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American Journal of Emergency Medicine (2007) 25, 564 – 571


Sepsis in the 21st century: recent definitions and therapeutic advances
H. Bryant Nguyen MD, MS*, Dustin Smith MD
Department of Emergency Medicine, Loma Linda University, Loma Linda, CA 92354, USA
Received 23 June 2006; revised 14 August 2006; accepted 29 August 2006

Abstract Sepsis asa disease has received renewed interests since recent publications of a revised clinical definition and crucial clinical trials showing the benefits of early goal-directed resuscitation, recombinant human activated protein C, and low-dose corticosteroids. The epidemiology of sepsis has also been further examined. Management guidelines and international quality improvement efforts have beendeveloped targeting increased disease identification, clinician education, and optimal patient care with the result of decreasing patient mortality. The evidence suggests that early recognition and early intervention are most important in affecting outcome. This article will summarize these developments in the diagnosis and management of sepsis at the turn of this century. D 2007 Elsevier Inc. All rightsreserved.

1. Introduction
Sepsis has been defined as a systemic response to a local infection [1]. However, clinicians often ponder and then skip over this diagnosis when a patient presents to the emergency department (ED) with a productive cough, fever, tachycardia, and a multitude of constitutional symptoms. Therapies for such patients in the ED have primarily consisted of antibiotics. Inaddition, fluids have been the mainstay for cardiovascular support, and vasopressors are initiated if the patient becomes hypotensive and unresponsive to fluid resuscitation. When a patient is admitted to the intensive care unit (ICU), he or she is further placed among a group of bcritically ill patients.Q It is not until a few days into the hospital stay when culture results are positive, thepatient is receiving multiple vasopressors, multiple antibiotics, and mechanical ventilation that the treating physicians seriously

* Corresponding author. E-mail address: (H.B. Nguyen). 0735-6757/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2006.08.015

consider the patient bseptic.Q However, we would argue that this patient is now in septicshock with multiorgan failure and with a risk for mortality approaching 80%. The patient was already septic the minute he or she presented at triage. The problem is that sepsis has been associated with the systemic inflammatory response syndrome (SIRS) [1], resulting in only 17% of physicians surveyed agreeing to this definition [2]. However, 83% of physicians in the same survey agreed that thesepsis diagnosis is frequently missed. With respect to therapies, many clinical trials examining novel therapies have failed miserably. Agents without therapeutic success included antilipid, interleukin-1-receptor antagonist, platelet activating factor inhibitor, antitumor necrosis factor monoclonal antibody, immunoglobulin, ibuprofen, high-dose corticosteroid, anti-endotoxin, antithrombin III, andmany others [3]. Thus, it is no surprise that sepsis often becomes a syndrome of last resort rather than a diagnosis until proven otherwise. Even when sepsis is timely recognized, the therapies would not change from what the patient was already receiving, that is, antibiotics, fluids, and vasopressors.

Sepsis in the 21st century At the turn of the century, starting in 2001, the tide changedfor sepsis with the publication of the first successful clinical trial examining a novel therapeutic agent, recombinant human activated protein C (rhAPC) [4]. It became the first Food and Drug Administration–approved agent for severe sepsis therapy, specifically for patients with high risk for mortality. Soon after, other successful clinical trials followed, including therapeutic strategies such...
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