血液及其相关制剂在特护病房、重病房的应用.ppt

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1、血液及其相关制剂在特护病房、血液及其相关制剂在特护病房、重病房的应用重病房的应用台大医院台大医院黄圣懿黄圣懿 医师医师1SY Huang大纲说明大纲说明l 药药(病生病生)理机转理机转l 临床应用临床应用l 实证效果实证效果l Single organ failureSingle organ failurel Severe sepsis Severe sepsisl Complication Complicationu activated protein C activated protein C u red blood cells red blood cells u platelets pl

2、atelets u plasma plasma u white blood cells white blood cells u r-tPAr-tPA u IVIG IVIG u moAbmoAb u others others 2SY Huang Annane D,et al.Lancet 2005Local infection Sepsis Severe sepsis Septic shockLocal infection Sepsis Severe sepsis Septic shock3SY Huang Annane D,et al.Lancet 20054SY Huang Coagul

3、ation in SepsisCoagulation in SepsisINTRINSICINTRINSICEXTRINSICEXTRINSICXIIXIIXIIaXIIaXIXIXIaXIaVIIIaVIIIaFactor XFactor XFactor XaFactor XaProthrombinProthrombinThrombinThrombinFibrinogenFibrinogenFibrinFibrinTFPITFPIaPCaPCAntithrombinAntithrombinVaVaIXIXIXaIXaFVIIFVIITissue FactorTissue FactorFVII

4、a-TFFVIIa-TF+Factor XFactor Xsepsist-PAP-antiPsepsis5SY HuangThrombinThrombomodulinProtein C(inactive)Protein C Activity(activated)Blood Vessel Blood Flow aProtein C ReceptorProteinSHuman Activated Protein CHuman Activated Protein CEndogenous Regulator of CoagulationEndogenous Regulator of Coagulati

5、onEndothelial cellsEndothelial cellsEndothelial cellsEndothelial cellsInversely correlate to morbidity and mortality of severe sepsisinflammatoryinflammatoryprocoagulantprocoagulantantifibrinolyticantifibrinolyticSepsisSepsisSepsisSepsis6SY HuangSevere Sepsis:New Concepts in Severe Sepsis:New Concep

6、ts in Pathogenesis and ManagementPathogenesis and Managementl Cytotoxic effects of microorganisms Cytotoxic effects of microorganismsl Endothelial injury&response Endothelial injury&responsel Coagulation(thrombosis)Coagulation(thrombosis)l Inflammation InflammationWarren et al.Am J Med Sci,2004.The

7、novel The novel agent?agent?7SY Huang Recombinant Recombinant Human Activated Protein CHuman Activated Protein C8SY HuangDrotrecogin Alfa(Activated)Drotrecogin Alfa(Activated)l XigrisR XigrisRl Recombinant human activated protein C Recombinant human activated protein Cl Mechanisms Mechanismsl MTD MT

8、Dl Adverse effects Adverse effectsl Clinical trials Clinical trialsl Pharmacoecnomics PharmacoecnomicsFrampton et al,ADIS Pharmacoeconomic Drug Evaluation,2004.9SY Huang Drotrecogin Alfa(Activated):MechanismsDrotrecogin Alfa(Activated):Mechanismsl Anti-thrombotic*(D-Anti-thrombotic*(D-dimerdimer ass

9、ay)assay)l Anti-inflammatory(inhibit protease-Anti-inflammatory(inhibit protease-activated receptors,PAR-1,IL-6)*activated receptors,PAR-1,IL-6)*inhibit cytokines production inhibit cytokines production downregulatedownregulate NFkBNFkB upregulateupregulate antiapoptosisantiapoptosisl Profibrinolyti

10、cProfibrinolytic*decreased PAI-1decreased PAI-1l AntiapoptosisAntiapoptosis on endothelial cells*on endothelial cells*.24ug/Kg/hr infusion:44.9 ng/ml in plasma level.24ug/Kg/hr infusion:44.9 ng/ml in plasma level*.proposed*.proposed10SY Huang3530252015105030.8%24.7%Placebo(n-840)Drotrecogin alfa(act

11、ivated)(n=850)Mortality(%)6.1%absolute reduction in mortalityPROWESS Study:28-Day All-Cause MortalityPROWESS Study:28-Day All-Cause Mortality 2-sided p-value 2-sided p-value 0.0050.005Adjusted relative risk reduction Adjusted relative risk reduction 19.4%19.4%Increase in odds of survival Increase in

12、 odds of survival 38.1%38.1%Adapted from Table 4,page 704,with permission from Bernard GR,Vincent JL,Laterre PF,et al.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

