Pathologic Mechanisms of Pathologic Mechanisms of Septic ShockSeptic ShockKenneth J. Goodrum, Ph.D. OUCOMTopics Topics Definitions: SIRS,sepsis,shock,MODSMorbidity/mortality of Sepsis/ShockPathogenesis of shockMicrobial triggers(endotoxin, TSSTs)Cytokine and non-cytokine mediators of SIRS and shockPathophysiology of shockTherapyS Systemic ystemic I Inflammatory nflammatory R Response esponse S Syndrome (SIRS)yndrome (SIRS)Systemic inflammatory response to a variety of severe clinical insults manifested by 2 of the following conditionsTemperature 38C or 90 beats/minRespiratory rate 20 breaths/min or PaCO2 ,12,000 cells/mm3, 10% immature (band) cellsSepsisSepsisThe presence of SIRS associated with a confirmed infectious process.Severe SepsisSevere SepsisSepsis with either hypotension or systemic manifestations of hypoperfusion Lactic acidosis, oliguria, altered mental statusSeptic ShockSeptic ShockSepsis with hypotension despite adequate fluid resuscitation, associated with hypoperfusion abnormalitiesMultiple Organ Dysfunction Multiple Organ Dysfunction Syndrome (MODS)Syndrome (MODS)Progressive distant organ failure (initially uninvolved) following severe infectious or noninfectious insults (severe burn, multiple trauma, shock, acute pancreatitis)Morbidity/Mortality of Sepsis Morbidity/Mortality of Sepsis and Septic Shockand Septic ShockLeading cause of death in noncoronary ICU patients500,000 episodes sepsis/year in U.S. (35% crude mortality)200,000 cases septic shock (40% of sepsis cases) (40-70% mortality)40% hospital deaths after injury due to MODSPathogenesis of ShockPathogenesis of ShockIn fec t i ous or non i nfec t i ous t r i gger sCytoki ne and in f l ammat o ry mediat o r cascadeCard i ac dysfunc t i on and microvascu la r i n ju ryHypotens ion and shockSome Characteristics of Some Characteristics of Septic ShockSeptic ShockSystemic vasodilation and hypotensionTachycardia; depressed contractilityVascular leakage and edema; hypovolemiaCompromised nutrient blood flow to organsDisseminated intravascular coagulationAbnormal blood gases and acidosisRespiratory distress and multiple organ failureMicrobial TriggersMicrobial TriggersGram-negative bacteria:lipopolysaccharideGram-positive bacteria: Lipoteichoic acid/cell wall muramyl peptides Superantigens Staphylocococal Toxic Shock Syndrome Toxin, TSSTStreptococcal pyrogenic exotoxin, SPEBacterialBacterial- -Mediated SepsisMediated SepsisBacteriaBacteriaMacrophageMacrophageLPSLPS+ LBP+ LBPLPSLPS = LipopolysaccharideLBPLBP = LPS-Binding ProteinTLRTLR= Toll-like receptor+ +deathdeathMediatorsMediators ofof InflammationInflammationCD14CD14TLR4TLR4Gram(- )Gram(+) LTALTATLR2TLR2LTALTA=Lipoteichoic acidSuperant i gen act ivat ion o f T LymphocytesM HC c la s s I ITcRVVTSST-1Gram-nega t i ve o r gan i s mT- lymphocyt eGram-pos i t i ve o rgan i smSuperan t igenExotox inMacrophageIn t e r l euk in - 1 Tumor nec r os i sf ac t or -LPS ( endo t ox in )IL-2IFN-Pr imary med ia to r s ( IL-1 , TNF)Endo t he l i a l / Leukocy te molecu la r a c t iva t i onSecondary mediat o r s ( NO,PAF, PG, LT, IL )Vasodi l a t i on, c ap i l l a ry l e ak , endo the l i a l damageShockM ODSDea thEFFECTS OF EXCESS CYTOKINE RELEASEILIL- -1 and TNF activities1 and TNF activitiesSynergistically induce genes in endothelial cells and monocytes/macrophages iNOS?NO (vasodilation, ?pulmonary artery pressure, ?cardiac output) PLA2?PAF(hypotension) COX-2?PGE2 (fever,pain)ILIL- -1 and TNF activities(1 and TNF activities(contcont.) .)Synergistically induce genes in endothelial cells and monocytes/macrophages Adhesion molecules(?leukocyteadhesion/activation Other Cytokines (?Acute phase proteins, recruits new phagocytes)ILIL- -1 and TNF activities(1 and TNF activities(contcont.) .)Cachexia (?lipoprotein lipase, disrupts glucose metabolismActivates coagulation (?intravascular thrombi, DIC, ?tissue factor, ? activated factor X, ? TFPI, ?activated protein C)EndotoxinMembrane PhospholipidsArachidonic AcidLyso- phospholipidPLA2ProstaglandinsLeukotrienesPlatelet Activating Factor+Cyclo- oxygenase5-Lipoxy- genaseThromboxanesActions of LeukotrienesActions of LeukotrienesVasoconstrictionBronchoconstrictionChemotaxisLeukocyte-Endothelial Cell AdhesionLeukocyte EmigrationVascular LeakageStimulate Leukotriene and Oxygen Free Radical ReleaseActions of PAFActions of PAFVasoconstriction/VasodilationHypotension hypodynamic in late shockVentricular dilation; decreased ejection fraction Loss of sympathetic responsivenessCardiovascularHypovolemia due to vascular leakage; central venous pressure may be decreased or increased depending upon fluid resuscitationCompromised nutrient blood flow to organs; decreased organ oxygen extractionCardiovascularCont.PATHOPHYSIOLOGYPATHOPHYSIOLOGYContCont. .Hyperventilation with respiratory alkalosisPulmonary