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Sepsis - Pathophysiology 22/8/10 OH Organisms - Bacteria -> Gram +ve’ cocci (staphylococci, streptococci) -> Gram –ve bacilli (E.coli, Klebsiella, Pseudomonas aeruginosa) - Fungi (Candida) - Viruses - Parasites Complex interaction between (1) (2) (3) (4) inciting microbe host immune response inflammatory pathway coagulation pathway Jeremy Fernando (2011) LPS = lipopolysaccharide TRAF6 = TNF receptor-associated factor 6 NIK = nuclear factor-KB inducing kinase NF-KB = nuclear factor-KB -> induction of immune response genes Jeremy Fernando (2011) - pathogen binds to toll-like receptors (TLR’s) on surface of immune cells (monocytes) - pro-inflammatory cytokines released -> TNF-alpha, IL-1ß, IL-2, IL-6 -> increased NO synthase activity on endothelial cells - anti-inflammatory cytokines released -> IL-4 and IL-10 - pro-coagulation cytokines -> TF -> FVII release -> endothelial injury and activation of coagulation cascade Inflammation –> neutrophil chemotaxis, increased capillary permeability, macrophage activation, lytic enzyme induction Jeremy Fernando (2011) Coagulation –> fibrin production Fibrinolytic pathway suppression –> decreased APC and tPa activity -> decreased plasmin production = microvascular thrombosis -> ischaemia -> organ dysfunction -> death Pro-inflammatory mediators and pathways Cytokines – TNF, IL-1, IL-6, IL-8, IFN-y Coagulation pathways Macrophages, monocytes, neutrophils Endothelial cells Platelets Oxygen free radicals Proteases NO Anti-inflammatory mediators IL-4, IL 10, IL-11, IL-13 Transforming growth factor Beta CSF Soluble TNF receptors IL-1 receptor antagonist Natural anticoagulants O2 delivery in Sepsis - DO2 increased in septic shock from increased Q - VO2 increased c/o raised tissue metabolic activity -> mitochondrial dysfunction Lactic acidosis in Sepsis - impaired regional microvascular blood flow & autoregulation - mitochondrial dysfunction with impaired pyruvate oxidation - excess catecholamines may impair hepatic lactate extraction (by reducing regional hepatic blood flow) - lactate clearance is decreased because pyruvate dehydrogenase activity is reduced in both skeletal muscle and liver. NB: - tissue hypoxia may not be a major mechanism & NMR spectroscopy suggests that hyperlactaemia may occur without tissue hypoxia - net lactate production from the hepatosplanchnic bed is uncommon in sepsis Jeremy Fernando (2011)