Timothy E. Bunchman Professor Nephrology & Transplantation Grand Rapids, MI

1. The Prospective Pediatric CRRT (ppCRRT) Registry Timothy E. BunchmanProfessor Nephrology & TransplantationGrand Rapids, MI

2. Outline • Why is the ppCRRT Registry needed? • Study aims • Registry design • Data acquisition and transfer • Grant funding and distribution • IRB requirement variations • Registry database fields and definitions • Published data • Future projects

3. ppCRRT Registry Rationale • No single pediatric center cares for enough CRRT patients annually to analyze the effect of more than a few variables on patient outcome • Mitigate geographical and institutional effects on • Patient demographics • CRRT practice patterns • SHARE INFORMATION • Generate hypotheses for future RCT’s

4. ppCRRT Rational: The Need For Power • An adequately powered study to detect the differences in percent fluid overload between survivors (16.4% +/- 13.8%) and non-survivors (34.0% +/- 21.0%) observed in a previous study1 requires 25 patients • To control for severity of illness and perform multivariate analysis requires more patients for each variable assessed 1. Pediatrics. 2001 107:1309-12

5. ppCRRT Registry: Phase 1 Aims • Assess for potential associations between various practices and pediatric patient outcomes • Assess for potential associations between varying practices and CRRT machine functioning • Determine CRRT clearance rates of various SIRS and CARS cytokines in children with sepsis

6. 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 • Centers agree to collect the same data on standardized forms

7. ppCRRT Data Decision #1: Primary Disease Definitions • ARF causes are often multi-factorial • To prevent artificial biases toward reporting of particular disease entities • no a priori primary disease classifications established at ppCRRT inception • site PI’s given full latitude to classify their patients’ primary diseases • Site PI diagnoses left unchanged for abstract reports • For manuscripts, ppCRRT PI reviews all diagnoses and created a standard definition list • list reviewed by each center PI who then have final option to reassign their patients

8. ppCRRT Data Decision #2: How to Control for Severity of Illness • Large single center pediatric CRRT study showed higher mortality in children with ARF on inotropes • Controlling for illness severity critical to make any valid statements regarding outcome • Many scoring systems all with different attributes • ppCRRT needs a severity of illness scoring system to control for SOI, NOT to predict outcome • SOI to be assessed at ICU admission and CRRT initiation 1.Bunchman TE et al: Ped Neph 16:1067-1071, 2001

9. ppCRRT Data Acquisition and Transfer • Each site sent a PC database program and an electronic database file via e-mail • Data coordinator from each site in contact with SLG by phone to enter first data set to ensure consistency • Data entered into program on PC or on hardcopy • Completed patient files e-mailed or faxed back to SLG at Texas Children’s Hospital • Site data merged into single ppCRRT database, which resides solely at Texas Children’s Hospital • Database modifications, based upon suggestions from the group, e-mailed back to sites

10. Grant Funding: Another ppCRRT Decision • Funding equally divided among all active centers as of January 1st of each year following date of grant award • Active IRB status • At least one patient enrolled • SLG provides frequent updates regarding grant awards, funding dates and amounts • Grants are for unrestricted use at the discretion of each site PI within the constraints of PI’s institution • No contracts exist between sites, only contract is between funding sources and SLG/Texas Children’s Hospital

11. Presentations/Abstracts/Manuscripts • All active ppCRRT members will have the opportunity to participate in ppCRRT related academic endeavors • First authorship to ppCRRT who performs data analysis and prepares abstract/manuscript • SLG edits all work to ensure format consistency

12. 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

13. 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

14. 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

15. 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)

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

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

18. 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

19. ppCRRT Registry Circuit Data • Clearance prescription • CVVH versus CVVHD versus CVVHDF • ml/1.73m2/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

20. ppCRRT Cytokine Clearance Study • Include patients with documented bacterial sepsis • Exclude patients receiving pharamacological immunosuppression or with an immunodeficiency • Measure cytokine levels from access port, post filter and dialysate/filtrate prior to, 1 and 24 hours after CRRT initiation • TNF-alpha • IL-1beta • IL-6 • IL-10 • GCSF

