Pathophysiology of sepsis

Abstract

Sepsis remains a critical problem with significant morbidity 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 of the 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, whereas others 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 richly illustrates 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.

Figure 1

Control of coagulation in normal and inflamed vasculature. Top panel: Normal function. Vascular injury, indicated on the lower portion of the blood vessel wall, initiates prothrombin (Pro) activation, which subsequently induces thrombin (T) formation. Prothrombin activation involves the formation of complexes between factor V_a and factor X_a. Thrombin then binds to thrombomodulin (TM) on the luminal side of the endothelial cell wall, and the thrombin-TM complex converts protein C to APC. APC then binds to protein S (S) on endothelial cell surfaces. The complex composed of protein S and APC then converts factor V_a into an inactive complex (V_I). Protein S and APC also interact with the endothelial cell protein C receptor (EPCR). Bottom panel: After inflammation. During inflammation, specific mediators cause the disappearance of thrombomodulin from the endothelial cell surface. The endothelial cell leukocyte adhesion molecules P-selectin and E-selectin are synthesized and expressed on the surfaces of endothelial cells or platelets. Tissue factor (TF) is expressed on monocytes where it binds to factor VII_a. The TF-VII_a complex converts factor X to factor X_a, which then complexes with factor V_a to generate thrombin from prothrombin. Very little APC is formed, and that which is formed does not function well because of low levels of protein S. Consequently, factor V_a is not activated, and the prothrombin activation complexes are stabilized. Modified from Br J Haematol, 131, Esmon CT, The interactions between inflammation and coagulation, 417–430, Copyright (2005), with permission from Blackwell Publishing.

Figure 2

Proposed model for dysregulation of neutrophil recruitment to bacterial infection in nonpulmonary tissue under normal conditions (left) and in sepsis (right). Colony stimulating factors [granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF)] induce the release of neutrophils from the bone marrow. Under normal conditions, large numbers of the peripheral blood neutrophils enter sites of bacterial infection by first adhering to activated endothelial cells and then migrating along a gradient of chemotactic factors. These chemotactic factors are produced at the local site of infection. Neutrophils use Toll-like receptors (TLR-2 or TLR-4) to interact with pathogen-associated molecular patterns on bacteria to phagocytize and eliminate the pathogens. In contrast, neutrophils from septic patients have increased expression of surface integrins, which promote firm adhesion to endothelial cells. As a consequence, the neutrophils remain bound more tightly to the endothelial cells and fail to migrate appropriately into the site of the bacterial infection. Redrawn from The Lancet, 368, Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF, Neutrophils in development of multiple organ failure in sepsis, 157–169, Copyright (2006), with permission from Elsevier.