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

15

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