The hyperinflammatory state, initiated by sepsis, triggers counterregulatory immunosuppressive mechanisms, which may involve both innate and adaptive immune cells. As a result, septic patients may oscillate between hyperinflammatory and immunosuppressed states during their clinical course. Proposed mechanisms for the immune suppression include a shift from proinflammatory (TH1) to anti-inflammatory (TH2) cytokines (Chapter 5), production of anti-inflammatory mediators (e.g., soluble TNF receptor, IL-1 receptor antagonist, and IL-10), lymphocyte apoptosis, the immunosuppressive effects of apoptotic cells, and the induction of cellular anergy. In some patients the counterregulatory mechanisms overshoot the inflammatory responses and the resultant immune suppression renders such patients susceptible to superinfections.
• Endothelial activation and injury. The proinflammatory state and endothelial cell activation associated with edema, which have deleterious effects on both nutrient delivery and waste removal. One effect of inflammatory cytokines is to loosen endothelial cell tight junctions, making vessels leaky and resulting in the accumulation of protein-rich edema fluid throughout the body. This alteration impedes tissue perfusion and may be exacerbated by attempts to support the patient with intravenous fluids. Activated endothelium also upregulates production of nitric oxide (NO) and other vasoactive inflammatory mediators (e.g., C3a, C5a, and PAF), which may contribute to vascular smooth muscle relaxation and systemic hypotension.
• Induction of a procoagulant state. The derangement in coagulation is sufficient to produce the formidable complication of disseminated intravascular coagulation in up to half of septic patients. Sepsis alters the expression of many factors so as to favor coagulation. Proinflammatory cytokines increase tissue factor production by monocytes and possibly endothelial cells as well, and decrease the production of endothelial anti-coagulant factors, such as tissue factor pathway inhibitor, thrombomodulin, and protein C (see
Fig. 4.11 ). They also dampen fibrinolysis by increasing plasminogen activator inhibitor-1 expression (see Fig.
4.10 ). The vascular leak and tissue edema decrease blood flow at the level sepsis lead to widespread vascular leakage and tissue of small vessels, producing stasis and diminishing the http://ebooksmedicine.net washout of activated coagulation factors. Acting in concert, these effects lead to systemic activation of thrombin and the deposition of fibrin-rich thrombi in small vessels, often throughout the body, further compromising tissue perfusion. In full-blown disseminated intravascular coagulation, the consumption of coagulation factors and platelets is so great that deficiencies of these factors appear, leading to concomitant bleeding and hemorrhage (Chapter 12).