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1、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,大纲说明,药(病生)理机转临床应用实证效果,Single organ failureSevere sepsisComplication,activated protein C red blood cells platelets plasma white blood cells r-tPA IVIG moAb others,Annane D, et al. Lancet 2005,Local infection Sepsis Severe sepsis Septic shock,SY Huang,4,Annane D, et al
2、. Lancet 2005,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,Human Activated Protein C Endogenous Regulator of Coagulation,Endo
3、thelial cells,Endothelial cells,Inversely correlate to morbidity and mortality of severe sepsis,inflammatory,procoagulant,antifibrinolytic,Sepsis,Sepsis,Severe Sepsis: New Concepts in Pathogenesis and Management,Cytotoxic effects of microorganismsEndothelial injury & responseCoagulation (thrombosis)
4、Inflammation,Warren et al. Am J Med Sci, 2004.,The novel agent?,SY Huang,8,Recombinant Human Activated Protein C,Drotrecogin Alfa (Activated),XigrisRRecombinant human activated protein CMechanismsMTDAdverse effectsClinical trialsPharmacoecnomics,Frampton et al, ADIS Pharmacoeconomic Drug Evaluation,
5、 2004.,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 antiapoptosisProfibrinolytic* decreased PAI-1Antiapoptosis on endothelial cells*,*. 24ug/Kg/
6、hr infusion: 44.9 ng/ml in plasma level *. proposed,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 s
7、afety 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,Mortality and APACHE II Quartile,Adapted from Figure 2, page S90, with permission from Bernard GR. Dr
8、otrecogin 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),Mortality and Numbers of Organs Failing,Adapted from Figure 4, page S91, with permission from Bern
9、ard 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),Recombinant Human Activated Protein C (rhAPC),High risk of death APACHE II 25 Sepsis-induced multip
10、le organ failure Septic shock Sepsis induced ARDS No absolute contraindications Weigh relative contraindicationsGrade B,Bleeding complications: 3.5% vs. 2.0% Formation of alloreactive antibody,Tolerability of rhAPC,Treatment efficacy,Quality adjusted life years/patient,Drotrecogin alfa (activated),D
11、rotrecogin alfa (activated),“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,SY Huang,20,Annane D, et al. Lancet 2005,Annane D, et al. Lance
12、t 2005,From Friedrich JO, N Eng J Med, 2006.,Debate on DrotAA The Questions remained: Efficacy? Mechanism? Safty ? $1700/d? Patient selection? Alternative choice ?,Heparin Effect in Drotrecogin alfa (activated) Treatment,Notably, heparin treatment appeared beneficial in all placebo groups, and resul
13、ted in an overall odds ratio for survival that was highly significant (p0.0001),Drotrecogin alfa (activated) Group,Placebo Group,Blood Products,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 m
14、ulticenter, 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,Blood Products Administration Red Blood Cells,Tissue hypoperfusion resolved No extenuating circumstances Coronary artery disease Acute hemorrhage Lactic acidosis Transfuse 7.0 g/dl to maintain 7.0-9.0 g/dL DO2 but not VO2; PVR & SVRGrade B,
