1. The Prospective Pediatric CRRT (ppCRRT) Registry Stuart L. Goldstein, MD Principal Investigator and Founder Timothy E Bunchman Helen DeVos Children’s Hospital Grand Rapids MI USA

2. How did the ppCRRT registry come to exist? Stu Goldstein MD originated the concept and identified a group who work well together to  Initially look at “what is being done as standard of practice ”  Perform studies on New devices Drug clearance  What can be done in the future

3. Bunchman Brophy Goldstein SymonsSomers The Founding Five

4. Co-Investigators/Data Coordinators Michael Somers Michelle Baum Cheryl Baker Pat Brophy Theresa Mottes Jordan Symons Nancy McAfee Tim Bunchman Rick Hackbarth Dawn Eding Mark Benfield David Askenazi James Fortenberry Kristine Rogers Renee Robinson John Mahan Deepa Chand Francisco Flores Kevin McBryde Steven Alexander Annabelle Chua Douglas Blowey Stuart Goldstein

5. ppCRRT Sponsors The ppCRRT Registry receives grant funding from Gambro Renal Products Dialysis Solutions, Incorporated Baxter Healthcare B Braun, Inc

6. ppCRRT Registry: Phase 1 Observational Data Assess for potential associations between various practices and pediatric patient outcomes in 300 patients Assess for potential associations between varying practices and CRRT machine functioning

7. ppCRRT Registry Design Prospective, observational format Informed consent required All centers practice according to their local protocol with respect to  initiation and termination criteria  modality  prescription clearance fluids anticoagulation

8. ppCRRT Data Collected Divided into three electronic or paper forms  Pre-Initiation/Demographic Data  ICU data  Filter data Each patient has unique identifier to describe center site and patient number (e.g., the third Texas Children’s patient is #1003) Some sites’ IRB’s prevent listing date of birth, so investigator calculates age

9. Pre-CRRT Registry Data Demographics  primary disease leading to CRRT  co-morbid illness  MODS (yes/no)  gender  days in PICU prior to CRRT  ICU admit weight and height/length CRRT specifics  Modality  CRRT reason(s) Treatment or prevention of fluid overload and/or Treatment or prevention of electrolyte imbalance  Access size, configuration and site Pediatric Risk of Mortality 2 (PRISM 2) score

10. PRISM 2 score 14 variables, 5 organ domains  Cardiovascular (SBP, DBP, pulse)  Respiratory (Resp rate, pO2, pCO2)  Neurological (Glasgow Coma score, pupillary reaction)  Hepatic (bilirubin)  Metabolic (potassium, calcium, total CO2, glucose) Direct assessment of renal function not included Easy to calculate Data remains with ppCRRT and not sent elsewhere for analysis Pollack M: Crit Care Med. 1988 16:1110-6

11. Pre-CRRT Registry Data: CRRT Initiation Renal failure indices at CRRT initiation  GFR (Schwartz)  Urine output in previous 24 hours Percent fluid overload (%FO) PRISM 2 score CVP Mean airway pressure Number of inotropic agents used Diuretics? (yes/no)

12. Percent Fluid Overload Calculation % FO at CVVH initiation = [ Fluid In - Fluid Out ICU Admit Weight ] * 100% Fluid In = Total Input from ICU admit to CRRT initiation Fluid Out = Total Output from ICU admit to CRRT initiation

13. Registry PICU Data Cardiopulmonary  Maximum inotrope doses  Pressors weaned? (yes/no)  MAP change ICU length of stay

14. ppCRRT Registry Circuit Data Separate dataset for each circuit Machine brand Extracorporeal circuit volume Priming fluid Dialysis or replacement fluid composition Anticoagulation  Citrate  Heparin rate ACT measured per hour Mean ACT # ACT < 180 seconds

15. ppCRRT Registry Circuit Data Clearance prescription  CVVH versus CVVHD versus CVVHDF  ml/1.73m 2 /hour Nutrition prescription at each circuit initiation  Kcal/kg/day  Grams protein/kg/day Total fluid intake Total fluid output Total and net ultrafiltration Percent blood volume UF’d per hour

16. ppCRRT Registry Patient Data: Outcome Survival versus death (discharge from PICU) Attainment of target dry weight Reason to discontinue CRRT  Death  Regained renal function  Underlying illness resolved  Tolerates intermittent hemodialysis

17. ppCRRT Registry Circuit Data: Outcome Filter life-span (hours) Reason for circuit change  clotting  access malfunction  machine malfunction  unrelated patient indication (e.g., needs CT scan)  CRRT discontinued

