Septic Shock - Pathophysiology

Pathophysiology

Most cases of septic shock (approximately 70%) are caused by endotoxin-producing Gram-negative bacilli. Endotoxins are bacterial wall lipopolysaccharides (LPS) consisting of a toxic fatty acid (lipid A) core common to all Gram-negative bacteria, and a complex polysaccharide coat (including O antigen) unique for each species. Analogous molecules in the walls of Gram-positive bacteria and fungi can also elicit septic shock. Free LPS attaches to a circulating LPS-binding protein, and the complex then binds to a specific receptor (CD14) on monocytes, macrophages, and neutrophils. Engagement of CD14 (even at doses as minute as 10 pg/mL) results in intracellular signaling via an associated "Toll-like receptor" protein 4 (TLR-4), resulting in profound activation of mononuclear cells and production of potent effector cytokines such as IL-1 and TNF-α. These cytokines act on endothelial cells and have a variety of effects including reduced synthesis of anticoagulation factors such as tissue factor pathway inhibitor and thrombomodulin. The effects of the cytokines may be amplified by TLR-4 engagement on endothelial cells. TLR-mediated activation helps to trigger the innate immune system to efficiently eradicate invading microbes. At high levels of LPS, the syndrome of septic shock supervenes; the same cytokine and secondary mediators, now at high levels, result in systemic vasodilation (hypotension), diminished myocardial contractility, widespread endothelial injury and activation, causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung activation of the coagulation system, culminating in disseminated intravascular coagulation (DIC). The hypoperfusion resulting from the combined effects of widespread vasodilation, myocardial pump failure, and DIC causes multiorgan system failure that affects the liver, kidneys, and central nervous system, among others. Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies.