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Plasma Exchange in Septic Shock

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    Plasma Exchange in Septic Shock Plasma Exchange in Septic Shock Presentation Transcript

    • 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
    • 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
    • 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
    • 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
        • Improved coagulation response with decreased organ thrombosis
        • Mechanical support of organ perfusion during acute episode
    • SIRS CARS SIRS/CARS Peak Concentration Model of Sepsis
    • Peak Concentration Model of Sepsis
    • 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)
    • TMAs: Link With Sepsis
      • Thrombotic microangiopathy (TMA)
      • Microvascular occlusive disorder
        • Platelet/vWf microthrombi  predispose to MOF
        • Thrombocytopenia
        • Abnormalities of vWf cleaving protease
    • TMAs: Link With Sepsis
      • Primary
        • Thrombotic thrombocytopenic purpura (TTP)
        • HUS
      • Secondary
        • Infection/sepsis
        • Organ transplants
        • Chemotherapy
    • 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
    • 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
    • Platelet vWF ADAMTS 13 (vWF-CP) tPA PGI Endothelium Platelet ADAMTS 13 (vWF-CP) Platelet vWF vWF Platelet Homeostasis tPA
    • Plasmin Plasminogen PAI-1 X PAI-1 PAI-1 PAI-1 TMA vWF
      • ADAMTS 13
      Platelet Platelet
    • Platelet TTP vWF vWF Shear stress
    • Endothelium vWF X TTP Platelet Platelet ADAMTS 13 (vWF-CP) ADAMTS 13 (vWF-CP Ab)
    • Fibrin Fibrin Platelet Platelet Platelet Platelet Platelet Platelet Platelet vWF Platelet Platelet Platelet Platelet Platelet Platelet vWF vWF
    • ADAMTS-13
      • Deficiency
        • Genetic
        • Consumptive
        • Autoimmune loss: acquired Abs
        • ADAMTS-deficient mice develop TTP phenotype with E. coli (Motto 2005)
        • Adult and pediatric sepsis
    • ADAMTS-13 Deficiency in Adult Sepsis -Martin et al., Crit Care Med 2007
    • Adult Sepsis-Survival by ADAMTS-13 Level Above median Below median -Martin et al., Crit Care Med 2007
    • ADAMTS-13 Deficiency Correlates with Organ Failure
    • ADAMTS-13 Deficiency in Pediatric Sepsis -Nguyen, Hematologica 2006
    • 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
    • -Martin et al., Crit Care Med 2007 ADAMTS-13 deficiency correlates with thrombocytopenia
    • 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
    • Thrombotic Microangiopathy: TAMOF IL- 8 TNF-  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 in Plasminogen 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-  IL- 6+R
    • Desperate but Reasonable?
    • 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
    • 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 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
    • Plasma Therapy: Filtration
      • B Braun McGaw Diapact
    • 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
    • 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
    • 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 *
    • Plasma Exchange vs. Infusion: Weight Gain - Darmon et al., Crit Care Med, 2006
    • Controlled Trials: Plasma Therapies and Sepsis Study Design Children Included? Technique Condition Treated Mortality Tx group Mortality Control Difference RC 81 Yes Plasma Exchange Meningococ-cemia 1/13 6/10 0.025 RC 82 Yes Leukaplasmapheresis Meningococ-cemia 3/13 7/9 0.02 RC 68 No Plasma exchange and CVVH Septic shock 1/7 8/21 0.25 RC 83 No Plasmapheresis/CVVH Surgical sepsis 11/19 13/24 0.94 PC 70 No Plasmapheresis versus plasma infusion TMA/sepsis 0/14 7/22 0.05 PRCT 63 Yes Plasmapheresis Sepsis 6/14 8/16 0.73 PRCT 69 No Plasmapheresis/exchange Sepsis 18/52 28/52 0.05
    • 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., submitted 2008
    • Children’s of Pittsburgh- Pediatric TAMOF Trial -Nguyen, Carcillo et al., submitted 2008
    • Plasma Exchange Replenishes ADAMTS-13 -Nguyen, Carcillo et al., submitted 2008
    • 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
      21 TAMOF patients 15 plasma exchange 6 standard therapy 2 survived (33%) 4 died 11 lived (73%) 4 died
    • Alexis- A Success Story
    • Conclusions
      • Sepsis/MOF: coagulopathy/thrombosis a major contributor
      • ADAMTS-13 deficiency may be a key component
      • Plasma exchange a promising therapy
      • Needs further study