407 STATE-OF-THE-ART CLINICAL ARTICLE Current Understanding of Sepsis Richard P. Wenzel, Michael R. Pinsky, Richard J. Ulevitch, and Lowell Young Sepsis and septic shock represent the thirteenth leading cause of death in the United States. It has been estimated that there are 500,000 new episodes each year, with an associated crude mortality of 35% [1]. Over the last 4 decades the age-adjusted mortality has climbed steadily from 0.5 to 7 per 100,000 epi- sodes [2]. Approximately one-third to one-half of patients who are septic have culture-positive blood, and much of our under- standing of this clinical syndrome derives from studies of noso- comial bacteremia and candidemia. Several approaches have been used to study the direct impact of bloodstream infections-and therefore of sepsis-apart from the impact of patients' underlying diseases. The first in- cludes the use of models such as logistic regression to adjust for underlying illness and to provide estimates of relative con- tribution to mortality from an individual-patient viewpoint. Risk ratios or odds ratios are provided in such analyses. A risk ratio of three among patients with bloodstream infections suggests that their risk of dying is three times greater than that expected from the underlying diseases alone. The second approach is to examine from a population view- point the absolute impact of the infection by subtracting the crude (overall) mortality among tightly matched controls with- out bloodstream infection from the crude mortality for cases of bloodstream infection. The difference is called the attributable mortality. For example, if mortality among patients with blood- stream infections is 35% and that among matched controls is 10%, the estimated direct or attributable mortality is 25%. The implication is that five-sevenths of the deaths (25 of 35) are due to the infection and two-sevenths are due to the underlying disease. Previous studies of bloodstream infections have identified Pseudomonas aeruginosa infection, Candida species infection, and polymicrobial infection as independent predictors of death, with estimated risk ratios of approximately three. More recent studies have confirmed these data and suggested that the occur- Received 8 August 1995; revised 13 November 1995. Reprints or correspondence: Dr. Richard P. Wenzel, VCU/MCV Internal Medicine, 1001 East Broad Street, Suite 405, P.O. Box 980663, Richmond, Virginia 23298-0663. Clinical Infectious Diseases 1996;22:407-13 © 1996 by The University of Chicago. All rights reserved. 1058-4838/96/2203-0001$02.00 From the Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia; University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; The Scripps Research Institute, La Jolla, California; and Kuzell Institute, San Francisco, California rence of pneumonia, as a source of nosocomial bloodstream infection, also predicts mortality. Seven published studies have examined attributable mortality [3-9], which is "'-' 15% for co- agulase-negative staphylococcal bloodstream infections, 25% for gram-negative rod infections, 30% for enterococcal infec- tions, and almost 40% for candidal bloodstream infections (figure 1). An overall estimate of attributable mortality is 25%, when all organisms are considered. Recently, the somewhat vague and ambiguous term sepsis has been replaced by terms for three clinical syndromes defin- ing a progressive increase in the systemic inflammatory re- sponse to infection. An initial systemic inflammatory response syndrome (SIRS) has been defined as well as the three hierar- chical stages associated with infection: sepsis, severe sepsis, and septic shock (table 1). The goal of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference group in creating new categories [10] was to pro- vide more precise definitions to apply both at the bedside and in clinical trials. The first epidemiological study of SIRS recently provided data supporting the clinical progression of SIRS from sepsis to severe sepsis and septic shock [11] (table 2). Progressive increases in end-organ failure, positive blood cultures, and mor- tality were seen with each hierarchical stage of sepsis. More- over, 44%- 71 % of the cases of sepsis in any single stage had progressed from the previous stage. Thus, for the first time we have working definitions that can be applied to studies of end-organ failure after sepsis, to an understanding of the chemical derangement and molecular and cellular responses occurring at different stages, and to clinical trials of new agents to treat sepsis. Organ Failure in Sepsis It can be argued that until the advent of critical care, and the ability to sustain life after severe insults, there was little opportunity for organ failure. Thus, organ failure could be viewed as an iatrogenic event, the result of advances in medical support systems. As sepsis advances toward the systemic inflammatory stage of shock, there is increased sympathetic tone, giving rise to tachycardia associated with hypotension. By reflex there is an increase in respiratory drive, and patients experience tachypnea