Apc Ups Quotes

The body’s initial response to a noxious local insult is to produce a local inflammatory response with sequestration and activation of white blood cells and the release of a variety of mediators to deal with the primary ‘insult’ and prevent further damage either locally or in distant organs. Normally, a delicate balance is achieved between pro- and anti-inflammatory mediators. However, if the inflammatory response is excessive, local control is lost and a large array of mediators, including prostaglandins, leukotrienes, free oxygen radicals and particularly pro-inflammatory cytokines (p. 72), are released into the circulation. The inflammatory and coagulation cascades are intimately related. The process of blood clotting not only involves platelet activation and fibrin deposition but also causes activation of leucocytes and endothelial cells. Conversely, leucocyte activation induces tissue factor expression and initiates coagulation. Control of the coagulation cascade is achieved through the natural anticoagulants, antithrombin (AT III), activated protein C (APC) and tissue factor pathway inhibitor (TFPI), which not only regulate the initiation and amplification of the coagulation cascade but also inhibit the pro-inflammatory cytokines. Deficiency of AT III and APC (features of disseminated intravascular coagulation (DIC)) facilitates thrombin generation and promotes further endothelial cell dysfunction. Systemic inflammation During a severe inflammatory response, systemic release of cytokines and other mediators triggers widespread interaction between the coagulation pathways, platelets, endothelial cells and white blood cells, particularly the polymorphonuclear cells (PMNs). These ‘activated’ PMNs express adhesion factors (selectins), causing them initially to adhere to and roll along the endothelium, then to adhere firmly and migrate through the damaged and disrupted endothelium into the extravascular, interstitial space together with fluid and proteins, resulting in tissue oedema and inflammation. A vicious circle of endothelial injury, intravascular coagulation, microvascular occlusion, tissue damage and further release of inflammatory mediators ensues. All organs may become involved. This manifests in the lungs as the acute respiratory distress syndrome (ARDS) and in the kidneys as acute tubular necrosis (ATN), while widespread disruption of the coagulation system results in the clinical picture of DIC. The endothelium itself produces mediators that control blood vessel tone locally: endothelin 1, a potent vasoconstrictor, and prostacyclin and nitric oxide (NO, p. 82), which are systemic vasodilators. NO (which is also generated outside the endothelium) is implicated in both the myocardial depression and the profound vasodilatation of both arterioles and venules that causes the relative hypovolaemia and systemic hypotension found in septic/systemic inflammatory response syndrome (SIRS) shock. A major component of the tissue damage in septic/SIRS shock is the inability to take up and use oxygen at mitochondrial level, even if global oxygen delivery is supranormal. This effective bypassing of the tissues results in a reduced arteriovenous oxygen difference, a low oxygen extraction ratio, a raised plasma lactate and a paradoxically high mixed venous oxygen saturation (SvO2). Role of splanchnic ischaemia In shock, splanchnic hypoperfusion plays a major role in initiating and amplifying the inflammatory response, ultimately resulting in multiple organ failure (MOF). The processes involved include: • increased gut mucosal permeability • translocation of organisms from the gastrointestinal tract lumen into portal venous and lymphatic circulation • Kupffer cell activation with production and release of inflammatory mediators.