SIRS ~~~~ The Systemic Inflammatory Response Syndrome Introdution Progress in managment of critically ill/major surgery Better Preop preparation Medical Co-morbidities Cardiac Respiratory Renal Drugs (Plavix, Warfarin, Steroids) Rapid transportation Paramedical care ATLS Better Surgery Minimally invasive Damage control Planned re-operation Volume of surgery in Unit (Outcome data) Better anaesthesia Invasive blood pressure monitoring Prediction of outcome Scoring systems Goldman APACHE POSSUM Genotypic markers Expression of CD16 on neutrophils Research into fluid administration Critical care Organ system support Respiratory Renal Coagulation ICU specialist Future progress Modulation of Inflammatory Response Definition SIRS Systemic Inflammatory Response Syndrome Presence of two or more of the variables below (1992 ACCP/SCCM) - ACCP American College of Chest Physicians - SCCM Society of Critical Care Medicine Variable Abnormality Temperature Less than 36 degree C More than 38 degree C Pulse Rate More than 90 beats per minute Resp Rate More than 20 per minute PCO2 less than 4.3 kPa White Cells Less than 4 More than 12 or More than 10% immature forms Other important definitions ARDS Adult Respiratory Distress Syndrome MOF Multiorgan dysfunction syndrome Infection Inflammatory response to the presence of microbes or Invasion of normally sterile tissue by microbes Sepsis SIRS due to a microbial origin Severe Sepsis Sepsis with organ dysfunction, hypoperfusion or hypotension; Manifestations include Lactic acidosis Oliguria Acute alteration in mental status Septic Shock Severe Sepsis with hypotension despite adequate fluid resuscitation Response to stresses; Cellular level Organism level Cells response to stress (Primitave) Oxidative Stress Response Ultra-Violet Damage Response Heat shock response Organism response to stress (Modern) Acute phase response Developed to co-ordinate the response of different tissues to an external threat Inflammatory Mediators PAF - Membrane phospholipid (platelets, endothelial cells, leucoctyes) - Release from endothelial cells stimulated by hypoxia - Leucocyte Receptor for PAF results in (Increased CD11/CD18 beta2 integrin expression) - Therefore increased vascular permeability - PAF casuses formation of oxygen free radicals, release of lactoferrin, myeloperoxidase LTB4 Lipo-oxygenase pathway from arachadinoic acid - Enhances vascular permeability - Chemoattractant - Promotes leucoctyes to release free radicals and proteolytic enzymes Cytokines Pro-Inflammatory Released in the main from macrophages Ramp up inflammation Upregulated by IF-gamma and IL-11 Main ones involved in septic shock are IL-1 and TNF-alfa Production of IL-1, 6 and TNF-alfa reduced by TGF-beta Production of all reduced by IL-4,10 and IL-13 - IL-1 o Blocked by IL-1ra (receptor antagonist) - IL-2 o T-cell o Acitivated T cells, B cells and NK cells o Used to treat Melanoma and Renal Cell Carcinoma * But dose dependent vascular leak syndrome (probably due to loss of the endothelial barrier function) * T cells initially increase then fall dramatically * Effect is dramatic in some but disappointing in most - IL-6 - IL-8 - TNF-alfa o Blocked by antibodies against TNF-alfa * Results in resistance to effects of endotoxin * Similar effect in TNF-alfa knockout mice o Blocked by soluble TNF-receptor blocker o Responsible for tumour associated cachexia o Released by Macrophages, Kupfer cells, NK cells and lymphocytes o Slight increase results in cell-proliferation and differentiation o Higher levels result in tissue remodelling, inflammation and cytotoxicity Anti-Inflammatory Released from T cells Turn off inflammation IL-4,10 and IL-13 - IL-10 o Protects mice from the effects of endotoxic shock Mixed effect - TGF-beta o Role in scar formation, neovascularisation and proliferation of connective tissue cells o Inhibits production of pro inflammatory cytokines * IL-1 * IL-6 * TNF-alfa o Chemo-attractant for * Unactivated monocytes * Neutrophils * T cells o Systemic TGF-beta is anti-inflammatory o Local TGF-beta is pro-inflammatory Leuco-cyte endothelial interations - Recruitement of inflammatory cells to an area of damage - Mostly in the Post Capillary Venule Rolling Endothelium Leucocyte P Selectin Sialyated Lewis/ L Selectin E Selectin L Selectin P Selectin is released from the Weibel Palade body in the endothelium: this is stimulated by; - Hypoxia - Free Radicale - Peroxidases - Histamine - Thrombin E Selectin expression on the endothelium is stimulated by - TNF alpha - Endotoxin - IL1 beta L Selectin is rapidly shed from the Leucocyte bound to the endothelium on stimulation by; - LTB4 - C5a - TNFalfa - IL1 - PAF Adhesion Endothelium Leucocyte ICAM-1 Beta 2 Integrins (MAC-1, LFA-1) VCAM-1 Beta 1 Integrin (VLA-4) Transmigration Mostly progression of Adhesion Selectin function not needed ICAM/Intergrin interation needed - Leaky endothelium Vascular leak syndrome limits therapy with IL-2 Causes of SIRS Infection Trauma Burns Pancreatitis Sepsis Ischaemia-Reperfusion Hypovolemic or Haemorrhagic shock Pathogenesis Final common pathway of many stresses Balance between pro and anti-inflammatory systems Balace set to pro-inflammatory with anergy Switch from Cell mediated immunity to antibody type immune response Rampant micro-vascular dysfunction Stages of SIRS 1 -- 3 1 - Local response o Recrutiment of neutrophils and monocytes 2 - Spill over of cytokines into circulation but balance maintained 3 - Balance lost, massive pro-inflammatory swing o vascular leak o Myocardial dysfunction * Leucocytes * Hypoperfusion Clinical features Stepwise progression in mortality depending on severity of surgical sepsis. Rangel-Fausto et al 1995. - SIRS 7% - Sepsis 16% - Severe Sepsis 20% - Shock 46% Modification of SIRS response - Activated Protein C treatment in Meningo-coccal septicaemia - Enteral feeding - Immuno-nutrition (Glutamine, omega-3 fatty acids, nucleotide supplementation) (c) Adrian P. Ireland, 2004. Released under the Gnu Free Documentation Licence % vim: set ai tw=78: