Sepsis starts as a focus of infection (urinary tract infection, pneumonia, cellulitis, abscess, or indwelling prosthetic device) resulting in either blood stream invasion or a proliferation of organisms at the infected site (Fig 28-2). These growing organisms release a large amount of exogenous toxins consisting of endotoxins, exotoxins, and other components of the organism's structural components. The host's reaction to these toxins results in the release of endogenous mediators and other humoral defense mechanisms including complement, kinins, and coagulation factors. Among the most prominent of the endogenous mediators are the cytokines (tumor necrosis factor, interleukins), platelet activating factor (PAF), arachidonic acid metabolites, and myocardial depressant substances (MDS). Release of MDS results in the depression of myocardial function, dilation of the ventricles, and vasodilation. These vascular and myocardial abnormalities combine to result in generalized cardiovascular insufficiency leading to refractory hypotension and multiple organ system failure, and death.
One of the most important of the vasoactive mediators is nitric oxide. Nitric oxide is a low-molecular weight membrane-permeable gas with both harmful and beneficial effects in shock. Under normal conditions, this gas is produced in the endothelium by a calcium and calmodulin-dependent nitric oxide synthase (NOS) which converts L-arginine and O2 to L-citrulline and nitric oxide. This pathway is normally well regulated by signal transduction pathways linked to cell-surface receptors for vasodilators such as acetylcholine and histamine. However, inflammatory mediators induce a calcium-independent form of nitric oxide synthase that is not controlled by this mechanism. This form may rise to abnormal amounts of nitric oxide in septic patients and patients given IL-2 for cancer treatment.
Three distinct NOS enzyme complexes have been described. The first, neuronal nitric oxide synthase (nNOS) is found in central nervous system cells and is thought to support a neurotransmitter function. The second, constitutive NOS (cNOS) is found in endothelial cells and is thought to play a role in the maintenance of normal vascular tone. The third, a high output inducible enzyme called inducible NOS (iNOS) is found in many cell types including, endothelial cells, vascular smooth muscle cells and macrophages.
Nitric oxide actions include functioning as a neurotransmitter; regulating vascular tone; and inhibiting platelet aggregation and leukocyte adhesion. At higher doses, nitric oxide has antitumor and antimicrobial activity. Nitric oxide is thought to have a beneficial role in sepsis. It is important in maintaining visceral and microvascular blood flow acting as a counter-regulatory mechanism to the vasoconstriction mediators (thromboxane and endothelin-1) released in inflammation. It is thought to be an important free radical scavenger that prevents microvascular stasis and thrombosis by blocking platelet aggregation and leukocyte adhesion.
Nitric oxide may have several harmful effects in sepsis. Nitric oxide has been implicated as a major mediator for vasodilation and hypotension in septic shock. The inducible form of nitric oxide synthase is stimulated by inflammatory mediators (including TNFa and interleukin-1), which leads to increased release of nitric oxide from endothelial cells, vascular smooth muscle cells, and macrophages. Once induced, iNOS is likely to persist for many hours to days. Peroxynitrite, which is formed from the reaction between superoxide radicals and nitric oxide, may cause direct cellular injury. Nitric oxide may also contribute to the myocardial depression and increased permeability seen in septic shock.
Anti-inflammatory substances are also released. These include endogenous steroids and catecholamines, interleukin-10 (IL-10), interleukin-4 (IL-4), prostaglandin E 2, interleukin-1 receptor antagonists, and tumor necrosis factor receptors. All of these substances alter immune function, which leads to a period of immune depression after the initial shock episode.
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