21. 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

22. 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

23. The ppCRRT Data • Center and Patient Demographics • Patient Sub-Populations • Infants • BMT • Circuit Function • MODS

24. ppCRRT Experience • First patient enrolled on 1/1/01 • 370 patients entered into database as of 07/12/05 • Currently 13 active pediatric centers • Texas Children’s • Boston Children’s • Seattle Children’s • UAB • University of Michigan • Mercy Children’s, KC • Egleston Children’s, Atlanta • All Children’s, St. Petersburg • DC Children’s • Columbus Children’s • Packard Children’s, Palo Alto • DeVos Children’s, Grand Rapids • Cleveland Clinic

25. Site Census

26. Patient Demographics • Newborn to 25 years • 59% males • Weights 1.3 – 160kg (mean 33.5 kg) • Mean 6.5 days in ICU prior to CRRT • (range 0 – 135 days, median 2) • Modality • CVVH (33%) • CVVHD (54%) • CVVHDF (13%)

27. ppCRRT Data: Size Distribution

28. N Survi vors Non - Survivors % Survival Indications for CRRT: Fluid overload and electrolyte imbalance 60 29 31 48 Fluid overload only 41 25 16 61 Electrolyte imbalance only 19 11 8 58 Prevent fluid overload to allow intake 8 6 2 75 Other 12 8 4 67 Diagnoses: Sepsis 37 20 17 54 Cardiac disease/transplant 21 13 8 62 Bone marrow transplant 13 4 9 31 Malignancy 13 6 7 46 Liver disease/transplant 6 3 3 50 Renal failure 12 9 3 75 Inborn error of metabolism ppCRRT Demographics 6 5 1 83 Pulmon ary failure 10 7 3 70 Hypovolemic Shock 4 3 1 75 Drug toxicity 3 3 0 100 Other 13 7 6 54

29. CRRT for Infants < 10kg • Previous retrospective data1 from 85 infants who received CRRT from 1993 to 2001 • 38% patients survived • 25% patients < 3 kg survived 1. Symons JM et al : Am J Kidney Dis. 2003 May;41(5):984-9

30. ppCRRT Data: Infants < 10 kg • 28 children < 10 kg • 14 boys; 14 girls • Median age 40 days old • range 3 days to 2.9 years old • Median weight 4.1 kg • range 1.3 to 9.5 kg • Indication for CRRT: • 75% fluid and electrolyte imbalance • 25% metabolic anomaly or toxin • CRRT vascular access location: • 67% femoral vein • 18% internal jugular vein • 15% subclavian vein

31. ppCRRT Infant Prescription Data • Modality: CVVHD (25/28 children) and CVVH (3/28) • Median blood flow: 9 ml/kg/min (range 0 to ml/kg/min) • Median dialysate or replacement fluid rates: 2600 ml/hr/1.73M2 (range 0 to 12,700 ml/hr/1.73M2) • Median net ultrafiltration: 780 ml/kg • Median CRRT duration 4 days • (range 1-99 days)

32. ppCRRT Infant Survival Data

33. ppCRRT Infant Data: Clinical Variables

34. Pediatric BMT/ARF Data • Single center trials demonstrate survival rates of 42% for patients needing RRT1,2 • Recent study suggests maintenance of fluid overload < 12% important for survival2 • Recent study showed aggressive CRRT in intubated BMT patients helpful3 1. Bunchman TE et al: Pediatr Nephrol. 2001 16:1067-71 2. Michael M et al: Pediatr Nephrol. 2004 19:91-5 3. Alexander SA et al: Blood Purification 21:2003 (CRRT meeting)

35. ppCRRT BMT Patient Data • 22 patients • Median age 9.45 years (range 2.2 - 23.5 years) • CRRT modalities • CVVHD (45%) • CVVH (41%) • CVVHDF (14%) • Diagnoses leading to CRRT • Sepsis (18%) • Hepatorenal syndrome (14%) • No single Dx (54%) • 8/22 (36%) patients survived

