1. WFPICCS World Congress, 2014 Istanbul, Turkey

2. SHOCK ACCM Guidelines ECMO LIVER FAILURE MARS CRRT PLASMA EXCHANGE SS disease Blood Exchange Immune/disease Plasmapheresis DIC/TAMOF Coagulopathy FFP + CRRT PLASMA EXCHANGE OLIGURIA/ARF DIURETICS CRRT ARDS SURFACTANT LEUKOPHERESIS CRRT/ECMO

3.  P. Blood Products and Plasma Therapies  1. We recommend similar hemoglobin targets in children as in adults. During resuscitation of low superior vena cava oxygen saturation shock (< 70%), hemoglobin levels of 10 g/dL are targeted. (Grade 2A).  2. We recommend similar platelet transfusion targets in children as in adults (Grade 2c)   3. We recommend the use of plasma therapies in children to correct sepsis induced thrombotic disorders including progressive Disseminated Intravascular Coagulation, Secondary Thrombotic Microangiopathy, and Thrombotic Thrombocytopenic Purpura (Grade 2c)

4. THROMBOCYTOPENIA ASSOCIATED MOF ICU PATIENT

5. F Mortality rate on Thr pts vs non-Thr pts F day 4 = 33% vs 16% F day 14 = 66% vs 16% (Akca et al., CCM 2002) Survivors Non-survivors Platelet count rises in survivors

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

7. TFPI Heparin ATIII Prot C APC + PGI Thrombomodulin PGI TFPIHomeostasis tPA

8. Platelet Fibrin vWF:Platelet Thrombus PAI-1 tPA Platelet vWF Platelet vWF

9. Fibrin PAI-1 Platelet Fibrin Platelet vWF Platelet Fibrin Platelet vWF Platelet Endothelium PAI-1 tPA Fibrin Thrombus

10. vWF Platelet vWF Shear stress TTP

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

12. Fibrin Platelet vWF Platelet Fibrin vWF TTP

13. Endothelium PAI-1 vWF TF vWF PAI-1 TF PAI-1 VII DIC

14. TF vWF PAI-1 TF VII vWF TF Platelet DIC Consumptive low fibrinogen

15. Endothelium PAI-1 TF PAI-1 vWF TFPI TMA  vWF CP  ADAMTS 13

16. Plasmin Plasminogen PAI-1 X TMA vWF Platelet  ADAMTS 14  vWF CP

17. TF PAI-1 vWF TFPI Platelet vW F Platelet TMA Nonconsumptive normal fibrinogen

18. Brain: 40x with no clots

19. Brain: 40x with clots

20. Kidney: 100x with no clots

21. Kidney: 100x with clot

22. DIAGNOSTIC CRITERIA FOR TAMOF  Thrombocytopenia + AKI  Increased LDH  Normal PT/aPTT or elevated  Multiple organ failure  Remove underlying cause and can respond to TTP like steroid/plasma exchange protocol.

23. PLASMA INFUSION OR EXCHANGE?  Plasma Infusion  Restores clotting factors (VII, VIII, X etc)  Restores vWF cleaving protease  Restores prostacyclin  Restores protein C and antithrombin III  Restores tPA  Plasma Exchange  Removes Abs to vWF cleaving protease  Removes vWF  Removes PAI-1  Removes Tissue Factor

24. PLASMA EXCHANGE MAN

25.  RCT comparing plasma infusion to plasma exchange for TTP showed a significant beneficial treatment effect with plasma exchange therapy  Plasma exchange:  2/51 (4%) deaths  40/51 (80%) responded  Plasma infusion:  8/51 (16%) deaths  25/51 (50%) responded (Rock et al., NEJM 1991)

26. Plasma Exchange Standard Therapy (Busund et al., Intensive Care Med 2002) Plasma Exchange Improved Outcome in Adult Severe Sepsis

30. © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. Published by Lippincott Williams & Wilkins, Inc. 6 Blood Purification and Mortality in Sepsis: A Meta-Analysis of Randomized Trials*. Zhou, Feihu; MD, PhD; Peng, Zhiyong; MD, PhD; Murugan, Raghavan; MD, MS; Kellum, John; MD, MCCM Critical Care Medicine. 41(9):2209-2220, September 2013. DOI: 10.1097/CCM.0b013e31828cf412 Figure 3. Risk ratios for different modality of blood purification versus conventional treatment. Pooled risk ratios are from a random effects model; size of the data markers indicates weight of the study. A, Different modalities of blood purification versus conventional treatment. B, Different geographic region and hemoperfusion analysis of blood purification versus conventional treatment. M-H = Mantel-Haenszel. Plasma Exchange associated With reduced mortality In adult sepsis trials RR 0.63 (0.42,0.96) p = 0.03 ASFA recommends plasma Exchange for Sepsis induced TAMOF Grade Level III C

32. PELOD decreased from 25.0  2.0 to 0.8  0.6 with plasma exchange at 28 d PELOD increased from 25.4  2.3 to 73.6  18.4 without plasma exchange 73.6  18.4 without plasma exchange at 28 d p < 0.001, power = 1.0, 2F-RM ANOVA

33.  Australian study – 40 + children with severe sepsis randomized to plasmafiltration showed no difference  US TAMOF cohort 81 patients showed sicker patients received plasma exchange with same survival  Turkey TAMOF cohort 46 patients showed improved survival with plasma exchange  My unofficial combination of the USA and Turkey TAMOF cohort studies (n =127) shows reduced mortality with plasma exchange. Mortality decreased from 56% to 30% (p < 0.05) NNT = 4.  Randomized controlled international trial is warranted for TAMOF (NOT severe sepsis without TAMOF).

34.  From 2004-2012 10.8% of Pediatric Severe Sepsis kids received ECMO(4.2%), CRRT (5.3%), and/ or PLEX (4.2%)  1, 162 received PLEX including 196 (11.9% of all ECMO); and 30 on CRRT + ECMO(1.8% of all ECMO).  PLEX and/or ECMO was more commonly used in infants and CRRT in adolescents  2004-2012 Hospital Mortality: PLEX = 20.9%; CRRT = 45%; ECMO = 49.5%

35.  7/8 survived with two volume plasma /whole blood exchange  Fluid balance maintained  Coagulation restored

37.  8/14 adults/children survived with 72 h plasmafitration and partial FFP replacement compared to 8/16 without.

40.  Follow ACCM shock Guidelines  Give 200 mL/kg/24 hr FFP infusion  Maintain fluid balance with CRRT  Mortality rate dropped from 21 % to 1% after 2002