13、Efficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med 2001;344:699-7092001;344:699-709Drotrecogin Alfa(Activated):Clinical trial(I)Drotrecogin Alfa(Activated):Clinical trial(I)Independent ofIndependent ofmicroorganismsmicroorganismsand whether or not and whether

14、 or not DICDIC11SY HuangMortality and APACHE II QuartileMortality and APACHE II QuartileAPACHE II Quartile*Numbers above bars indicate total deathsMortality(percent)26:3357:4958:48118:80Adapted from Figure 2,page S90,with permission from Bernard GR.Drotrecogin alfa Adapted from Figure 2,page S90,wit

15、h permission from Bernard GR.Drotrecogin alfa(activated)(recombinant human activated protein C)for the treatment of severe sepsis.Crit(activated)(recombinant human activated protein C)for the treatment of severe sepsis.Crit Care Med 2003;31Suppl.:S85-S90Care Med 2003;31Suppl.:S85-S90I II I II III IV

16、III IVDrotrecogin Alfa(Activated):Clinical trial(II)Drotrecogin Alfa(Activated):Clinical trial(II)12SY HuangMortality and Numbers of Organs FailingMortality and Numbers of Organs FailingPercent Mortality 010203040506012345PlaceboDrotrecoginNumber of Organs Failing at EntryAdapted from Figure 4,page

17、S91,with permission from Bernard GR.Drotrecogin alfa 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(activated)(recombinant human activated protein C)for the treatment of severe s

18、epsis.Crit Care Med 2003;31Suppl.:S85-S90Care Med 2003;31Suppl.:S85-S90Drotrecogin Alfa(Activated):Clinical trial(III)Drotrecogin Alfa(Activated):Clinical trial(III)13SY HuangRecombinant Human Activated Protein C Recombinant Human Activated Protein C(rhAPC)(rhAPC)lHigh risk of deathHigh risk of deat

19、hlAPACHE II 25APACHE II 25lSepsis-induced multiple organ failureSepsis-induced multiple organ failurelSeptic shockSeptic shocklSepsis induced ARDSSepsis induced ARDSlNo absolute contraindicationsNo absolute contraindicationslWeigh relative contraindicationsWeigh relative contraindicationslGrade BGra

20、de B14SY Huang lBleeding complications:3.5%vs.2.0%lFormation of alloreactive antibody Tolerability of rhAPCTolerability of rhAPC15SY Huang Treatment efficacyTreatment efficacyQuality adjusted life years/patientQuality adjusted life years/patientDrotrecogin alfa(activated)Drotrecogin alfa(activated)1

21、6SY Huang Drotrecogin alfa(activated)Drotrecogin alfa(activated)17SY Huang 18SY Huang“Who?“Who?Patient selection for rhAPCPatient selection for rhAPClFull support patientFull support patientlSevere sepsisSevere sepsislHigh risk of deathHigh risk of deathlNo absolute contraindicationsNo absolute cont

22、raindications“When?“When?and“How?and“How?lAs soon as possible?As soon as possible?l24 ug/Kg/h for 96 hours24 ug/Kg/h for 96 hourslPlatelet level 30,000/ulPlatelet level 30,000/ul19SY Huang Annane D,et al.Lancet 200520SY Huang Annane D,et al.Lancet 200521SY Huang From Friedrich JO,N Eng J Med,2006.De

23、bate on DrotAADebate on DrotAAThe Questions remained:Efficacy?Mechanism?Safty?The Questions remained:Efficacy?Mechanism?Safty?$1700/d?Patient selection?Alternative choice?$1700/d?Patient selection?Alternative choice?22SY HuangHeparin Effect in Drotrecogin alfa(activated)Heparin Effect in Drotrecogin

24、 alfa(activated)TreatmentTreatment Notably,heparin treatment appeared beneficial in all placebo groups,and resulted in an overallodds ratio for survival that was highlysignificant(p0.0001)Drotrecogin alfa(activated)GroupDrotrecogin alfa(activated)GroupPlacebo GroupPlacebo Group23SY Huang Blood Produ

25、ctsBlood Products24SY HuangTransfusion Strategy(PRBC)in the Critically Ill Transfusion Strategy(PRBC)in the Critically Ill PatientsPatients Figure 2A,page 414,reproduced with permission from Hebert PC,Wells G,Blajchman MA,et al.A multicenter,Figure 2A,page 414,reproduced with permission from Hebert

26、PC,Wells G,Blajchman MA,et al.A multicenter,randomized,controlled clinical trial of transfusion requirements in critical care.N Engl J Med 1999;randomized,controlled clinical trial of transfusion requirements in critical care.N Engl J Med 1999;340:409-417340:409-417Canadian Critical Care Trials Grou

