1. 0 CRRT in Liver Failure Akash Deep Director - PICU King’s College Hospital London Chair Renal/CRRT Section European Society of Pediatric and Neonatal Intensive Care (ESPNIC)

2. Speaker Disclosure XNo, nothing to disclose Yes, please specify: Company Name Honoraria/ Expenses Consulting/ Advisory Board Funded Research Royalties/ Patent Stock Options Ownership/ Equity Position Employee Other (please specify) Example: company XYZ xxx

3. Overview AKI and CRRT in ALF CRRT in CLD/ AoCLF Role of MARS and TPE in Liver failure Anticoagulation in liver Patients 2

4. RRT in liver patients ALF AoCLF Post Liver Transplant Metabolic disease- hyperammonaemia, primary hyperoxaluria CRRT – standard ICU indications in patients with liver disease

5. pCCRT Rome 2010 4 Survival in patients treated by RRT according to diagnoses: ppCRRT Registry Symons, Clin J Am Soc Nephrol, 2: 732, 2007

6. CRRT in ALF 5

7. ELAD ? ? Bridging means identifying which patient is sufficiently lucky to survive

8. Why use liver support? Survival ? Improved Cardiovascular Stability Improved HE, decreased ammonia Control fluid balance (before/after ELT) Increase delay to ELT, bridge to ELT Standard use in ICU setting Conducive Environment for Either Liver Regeneration /Liver Transplant Hepatology 1998:27:1050-5

9. Controversies in RRT in Liver Failure Why do patients with Liver failure develop AKI? What is the best time to initiate RRT in patients with ALF? - Elective versus standard CRRT What dose of RRT is the best dose? Anticoagulation in CRRT for ALF Ideal Extracorporeal Liver Assist Device (ELAD) – excretory and synthetic function 8

10. Mechanisms of AKI in ALF 9 Multifactorial Pre-renal AKI Acute tubular necrosis due to profound hypovolemia and hypotension Direct drug nephrotoxicity (paracetamol, NSAIDs) Hepatorenal syndrome Intra-abdominal hypertension (IAH) and development of abdominal compartment syndrome

11. Pathogenesis of AKI in ALF Arterial vasodilatation (‘’VASOPLEGIA’’) Decreased SVR High Cardiac Output Renal Auto-regulation becomes Pressure Dependent - Intra-renal Vasoconstriction 10

12. Why patients with FHF die ? Cerebral edema/intracranial hypertension Sepsis – MOSF SIRS at presentation associated with mortality - immune modulation

14. Ammonia levels and its brain delivery predicts brain swelling and advanced HE Bernal et al. Hepatology, 2007 Clemmesen et al. Jalan et al. J Hepatology; 2004 Oct;41(4):613-20 Bhatia et al. Gut. 2006 Jan;55(1):98-104.

15. Evidence for Ammonia Comparison of arterial ammonia levels at admission between survivors and non ‐ survivors among acute liver failure patients Gut. 2006 January; 55(1): 98–104

17. Hyponatremia potentiate ammonia effect on HE Gines et al Hepathology 2008

18. 17 WITH 35 MLS/KG/HR - At 1 hour AC – 39 AND AT 24 HOURS – 44MLS/MIN WITH 90 MLS/KG/HR – AT 1 HOUR – 85 AND AT 24 HOURS 105 MLS/MIN. Ammonia clearance is closely correlated with ultrafiltration rate. HF was associated with a fall in arterial ammonia concentration

19. 18 Overall mortality was 45.4% (n = 10). Emergency liver transplantation was performed in eight children. Five patients spontaneously recovered liver function HVHF - > 80mls/kg ultrafiltrate, Median flow of ultrafiltrate was 119 mL/kg/hr(80– 384). After 48 hours of treatment, mean arterial pressure (p = 0.0005), grade of hepatic encephalopathy (p = 0.04), and serum creatinine

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21. Authors – Akash Deep, Anil Dhawan

22. RRT – Indications in ALF Hepatic encephalopathy grade 3-4 NH3 >150 µmol /litre and not getting controlled or an absolute value >200 µmol /litre Renal dysfunction (Oligo-anuria, Hyperkalemia, fluid overload) Metabolic abnormalities ( hyponatremia Na <125 meq/litre, High lactate and increasing despite optimising fluid therapy, Metabolic acidosis) No one indication is an absolute one for initiation of RRT 21

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24. 23 Primary outcome : Survival to hospital discharge with or without liver transplantation Secondary outcome: arterial ammonia, lactate, percentage fluid overload, creatinine and mean arterial pressure

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27. 26 Box plot of the trend in ammonia level (umol/L) by survival.

