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Potential Use of Plasma Exchange in Septic Shock James D. Fortenberry MD, FCCM, FAAP Associate Professor of Pediatrics Emory University School of Medicine.

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Presentation on theme: "Potential Use of Plasma Exchange in Septic Shock James D. Fortenberry MD, FCCM, FAAP Associate Professor of Pediatrics Emory University School of Medicine."— Presentation transcript:

1 Potential Use of Plasma Exchange in Septic Shock James D. Fortenberry MD, FCCM, FAAP Associate Professor of Pediatrics Emory University School of Medicine Director, Critical Care Medicine and Pediatric ECMO/Advanced Technologies Childrens Healthcare of Atlanta at Egleston

2 2 Overwhelming Sepsis: Desperate Times… Diseases desperate grown By desperate appliance are relieved, Or not at all. -Claudius, King of Denmark In Hamlet Act IV Scene 3 W. Shakespeare

3 3 The Problem of Sepsis in Children 42,000 pediatric sepsis cases/year Annual cost > $2 billion Severe sepsis in pediatric males increased from Increased mortality /100, % hospitalized pediatric sepsis mortality rate overall in US

4 4 Potential Desperate Devices For Extracorporeal Use In Sepsis Continuous renal replacement therapies (CRRT) Extracorporeal membrane oxygenation (ECMO) Extracorporeal liver support devices Plasma Exchange/Plasmapheresis

5 5 Extracorporeal Therapies in Septic Shock Potential benefits Immunohomeostasis: pro/anti- inflammatory mediators Improved coagulation response with decreased organ thrombosis Mechanical support of organ perfusion during acute episode

6 6 SIRS CARS SIRS/CARS Peak Concentration Model of Sepsis

7 7

8 8 Mechanisms of Sepsis and Multiple Organ Failure Death still related to development of MOF Improved-fluid resuscitation, antibiotics Net effect: conversion of anticoagulant/profibrinolytic state procoagulant/antifibrinolytic state Microvascular coagulation Tissue factor (TF) activation Thrombotic microangiopathy (TMA)

9 9 TMAs: Link With Sepsis Thrombotic microangiopathy (TMA) Microvascular occlusive disorder Platelet/vWf microthrombi predispose to MOF Thrombocytopenia Abnormalities of vWf cleaving protease

10 10 TMAs: Link With Sepsis Primary Thrombotic thrombocytopenic purpura (TTP) HUS Secondary Infection/sepsis Organ transplants Chemotherapy

11 11 TTP: A TMA Syndrome Critical defect: ADAMTS-13 deficiency (< 10%) Ultra-large vWf multimer-platelet thrombi Microthrombotic multi-organ vascular injury: MOF and autopsy findings

12 12 ADAMTS-13 ADAMTS-13 = A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif The molecule formerly known as vWf-CP Processes vWf multimers and cleaves, reduces thrombogenic potential

13 13 Platelet vWF ADAMTS 13 (vWF-CP) tPA PGI Endothelium Platelet ADAMTS 13 (vWF-CP) Platelet vWF Platelet Homeostasis tPA

14 14 Plasmin Plasminogen PAI-1 X TMA vWF Platelet ADAMTS 13

15 15 vWF Platelet vWF Shear stress TTP

16 16 Endothelium Platelet vWF X ADAMTS 13 (vWF-CP) ADAMTS 13 (vWF-CP Ab) TTP

17 17 Fibrin Platelet vWF Platelet Fibrin vWF

18 18 ADAMTS-13 Deficiency Genetic Consumptive Autoimmune loss: acquired Abs ADAMTS-deficient mice develop TTP phenotype with E. coli (Motto 2005) Adult and pediatric sepsis

19 19 ADAMTS-13 Deficiency in Adult Sepsis -Martin et al., Crit Care Med 2007

20 20 Adult Sepsis-Survival by ADAMTS-13 Level Above median Below median -Martin et al., Crit Care Med 2007

21 21 ADAMTS-13 Deficiency Correlates with Organ Failure

22 22 ADAMTS-13 Deficiency in Pediatric Sepsis -Nguyen, Hematologica 2006

23 23 Thrombocytopenia and MOF New-onset thrombocytopenia independent risk factor for MOF in adults and children (Carcillo 2001) OR 11.9 Thrombocytopenia with MOF increased death (OR 6.3) vs. MOF alone Autopsies: thrombosis in 4 of 6

24 24 -Martin et al., Crit Care Med 2007 ADAMTS-13 deficiency correlates with thrombocytopenia

25 25 Thrombocytopenia-Associated Multiple Organ Failure (TAMOF) Recently described entity (Nguyen, Carcillo 2001) MOF>2 organs Platelet count < 100K Similarities to TTP Primarily secondary to sepsis High mortality in children Deficient ADAMTS-13 Increased ADAMTS-13 antibodies Increased ulvWf multimers

26 26 Thrombotic Microangiopathy: TAMOF

27 27 Desperate but Reasonable?

