Potential Use of Plasma Exchange in Septic Shock
James D. Fortenberry MD, FCCM, FAAPAssociate Professor of Pediatrics
Emory University School of MedicineDirector, Critical Care Medicine and
Pediatric ECMO/Advanced TechnologiesChildren’s Healthcare of Atlanta at Egleston
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Overwhelming Sepsis: Desperate Times…
Diseases desperate grownBy desperate appliance are relieved, Or not at all.
-Claudius, King of DenmarkIn Hamlet Act IV Scene 3W. Shakespeare
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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 5.49.5/100,000 10.3% hospitalized pediatric sepsis mortality
rate overall in US
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Potential “Desperate Devices”For 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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Pro-I nflammatoryMediators
Anti-I nflammatoryMediators (I nhibitors)
Pro/ Anti-I nflammatoryMediators
Activation Depression
Time
Time
Parallel
Serial
IL1TNF
PAF
IL10
IL6
Med
iato
r Le
vels
Med
iato
r Le
vels
Adapted f rom Ronco et al. Artifi cial Organs 27(9) 792-801, 2003
SIRS CARS
SIRS/CARS
Peak Concentration Model of Sepsis
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CRRT/Plasma Exchange
CRRT/Plasma Exchange
Time
Time
SIRS/CARS
SIRS CARS SIRS CARS
I mmunohomeostasis
I mmunohomeostasis
Pro-inflammatoryMediators
Anti-inflammatoryMediators
IL-1TNF PAF
IL-10
Adapted f rom Ronco et al. Artificial Organs 27(9) 792-801, 2003
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/profibrinolytic 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 microthrombipredispose 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 (< 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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Platelet
vWF
ADAMTS 13 (vWF-CP)
tPA PGI
Endothelium
Platelet
ADAMTS 13(vWF-CP)
Platelet
vWF
vWF Platelet
Homeostasis
tPA
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PlasminPlasminogen
PAI-1
X
PAI-1 PAI-1
PAI-1
TMA
vWF
Platelet
Platelet
ADAMTS 13
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vWF
Platelet
vWFShear stress
TTP
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Endothelium
Platelet
Platelet
vWFX ADAMTS 13 (vWF-CP)
ADAMTS 13 (vWF-CP Ab)
TTP
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Fibrin
Platelet
Platelet
PlateletPlatelet
Platelet
Platelet
PlateletvWF
Platelet
Platelet
Platelet
Platelet
Platelet
Platelet
Fibrin
vWFvWF
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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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-Martin et al., Crit Care Med 2007
ADAMTS-13 deficiency correlates with thrombocytopenia
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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
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Thrombotic Microangiopathy: TAMOF
IL- 8TNF-IL- 6+R
ADAMTS13 AbIL-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
PlasminPlasminogen
PAI-1
X
Platelet
Platelet
Platelet
Platelet
Platelet
Platelet
TF TF
Shear stress
Platelet
Platelet
Platelet
ADAMTS13 AbIL-6
ADAMTS13(vWF-CP)
xIL- 8
TNF-IL- 6+R
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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
Advantages• more efficient
removal of all plasma components
• can be adapted for cytopheresis
Disadvantages• Loss of cellular
elements of blood• system complexity• expensive
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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 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
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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
31.8
0
0
5
10
15
20
25
30
35
Plasma
Infusion
Plasma
Exchange
*
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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 2002;28:1410
53.8
33.3
0
10
20
30
40
50
60
Standard Plasma
*
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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 < .05)
-Nguyen, Carcillo et al., submitted 2008
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Children’s of Pittsburgh-Pediatric TAMOF Trial
Pediatric Logistic Organ Dysfunction Score
DAY
0 5 10 15 20 25 30
PE
LOD
0
20
40
60
80
100
Plasma ExchangeNo Plasma Exchange
Figure 3. Pediatric Logistic Organ Dysfunction Score, Mean with standarderror 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
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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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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
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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 died11 lived(73%)
4 died
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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