,按一下以編輯母片,第二層,第三層,第四層,第五層,SY Huang,*,按一下以編輯母片標題樣式,血液及其相关制剂在特护病房、重病房的应用,台大医院,黄圣懿 医师,1,SY Huang,大纲说明,药,(,病生,),理机转,临床应用,实证效果,Single organ failure,Severe sepsis,Complication,activated protein C,red blood cells,platelets,plasma,white blood cells,r-tPA,IVIG,moAb,others,2,SY Huang,Annane D,et al.Lancet 2005,Local infection Sepsis Severe sepsis Septic shock,3,SY Huang,Annane D,et al.Lancet 2005,4,SY Huang,Coagulation in Sepsis,INTRINSIC,EXTRINSIC,XII,XIIa,XI,XIa,VIIIa,Factor X,Factor,Xa,Prothrombin,Thrombin,Fibrinogen,Fibrin,TFPI,aPC,Antithrombin,Va,IX,IXa,FVII,Tissue Factor,FVIIa,-TF,+,Factor X,sepsis,t-PA,P-,antiP,sepsis,5,SY Huang,Thrombin,Thrombomodulin,Protein C(inactive),Protein C Activity,(activated),Blood Vessel,Blood Flow,aProtein,C Receptor,Protein,S,Human Activated Protein CEndogenous Regulator of Coagulation,Endothelial cells,Endothelial cells,Inversely correlate to morbidity and mortality of severe sepsis,inflammatory,procoagulant,antifibrinolytic,Sepsis,Sepsis,6,SY Huang,Severe Sepsis:New Concepts in Pathogenesis and Management,Cytotoxic,effects of microorganisms,Endothelial injury&response,Coagulation(thrombosis),Inflammation,Warren et al.Am J Med,Sci,2004.,The novel,agent?,7,SY Huang,Recombinant,Human Activated Protein C,8,SY Huang,Drotrecogin,Alfa(Activated),XigrisR,Recombinant human activated protein C,Mechanisms,MTD,Adverse effects,Clinical trials,Pharmacoecnomics,Frampton et al,ADIS Pharmacoeconomic Drug Evaluation,2004.,9,SY Huang,Drotrecogin,Alfa(Activated):Mechanisms,Anti-thrombotic*(D-,dimer,assay),Anti-inflammatory(inhibit protease-activated receptors,PAR-1,IL-6)*inhibit cytokines production,downregulate,NFkB,upregulate,antiapoptosis,Profibrinolytic,*decreased PAI-1,Antiapoptosis,on endothelial cells*,*,.24ug/Kg/hr infusion:44.9,ng,/ml in plasma level,*.proposed,10,SY Huang,35,30,25,20,15,10,5,0,30.8%,24.7%,Placebo,(n-840),Drotrecogin,alfa,(activated)(n=850),Mortality(%),6.1%absolute reduction in mortality,PROWESS Study:28-Day All-Cause Mortality,2-sided p-value 0.005,Adjusted relative risk reduction 19.4%,Increase in odds of survival 38.1%,Adapted from Table 4,page 704,with permission from Bernard GR,Vincent JL,Laterre,PF,et al.Efficacy and safety of recombinant human activated protein C for severe sepsis.N,Engl,J Med 2001;344:699-709,Drotrecogin,Alfa(Activated):Clinical trial(I),Independent of,microorganisms,and whether or not,DIC,11,SY Huang,Mortality and APACHE II Quartile,APACHE II Quartile,*,Numbers above bars indicate total deaths,Mortality(percent),26:33,57:49,58:48,118:80,Adapted from Figure 2,page S90,with permission from Bernard GR.,Drotrecogin,alfa,(activated)(recombinant human activated protein C)for the treatment of severe sepsis.,Crit,Care Med 2003;31Suppl.:S85-S90,I II III IV,Drotrecogin,Alfa(Activated):Clinical trial(II),12,SY Huang,Mortality and Numbers of Organs Failing,Percent,Mortality,0,10,20,30,40,50,60,1,2,3,4,5,Placebo,Drotrecogin,Number of Organs Failing at Entry,Adapted from Figure 4,page S91,with permission from Bernard GR.,Drotrecogin,alfa,(activated)(recombinant human activated protein C)for the treatment of severe sepsis.,Crit,Care Med 2003;31Suppl.:S85-S90,Drotrecogin,Alfa(Activated):Clinical trial(III),13,SY Huang,Recombinant Human Activated Protein C(,rhAPC,),High risk of death,APACHE II 25,Sepsis-induced multiple organ failure,Septic shock,Sepsis induced ARDS,No absolute contraindications,Weigh relative contraindications,Grade B,14,SY Huang,Bleeding complications:3.5%vs.2.0%,Formation of,alloreactive,antibody,Tolerability of,rhAPC,15,SY Huang,Treatment efficacy,Quality adjusted life years/patient,Drotrecogin,alfa,(activated),16,SY Huang,Drotrecogin,alfa,(activated),17,SY Huang,18,SY Huang,“,Who?,Patient selection for,rhAPC,Full support patient,Severe sepsis,High risk of death,No absolute contraindications,“,When?,and,“,How?,As soon as possible?,24,ug/Kg/h,for 96 hours,Platelet level 30,000/ul,19,SY Huang,Annane D,et al.Lancet 2005,20,SY Huang,Annane D,et al.Lancet 2005,21,SY Huang,From Friedrich JO,N Eng J Med,2006.,Debate on,DrotAA,The Questions remained:Efficacy?Mechanism?,Safty,?$1700/d?Patient selection?Alternative choice?,22,SY Huang,Heparin Effect in,Drotrecogin,alfa,(activated)Treatment,Notably,heparin treatment,appeared beneficial in all placebo,groups,and resulted in an overall,odds ratio for survival that was highly,significant(p0.0001),Drotrecogin,alfa,(activated)Group,Placebo Group,23,SY Huang,Blood Products,24,SY Huang,Transfusion Strategy(PRBC)in the Critically Ill Patients,Figure 2A,page 414,reproduced with permission from Hebert PC,Wells G,Blajchman,MA,et al.A multicenter,randomized,controlled clinical trial of transfusion requirements in critical care.N,Engl,J Med 1999;340:409-417,Canadian Critical Care Trials Group,Hb,=1012,Hb,=79,Age55,APACH20,CAD,25,SY Huang,Blood Products AdministrationRed Blood Cells,Tissue,hypoperfusion,resolved,No extenuating circumstances,Coronary artery disease,Acute hemorrhage,Lactic acidosis,Transfuse 7.0 g/dl t