28 28 Benefits of Plasma Exchange in TTP Has resulted in remarkable improvement in outcome 80-90% mortality 10% Replenishes ADAMTS-13 Removes ADAMTS- 13 inhibitors Removes thrombogenic ULvWf multimers -Rock, NEJM 1991

29 29 Plasma Therapies Plasmapheresis: plasma removed replaced with 5% albumin Plasma exchange: plasma removed replaced with donor plasma centrifugation filtration

30 30 Plasma Therapy: Centrifugation COBE Spectra Apheresis System

31 31 Plasma Exchange: Centrifugation Advantages more efficient removal of all plasma components can be adapted for cytopheresis Disadvantages Loss of cellular elements of blood system complexity expensive

32 32 Plasma Therapy: Filtration B Braun McGaw Diapact

33 33 Plasma Exchange: Filtration Advantages no loss of cellular elements ease of set up cost effective ability to treat smaller patients Disadvantages removal of substances limited by sieving coefficient of membrane unable to perform more complex therapies

34 34 Why Not Plasma Infusion Alone? Plasma Infusion Restores procoagulant factors Restores anticoagulant factors (protein C, AT III, TFP-I) Restores prostacyclin Restores tPA Restores ADAMTS-13 Requires additional volume Plasma Exchange Restores factor homeostasis as per plasma infusion In addition: Removes ADAMTS-13 inhibitors Removes ultra-large vWF multimers Removes tissue factor Removes excess PAI-1 Maintains fluid balance during procedure

35 35 Course of Organ Dysfunction and TMA: Plasma Infusion vs. Plasma Exchange 36 adult TMA patients Decreased mortality with plasma exchange Plasma infusion group received larger volume of plasma Plasma infusion group had larger weight gain - Darmon et al., Crit Care Med, 2006 *

36 36 Plasma Exchange vs. Infusion: Weight Gain - Darmon et al., Crit Care Med, 2006

37 37 Controlled Trials: Plasma Therapies and Sepsis Study Design Children Included ? TechniqueCondition Treated Mortality Tx group Mortality Control Difference RC 81 YesPlasma Exchange Meningococ- cemia 1/136/ RC 82 YesLeukaplasmaph eresis Meningococ- cemia 3/137/90.02 RC 68 NoPlasma exchange and CVVH Septic shock1/78/ RC 83 NoPlasmapheresis/ CVVH Surgical sepsis 11/1913/ PC 70 NoPlasmapheresis versus plasma infusion TMA/sepsis0/147/ PRCT 63 YesPlasmapheresisSepsis6/148/ PRCT 69 NoPlasmapheresis/ exchange Sepsis18/5228/520.05

38 38 Plasmapheresis in Severe Sepsis and Septic Shock PRCT, Russian adult ICU 106 sepsis patients randomized to: Standard therapy Addition of plasmapheresis (1/2 FFP, 1/2 albumin) Decreased mortality with plasma exchange - Busund et al., Intensive Care Medicine 2002;28:1410 *

39 39 TAMOF In Children: CHP Trial 10 children with TAMOF Decreased ADAMTS-13 (mean 33.3% of normal) Randomized trial: stopped after 10 patients: 28-day survival 1/5 standard therapy 5/5 plasma exchange (p <.05) -Nguyen, Carcillo et al., submitted 2008

40 40 Childrens of Pittsburgh- Pediatric TAMOF Trial -Nguyen, Carcillo et al., submitted 2008

41 41 Plasma Exchange Replenishes ADAMTS-13 -Nguyen, Carcillo et al., submitted 2008

42 42 TAMOF in Children: Further Studies 10 institution pediatric multicenter TAMOF study network Registry of TAMOF patients Biochemical measurements Plasma exchange in 6 centers Obtaining data to inform development of randomized trial

43 43 Childrens TAMOF Network Actively participating centers: Childrens of Atlanta at Egleston: coordinating center Childrens of Atlanta at Scottish Rite Childrens of Pittsburgh Cook Childrens-Fort Worth Vanderbilt Childrens Cincinnati Childrens Columbus Childrens LSU-Shreveport Childrens Arkansas Childrens University of Michigan-Mott Childrens

44 44 Childrens TAMOF Network Preliminary Data 53 TAMOF patients registered to date-21 data complete Median age 12 years Median OFI: 4 Similar PRISM, PELOD at admission 21 TAMOF patients 15 plasma exchange 11 lived (73%) 4 died 6 standard therapy 2 survived (33%) 4 died

45 45 Alexis- A Success Story

46 46 Conclusions Sepsis/MOF: coagulopathy/thrombosis a major contributor ADAMTS-13 deficiency may be a key component Plasma exchange a promising therapy Needs further study

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