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)

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

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

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

CRRT in ALF 5

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

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

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

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

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

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

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): Bhatia et al. Gut Jan;55(1):

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

Hyponatremia potentiate ammonia effect on HE Gines et al Hepathology 2008

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

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 = ), grade of hepatic encephalopathy (p = 0.04), and serum creatinine

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Authors – Akash Deep, Anil Dhawan

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

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

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

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

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

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

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

MARS

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35 Courtesy – Fin Larsen

36 Courtesy – Fin Larsen

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

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

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

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

Background : Coagulopathy & Liver Disease

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

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

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

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