Pathophysiology Of Sepsis

IP al am S A urn gr o Jo Pr E M C

The American Journal of Pathology, Vol. 170, No. 5, May 2007 Copyright © American Society for Investigative Pathology DOI: 10.2353/ajpath.2007.060872

Biological Perspectives
Pathophysiology of Sepsis

Daniel G. Remick, M.D.
From the Boston University School of Medicine, Boston, Massachusetts

Sepsis remains a critical problem with significantmorbidity and mortality even in the modern era of critical care management. Multiple derangements exist in sepsis involving several different organs and systems, although controversies exist over their individual contribution to the disease process. Septic patients have substantial, life-threatening alterations in their coagulation system, and currently, there is an approved therapy with a component ofthe coagulation system (activated protein C) to treat patients with severe sepsis. Previously, it was believed that sepsis merely represented an exaggerated, hyperinflammatory response with patients dying from inflammation-induced organ injury. More recent data indicate that substantial heterogeneity exists in septic patients’ inflammatory response, with some appearing immuno-stimulated, whereasothers appear suppressed. Cellular changes continue the theme of heterogeneity. Some cells work too well such as neutrophils that remain activated for an extended time. Other cellular changes become accelerated in a detrimental fashion including lymphocyte apoptosis. Metabolic changes are clearly present, requiring close and individualized monitoring. At this point in time, the literature richlyillustrates that no single mediator/system/pathway/pathogen drives the pathophysiology of sepsis. This review will briefly discuss many of the important alterations that account for the pathophysiology of sepsis. (Am J Pathol 2007, 170:1435–1444; DOI:
10.2353/ajpath.2007.060872)

Sepsis has been active as long as infectious agents have been present. Because bacteria predate humans, sepsis probablypredates modern man.1 Despite intense efforts, sepsis remains a serious clinical problem, accounting for thousands of deaths every year. A recent review by Angus et al estimated the 1995 incidence of sepsis in the United States to be 751,000 cases, resulting in 215,000 deaths.2 The average cost per case of sepsis was $22,100 with total costs of $16.7 billion nationally. A more

recent analysisof hospital records indicates that the total number of patients who are dying is actually increasing.3 This study also confirmed the work of Angus et al2 that the incidence of sepsis is increasing and projected to continue to grow as the population ages. These studies concluded that “severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those fromacute myocardial infarction.”3 It is important to bear in mind that sepsis mortality is based on 28-day survival, in contrast to most mortality studies, which are based on 5-year survival. Therefore, in addition to its high lethality, sepsis also accounts for a significant number of years of life lost. Two major consensus conferences have defined sepsis. The first, in 1992, put forth the concept ofthe Systemic Inflammatory Response Syndrome (SIRS), recognizing that lethally altered pathophysiology could be present without positive blood cultures.4 The SIRS criteria are listed in Table 1. Some clarification concerning terminology will assist the reader in this review. Sepsis represents SIRS that has been induced by an infection.5 Severe sepsis is sepsis with dysfunction of a least one organor organ system, and septic shock is severe sepsis with hypotension. The 2001 International Sepsis Definitions Conference modified the model of SIRS and developed an expanded view of sepsis after revisiting the literature.6 This conference developed the concept of a staging system for sepsis based on four separate characteristics designated by the acronym PIRO. P stands for the predisposition,...