CRRT in Liver Failure: Overview, Controversies, and Survival

1. CRRT in Liver FailureAkash DeepDirector - PICU King’s College HospitalLondonChairRenal/CRRT SectionEuropean Society of Pediatric and Neonatal Intensive Care (ESPNIC) 0

2. Speaker Disclosure

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

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

6. CRRT in ALF

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

10. Mechanisms of AKI in ALF • 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

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 Clemmesen et al. Bernal et al. Hepatology, 2007 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. Hyponatremiapotentiateammoniaeffect on HE Gines et al Hepathology 2008

18. 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. 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 Overall mortality was 45.4% (n = 10). Emergency liver transplantation was performed in eight children. Five patients spontaneously recovered liver function

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

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

27. 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 and > 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 17 infants, 88% survival Ide and coll. PCCM Accepted

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

34. MARS

35. SURVIVAL

36. Courtesy – Fin Larsen

37. Courtesy – Fin Larsen

38. Courtesy – Fin Larsen Ideal ELAD – Tackles synthetic and excretory dysfunction

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?

42. Background :Coagulopathy & Liver Disease • INR, PT, aPTT • "rebalanced haemostasis"

43. No Anticoagulation • Low dose Heparin • Prostacyclin • Citrate ??? 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 Catot/Caion • 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 Catot/Caion > 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 ? Option of CVVHD vs CVVHF the former allowing lower blood flow and greater clearance of citrate 29 fold increase in 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