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Potential Use of Plasma Exchange in Septic Shock

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Presentation on theme: "Potential Use of Plasma Exchange in Septic Shock"— 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 Children’s Healthcare of Atlanta at Egleston

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 The Problem of Sepsis in Children
42,000 pediatric sepsis cases/year Annual cost > $2 billion Severe sepsis in pediatric males increased from 1993 2003 Increased mortality 5.49.5/100,000 10.3% hospitalized pediatric sepsis mortality rate overall in US

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 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 Peak Concentration Model of Sepsis

7 Peak Concentration Model of Sepsis

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

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

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

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

15 TTP Platelet vWF vWF Shear stress

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

17 vWF vWF Platelet Fibrin Platelet vWF Fibrin

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

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

21 ADAMTS-13 Deficiency Correlates with Organ Failure

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

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

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 Thrombotic Microangiopathy: TAMOF
IL- 8 TNF- IL- 6+R ADAMTS13 Ab IL-6 X ADAMTS13 (vWF-CP) Endothelium PAI-1 vWF TFPI Plasm in Plasminogen Platelet TF Shear stress x

27 Desperate but Reasonable?

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

30 Plasma Therapy: Centrifugation
COBE Spectra Apheresis System

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 Plasma Therapy: Filtration
B Braun McGaw Diapact

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 Why Not Plasma Infusion Alone?
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 - Darmon et al., Crit Care Med, 2006
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 Plasma Exchange vs. Infusion: Weight Gain
- Darmon et al., Crit Care Med, 2006

37 Controlled Trials: Plasma Therapies and Sepsis
Study Design Children Included? Technique Condition Treated Mortality Tx group Mortality Control Difference RC81 Yes Plasma Exchange Meningococ-cemia 1/13 6/10 0.025 RC82 Leukaplasmapheresis 3/13 7/9 0.02 RC68 No Plasma exchange and CVVH Septic shock 1/7 8/21 0.25 RC83 Plasmapheresis/CVVH Surgical sepsis 11/19 13/24 0.94 PC70 Plasmapheresis versus plasma infusion TMA/sepsis 0/14 7/22 0.05 PRCT63 Plasmapheresis Sepsis 6/14 8/16 0.73 PRCT69 Plasmapheresis/exchange 18/52 28/52

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 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 Children’s of Pittsburgh- Pediatric TAMOF Trial
-Nguyen, Carcillo et al., submitted 2008

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

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

44 Children’s 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

45 Alexis- A Success Story

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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