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Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
Plasma Exchange in Septic Shock
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Plasma Exchange in Septic Shock

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  • 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. 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 1993 2003  Increased mortality 5.49.5/100,000  10.3% 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 Pro-Inflammatory Mediators Anti-Inflammatory Mediators (Inhibitors) Pro/Anti-Inflammatory Mediators Activation Depression Time Time Parallel Serial IL1 TNF PAF IL10 IL6 MediatorLevelsMediatorLevels Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003 SIRS CARS SIRS/CARS Peak Concentration Model of Sepsis
  • 7. 7 CRRT/Plasma Exchange CRRT/Plasma Exchange Time Time SIRS/CARS SIRS CARS SIRS CARS Immunohomeostasis Immunohomeostasis Pro-inflammatory Mediators Anti-inflammatory Mediators IL-1 TNF PAF IL-10 Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003 Peak Concentration Model of Sepsis
  • 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 vWF Platelet Homeostasis tPA
  • 14. 14 PlasminPlasminogen PAI-1 X PAI-1 PAI-1 PAI-1 TMA vWF Platelet Platelet ↓ADAMTS 13
  • 15. 15 vWF Platelet vWF Shear stress TTP
  • 16. 16 Endothelium Platelet Platelet vWF X ADAMTS 13 (vWF-CP) ADAMTS 13 (vWF-CP Ab) TTP
  • 17. 17 Fibrin Platelet Platelet Platelet Platelet Platelet Platelet Platelet vWF Platelet Platelet Platelet Platelet Platelet Platelet Fibrin vWF 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
  • 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 IL- 8 TNF-α IL- 6+R ADAMTS13 Ab IL-6 X ADAMTS13 (vWF-CP) Endothelium Endothelium PAI-1 PAI-1 PAI-1 PAI-1 PAI-1 PAI-1 vWF vWF PAI-1 TFPI TFPI Plasm inPlasminogen PAI-1 X Platelet Platelet Platelet Platelet Platelet Platelet TF TF Shear stress Platelet Platelet Platelet ADAMTS13 Ab IL-6 ADAMTS13 (vWF-CP) x IL- 8 TNF-α IL- 6+R
  • 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 31.8 0 0 5 10 15 20 25 30 35 Plasma Infusion Plasma Exchange *
  • 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 ? Technique Condition Treated Mortality Tx group Mortality Control Difference RC81 Yes Plasma Exchange Meningococ- cemia 1/13 6/10 0.025 RC82 Yes Leukaplasmaph eresis Meningococ- cemia 3/13 7/9 0.02 RC68 No Plasma exchange and CVVH Septic shock 1/7 8/21 0.25 RC83 No Plasmapheresis/ CVVH Surgical sepsis 11/19 13/24 0.94 PC70 No Plasmapheresis versus plasma infusion TMA/sepsis 0/14 7/22 0.05 PRCT63 Yes Plasmapheresis Sepsis 6/14 8/16 0.73 PRCT69 No Plasmapheresis/ exchange Sepsis 18/52 28/52 0.05
  • 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 53.8 33.3 0 10 20 30 40 50 60 Standard Plasma *
  • 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 Children’s of Pittsburgh- Pediatric TAMOF Trial Pediatric Logistic Organ Dysfunction Score DAY 0 5 10 15 20 25 30 PELOD 0 20 40 60 80 100 Plasma Exchange No Plasma Exchange Figure 3. Pediatric Logistic Organ Dysfunction Score, Mean with standard error for patients who received plasma exchange therapy (N = 5) and who did not receive plasma exchange therapy (N = 5) for each day x 28 days. 17 -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 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. 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 21 TAMOF patients 15 plasma exchange 6 standard therapy 2 survived (33%) 4 died 11 lived (73%) 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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