36. ppCRRT BMT Data: Clinical Variables

37. ppCRRT MODS Data

38. ppCRRT MODS Data • BASELINE DEMOGRAPHICS • 134 patients entered (1/1/2001 to 5/15/03) • 102/134 (76%) with MODS (2+ organs involved) • Mean age 8.8 + 7.1 years (2 days to 25.1 years) • Mean weight 34.1 + 23.6 kg (3.2 to 95.4 kg) • Mean GFR 36.9+ 28.7 at CRRT initiation • Median 3 ICU days prior to CRRT initiation • Range 0 to 103 days • 66/102 (65%) less than 7 days

39. ppCRRT MODS Data • MOST COMMON PRIMARY DISEASES • Sepsis (28.4%) • Cardiovascular shock (21.6%) • BMT/Malignancy (13.6%)

40. ppCRRT MODS Data: Modality

41. ppCRRT MODS Data: Survival

42. ppCRRT MODS Data • BASELINE DEMOGRAPHICS • 157 patients entered (1/1/2001 to 5/31/04) • 116 with MODS (2+ organs involved) • Mean age 8.5 + 6.8 years (2 days to 25.1 years) • Mean weight 33.7 + 25.1 kg (1.9 to 160 kg) • Median 3 ICU days prior to CRRT initiation • Range 0 to 103 days • 67%less than 7 days Goldstein SL et al: Kidney International 2005

43. ppCRRT MODS Data: Clinical Variables Goldstein SL et al: Kidney International 2005

44. ppCRRT MODS Data: Other Analyses • 77% of non-survivors die within 3 weeks of ICU admission • Survival rates similar by CRRT modality (H 57%), (DF 53%), (HD 50%) • Survival rates similar for patients on: 0-1 (53%), 2 (54%) or 3+ (39%) pressors • Survival rates better for patients with: <20% FO (59%) versus >20% FO (35%) at CRRT initiation (p<0.001) Goldstein SL et al: Kidney International 2005

45. ppCRRT: Anticoagulation HepACG Protocol and Data Analyzed • Heparin rates and boluses adjusted to keep activated clotting times (ACT) 180-240 seconds • Mean heparin rate (units/kg/hour) • ACT measurement rate (#ACT’s/hour) • #ACT’s less than 180 seconds CitACG Protocol • Regional citACG in CVVH-D mode • ACD-A infusion into circuit arterial line to keep circuit ionized calcium 0.25-0.5 mmol/L • Central calcium chloride infusion to keep patient ionized calcium between 1.1 and 1.3 mmol/L

46. ppCRRT: Anticoagulation Complications • Circuit clotting • Patient systemic bleeding • Metabolic • Alkalosis • Citrate lock: elevated total serum calcium with decreased serum ionized calcium Statistical Analysis • Log-rank analysis comparing circuit survival between hepACG, citACG, and noACG • Circuit survival data censored for log-rank analysis included circuits discontinued for: patient test, patient death, change to hemodialysis, or scheduled circuit change

47. ppCRRT- Anticoagulation Center, Patient and Circuit Demographics • Data collected from 1/1/01 through 10/31/02 • HepACG only: 3 centers (1 CVVH, 2 CVVHD) • CitACG only: 2 centers • HepACG changed to CitACG: 2 centers • 138 patients total • 18208 hours of CRRT circuit time • 230 hepACG circuits (52%) (9468.hrs) • 158 citACG circuits (36%) (6545 hrs) • 54 noACGcircuits (12%) (2185 hrs)

48. ppCRRT-Anticoagulation Reasons for Circuit Change

49. ppCRRT: Anticoagulation

50. HepACG CitACG p Hep or NoACG p CitACG Mean duration 42 + 27 44 + 36 NS 43 + 32 27 + 22 <0.01 (hours) % functioning @ 69 69 NS 69 28 <0.01 60 hours ppCRRT Data: Anticoagulation