1. Does CRRT Improve Renal Recovery and Outcomes? UK Kidney Research Keynote Lecture Patrick D Brophy, MD, MHCDS Director Pediatric Nephrology Professor The University of Iowa London 2015

2. UnEqual

3. Many questions remain unanswered What therapy should we use?What therapy should we use? When should we start it?When should we start it? What are we trying to achieve?What are we trying to achieve? How much therapy is enough?How much therapy is enough? When do we stop/switch?When do we stop/switch? Can we improve outcomes?Can we improve outcomes? Throughout the conference these are the basic questions we have tried to address!Throughout the conference these are the basic questions we have tried to address! What therapy should we use?What therapy should we use? When should we start it?When should we start it? What are we trying to achieve?What are we trying to achieve? How much therapy is enough?How much therapy is enough? When do we stop/switch?When do we stop/switch? Can we improve outcomes?Can we improve outcomes? Throughout the conference these are the basic questions we have tried to address!Throughout the conference these are the basic questions we have tried to address!

4. Overview

5. Pediatric AKI: Definition Past: So many definitions…. Risk Injury Failure End-Stage Kidney Disease (RIFLE) Pediatric RIFLE (pRIFLE) Acute Kidney Injury Network definition Crit Care. 2005; 9(5): 523–527

6. Pediatric AKI: Incidence in PICU Population & Definition-dependent  Cardiac Surgery Kidney Int. 2009 Oct;76(8):885-92 Anesth Analg 2009;109:45–52 (Aprotinin study) N = 395 AKI: 21% AKI: 34%

7. Pediatric AKI: Incidence in PICU Population & Definition-dependent  General PICU Pediatr Crit Care Med 2007; 8:29 –35 Al-Kandari et al, ASN, 2008 Kid Int 2007; 71: 1028-35 82% AKI 4.5% AKI42% AKI Most Critically ill children Vasopressors/Ventilated Urinary catheter pRIFLE All PICU Admx SCr baseline SCr Doubling (pRIFLE I) All PICU stay>48hrs pRIFLE

8. Pediatric AKI: Changing Epidemiology Stickle SH et al: Am J Kid Dis 45:96-101, 2005 Previously: Primary renal diseases

9. CRRT Diagnoses

10. RRT Options  Hemodialysis, Peritoneal Dialysis, CRRT, SLEDD  Each has advantages & disadvantages  Choice is guided by  Patient Characteristics oDisease/Symptoms oHemodynamic stability  Goals of therapy oFluid removal oElectrolyte correction oBoth  Availability, expertise and cost Pediatr Nephrol (2009) 24:37–48

11. Trends in Pediatric RRT Warady et al, Pediatr Neph 2000, 15:11-3 CRRT Increasing 12-US Multicentre ppCRRT Most include Dialysis

12. Why CRRT?  Reduces hemodynamic instability preventing secondary ischemia  Precise Volume control/immediately adaptable  Uremic toxin removal  Effective control of uremia, hypophosphatemia, hyperkalemia  Acid base balance  Rapid control of metabolic acidosis  Electrolyte management  Control of electrolyte imbalances  Allows for improved provision of nutritional support  Management of sepsis/plasma cytokine filter  Safer for patients with head injuries

13. Indications for Pediatric RRT  Electrolyte (metabolic) imbalance  Uremia with bleeding and or encephalopathy  Acuity/Degree of Kidney Injury  reduction in GFR/elevated creatinine  reduction in urine output  Nutritional support  Intoxications, Inborn errors of Metabolism (IEM)  Fluid Overload (hypervolemia with pulmonary edema/respiratory failure)

14. Implications of the available data notan innocent bystander AKI is not an innocent bystander in ICU adequate dosing We must ensure adequate dosing of RRT may Choice of RRT mode may not be critical may be a different beast Septic AKI may be a different beast avert We must strive to avert acute kidney injury

