1. Thrombocytopenia-Associated Multiple Organ Failure and Pediatric Septic Shock: Is Plasma Exchange a Promising Therapy? James D Fortenberry MD, FCCM, FAAP Pediatrician in Chief Children’s Healthcare of Atlanta Professor, Pediatric Critical Care Emory University School of Medicine Atlanta, Georgia

2. 2 Disclosures  No financial disclosures  I am an intensivist Dumber than smartest nephrologist Able to intubate dumbest kidney

3. 3 Respiratory Failure Cardiovascular Failure Renal Failure Hematologic Failure Immunologic Failure The MODS Patient HIGH MORTALITY 50-90% -Courtesy of Matt Paden

4. 4 Thrombotic Thrombocytopenic Purpura (TTP)  A thrombotic microangiopathy syndrome  Critical defect: deficiency of ADAMTS-13 (< 10%): A disintegrin and metalloprotease with thrombospondin motifs-13 (formerly vWf cleaving protease)  Ultra-large vWf multimer-platelet thrombi  Microthrombotic multi-organ vascular injury: MOF and autopsy findings

5. 5 Thrombotic Microangiopathy: TTP/TAMOF

6. 6 Thrombocytopenia-Associated Multiple Organ Failure (TAMOF)  A thrombotic microangiopathy described in children (Nguyen, Carcillo 2001)  Similarities to TTP Deficient ADAMTS-13 Increased ADAMTS-13 inhibitors Increased vWF antigen Increased ULvWF multimers Thrombocytopenia  Primarily secondary to sepsis  3 or greater organ failure  High mortality in children

7. 7 ADAMTS-13 Deficiency in Adult Sepsis -Martin et al., Crit Care Med 2007

8. 8 Adult Sepsis-Survival by ADAMTS-13 Level ADAMTS-13 above median Below median -Martin et al., Crit Care Med 2007

9. 9 ADAMTS-13 Deficiency in Pediatric Sepsis -Nguyen, Hematologica 2006

10. 10 Refractory Sepsis/MOSF: Desperate Times… Diseases desperate grown By desperate appliance are relieved, Or not at all. -Claudius, King of Denmark, Hamlet Act IV Scene 3 W. Shakespeare

11. 11 Rationale for Plasma Exchange: TTP  80-90% mortality  Plasma Exchange  10% mortality: Replenishes ADAMTS- 13 Removes ADAMTS-13 inhibitors Removes thrombogenic ULvWf multimers -Rock, NEJM 1991

12. 12 Plasma Exchange: Rationale In Sepsis  Subset of patients who demonstrate thrombotic microangiopathy similar to TTP  Similar clinical and coagulation factor profile Deficiency of vWf cleaving protease (ADAMTS- 13) Platelet/vWf microthrombi Thrombocytopenia

13. 13

14. 14 Peak Concentration Model of Sepsis

15. 15 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 plasmapheresis - Busund et al., Intensive Care Medicine 2002;28:1410 * *P<.05

16. 16 TAMOF/Plasma Exchange in Children: CHP Trial  28 children with TAMOF Decreased ADAMTS-13 vs. non-TAMOF Correlated with outcome  Small RCT (10 patients)  28-day survival No PEx: 1/5 PEx: 5/5 (p <.05) -Nguyen et al., CCM 2008

17. 17 CHP Trial: PELOD Improved with PEx -Nguyen et al., CCM 2008 PEx

18. 18 Plasma Exchange Replenishes ADAMTS-13 -Nguyen et al., CCM 2008

19. 19 Children’s TAMOF Network  Broader group of Pediatric ICUs  Goals: Create a study group to perform prospective, observational studies Identify TAMOF and evaluate:  Clinical and biochemical course  Use of specific therapies  Associated outcomes Inform development of future prospective trials

20. 20 Children’s TAMOF Network  Enrolling centers (site co-I): Children’s of Atlanta at Egleston: coordinating center (Fortenberry) Children’s of Pittsburgh (Raj Aneja/Joe Carcillo) Cincinnati Children’s (Derek Wheeler) Nationwide Children’s-Columbus OH (Mark Hall) Phoenix Children’s Hospital (Sandra Buttram/Heidi Dalton) Texas Childrens’ Hospital (Laura Loftis/Trung Nguyen) Michigan-Mott Children’s (Yong Han) Minnesota (Rod Tarrago) Vanderbilt-Carrell Children’s (Rick Barr/Geoffrey Fleming)

21. 21 Hypotheses  Children with TAMOF demonstrate decreased ADAMTS-13 levels and increased vWf antigen levels.  Children with TAMOF receiving PEx demonstrate associated improvement of organ dysfunction and survival vs. those receiving standard therapy alone.

22. 22 Methods  Prospective, observational, nonrandomized cohort study  Enrolled patients 1 month-21 years of age meeting TAMOF criteria: Sepsis, transplant, chemotherapy Platelet count < 100,000/mm 3 Organ failure index (OFI) > 2  Data collected via web-based registry

23. 23 Methods  Blood obtained for: ADAMTS-13 vWf antigen levels Studies performed at Baylor College of Medicine (Trung Nguyen MD)  Therapy, and use of PEx at attending/center discretion Typical: centrifugation approach Suggested protocol:  FFP: 1.5x plasma volume day 1  1x plasma volume daily exchanges x 4 days Duration at MD discretion

