Plasma Exchange and Plasmapheresis in Septic Shock and Acute Kidney Injury

1. Plasma Exchange and Plasmapheresis in Septic Shock and Acute Kidney Injury 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

3. The Problem of Sepsis in Children • 42,000 pediatric sepsis cases/year • Annual cost > $2 billion • Increased mortality 5.49.5/100,000 • 10.3% hospitalized pediatric sepsis mortality rate overall in US = the potential target

4. 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

5. Desperate but Reasonable?

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

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

8. Mechanisms of Sepsis and Multiple Organ Failure • Death still related to development of MOF • Net effect: conversion of anticoagulant/profibrinolytic state procoagulant/antifibrinolytic state • Microvascular coagulation • Thrombotic microangiopathy (TMA) • Link with sepsis: Platelet/vWf microthrombipredispose to MOF

9. Thrombotic Thrombocytopenic Purpura (TTP): A TMA Syndrome • Critical defect: ADAMTS-13 deficiency (< 10% of normal) • Ultra-large vWf multimer-platelet thrombi • Microthrombotic multi-organ vascular injury • AKI central injury

10. ADAMTS-13 • ADAMTS-13 = A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif • “The molecule formerly known as vWf-CP” = a “good” molecule • Cleaves vWf multimers, reduces thrombogenic potential

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

12. Shear stress vWF vWF TTP Platelet

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

14. vWF vWF Platelet Platelet Platelet Platelet Platelet Platelet Platelet Platelet Platelet Platelet Platelet vWF Platelet Platelet Fibrin Fibrin

15. 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

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

17. Decreased Sepsis Survival with Decreased ADAMTS-13 Above median Below median -Martin et al., Crit Care Med 2007

18. ADAMTS-13 Deficiency Correlates with Organ Failure

19. ADAMTS-13 Deficiency Seen in Pediatric Sepsis -Nguyen, Hematologica 2006

20. Thrombocytopenia and MOF • New-onset thrombocytopenia is independent risk factor for MOF (Carcillo 2001) • OR 11.9 • Thrombocytopenia with MOF increased death (OR 6.3) vs. MOF alone

21. Thrombocytopenia-Associated Multiple Organ Failure (TAMOF) • Recently described entity (Nguyen, Carcillo 2001) • Children • MOF>2 organs • Platelet count < 100K • Similarities to TTP • Primarily secondary to sepsis • High mortality • Deficient ADAMTS-13 • Increased ADAMTS-13 antibodies • Increased ul-vWf multimers

22. 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

23. Could plasma exchange be beneficial in severe sepsis and MOF/AKI?

24. Peak Concentration Model of Sepsis

25. Controlled Trials: Plasma Therapies and Sepsis

26. 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

27. 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., CCM 2008

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

29. Plasma Exchange Replenishes ADAMTS-13 -Nguyen, Carcillo et al., CCM 2008

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

31. Plasma Therapy: Centrifugation COBE Spectra Apheresis System

32. Plasma Therapy: Filtration B Braun Diapact

33. 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

34. 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

35. Pediatric Patients Receiving CVVHFluid Overload Increases Mortality - Foland, Fortenberry et al., CCM 2004

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

37. 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

38. 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

39. 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

40. Conclusions • Sepsis/MOF (including AKI): coagulopathy/thrombosis a major contributor • ADAMTS-13 deficiency may be a key component • Plasma exchange a promising therapy • Needs further study

41. I hope I haven’t led you astray

42. TAMOF Network Preliminary Data Dying with standard therapy Surviving with plasma exchange PELOD Score