28. Kaplein Meier 60 day survival curves according to age- CRRT pts 1 year <1 gray >=1 black P=0.0095 Y = probability of survival X = time in days

29. Kaplan Meier Curve for CRRT pts no transplant; shows improved survival with CRRT severity adjusted by PELD Non CRRT dotted CRRT solid p=0.002 Y = probability of survival X = time in days Since transplantation interferes with the natural progression of PALF; analysed pts didn’t undergo transplant; Severity adjusted for case mix with PELD

30. Kaplan Meier Curve for Survival of PELD Adjusted PALF on CRRT – Severity by PELD Score; <2011 dotted >= 2011 solid P= 0.4 (not) Y = probability of survival X = time in days

31. HV-CVVH in Pediatric FHF Reduces ELT requirement ? Improved hemodynamic, renal and neurological function Allows a prolonged delay to ELT ?

32. Continuous vv hemofiltration and plasma exchange in infantile ALF - NCCH, Tokyo, Japan Ide and coll. PCCM Accepted 17 infants, 88% survival

33. Modalities CRRT – CVVH, CVVHD, CVVHDF – no evidence which is better TPE – Therapeutic Plasma Exchange MARS SPAD – Single Pass Albumin Dialysis 32

34. MARS

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36. 35 Courtesy – Fin Larsen

37. 36 Courtesy – Fin Larsen

38. 37 I deal ELAD – Tackles synthetic and excretory dysfunction Courtesy – Fin Larsen

39. SUMMARY No Evidence for RRT in Liver patients Should we undertake CRRT in ALF Yes - and review : population data vs individual care Why ? –Neuro-protection, metabolic disarray, bridge for recovery or transplant When Earlier - need new markers Mode CRRT – unstable, TPE coming in fashion !! Access sites Internal Jugular Dose No evidence in Paediatrics High – gaining popularity Anticoagulation - YES PGI2 and /or low dose heparin

40. RRT in CLD / AoCLF Mainstay of supportive therapy for patients who deteriorate despite aggressive resuscitation Volume overload, intractable metabolic acidosis, and hyperkalemia Delay in RRT – MORTALITY > 90% High risk in hepatic encephalopathy, hypotension, and coagulopathy Serves as bridge to transplant If RRT > 8 weeks before LT - ???? Combined Liver- Kidney Transplantation

41. Anticoagulation Anticoagulation in RRT in liver patients – is it different ? Should CRRT circuits in patients with hepatic failure be anti-coagulated? 40

42. Background : Coagulopathy & Liver Disease

43. No Anticoagulation Low dose Heparin Prostacyclin Citrate ??? 42 HEPARIN PROSTACYCLIN

44. CVVHD + regional citrate in liver failure Observational study Schultheiss C et al Crit Care 2012 Accumulation in citrate correlated with an increase in Ca tot /Ca ion –Critical ratio of 2.5 exceeded 10 times (of 273) in 7 of 43 runs; Seen at 12 hours(3), 24 hours (6) and 1 at 72 hours Equalization of acid base was possible Standard lab values did not correlate with citrate accumulation ratio > 2.5 Lactate > 3.5 mmol/L or prothrombin ratio < 26% –Predict ratio Ca tot /Ca ion > 2.5 Sensitivity 86% for both Specificity of 86% for lactate and 92% for prothrombin

45. Schultheiss C et al Crit Care 2012 16:R162 Decreased citrate clearance in cirrhosis 340 ml/min Vs 710 ml/min in normals Krammer et al 2003 29 fold increase in citrate ? Option of CVVHD vs CVVHF the former allowing lower blood flow and greater clearance of citrate

46. CRRT in Liver Disease Different from non-liver ICU patients Indications Timing ?Dose – Role of HVHF Role of TPE – is there a role in combining TPE with CRRT ?? Anticoagulation Main Role – Bridge to LT or spontaneous recovery 45