18. ppCRRT Experience First patient enrolled on 1/1/01 376 patients entered into database as of 07/31/05 (study end) 342 with complete data >60,000 hours of CRRT –Texas Children’s –Boston Children’s –Seattle Children’s –UAB –University of Michigan –Mercy Children’s, KC –Egleston Children’s, Atlanta –All Children’s, Tampa –DC Children’s –Columbus Children’s –Packard Children’s, Palo Alto –DeVos Children’s, Grand Rapids

23. Fluid Overload and CRRT

24. 22 pt (12 male/10 female) received 23 courses (3028 hrs) of CVVH (n=10) or CVVHD (n=12) over study period. Overall survival was 41% (9/22). Survival in septic patients was 45% (5/11). PRISM scores at ICU admission and CVVH initiation were 13.5 +/- 5.7 and 15.7 +/- 9.0, respectively (p=NS). Conditions leading to CVVH (D)  Sepsis (11)  Cardiogenic shock (4)  Hypovolemic ATN (2)  End Stage Heart Disease (2)  Hepatic necrosis, viral pneumonia, bowel obstruction and End-Stage Lung Disease (1 each)

25. Percent Fluid Overload Calculation % FO at CVVH initiation = [ Fluid In - Fluid Out ICU Admit Weight ] * 100% Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12 Fluid In = Total Input from ICU admit to CRRT initiation Fluid Out = Total Output from ICU admit to CRRT initiation

26. Lesser % FO at CVVH (D) initiation was associated with improved outcome (p=0.03) Lesser % FO at CVVH (D) initiation was also associated with improved outcome when sample was adjusted for severity of illness (p=0.03; multiple regression analysis)

27. N=113 *p=0.02; **p=0.01

28. Kaplan-Meier survival estimates, by percentage fluid overload category

29. Seven center study from the ppCRRT Registry 116 patients with MODS PRISM 2 score used to assess patient severity of illness Survival defined at PICU discharge

30. Anticoagulation and CRRT Heparin and citrate anticoagulation most commonly used methods Heparin: bleeding risk Citrate: alkalosis, citrate lock

31. (Citrate = 1.5 x BFR 150 mls/hr) (Ca = 0.4 x citrate rate 60 mls/hr) Normocarb Dialysate Normal Saline Replaceme nt Fluid Calcium can be infused in 3 rd lumen of triple lumen access if available. (BFR = 100 mls/min) ACD-A/Normocarb Wt range 2.8 kg – 115 kg Average life of circuit on citrate 72 hrs (range 24-143 hrs) Pediatr Neph 2002, 17:150-154

32. Seven ppCRRT centers  138 patients/442 circuits  3 centers: hepACG only  2 centers: citACG only  2 centers: switched from hepACG to citACG HepACG = 230 circuits CitACG= 158 circuits NoACG = 54 circuits Circuit survival censored for  Scheduled change  Unrelated patient issue  Death/witdrawal of support  Regain renal function/switch to intermittent HD

35. Access If you don’t have a functional access, you may as well go home Small studies show  Short femoral catheters have greater recirculation  Femoral catheters have shorter functional survival

36. ppCRRT Access Data from entire ppCRRT Assessed for association between functional survival and  Catheter size  Catheter site  Modality (convection vs. diffusion) Femoral (69%) IJ (16%) SCV (8%) Not specified (7%) Hackbarth R et al: IJAIO Dec 2007, 30: 1116-1121

39. p<0.03 in favor of IJ 5 Fr removed from analysis All ACG No difference in citACG Hackbarth R et al: IJAIO Dec 2007, 30: 1116-1121

40. p<0.02 All ACG 8 Fr > 9Fr survival 9 Fr > 8 Fr femoral Hackbarth R et al: IJAIO Dec 2007, 30: 1116-1121

41. p<0.001 No difference in cath size or ACG used between three modalities Modality strongest predictor in Cox Proportional hazards model Hackbarth R et al: IJAIO Dec 2007, 30: 1116-1121

42. At high risk for death with AKI needing CRRT Fluid overload >12% associated with mortality in BMT patients with AKI

43. Stem Cell Transplant: ppCRRT 51 patients in ppCRRT with SCT Mean %FO = 12.41 + 3.7%. 45% survival  Convection: 17/29 survived (59%)  Diffusion: 6/22 (27%), p<0.05 Survival lower in MODS and ventilated patients Flores FX et al: Pediatric Nephrology 2008, 23: 625-630

44. ppCRRT & SCT Patients kept dry prior to CRRT initiation No difference in any parameter at CRRT initiation Paw worse for non- survivors at CRRT end Flores FX et al: Pediatric Nephrology 2008, 23: 625-630

45. ppCRRT Under the guidance of Stu this group has been very productive producing to data 11 papers in CRRT Under the guidance of Stu we are now looking prospectively  Impact of cytokine clearance by modality  Drug clearance by modality