24. 24 Results: Demographics OverallNo PEx (21)PEx (60) Mean age (yr)8.6 + 6.26.7 + 6.39.2 + 6.4 Mean weight (kg) 35.2 + 27.929.8 + 27.637.2 + 28.5 Race: White (%)65.463.666.1 Race: A-A19.822.718.6 Diagnosis- Sepsis 79/8120/2159/60 Ever on ECMO30/81 (37%)4/21 (13)26/60 (43.3) Ever on CRRT46/81 (56.8%)8/21 (41.1)38/60 (63.3) -No differences between groups - 81 patients enrolled and met criteria

25. 25 Results: Severity of Ilness OverallNo PEx (21)PEx (60)P value Baseline PELOD 20.2 + 12.115.8 + 10.121.9 + 12.4.04 Baseline PRISM18.2 + 6.816.9 + 5.518.7 + 7.20.28 Baseline OFI4.5 + 1.24.2 + 1.04.6 + 1.20.21 Baseline Platelet Count (x 1000) 62.2 + 42.155.9 + 3564.6 + 44.70.42 Baseline ADAMTS-13 (%) 52.9 + 27.863.7 + 2649.9 + 280.22 Baseline vWF Ag (%) 161 + 66.3217 + 73146 + 56.40.005

26. 26 Results: Therapies  Treatment: No PEx: 21 patients PEx: 60 patients  Use of CVVH: 46 patients (57%) No PEx 8 (41%) PEx 38 (63%) p = 0.07  Use of ECMO: 30 patients (37%) No PEx: 4 (13%) PEx: 26 (44%) p = 0.07

27. 27 TAMOF Network Results: 28 Day Survival No PEx: 61.9% PEx: 68.3% P = 0.5

28. -PELOD scores decreased more rapidly in patients receiving PEx (p <.05) *

29. - PEx associated with increase in ADAMTS-13 in first 4 days

30. 30 Multivariable Risk Factors for Death: PELOD and Plasma Exchange Variable Descriptive Statistics No. (%) / Mean (SD) Estimate Standard Error Odds Ratio 95% CIP-value ECMO30/81 (37.0%)0.46760.61671.5960.48-5.40.45 CVVH45/81 (55.6%)0.74840.62152.1140.63-7.20.23 Baseline PELOD (per 5 pt increase) 21.2 (11.4)0.11000.03211.7341.27-2.40.0006 MRSA Infection12/81 (14.8%)0.86181.22002.367 0.51- 10.9 0.27 Plasma Exchange 60/81 (74.1%)-1.32130.68010.267 0.07- 1.01 0.05

31. 31 Risk Factors  For every 5 unit increase in PELOD score at baseline (day 1 on study) mortality risk increases 1.73 times (p=0.0006)  PEx reduced risk of death by 73.3% = odds of survival 3.75 times higher with PEx (p = 0.05)

32. 32 Conclusions  TAMOF patients demonstrated: Decreased ADAMTS-13, increased vWf antigen, consistent with TTP profile  Use of PEx vs. standard therapy was associated with:  Greater improvement in organ dysfunction  Better survival (adjusted for severity, risk factors)  Cannot conclude outcome benefit

33. 33 Next Steps  These results could inform a randomized trial to determine contribution of PEx to TAMOF outcome  Need to better define subgroups; use biomarkers ADAMTS-13 real-time  Submitted a U34 Planning Grant: Rare Thrombotic and Hemostatic Disorders

34. 34 Alexis- A Success Story

35. 35 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  Plasma Exchange Restores factor homeostasis like 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 vs. infusion

36. 36 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 volumes had larger weight gain - Darmon et al., Crit Care Med, 2006 *

37. 37 Days of Plasma Exchange Non-survivors (n = 19) Survivors (n = 40) No. / Total (%) Total Days on PEx Therapy16/19 (31.6%)0/40 (0%) 24/19 (21.1%)1/40 (2.5%) 31/19 (5.3%)7/40 (17.5%) 41/19 (5.3%)1/40 (2.5%) 52/19 (10.5%)14/40 (35.0%) 61/19 (5.3%)6/40 (15.0%) 71/19 (5.3%)9/40 (22.5%) 82/19 (10.5%)0/40 (0%) 100/19 (0%)2/40 (5.0%) 141/19 (5.3%)0/40 (0%)

38. 38 Results: Site Enrollment Non-Plasma Exchange Group (n = 21) Plasma Exchange Group (n = 60) Deaths by Site CHOA-Egleston0/1 (0%)10/22 (45.5%) Pittsburgh-0/6 (0%) Columbus3/5 (60.0%)- Cincinnati0/2 (0%)- Texas Children’s3/5 (60.0%)1/2 (50.0%) Minnesota0/1 (0%)3/13 (23.1%) Vanderbilt1/6 (16.7%)2/4 (50.0%) Michigan-1/9 (11.1%) Phoenix1/2 (50.0%)2/3 (66.7%) All sites8/21 (36.4%)19/60 (32.2%)

39. 39 Results: TAMOF Patients  Overall survival 54/81 (67%) No PEx: 13/21 (61.9%) PEx: 41/60 (68.3%) NS  Survival: PELOD > 21 (47) No PEx 50 % PEx 56.4 %  Survival: PELOD < 21 (34) No PEx 77.8 % PEx 90.5 %

40. 40 Everything will be all right in the end. So if it is not all right, then it is not yet the end.

41. 41 Desperate but Reasonable?

42. 42 Plasma Therapies in Sepsis- Why Use Them?  General: exchange “transfer factors”  Specific: control thrombotic microangiopathy (TMA)  Slow progression of TMA-induced organ failure  Treat coagulation abnormalities