1. 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
Children’s Healthcare of Atlanta at Egleston

2. 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

3. 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 5.49.5/100,000
10.3% hospitalized pediatric sepsis mortality rate overall in US

4. Potential “Desperate Devices” For Extracorporeal Use In Sepsis
Continuous renal replacement therapies (CRRT)
Extracorporeal membrane oxygenation (ECMO)
Extracorporeal liver support devices
Plasma Exchange/Plasmapheresis

5. 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

6. Peak Concentration Model of Sepsis
SIRS
CARS
SIRS/CARS

7. Peak Concentration Model of Sepsis

8. 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)

9. Thrombotic microangiopathy (TMA) Microvascular occlusive disorder
TMAs: Link With Sepsis
Thrombotic microangiopathy (TMA)
Microvascular occlusive disorder
Platelet/vWf microthrombipredispose to MOF
Thrombocytopenia
Abnormalities of vWf cleaving protease

10. TMAs: Link With Sepsis Primary
Thrombotic thrombocytopenic purpura (TTP)
HUS
Secondary
Infection/sepsis
Organ transplants
Chemotherapy

11. 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

12. 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

13. Homeostasis Platelet vWF ADAMTS 13 (vWF-CP) tPA PGI Endothelium

14. TMA X vWF ADAMTS 13 Platelet PAI-1 PAI-1 PAI-1 Plasminogen Plasmin

15. TTP
Platelet
vWF
vWF
Shear stress

16. TTP X Platelet Platelet Endothelium ADAMTS 13 (vWF-CP) vWF
ADAMTS 13 (vWF-CP Ab)
Platelet

17. vWF
vWF
Platelet
Fibrin
Platelet
vWF
Fibrin

18. ADAMTS-13 Deficiency Genetic Consumptive Autoimmune loss: acquired Abs
ADAMTS-deficient mice develop TTP phenotype with E. coli (Motto 2005)
Adult and pediatric sepsis

19. ADAMTS-13 Deficiency in Adult Sepsis
-Martin et al., Crit Care Med 2007

20. Adult Sepsis-Survival by ADAMTS-13 Level
Above median
Below median
-Martin et al., Crit Care Med 2007

21. ADAMTS-13 Deficiency Correlates with Organ Failure

22. ADAMTS-13 Deficiency in Pediatric Sepsis
-Nguyen, Hematologica 2006

23. 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

24. ADAMTS-13 deficiency correlates with thrombocytopenia
-Martin et al., Crit Care Med 2007

25. 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

26. Thrombotic Microangiopathy: TAMOF
IL- 8
TNF-
IL- 6+R
ADAMTS13 Ab
IL-6 X
ADAMTS13
(vWF-CP)
Endothelium
PAI-1
vWF
TFPI
Plasm in
Plasminogen
Platelet TF
Shear stress x

27. Desperate but Reasonable?

28. 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

29. Plasma Therapies
Plasmapheresis: plasma removed  replaced with 5% albumin
Plasma exchange: plasma removed  replaced with donor plasma
centrifugation
filtration

30. Plasma Therapy: Centrifugation
COBE Spectra
Apheresis System

31. 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

32. Plasma Therapy: Filtration
B Braun McGaw Diapact

33. 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

34. Why Not Plasma Infusion Alone?
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

35. - Darmon et al., Crit Care Med, 2006
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

36. Plasma Exchange vs. Infusion: Weight Gain
- Darmon et al., Crit Care Med, 2006

37. 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
Leukaplasmapheresis
3/13
7/9
0.02
RC68 No
Plasma exchange and CVVH
Septic shock
1/7
8/21
0.25
RC83
Plasmapheresis/CVVH
Surgical sepsis
11/19
13/24
0.94
PC70
Plasmapheresis versus plasma infusion
TMA/sepsis
0/14
7/22
0.05
PRCT63
Plasmapheresis
Sepsis
6/14
8/16
0.73
PRCT69
Plasmapheresis/exchange
18/52
28/52

38. 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

39. 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

40. Children’s of Pittsburgh- Pediatric TAMOF Trial
-Nguyen, Carcillo et al., submitted 2008

41. Plasma Exchange Replenishes ADAMTS-13
-Nguyen, Carcillo et al., submitted 2008

42. 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

43. 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

44. 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

45. Alexis- A Success Story

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