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CRRT in Acute Liver Failure

This presentation explores the controversies and clinical evidence surrounding the use of continuous renal replacement therapy (CRRT) in acute liver failure (ALF). Topics include hyperammonemia, intracranial hypertension, sepsis, and anticoagulation in liver patients.

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CRRT in Acute Liver Failure

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

  2. DISCLOSURE • Research grant from Mallinckrodt Pharmaceuticals– Terlipressin in paediatric HRS • Taskforce member for ESPNIC/SCCM joint septic shock guidelines – Adjunctive therapies in septic shock

  3. Overview • Hyperammonaemia – raised ICP in ALF • Controversies in CRRT in ALF – why, when, how ? • Role of MARS, SPAD and TPE in Liver failure • Anticoagulation in liver Patients

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

  5. Clinical Evidence of Intracranial Hypertension. All ALF, n=1549. Incidence of Intracranial Hypertension in 3300 patients at King’s over 35 years Error bars are 95% CI. p<0.00001 Bernal et al. J Hepatol. 2011

  6. Ammonia is central in the pathogenesis of Hepatic Encephalopathy 400 300 200 mol/L 100 0 AoCLF ALF Healthy Cirrhosis TIPSS ICP>25mmHg Olde Damink et al. Neurochem. Int. 2001

  7. Arterio-Venous Ammonia in various beds P Arterial ammonia 92 (71-144) Venous ammonia 45 (29-95) a % extraction 46 % (32-59) Bernal Liver International 2008 Arterial ammonia 92 (71-144) Venous ammonia 77 (59-119) a Arterial and venous levels should not be used interchangeably in the assessment of risk of Cerebral Oedema

  8. NH3 Inflammatory Mediators (e.g. NO) Hepatocellular necrosis and apoptosis Cerebral Blood Flow ICP Astrocyte swelling

  9. GLUTAMINE GLUTAMATE H20 NH3 H20 H20 GLUTAMINE H20 H20 Astrocyte swelling & increased brain water Ammonia-glutamine-brain swelling hypothesis ASTROCYTE Ammonia

  10. 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.

  11. AKI in ALF exacerbates ammonia toxicity

  12. Hyponatraemia potentiate ammonia effect on HE Gines et al Hepathology 2008

  13. Controversies in RRT in Liver Failure • Why do patients with Liver failure develop AKI and why do they need to go on CRRT? • 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

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

  15. CRRT in ALF

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

  17. Acute Liver Failure Liver in some IMD (normal architecture) Cirrhotic Liver

  18. Role of Liver Assist Devices • Survival Benefit ? • 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

  19. When to initiate ?

  20. Authors – Akash Deep, Anil Dhawan

  21. Guidelines for CRRT in ALF at KCH No one indication is an absolute one for initiation of CRRT

  22. 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

  23. 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

  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

  25. Need for more bridging modalities

  26. Kaplan Meier Curve for CRRT patients who did not undergo transplant Since transplantation interferes with the natural progression of PALF; analysed patients didn’t undergo transplant

  27. Conclusions Early implementation of high intensity CRRT which reduces ammonia within 48 hours may provide an increased window for either spontaneous regeneration of liver to take place or for the emergency liver transplant to become available probably by : improving haemodynamics, decreasing ammonia and brain swelling

  28. CRRT modalities and Liver Assist Devices • CRRT – CVVH, CVVHD, CVVHDF – no evidence which is better • TPE – Therapeutic Plasma Exchange • TPE plus CVVH/HD • MARS • SPAD – Single Pass Albumin Dialysis

  29. MARS

  30. SURVIVAL

  31. Courtesy – Fin Larsen

  32. Performs the excretory as well as synthetic functions of the failing liver Courtesy – Fin Larsen

  33. Primary endpoint - Liver transplantation-free survival during hospital stay. Secondary- endpoints- survival after liver transplantation with or without HVP with intention-to-treat analysis. Part B - A proof-of- principle study evaluating the effect of HVP on the immune cell function was also undertaken.

  34. Nor-epinephrine need Effect on INR

  35. Overall hospital survival - 58.7% HVP group vs. 47.8% for controls • The incidence of severe adverse events was similar in the two groups. • Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group

  36. Modulation of innate immune cells following HVP

  37. Conclusions on plasma exchange in ALF a) Increases blood pressure and reduces need for vasopressorsb) Reduces WC and SIRS1. Works by reducing the pro-inflammatory response - probably by immune modulation – the pro-inflammatory response2. Improves transplant-free survival and Liver functiona) by attentuating innate immune activation and amelioration of MOSFb) Reduces INR, Bilirubin, ALT and circulating ammonia3. Attenuates multiorgan failure - Reduce SIRS, SOFA and CLIF-SOFA scores

  38. Continous vv hemofiltration and plasma exchange in infantile ALF - NCCH, Tokyo, Japan Simultaneous CVVHDF and PEX PEX circuit was attached as a side flow to the CVVHDF circuit and was removed after each PEX treatment course 17 infants, 88% survival Ide and coll. PCCM Accepted

  39. Excellent safety profile Bridged 75% patients to LT

  40. Role of Tandem therapies • CRRT plus TPE /Plasmapheresis • Combination of therapies – CRRT, TPE, MARS Safety and Efficacy of Tandem Hemodialysis and Plasma Exchange in Children Schaefer, Akos Ujszaszi, Susanne Schaefer, Karl Heinz Heckert, Franz Schaefer, and   Claus Peter Schmitt Paglialonga F, Ardissino G, Biasuzzi A, Testa S, Edefonti A. Tandem plasma-exchange and haemodialysis in a paediatric dialysis unit. Pediatric Nephrology March 2012, Volume 27, Issue 3, pp 493–495

  41. 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

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