Transcript Plasma Exchange and Plasmapheresis in Septic Shock and Acute Kidney Injury

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
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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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Desperate but Reasonable?
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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/antiinflammatory mediators
• Control of fluid overload
• Mechanical support of organ perfusion
during acute episode
• Improved coagulation response with
decreased organ thrombosis
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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
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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
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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
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Homeostasis
PGI
tPA
Platelet
Platelet
vWF
Platelet
ADAMTS 13
(vWF-CP)
vWF
Platelet
vWF
ADAMTS 13 (vWF-CP)
Endothelium
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tPA
TTP
Platelet
vWF
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Shear stress
vWF
Endothelium
TTP
Platelet
X
vWF
ADAMTS 13 (vWF-CP)
Platelet
ADAMTS 13 (vWF-CP Ab)
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vWF
Platelet
Platelet
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vWF
Fibrin
Platelet Platelet
Platelet
Platelet
Platelet Platelet
Platelet
PlateletPlatelet
Fibrin
vWF
Platelet
Platelet
Benefits of Plasma
Exchange in TTP
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 Has resulted in
remarkable
improvement in
outcome
 80-90% mortality 
10%
• Replenishes
ADAMTS-13
• Removes ADAMTS13 inhibitors
• Removes
thrombogenic ULvWf
multimers
-Rock, NEJM 1991
ADAMTS-13 Deficiency Is
Also Seen in Adult Sepsis
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-Martin et al., Crit Care Med 2007
Decreased Sepsis Survival
with Decreased ADAMTS-13
Above median
Below median
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-Martin et al., Crit Care Med 2007
ADAMTS-13 Deficiency
Correlates with Organ Failure
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ADAMTS-13 Deficiency
Seen in Pediatric Sepsis
-Nguyen, Hematologica 2006
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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
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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
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Thrombotic Microangiopathy:
TAMOF
TF
PAI-1
Endothelium
PAI-1
PAI-1
TF
TFPI
TFPI
PAI-1
PAI-1
PAI-1
PAI-1
Platelet
PAI-1
Plasminogen
ADAMTS13
(vWF-CP) Platelet
x
IL- 8
IL8
TNF-
TNF-
IL- 6+R
IL- 6+R
Endothelium
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vWF
Shear
stress
Plasm
in
X
Platelet
vWF
X
ADAMTS13 Platelet
Platelet
(vWF-CP)
ADAMTS13 Ab
IL-6
ADAMTS13 Ab
IL-6
Platelet
Platelet
Platelet
Platelet
Could plasma exchange be
beneficial in severe sepsis and
MOF/AKI?
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Peak Concentration
Model of Sepsis
Pro-inflammatory
Mediators
Anti-inflammatory
Mediators
Immunohomeostasis
IL-10
CRRT/Plasma Exchange
TNF
PAF
IL-1
SIRS
CARS
SIRS
CARS
Time
Immunohomeostasis
CRRT/Plasma Exchange
SIRS/CARS
Time
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Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003
Controlled Trials:
Plasma Therapies and Sepsis
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Study
Design
Children
Included
?
Technique
Condition
Treated
Mortality
Tx group
Mortality
Control
Difference
RC81
Yes
Plasma
Exchange
Meningococcemia
1/13
6/10
0.025
RC82
Yes
Leukaplasmaph
eresis
Meningococcemia
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
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
60
53.8
50
*
33.3
40
30
20
10
0
Standard
Plasma
- Busund et al., Intensive Care Medicine 2002;28:1410
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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)
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-Nguyen, Carcillo et al., CCM 2008
Children’s of PittsburghPediatric TAMOF Trial
Pediatric Logistic Organ Dysfunction Score
100
PELOD
80
60
40
20
0
0
5
10
15
20
25
30
DAY
Plasma Exchange
No Plasma Exchange
Figure 3. Pediatric Logistic Organ Dysfunction Score, Mean with standard
error 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.
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-Nguyen, Carcillo et al., CCM 2008
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Plasma Exchange
Replenishes ADAMTS-13
ADAMTS13 Activity and PEx vs No PEx
ADAMTS13 Activity (% relative to controls)
100
2F ANOVA p<0.05
80
Plasma Exchange
n=4
60
40
20
No Plasma Exchange
n=4
0
-20
0
1
2
3
4
5
6
7
8
Day
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-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
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Plasma Therapy:
Centrifugation
COBE Spectra
Apheresis System
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Plasma Therapy: Filtration
B Braun Diapact
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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
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 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
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 36 adult TMA patients
 Decreased mortality
with plasma exchange
 Plasma infusion group
received larger volume
of plasma
 Plasma infusion group
had larger weight gain
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31.8
30
25
*
20
15
10
5
0
0
Plasma
Plasma
Infusion
Exchange
- Darmon et al., Crit Care Med, 2006
Pediatric Patients Receiving CVVH
Fluid Overload Increases Mortality
MODS &  3 Organ Involvement
Effect

SE
OR
95% CI
p
PRISM III
0.049 0.058 1.10
0.88, 1.39
0.4
% FO
0.058 0.023 1.78
1.13, 2.82
0.01
- Foland, Fortenberry et al., CCM 2004
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Plasma Exchange vs.
Infusion: Weight Gain
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- 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
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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
11 lived
(73%)
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4 died
6 standard therapy
2 survived
(33%)
4 died
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
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I hope I
haven’t led
you astray
TAMOF Network
Preliminary Data
Dying
with
standard
therapy
Surviving
with
plasma
exchange
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PELOD Score