plasma exchange in septic shock
TRANSCRIPT
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