Sepsis

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review article

Drug Therapy

Management of Sepsis
James A. Russell, M.D.

better understanding of the inflammatory, procoagulant, and immunosuppressive aspects of sepsis has contributed to rational therapeutic plans from which several important themes emerge.1 First, rapid diagnosis (within the first 6 hours) and expeditioustreatment are critical, since early, goaldirected therapy can be very effective.2 Second, multiple approaches are necessary in the treatment of sepsis.1 Third, it is important to select patients for each given therapy with great care, because the efficacy of treatment — as well as the likelihood and type of adverse results — will vary, depending on the patient.

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From the University ofBritish Columbia, Critical Care Medicine, St. Paul’s Hospital, Vancouver, BC, Canada. Address reprint requests to Dr. Russell at the University of British Columbia, Critical Care Medicine, St. Paul’s Hospital, 1081 Burrard St., Vancouver, BC V6Z 1Y6, Canada, or at jrussell@mrl.ubc.ca. N Engl J Med 2006;355:1699-713.
Copyright © 2006 Massachusetts Medical Society.

THE SPEC T RUM OF SEPSISNomenclature is important when it helps us understand the pathophysiology of a disease. This is true for sepsis, since nomenclature has informed the design of randomized, controlled trials and, ultimately, the prognosis of sepsis. Sepsis is defined as suspected or proven infection plus a systemic inflammatory response syndrome (e.g., fever, tachycardia, tachypnea, and leukocytosis).3 Severe sepsis isdefined as sepsis with organ dysfunction (hypotension, hypoxemia, oliguria, metabolic acidosis, thrombocytopenia, or obtundation). Septic shock is defined as severe sepsis with hypotension, despite adequate fluid resuscitation. Septic shock and multiorgan dysfunction are the most common causes of death in patients with sepsis.4 The mortality rates associated with severe sepsis and septic shock are 25to 30%5 and 40 to 70%,6 respectively. There are approximately 750,000 cases of sepsis a year in the United States,7 and the frequency is increasing, given an aging population with increasing numbers of patients infected with treatment-resistant organisms, patients with compromised immune systems, and patients who undergo prolonged, high-risk surgery.7

PATHOPH YSIOL O GY
Sepsis is theculmination of complex interactions between the infecting microorganism and the host immune, inflammatory, and coagulation responses.8 The rationale for the use of therapeutic targets in sepsis has arisen from concepts of pathogenesis (Table 1). Both the host responses and the characteristics of the infecting organism influence the outcome of sepsis. Sepsis with organ dysfunction occurs primarily when hostresponses to infection are inadequate. In addition, sepsis often progresses when the host cannot contain the primary infection, a problem most often related to characteristics of the microorganism, such as a high burden of infection and the presence of superantigens and other virulence factors, resistance to opsonization and phagocytosis, and antibiotic resistance.

n engl j med 355;16www.nejm.org

october 19, 2006

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Downloaded from www.nejm.org by ALEJANDRO J. MUNIZ MD on February 14, 2010 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.

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Table 1. Pathways and Mediators of Sepsis, Potential Treatments, and Results of Randomized, Controlled Trials (RCTs).* Pathway MediatorsSuperantigens: TSST-1 Streptococcal exotoxins (e.g., streptococcal pyrogenic exotoxin A) Lipopolysaccharide (endotoxin) Innate immunity TLR-2, TLR-4 Monocytes, macrophages Neutrophils Adaptive immunity B cells (plasma cells and immunoglobulins) CD4+ T cells (Th1, Th2) Proinflammatory pathway TNF-α Interleukin-1β Interleukin-6 Prostaglandins, leukotrienes Bradykinin Platelet-activating factor Proteases...