15. Major Renal Replacement Techniques Intermittent Continuous Hybrid IHD Intermittent haemodialysisIHD IUF Isolated UltrafiltrationIUF SLEDD Sustained (or slow) low efficiency daily dialysisSLEDD SLEDD-F Sustained (or slow) low efficiency daily dialysis with filtrationSLEDD-F CVVH Continuous veno- venous haemofiltrationCVVH CVVHD Continuous veno- venous haemodialysisCVVHD CVVHDF Continuous veno- venous haemodiafiltrationCVVHDF SCUF Slow continuous ultrafiltrationSCUF

16. Intermittent Therapies - PRO (Relatively) InexpensiveFlexible timing allows for mobility/transportRapid correction of fluid overloadRapid removal of dialyzable drugs Rapid correction of acidosis & electrolyte abnormality Minimizes anticoagulant exposure

17. Intermittent Therapies - CON Hypotension 30- 60% Cerebral Edema Nutritional Provision Limited therapy duration Renal injury & ischemia Gut/coronary ischemia

18. Intradialytic Hypotension: Risk Factors Age < 5, weight < 10 kg Pressor requirement, Low Predialysis SBP Cardiac disease- congenital repairs Poor nutritional status / hypoalbuminaemia Uremic neuropathy or autonomic dysfunction Severe anemia High volume ultrafiltration requirements

19. Managing Intra-dialytic Hypotension  Dialysate temperature modeling  Low temperature dialysate  Dialysate sodium profiling  Hypertonic Na at start decreasing to 135 by end  Prevents plasma volume decrease  Midodrine if not on pressors  UF profiling  Colloid/crystalloid boluses  Reducing dosing 2005 National Kidney Foundation K/DOQI GUIDELINES

20. Continuous Therapies - PRO **Hemodynamic stability => ??? better renal recovery Stable and predictable volume control (nutrition!) Stable and predictable control of chemistryStable intracranial pressure Disease modification by cytokine removal (CVVH)? ** Depends on strategy and management

21. Continuous Therapies - CON Anticoagulation requirements Higher potential for filter clotting Expense – fluids etc. Immobility & Transport issues Increased bleeding risk High heparin exposure

22. SLED(D) & SLED(D)-F : Hybrid therapy  Conventional dialysis equipment  Online dialysis fluid preparation  Excellent  Excellent small molecule detoxification  Cardiovascular stability maybe as good as CRRT  Reduced anticoagulation requirement  Decreased costs compared to CRRT?  Phosphate supplementation required like CRRT  Conventional dialysis equipment  Online dialysis fluid preparation  Excellent  Excellent small molecule detoxification  Cardiovascular stability maybe as good as CRRT  Reduced anticoagulation requirement  Decreased costs compared to CRRT?  Phosphate supplementation required like CRRT Fliser, T & Kielstein JT. Nature Clin Practice Neph 2006; 2: 32-39 Berbece, AN & Richardson, RMA. Kidney International 2006; 70: 963-968

23. Uremia Control Liao, Z et al. Artificial Organs 2003; 27: 802-807

24. Large molecule clearance Liao, Z et al. Artificial Organs 2003; 27: 802-807

25. Comparison of IHD and CVVH John, S & Eckardt K-U. Seminars in Dialysis 2006; 19: 455-464

26. RRT for Acute Kidney Injury There is some evidence There is some evidence for a relationship between higher therapy dose and better outcome, at least up to a point This is true for IHD* and for CVVH** nodefinitive evidence There is no definitive evidence for superiority of one therapy over another, and wide practice variation exists*** Accepted indications for RTT vary No definitive evidence No definitive evidence on timing of RRT There is some evidence There is some evidence for a relationship between higher therapy dose and better outcome, at least up to a point This is true for IHD* and for CVVH** nodefinitive evidence There is no definitive evidence for superiority of one therapy over another, and wide practice variation exists*** Accepted indications for RTT vary No definitive evidence No definitive evidence on timing of RRT *Schiffl, H et al. NEJM 2002; 346: 305-310 ** Ronco, C et al. Lancet 2000; 355: 26-30 *** Uchino, S. Curr Opin Crit Care 2006; 12: 538-543

