1. Use of CRRT in ECMO: Is It Valuable? 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. 2 CRRT and ECMO  What are potential benefits?  What is the experience?  How do you do it?  What are there risks?  What more do we need to know?

3. 3 CRRT on ECMO: Potential Benefits  Management of fluid balance  Decreasing fluid overload  Removal of inflammatory mediators  Enhanced nutritional support  Control of electrolyte abnormalities  Decreased use of furosemide

4. 4 Is Fluid Overload Bad?  Fluid is good in resuscitation!  However, multiple studies (adults, pediatric) suggest survival benefit with decreased fluid overload in critical illness

5. 5 Fluid Overload  Texas Children’s Hospital  21 pediatric ARF patients  Survival benefit remains even after adjusted for PRISM scores Goldstein SL, et al: Pediatrics 107:1309-1312, 2001 Percent Fluid Overload *

6. 6 Fluid Overload  Children’s Healthcare of Atlanta at Egleston  Retrospective review  113 Pediatric patients on CVVH  Multivariate analysis Percent fluid overload independently associated with survival in ≥ 3 organ MODS -Foland JA, Fortenberry et al. Crit Care Med, 2004 * Percent Fluid Overload

7. 7 Fluid Overload Decreased in 3 Organ MODS CRRT Survivors -Foland JA, Fortenberry et al. Crit Care Med, 2004

8. 8 Pediatric Patients Receiving CVVH Factors Associated with Mortality - Foland, Fortenberry et al., CCM 2004

9. 9 Fluid Overload and ECMO: Neonates  As weight gain decreases, ECMO flow decreases  which comes first? As weight reduces, ECMO flow reduces -Kelley RE, et al. J Pediatr Surg, 1991

10. 10 Fluid Overload and Outcome  Seattle Children’s Hospital  77 pediatric patients If pre-CRRT percent fluid overload >10%  3.02 times greater risk of mortality (95% CI 1.5-6.1, p=0.002) Gillespie RS, et al. Pediatr Nephrol 19:1394-1399, 2004

11. 11 We Know UOP Decreases on ECMO!  Children's Healthcare of Atlanta  30 consecutive neonates meeting ECMO criteria – 18 VV ECMO, 12 conventional management Patients who went onto ECMO had:  Greater fluid overload  Lower UOP  Higher BUN  Higher creatinine -Roy BJ, Cornish JD, Clark RH. Pediatrics 1995

12. 12 ECMO and Urine Output - Ref

13. 13 Hemofiltration Cytokine Clearance  Children’s Healthcare of Atlanta at Egleston  6 pediatric patients with culture proven bacterial septic shock and ARF 2 on ECMO  Compared to 3 ARF patients without septic shock 1 on ECMO

14. 14 Blood Black Bile Yellow Bile Phlegm Requisite Bad Humour Slide

17. 17 Absolute cytokine changes in septic shock/ARF patients Log Concentration (pg/ml) p<0.02 * p=0.04 * -Paden M et al., submitted 2008

18. 18 CVVH Associated With Decreased Cytokines in Children with Septic Shock Septic ARF Patients Non-septic ARF Patients * p<0.05 * * -Paden M et al., submitted 2008

19. 19 Cytokine Results: Sample CVVH Patient-Nonseptic Pre-CVVH 12 Hours 24 Hours 48 Hours End of CVVH24 Hours off CVVH Note Scale

20. 20 Cytokine Results in Sample CVVH Patient: Septic Pre-CVVH 12 Hours 24 Hours 48 Hours End of CVVH 24 Hours off CVVH

21. 21 ECMO/CVVH Produces Cytokine Reduction  In vitro study – Increased cytokine levels overall due to ECMO membrane activation Adding a hemofiltration circuit significantly reduced :  IL-1beta  IL-1ra  IL-6  IL-8 -Skogby M, et al. Scand Cardiovasc J. 2000

22. 22 Skogby M, et al. Scand Cardiovasc J. 2000 Jun;34(3):315-20 IL – 8 Reduction with CRRT in ECMO

23. 23 Is Avoiding Lasix Overuse Important?  Potential ototoxicity-particularly in neonates  Lasix use associated with worsened outcomes in adult renal failure

