these insights, mortality rates of patients with severe sepsis are still too high (between 28% and 50% or greater) [ 1 Brun-Buisson C. Doyon F. Carlet J. et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA. 1995; 274: 968-974 Crossref PubMed Google Scholar , 2 Linde-Zwirble W.T. Angus D.C. Carcillo J. et al. Age-specific incidence and outcome of sepsis in the US [abstract]. Crit Care Med. 1999; 27: A33 Crossref Scopus (48) Google Scholar , 3 Angus D.C. Linde-Zwirble W.T. Lidicker J. et al. Epidemiology of severe sepsis in the United States analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29: 1303-1310 Crossref PubMed Scopus (6566) Google Scholar ]. Therefore, basic scientists and clinical researchers have attempted to categorize specific components of the septic process that could be modulated to reduce the morbidity and mortality associated with the disease. Many of these investigations have attempted, with limited success, to identify several novel compounds for the treatment of sepsis (eg, antiendotoxin, anti–tumor necrosis factor, interleukin-1 receptor antagonist) [ 4 Abraham E. Wunderink R. Silverman H. et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995; 273: 934-941 Crossref PubMed Scopus (775) Google Scholar , 5 Cohen J. Carlet J. INTERSEPT an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med. 1996; 24: 1431-1440 Crossref PubMed Scopus (428) Google Scholar , 6 Reinhart K. Wiegand-Lohnert C. Grimminger F. et al. Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock a multicenter, randomized, placebo-controlled, dose-ranging study. Crit Care Med. 1996; 24: 733-742 Crossref PubMed Scopus (302) Google Scholar , 7 Opal S.M. Fisher Jr, C.J. Dhainaut J.F. et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med. 1997; 25: 1115-1124 Crossref PubMed Scopus (686) Google Scholar , 8 Angus D.C. Birmingham M.C. Balk R.A. et al. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis a randomized controlled trial. E5 Study Investigators. JAMA. 2000; 283: 1723-1730 Crossref PubMed Scopus (208) Google Scholar , 9 Panacek E. Marshall J. Fischkoff S. et al. Neutralization of TNF by a monoclonal antibody improves survival and reduces organ dysfunction in human sepsis. Results of the MONARCS trial. Chest. 2000; 118: S88 Google Scholar ]. However, the recently completed Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial of activated protein C (drotrecogin alfa [activated], Xigris; Eli Lilly and Company, Indianapolis, IN) documented clinically and statistically significant reductions in mortality and is considered to be a landmark advance in the care of critically ill septic patients [ [10] Bernard G.R. Vincent J.L. Laterre P.F. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344: 699-709 Crossref PubMed Scopus (5035) Google Scholar ]. The PROWESS trial demonstrated that treatment with drotrecogin alfa (activated) produced a 6.1% absolute reduction in mortality and a 19.4% relative reduction in the adjusted risk of death from any cause within 28 days in patients with severe sepsis. Because drotrecogin alfa (activated) is the first approved agent in a new category of antisepsis interventions, clinicians lack familiarity with the drug, its indications, and its contraindications. Additionally, use of the drug outside the clinical trial setting, determination of a treatment algorithm, and integration of the drug into the classic treatment regimen need to be addressed further. This supplement attempts to define and clarify these issues.