1. 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

3. 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

4. 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

5. Desperate but Reasonable?

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

7. Extracorporeal Therapies in Septic Shock
Potential benefits
Immunohomeostasis: pro/anti-inflammatory mediators
Control of fluid overload
Mechanical support of organ perfusion during acute episode
Improved coagulation response with decreased organ thrombosis

8. 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

9. 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

10. 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

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

12. TTP
Platelet
vWF
vWF
Shear stress

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

14. vWF
vWF
Platelet
Fibrin
Platelet
vWF
Fibrin

15. 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

16. ADAMTS-13 Deficiency Is Also Seen in Adult Sepsis
-Martin et al., Crit Care Med 2007

17. Decreased Sepsis Survival with Decreased ADAMTS-13
Above median
Below median
-Martin et al., Crit Care Med 2007

18. ADAMTS-13 Deficiency Correlates with Organ Failure

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

20. 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

21. 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

22. 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

23. Could plasma exchange be beneficial in severe sepsis and MOF/AKI?

24. Peak Concentration Model of Sepsis

25. 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

26. 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

27. 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., CCM 2008

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

29. Plasma Exchange Replenishes ADAMTS-13
-Nguyen, Carcillo et al., CCM 2008

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

31. Plasma Therapy: Centrifugation
COBE Spectra
Apheresis System

32. Plasma Therapy: Filtration
B Braun Diapact

33. 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

34. - 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

35. Pediatric Patients Receiving CVVH Fluid Overload Increases Mortality
- Foland, Fortenberry et al., CCM 2004

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

37. 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

38. 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

39. 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

40. 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

41. I hope I haven’t led you astray

42. TAMOF Network Preliminary Data
Dying with standard therapy
Surviving with plasma exchange
PELOD Score