血液及其相关制剂在特护病房、重病房的应用

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1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 Annane D, et al. Lancet 2005Local infection Sepsis Severe sepsis Septic shock3 Annane D, et al. Lance

2、t 20054 Coagulation in SepsisINTRINSICEXTRINSICXIIXIIaXIXIaVIIIaFactor XFactor XaProthrombinThrombinFibrinogenFibrinTFPIaPCAntithrombinVaIXIXaFVIITissue FactorFVIIa-TF+Factor Xsepsist-PAP-antiPsepsis5ThrombinThrombomodulinProtein C (inactive)Protein C Activity(activated)Blood Vessel Blood Flow aProt

3、ein C ReceptorProteinSHuman Activated Protein CEndogenous Regulator of CoagulationEndothelial cellsEndothelial cellsInversely correlate to morbidity and mortality of severe sepsisinflammatoryprocoagulantantifibrinolyticSepsisSepsis6Severe Sepsis: New Concepts in Pathogenesis and Management Cytotoxic

4、 effects of microorganisms Endothelial injury & response Coagulation (thrombosis) InflammationWarren et al. Am J Med Sci, 2004.The novel agent?7 Recombinant Human Activated Protein C8Drotrecogin Alfa (Activated) XigrisR Recombinant human activated protein C Mechanisms MTD Adverse effects Clinical tr

5、ials PharmacoecnomicsFrampton et al, ADIS Pharmacoeconomic Drug Evaluation, 2004.9 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 P

6、rofibrinolytic* decreased PAI-1 Antiapoptosis on endothelial cells*. 24ug/Kg/hr infusion: 44.9 ng/ml in plasma level*. proposed103530252015105030.8%24.7%Placebo(n-840)Drotrecogin alfa (activated) (n=850)Mortality (%)6.1% absolute reduction in mortalityPROWESS Study: 28-Day All-Cause MortalityAdjuste

7、d 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; 344:699-709Drotrecogin Alfa (Activated):

8、 Clinical trial (I)Independent ofmicroorganismsand whether or not DIC11Mortality 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 (activated) (re

9、combinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003; 31Suppl.:S85-S90I II III IVDrotrecogin Alfa (Activated): Clinical trial (II)12Mortality and Numbers of Organs FailingPercent Mortality 010203040506012345PlaceboDrotrecoginNumber of Organs Failing at EntryAda

10、pted 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-S90Drotrecogin Alfa (Activated): Clinical trial (III)13Recombinant Human Activated Protein C (rhAPC

11、)High risk of deathAPACHE II 25Sepsis-induced multiple organ failureSeptic shockSepsis induced ARDSNo absolute contraindicationsWeigh relative contraindicationsGrade B14 Bleeding complications: 3.5% vs. 2.0%Formation of alloreactive antibody Tolerability of rhAPC15 Treatment efficacyQuality adjusted

12、 life years/patientDrotrecogin alfa (activated)16 Drotrecogin alfa (activated)17 18“Who ?Patient selection for rhAPCFull support patientSevere sepsisHigh risk of deathNo absolute contraindications“When ? and “How ?As soon as possible ?24 ug/Kg/h for 96 hoursPlatelet level 30,000/ul19 Annane D, et al

13、. Lancet 200520 Annane D, et al. Lancet 200521 From Friedrich JO, N Eng J Med, 2006.Debate on DrotAAThe Questions remained: Efficacy? Mechanism? Safty ? $1700/d? Patient selection? Alternative choice ?22Heparin Effect in Drotrecogin alfa (activated) Treatment Notably, heparin treatment appeared bene

14、ficial in all placebo groups, and resulted in an overallodds ratio for survival that was highlysignificant (p0.0001) Drotrecogin alfa (activated) GroupPlacebo Group23 Blood Products24Transfusion Strategy (PRBC) in the Critically Ill Patients Figure 2A, page 414, reproduced with permission from Heber

15、t PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340:409-417Canadian Critical Care Trials GroupHb=1012Hb=79Age55APACH20CAD25Blood Products AdministrationRed Blood CellsTissue hypoperfusion resolv

16、edNo extenuating circumstancesCoronary artery diseaseAcute hemorrhageLactic acidosisTransfuse 7.0 g/dl to maintain 7.0-9.0 g/dLDO2 but not VO2; PVR & SVRGrade BQ1: Why the anemia?Q2: What is the appropriate Hb threshold for transfusion?Q3: Which types of red blood cells should be applied?Q4: Whether

17、 or not contraindicate?Zimmerman, Cri Care Med 2004; Drews, Clin Chest Med 200326Conditions in Septic Patients that May Require a Higher HemoglobinAcute instabilityCardiovascular disease coronary artery disease low cardiac outputPulmonary disease severe arterial hypoxemiaOrgan or tissue ischemia sev

18、ere mixed venous desaturation elevated lactate level27Documented coagulopathyBleeding Planned invasive proceduresWarfarin intoxicationGrade EBlood Products AdministrationFresh Frozen Plasma*/ Cryoprecipitate*Q1: Why the coagulopathy?Q2: What is the appropriate PT/PTT threshold for transfusion?Q3: Wh

19、ich types of plasma (coagulation factors) should be applied?Q4: Whether or not contraindicate?*. 1015ml/Kg BW*. 1u/10Kg BW28 Platelet administration Transfuse for 5000/mm3 (prophylaxis) Transfuse for 5000/mm3 30,000/mm3 with significant bleeding risk Transfuse 7 gm/dl一般外科病人 710 gm/dlAcute coronary s

20、yndrome 10 gm/dl化疗及放射线治疗 10 gm/dl血色素低到多少要输血?失血5001000输水yesyesyes输浆noyesyes输血nonoyes30治疗性, 视出血状况而定预防性 (感染发热) 20,000/ul (非感染发热) 17.5 seconds 预防性输血PT17.5 seconds 肝病合并多凝血因子缺乏 血栓性血小板低下症输血问答 Q & A凝血时间长到多少要输血?32什么时候可以输白血球? ANC 50,000/ul) 输冷冻沉淀品 (fibrinogen 150 mg/dl) 输血浆 (要小心, PT 1720 seconds) 抗凝剂 (heparin

21、, xigris)34 Coagulation in DICINTRINSICXIIXIIaXIXIaVIIIaFactor XFactor XaProthrombinThrombinFibrinogenFibrinaPC*AntithrombinVaIXIXaFVIITissue FactorFVIIa-TF+Factor Xsepsisfibrinolysistumortissue injuryProtein SplateletconsumptionmonocyteplateletEndothelial cellactivation*. Physiological level: 2ng/m

22、l35 避免TA-GvHD by lymphocytes Donors 是HLA-haplotype 相似 Recipients 是细胞免疫不全 理论上只有washed PRBC, FFP, cryoprecipitate不用照血液制品何时需要照光?36所有的血品理论上都要加粗过滤器(170um)白血球过滤器 vs 减白血球制品 (5x106)参考价 输血问答 Q & A何时要加装过滤器?37 RAPID TRANSFUSION COLD AGGLUTININ PAROXYSMAL COLD HEMOGLOBINURIA COLD ALLOANTIBODY何时要加装加温器?38输血速度怎么决定?PRBCs, 最长4hr, 最慢1ml/kg/hr, 最快50ml/min Platelets, bolus 优于 continuous 注射FFP/Cryoprecipi