27. Therapy Dose in IRRT p = 0.01 p = 0.001 Schiffl, H et al. NEJM 2002; 346: 305-310

28.  The “Ronco Study”  Improved survival in all patients with convective clearance of 35mL/kg/hr  Trend towards improved survival in septic patients with convective clearance of 45mL/kg/hr Ronco, C et al. Lancet 2000; 355: 26-30 Therapy Dose in CVVH

29.  The “ATN Study”  1124 adults in the ICU  563 had intensive therapy  561 had less-intensive therapy

30. ATN Study

32. Intensity of CRRT in Critically Ill Patients (The “RENAL” Study) NEJM 361(17); Oct 2009

33. Intensity of CRRT in Critically Ill Patients (The “RENAL” Study)

34. Outcome with IRRT vs CRRT  Trial quality low: many non- randomized  Therapy dosing variable  Illness severity variable or details missing  Small numbers  Uncontrolled technique, membrane  Definitive trial would require 660 patients in each arm!  Unvalidated instrument for sensitivity analysis Kellum, J et al. Intensive Care Med 2002; 28: 29-37 “there is insufficient evidence to establish whether CRRT is associated with improved survival in critically ill patients with ARF when compared with IRRT”

35. Outcome with IRRT vs CRRT Tonelli, M et al. Am J Kidney Dis 2002; 40: 875-885 No mortality difference between therapies No renal recovery difference between therapies Unselected patient populations Majority of studies were unpublished

36. Outcome with IRRT vs CRRT Vinsonneau, S et al. Lancet 2006; 368: 379-385

37. Summary  There is some evidence  There is some evidence for a relationship between higher therapy dose and better outcome for IHD nodefinitive evidence  There is no definitive evidence for beneficial effects of high dose CRRT despite major attempts to do so  Trials have demonstrated it is difficult to deliver this dose due to unpredictable breaks in treatment-clotting, bag changes, nursing (Vesconi 2009)  Modern IHD approaches may reduce overt hemodynamic instability even in unstable ITU patients  CRRT greater exposure to anticoagulation  There is some evidence  There is some evidence for a relationship between higher therapy dose and better outcome for IHD nodefinitive evidence  There is no definitive evidence for beneficial effects of high dose CRRT despite major attempts to do so  Trials have demonstrated it is difficult to deliver this dose due to unpredictable breaks in treatment-clotting, bag changes, nursing (Vesconi 2009)  Modern IHD approaches may reduce overt hemodynamic instability even in unstable ITU patients  CRRT greater exposure to anticoagulation *Schiffl, H et al. NEJM 2002; 346: 305-310 ** Ronco, C et al. Lancet 2000; 355: 26-30 *** Uchino, S. Curr Opin Crit Care 2006; 12: 538-543

38. Summary  RCT (Uchino 2009) 3-5% incidence of significant bleeding problems as opposed to 1% with IHD  HIT  Filter downtime up to 8 hours per day due to clotting problems and short filter life  Delayed procedures, tests,surgery  The legion of alternatives used emphasize the problem **citrate looks promising  Costs– although this is variable (Srisawat N et al. Crit Care. (2010))

39. Death Approach to Pediatric AKI Normal Increased risk Kidney failure Damage  GFR Antecedents Intermediate Stage AKI Outcomes EGDT Defend Blood Pressure Restore & Optimize Perfusion Use inotropes with care Mitigate Inflammatory Injury Optimize RRT

40. Reference Tools  Adqi.net-web site for information on CRRT  Crrtonline.com-web site for info on Dr Mehta’s meeting  www.PCRRT.com Pediatric CRRT with links to other meetings, protocols, industry www.PCRRT.com  PCRRT list serve (contact Bunchman)