Potential Use of Plasma Exchange in Septic Shock

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 SIRS CARS SIRS/CARS

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

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

15. Shear stress vWF vWF TTP Platelet

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

17. vWF vWF Platelet Platelet Platelet Platelet Platelet Platelet Platelet Platelet Platelet Platelet Platelet vWF Platelet Platelet Fibrin 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 TF TF PAI-1 PAI-1 PAI-1 Endothelium TFPI TFPI PAI-1 PAI-1 PAI-1 PAI-1 Plasm Platelet Plasminogen X in X Platelet vWF PAI-1 x ADAMTS13 (vWF-CP) Platelet Platelet IL- 8 TNF- IL- 6+R Shear stress ADAMTS13 (vWF-CP) Platelet vWF IL- 8 TNF- IL- 6+R Platelet ADAMTS13 Ab IL-6 Platelet Platelet ADAMTS13 Ab IL-6 Platelet Endothelium

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? 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. 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

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