27、pCanadian Critical Care Trials GroupHb=1012Hb=1012Hb=79Hb=79Age55Age55APACH20APACH20CADCAD25SY HuangBlood Products AdministrationBlood Products AdministrationRed Blood CellsRed Blood CellslTissue hypoperfusion resolvedTissue hypoperfusion resolvedlNo extenuating circumstancesNo extenuating circumsta

28、nceslCoronary artery diseaseCoronary artery diseaselAcute hemorrhageAcute hemorrhagelLactic acidosisLactic acidosislTransfuse 7.0 g/dl to maintain 7.0-9.0 g/dLTransfuse 7.0 g/dl to maintain 7.0-9.0 g/dLlDO2 but not VO2;PVR&SVRDO2 but not VO2;PVR&SVRlGrade BGrade BQ1:Why the anemia?Q1:Why the anemia?

29、Q2:What is the appropriate Hb threshold for transfusion?Q2:What is the appropriate Hb threshold for transfusion?Q3:Which types of red blood cells should be applied?Q3:Which types of red blood cells should be applied?Q4:Whether or not contraindicate?Q4:Whether or not contraindicate?Zimmerman,Cri Care

30、 Med 2004;Drews,Clin Chest Med 200326SY HuangConditions in Septic Patients that May Conditions in Septic Patients that May Require a Higher HemoglobinRequire a Higher HemoglobinlAcute instabilityAcute instabilitylCardiovascular disease Cardiovascular disease coronary artery disease coronary artery d

31、isease low cardiac outputlow cardiac outputlPulmonary disease Pulmonary disease severe arterial hypoxemiasevere arterial hypoxemialOrgan or tissue ischemia Organ or tissue ischemia severe mixed venous desaturation severe mixed venous desaturation elevated lactate levelelevated lactate level27SY Huan

32、glDocumented Documented coagulopathycoagulopathylBleeding Bleeding lPlanned invasive proceduresPlanned invasive procedureslWarfarinWarfarin intoxication intoxicationlGrade EGrade EBlood Products AdministrationBlood Products AdministrationFresh Frozen Plasma*/Cryoprecipitate*Fresh Frozen Plasma*/Cryo

33、precipitate*Q1:Why the coagulopathy?Q1:Why the coagulopathy?Q2:What is the appropriate PT/PTT threshold for transfusion?Q2:What is the appropriate PT/PTT threshold for transfusion?Q3:Which types of plasma(coagulation factors)should be applied?Q3:Which types of plasma(coagulation factors)should be ap

34、plied?Q4:Whether or not contraindicate?Q4:Whether or not contraindicate?*.1015ml/Kg BW.1015ml/Kg BW*.1u/10Kg BW*.1u/10Kg BW28SY Huangl Platelet administration Platelet administrationl Transfuse for 5000/mm3(prophylaxis)Transfuse for 5000/mm3(prophylaxis)l Transfuse for 5000/mm3 30,000/mm3 with Trans

35、fuse for 5000/mm3 30,000/mm3 with significant bleeding risksignificant bleeding riskl Transfuse 50,000/mm3 for invasive procedures or Transfuse 7 gm/dl7 gm/dll一般外科病人一般外科病人 710 gm/dl710 gm/dllAcute coronary syndrome 10 gm/dlAcute coronary syndrome 10 gm/dll化疗及放射线治疗化疗及放射线治疗 10 gm/dl 10 gm/dl血色素低到多少要输血

36、血色素低到多少要输血?失血失血5001000输水输水yesyesyes输浆输浆noyesyes输血输血nonoyes30SY Huangl治疗性治疗性,视出血状况而定视出血状况而定l预防性预防性 (感染发热感染发热)20,000/ul )20,000/ul (非感染发热非感染发热)15,000-5000/ul)17.5 secondsPT17.5 secondsl 预防性输血预防性输血PT17.5 secondsPT17.5 secondsl 肝病合并多凝血因子缺乏肝病合并多凝血因子缺乏l 血栓性血小板低下症血栓性血小板低下症输血问答输血问答 Q&AQ&A凝血时间长到多少要输血凝血时间长到多少

37、要输血?32SY Huang什么时候可以输白血球什么时候可以输白血球?l ANC 500/ul ANC 50,000/ul)(pla 50,000/ul)l 输冷冻沉淀品输冷冻沉淀品 (fibrinogen 150(fibrinogen 150 mg/dl)mg/dl)l 输血浆输血浆 (要小心要小心,PT 1720 seconds),PT 1720 seconds)l 抗凝剂抗凝剂 (heparin,xigris)(heparin,xigris)34SY Huang Coagulation in DICCoagulation in DICINTRINSICINTRINSICXIIXIIXII