24. 24 Diuretics and Critical Illness  4 University of California Hospitals  552 adults  Use of diuretics increased risk of death or renal non-recovery in adults with ARF Overall 1.77 times greater risk Some subgroups had as much as 3.12 times increased risk. -Mehta RL, et al. JAMA 2002

25. 25 CRRT on ECMO: Published Experience with Use  Michigan PICU Cardiac surgery  Vanderbilt  Atlanta  Chile

26. 26 CRRT/ECMO Experience: Michigan  U of M ECMO Database  35 neonatal and pediatric patients who received ECMO + hemofiltration 15 Survivors  Renal recovery in 14 of 15 (93%) survivors One had Wegener’s as underlying cause of renal failure-subsequently transplanted -Meyer RJ, et al Pediatr Crit Care Med 2001

27. 27 CRRT/ECMO Experience: Cardiac Surgery  University of Michigan  74 post-operative congenital heart disease patients Use of hemofiltration in 35%  5.01 times increased risk of death  Use of hemofiltration indicative of longer ECMO support time  worse outcome was from duration, not hemofiltration -Kolovos et al. Ann Thorac Surg 2003

28. 28 CRRT/ECMO Experience: Cardiac Surgery  Vanderbilt University  84 post-operative congenital heart disease patients Temporary renal insufficiency in 41 patients (48.9%)  CVVH NOT associated with : Ability to wean off ECMO Survival to discharge -Shah SA et al. ASAIO J 2005

29. 29 ECMO/CVVH Experience: Atlanta  Children’s at Egleston ECMO Database (11/97-12/05)  95 neonatal and pediatric patients who received ECMO + CVVH 55 Survivors 14 came off ECMO on RRT (1 on prior to ECMO) 1 needed RRT chronically 1 with CRF but does not need RRT  Renal recovery in 53/55 (96%) survivors Both CRF patients had primary vasculitis -Paden et al., CCM 2007 (abstr)

30. 30 Comparison of CVVH/ECMO vs. ECMO without CVVH  26/86 peds respiratory failure patients received CVVH for >24 hours  Case control comparison: 26 CVVH/ECMO pts. and 26 pts. receiving ECMO without CVVH  No difference in survival or vent days during or after ECMO  Significant differences in fluid balance  Significant treatment differences -Hoover et al., Intensive Care Medicine, in press 2008

31. 31 Fluid Balance With CVVH/ECMO vs. No CVVH/ECMO -Hoover et al., Intensive Care Medicine, in press 2008

32. 32 Comparison of CVVH/ECMO vs. ECMO without CVVH -Hoover et al., Intensive Care Medicine, in press 2008 * * *

33. 33 CRRT/ECMO Experience in Infants: Chile  6 of 12 infants on ECMO received CRRT  Observed complication: excessive ultrafiltration  Survival to discharge in 5 of 6 (83%)  All with normal renal function at discharge -Cavagnaro et al., Int J Artif Organs 2007

34. 34 CRRT on ECMO: How to Perform It  Options: Parallel use of stand-alone CRRT devices (Gambro, Braun)  Pros  Cons Use of inline hemofilter with syringe pumps  Pros  Cons

35. ECMO/CRRT Arrangement: The “Michigan Method”

36. 36 Use of CRRT Devices for Delivery on ECMO

37. 37 CVVH/ECMO: Are There Risks?  Complexity of machinery  Errors due to replacement fluids  Underestimation of fluid removal

38. 38 Sometimes it gets a little crowded

39. 39 CRRT Error Rate Increases with Increasing Flow/Pressure -Sucosky, Paden et al., JMD, in press 2008

40. 40 Error Rate in CRRT/ECMO Circuits  Potential error rate noted in stand-alone CVVH  Ex vivo ECMO circuit  Compared measured versus actual fluid removal rates with inline hemofilter arrangement and with Braun Diapact for CVVH  Significant excess fluid removal over “expected” both for inline device and commercial device -Paden et al., ppCRRT Conference 2008 (abstr)

41. 41 What Further Work Needs to be done?  Improved control of fluid management  Randomized trial to compare CVVH/ECMO

42. 42 Conclusions  CRRT on ECMO can potentially provide a variety of benefits  Experience suggests CRRT can be provided without worsening renal insufficiency and with improved fluid balance, decreased furosemide exposure  Potential risks of excessive fluid removal  Further work to improve accuracy of fluid balance and to determine if use translates into outcome benefit