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

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

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

Desperate but Reasonable?

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

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

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

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

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

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

TTP Platelet vWF vWF Shear stress

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

vWF vWF Platelet Fibrin Platelet vWF Fibrin

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

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

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

ADAMTS-13 Deficiency Correlates with Organ Failure

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

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

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

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

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

Peak Concentration Model of Sepsis

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

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

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

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

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

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

Plasma Therapy: Centrifugation COBE Spectra Apheresis System

Plasma Therapy: Filtration B Braun Diapact

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

- 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

Pediatric Patients Receiving CVVH Fluid Overload Increases Mortality - Foland, Fortenberry et al., CCM 2004

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

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

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

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

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

I hope I haven’t led you astray

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