Pediatric CRRT: The Prescription for Acute Kidney Injury Management

1. Pediatric CRRT: The Prescription Stuart L. Goldstein, MD Associate Professor of Pediatrics Baylor College of Medicine

2. What’s in a CRRT Prescription? • Indication (Why? Who? When?) • Technical Aspects (What?) • Fluids (Symons) • Anticoagulation (Brophy) • Access (Hackbarth) • CRRT Delivery (How?) • Blood pump flow rates • Modality • Priming • Dose

3. Why CRRT in AKI? • Critically ill patient • Advantages • Slower blood flows • Slower UF rates • UF rates can be prescriptive (versus PD) • Adjust UF rates with hourly patient intake • Increased cytokine (bad humors) removal? • Disadvantages • Increased cytokine (good humors) removal? • Non-dialysis personnel with many other bedside responsibilities required to monitor circuit

5. When Should CRRT Be Started? • Standard AKI criteria not responsive to medical therapy OR only preventable with limiting adequate nutrition • Uremia • Hyperkalemia • Acidosis • Fluid Overload • Prevention of worsening fluid overload?

6. Timing of Pediatric RRT • No adequate definition for “timing of initiation” • Absence of a generally accepted, validated and applied AKI definition has impeded the adequate investigation of this question • The decision to initiate RRT affected by • Strongly held physician beliefs • Patient characteristics • Organizational characteristics

7. Retrospective evaluation of 226 children who received RRT for AKI from 1992-1998 • Pressor use surrogate marker for patient severity of illness • Survival defined at PICU discharge

9. Retrospective review of all patients who received CVVH(D) in the Texas Children’s Hospital PICU from February 1996 through September 1998 (32 months) • Pre-CVVH initiation data: • Age • Primary disease leading to need for CVVH • Co-morbid diseases • Reason for CVVH • Fluid intake (Fluid In) from PICU admission to CVVH initiation • Fluid output (Fluid Out) from PICU admission to CVVH initiation • GFR (Schwartz formula) at CVVH initiation

10. 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

11. 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)

12. Survival curve demonstrates that nearly 75% of deaths occurred less than 25 days into the ICU course

13. 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)

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

15. N = 77

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

17. The Evolution of Idea to Practice Paradigm Registry Single center study Randomized Trial

18. Prospective Pediatric CRRT (ppCRRT ) Registry: Phase 1 Design • Collect prospective data from 10 pediatric centers treating 15 to 20 patients annually (376 patients over 5 years) • Each center follows own institutional practice • Patient selection • Initiation and termination • Anti-coagulation protocols • Convection versus diffusion versus hemodiafiltration • Fluid composition

19. 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

20. 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 (40%) at CRRT initiation (p<0.001)

21. The PCRRT Prescription: How? • Blood pump flow rates • Membranes • Priming • Modality • Dose • UF rates

22. Blood flow rates vary by patient size • Mean 5 ml/min/kg • CRRT clearance not limited by Qb • 50% of ppCRRT patients received some convection

24. Pediatric CRRT Circuit Priming • Heparinized (5000 units/L) for most patients • Smaller patients require blood priming to prevent hypotension/hemodilution • Circuit volume > 10-15% patient blood volume • Packed RBCs • Citrated – low ionized calcium • Acid load • Potassium load

25. Bradykinin Release Syndrome • Mucosal congestion, bronchospasm, hypotension at start of CRRT • Resolves with discontinuation of CRRT • Thought to be related to bradykinin release when patient’s blood contacts hemofilter • Most common with AN-69 membranes • Exquisitely pH sensitive

26. Technique Modifications to Prevent Bradykinin Release Syndrome • Buffered system • THAM, CaCl, NaBicarb to PRBCs • Bypass system • prime circuit with saline, run PRBCs into patient on venous return line • Recirculation system • recirculate blood prime against dialysate

27. Waste PRBC

28. Normalize pH D Normalize K+ Waste Recirculation Plan: Qb 200ml/min Qd ~40ml/min Time 7.5 min

29. Does Modality Make A Difference? • Equal clearance of smaller molecules • Middle and large molecule clearance enhanced by convection

30. IgG 150,000 D Creatinine 113 D 2-M 11,800 D Urea 60 D Vit. B12 1,355 D Albumin 66,000 D Glucose 180 D Membrane Selectivity Courtesy of J. Symons

31. Clearance: Convection vs. Diffusion

32. Solute Molecular Weight and Clearance Solute (MW) Sieving Coefficient Diffusion Coefficient Urea (60) 1.01 ± 0.05 1.01 ± 0.07 Creatinine (113) 1.00 ± 0.09 1.01 ± 0.06 Uric Acid (168) 1.01 ± 0.04 0.97 ± 0.04* Vancomycin (1448) 0.84 ± 0.10 0.74 ± 0.04** *P<0.05 vs sieving coefficient**P<0.01 vs sieving coefficient

33. Flores FX et al: CRRT 2006 abstract

34. Flores FX et al: CRRT 2006 abstract

36. ppCRRT Pediatric Sepsis Outcome Data • 57/102 (56%) pts survived. • Ventilated pts had similar survival rate as non-ventilated pts (53% vs. 68%, p=0.1). • There was no significant difference in the survival rate among CRRT modalities. • Tendency toward better survival with convective therapies Flores FX et al: CRRT 2006 abstract

37. Survival Based on CRRT Modality? • Confounded • Center • Timing of initiation • Sepsis definition not standardized • Suggestive • If all else equal, why not convect? Flores FX et al: CRRT 2006 abstract

38. Dialysate/ Ultrafiltration Rates • The UF rate/plasma flow rate [=BFRx(1-HCT)] ratio should < 0.35-0.4 in order to avoid filter clotting (Golper AJKD 6: 373-386,1985) • Dialysate flow rates ranging from 20-30 ml/min/m2 (~2000ml/1.72m2/hr) are usually adequate (experiential but consistent with adult data)

40. Median survival • Group 1 (19 days) • Group 2 (33 days) • Group 3 (46 days) • Groups 2 and 3 with longer survival than Group 1

41. Minimum UF rates > 35 ml/kg/hr • Translates to approximately 2000ml/1.73m2/hour for children

42. Dose: Pediatric CRRT • No published data to suggest an adequate or optimal CRRT dose in children • Small molecule clearance and electrolyte homeostasis is generally easy to achieve • Is more better? • Nutrition balance (what are we removing that we’d like to leave behind?)