38、aXIIaXIXIXIaXIaVIIIaVIIIaFactor XFactor XFactor XaFactor XaProthrombinProthrombinThrombinThrombinFibrinogenFibrinogenFibrinFibrinaPC*aPC*AntithrombinAntithrombinVaVaIXIXIXaIXaFVIIFVIITissue FactorTissue FactorFVIIa-TFFVIIa-TF+Factor XFactor Xsepsissepsisfibrinolysisfibrinolysistumortumortissue tissu

39、e injuryinjuryProtein SProtein SplateletplateletconsumptionconsumptionmonocytemonocyteplateletplateletEndothelial cellEndothelial cellactivationactivation*.Physiological level:2ng/ml35SY Huangl 避免避免TA-GvHD by lymphocytesTA-GvHD by lymphocytesl Donors Donors 是是HLA-haplotype HLA-haplotype 相似相似l Recipi

40、ents Recipients 是细胞免疫不全是细胞免疫不全l 理论上只有理论上只有washed PRBC,FFP,washed PRBC,FFP,cryoprecipitatecryoprecipitate不用照不用照血液制品何时需要照光血液制品何时需要照光?36SY Huangl所有的血品理论上都要加粗过滤器所有的血品理论上都要加粗过滤器(170um)(170um)l白血球过滤器白血球过滤器 vs vs 减白血球制品减白血球制品 (5x106)(5x106)l参考价参考价 reduced WBCs,NT 4200 reduced WBCs,NT 4200 leucocyte filter,

41、NT 900-1200 leucocyte filter,NT 900-1200 usual iv set,NT 6.7 usual iv set,NT 6.7 transfusion set,NT 16.7transfusion set,NT 16.7输血问答输血问答 Q&AQ&A何时要加装过滤器何时要加装过滤器?37SY Huangl RAPID TRANSFUSIONRAPID TRANSFUSIONl COLD AGGLUTININ COLD AGGLUTININl PAROXYSMAL COLD HEMOGLOBINURIA PAROXYSMAL COLD HEMOGLOBINURI

42、Al COLD ALLOANTIBODY COLD ALLOANTIBODY何时要加装加温器何时要加装加温器?38SY Huang输血速度怎么决定输血速度怎么决定?lPRBCs,PRBCs,最长最长4hr,4hr,最慢最慢1ml/kg/hr,1ml/kg/hr,最快最快50ml/min 50ml/min lPlatelets,bolus Platelets,bolus 优于优于 continuous continuous 注射注射lFFP/Cryoprecipitate/FVIII in 4 hoursFFP/Cryoprecipitate/FVIII in 4 hourslAlbumin,1

43、2ml/minAlbumin,12ml/minlIVIG,0.30.61.22.4 ml/Kg/hrIVIG,0.30.61.22.4 ml/Kg/hr39SY HuangRisks of Transfusion of Blood ProductsRisks of Transfusion of Blood ProductslMinor&Major transfusion reactionsMinor&Major transfusion reactionslTransmission of infectionsTransmission of infectionslGraft-versus-host

44、 disease(GvHD)Graft-versus-host disease(GvHD)lAcute lung injury(TRALI)Acute lung injury(TRALI)lVolume overloadVolume overloadlHypothermiaHypothermialImmunomodulation(suppression)Immunomodulation(suppression)lElectrolytes imbalanceElectrolytes imbalance40SY HuanglDo not use erythropoietin(EPO)to trea

45、t sepsis-Do not use erythropoietin(EPO)to treat sepsis-related anemia.related anemia.lGranulocyte growth factor(G-CSF)Granulocyte growth factor(G-CSF)lIntraVenous ImmunoGlobulin:IVIGIntraVenous ImmunoGlobulin:IVIGlMonoclonal anti-CD14 antibodyMonoclonal anti-CD14 antibodylAntithrombinAntithrombinlAl

46、bumin(5%)Albumin(5%)lCoagulation factors(PCC20-30U/Kg,VIIa60-Coagulation factors(PCC20-30U/Kg,VIIa60-120ug/Kg,q2-6h,VIII,IX)120ug/Kg,q2-6h,VIII,IX)lCryoprecipitateCryoprecipitatelArtificial bloodArtificial bloodBlood Products AdministrationBlood Products AdministrationOthersOthers 41SY HuangTake Home MessageTake Home Message u activated protein C activated protein C u red blood cells red blood cells u platelets platelets u plasma plasma u white blood cells white blood cells u r-tPA r-tPA u IVIG IVIG u moAb(CD14)moAb(CD14)u others others 42SY Huang