Potential Use of Plasma Exchange in Septic Shock

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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
• Childrens Healthcare of Atlanta at Egleston

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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
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The Problem of Sepsis in Children

• 42,000 pediatric sepsis cases/year
• Annual cost gt 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

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Potential Desperate DevicesFor Extracorporeal
Use In Sepsis

• Continuous renal replacement therapies (CRRT)
• Extracorporeal membrane oxygenation (ECMO)
• Extracorporeal liver support devices
• Plasma Exchange/Plasmapheresis

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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

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Peak Concentration Model of Sepsis
SIRS
CARS
SIRS/CARS
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Peak Concentration Model of Sepsis
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Mechanisms of Sepsis and Multiple Organ Failure

• Death still related to development of MOF
• Improved-fluid resuscitation, antibiotics
• Net effect conversion of anticoagulant/profibrino
  lytic state? procoagulant/antifibrinolytic state
• Microvascular coagulation
• Tissue factor (TF) activation
• Thrombotic microangiopathy (TMA)

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TMAs Link With Sepsis

• Thrombotic microangiopathy (TMA)
• Microvascular occlusive disorder
• Platelet/vWf microthrombi?predispose to MOF
• Thrombocytopenia
• Abnormalities of vWf cleaving protease

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TMAs Link With Sepsis

• Primary
• Thrombotic thrombocytopenic purpura (TTP)
• HUS
• Secondary
• Infection/sepsis
• Organ transplants
• Chemotherapy

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TTP A TMA Syndrome

• Critical defect ADAMTS-13 deficiency (lt 10)
• Ultra-large vWf multimer-platelet thrombi
• Microthrombotic multi-organ vascular injury MOF
  and autopsy findings

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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

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vWF
PAI-1
PAI-1
PAI-1
X
Plasmin
Plasminogen
TMA

• ADAMTS 13

PAI-1
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TTP
Platelet
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Endothelium
TTP
X
vWF
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Fibrin
Fibrin
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ADAMTS-13

• Deficiency
• Genetic
• Consumptive
• Autoimmune loss acquired Abs
• ADAMTS-deficient mice develop TTP phenotype with
  E. coli (Motto 2005)
• Adult and pediatric sepsis

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ADAMTS-13 Deficiency in Adult Sepsis
-Martin et al., Crit Care Med 2007
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Adult Sepsis-Survival by ADAMTS-13 Level
Above median
Below median
-Martin et al., Crit Care Med 2007
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ADAMTS-13 Deficiency Correlates with Organ Failure
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ADAMTS-13 Deficiency in Pediatric Sepsis
-Nguyen, Hematologica 2006
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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

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ADAMTS-13 deficiency correlates with
thrombocytopenia
-Martin et al., Crit Care Med 2007
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Thrombocytopenia-Associated Multiple Organ
Failure (TAMOF)

• Recently described entity (Nguyen, Carcillo 2001)
• MOFgt2 organs
• Platelet count lt 100K
• Similarities to TTP
• Primarily secondary to sepsis
• High mortality in children
• Deficient ADAMTS-13
• Increased ADAMTS-13 antibodies
• Increased ulvWf multimers

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Thrombotic Microangiopathy TAMOF
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Desperate but Reasonable?
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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
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Plasma Therapies

• Plasmapheresis plasma removed ? replaced with 5
  albumin
• Plasma exchange plasma removed ? replaced with
  donor plasma
• centrifugation
• filtration

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Plasma Therapy Centrifugation
COBE Spectra Apheresis System
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Plasma Exchange Centrifugation

• Disadvantages
• Loss of cellular elements of blood
• system complexity
• expensive

• Advantages
• more efficient removal of all plasma components
• can be adapted for cytopheresis

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Plasma Therapy Filtration

• B Braun McGaw Diapact

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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

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Why Not Plasma Infusion Alone?

• 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

• Plasma Infusion
• Restores procoagulant factors
• Restores anticoagulant factors (protein C, AT
  III, TFP-I)
• Restores prostacyclin
• Restores tPA
• Restores ADAMTS-13
• Requires additional volume

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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
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Plasma Exchange vs. Infusion Weight Gain
- Darmon et al., Crit Care Med, 2006
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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 Leukaplasmapheresis 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
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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
2002281410
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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 lt .05)

-Nguyen, Carcillo et al., submitted 2008
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Childrens of Pittsburgh-Pediatric TAMOF Trial
-Nguyen, Carcillo et al., submitted 2008
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Plasma Exchange Replenishes ADAMTS-13
-Nguyen, Carcillo et al., submitted 2008
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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

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Childrens TAMOF Network

• Actively participating centers
• Childrens of Atlanta at Egleston coordinating
  center
• Childrens of Atlanta at Scottish Rite
• Childrens of Pittsburgh
• Cook Childrens-Fort Worth
• Vanderbilt Childrens
• Cincinnati Childrens
• Columbus Childrens
• LSU-Shreveport Childrens
• Arkansas Childrens
• University of Michigan-Mott Childrens

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Childrens 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

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Alexis- A Success Story
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Conclusions

• Sepsis/MOF coagulopathy/thrombosis a major
  contributor
• ADAMTS-13 deficiency may be a key component
• Plasma exchange a promising therapy
• Needs further study