Editing Sepsis/SIRS (section)

== '''Pathophysiology:''' ==

=== '''Normal response to infection''' ===

** Host response initiated when innate immune cells (especially macrophages) recognise and to microbial components
*** Pattern-recognition receptors (PRRs) on the surface of immune cells recognise and bind to microbial pathogen-associated molecular patterns (PAMPs) or endogenous danger signals
**** PRRs include toll-like receptors (TLRs) and others
*** Neutrophils begin to defend against pathogens - phagocytosis, secretion of antimicrobial peptides, and the release of neutrophil extracellular traps (NETs)
*** Signalling cascade developed via the activation of cytosolic nuclear factor-kb (NF-kb), which leads to activation of genes involved in host inflammatory response such as TNF-a, IL-1, IL-6, chemokines, vascular adhesion molecule-1, and nitric oxide
*** Polymorphonuclear leucocytes become activated and aggregate at site of infection, causing warmth and erythema due to local vasodilation and hyperaemia
*** Pro-coagulant status causes micro-thrombosis
*** Some anti-inflammatory mediators balance this activation
*** If the inflammatory process is balanced, haemostasis is restored, leading to tissue repair and healing

=== '''Transition to sepsis''' ===

** Sepsis occurs when the release of pro-inflammatory mediators exceeds the boundaries of the local environment, leading to a more generalised response (can also occur without sepsis, as SIRS). This can also be characterised as malignant intra-vascular inflammation
** It is unclear why this happens, but likely multifactorial
*** Direct effects of invading micro-organisms and their toxins
*** Release of large quantities of pro-inflammatory mediators - mainly IL-1 and TNF-a
*** Complement activation
*** Possible genetic susceptibility
*** Loss or reduction of Compensatory Anti-inflammatory Response Syndrome (CARS) which includes factors like IL-4 and 10
** Excessive and prolonged activation of these pathways probably contributes to the development of multiple organ dysfunction
** Leads to vasodilation, enhanced capillary leak and eventually myocardial depression

=== '''Systemic effects of sepsis''' ===

** Organ dysfunction
*** Circulation - hypotension due to diffuse vasodilation - distributive shock, largely mediated by NO and prostacyclin
*** Lung - endothelial injury leads to pulmonary oedema and ARDS
*** GIT - depressed function allowing translocation
*** Liver dysfunction
*** Kidney - pre-renal injury, including ATN
*** CNS - often fails before other organs - encephalopathy
** Multiple organ dysfunction syndrome (MODS) - see below
** Tissue ischaemia - due to derangements in metabolic autoregulation, and also endothelial injury
** Cytopathic injury
** Cell death pathways activated
** Immunosuppression
** Activation of coagulation system and vascular endothelium - DIC