It is unlikely that one solution will work……..

What are the aims of a liver support device? Decompensated cirrhosis Prevention of further deterioration (ie) AoCLD Stability on the transplant list : decreased infections, portal pressure and variceal bleeding, control of ascites Acute on chronic liver disease Reversal of type I HRS, stabilization type II HRS Reversal of hepatic encephalopathy Improved synthetic function / nutritional status Control pruritis Critically ill cirrhotic Reversal of organ failure - ability to transplant Acute liver failure Control ICP Avoidance transplantation / Regeneration or stability to transplant

Biochemical Effects: Co-founders? Kramer et al Int J Artif Org 2002;25: AOCLF n=8 Effect of IV Colloid on bilirubin level prior to liver support Bilirubin measured; baseline, post colloid (10 ml/kg 6% HAES solution) Bilirubin Fallp Baseline to post-colloid18% (1-44)<0.03 Conjugated Bilirubin decreases only – water soluble

Relationship of Bilirubin to serum albumin in 11 patients with MOF and liver failure

5 Gambro standard presentation November 1© 2011, Gambro Albumin Dialysis : membrane 50 KD pore size MARS ® vs. Renal Replacement Blood Circuit Dialysate Circuit Albumin Circuit Courtesy: Gambro (Josep Torner)

Number of improved assessments : study 5 days Responder : 1 or more episode of 2 grade improvement 70 enrolled GCS 6/15 Sedation undertaken in 10 and 13% Platelets decreased 21% - Rx needed in 49 and 32% 5 episodes of stopping Rx During follow -up 7 episodes GI bleeding MARS vs 1 in SMT

2-grade improvement in HE 34% in MARS group 19% in SMT group (p=0.044)

Table 1: Baseline characteristics (per protocol)

SMT +MARSSMT Overall 28 days mortality: SMT: 39.3 % SMT + MARS: 41.4 % Overall 28 days mortality: SMT: 40 % SMT + MARS: 41.2 % SMT +MARSSMT ITT populationPP population 10 Confidential Log-rank test: p=0.79 Log-rank test: p=0.88 reduces toxins improves hepatic coma improves hemodynamic instability RELIEF (MARS) study n=185 Fall in creatinine (p=0.02) and bilirubin (p=0.01) Improvement in HE from II/IV at inclusion to 0-I, 56 vs 39% 28 day survival 40 vs 40.8%

HELIOS study Objective:  To test survival under Prometheus therapy with standard medical therapy (SMT) compared to SMT alone Patients:  Acute decompensation of chronic liver disease  Presence within last 72 hours of -CP-Score  10 -Bilirubin  5 mg/dl  Exclusion: 16 major comorbidities

Effect of PROMETHEUS on survival Day 28 SMT+FPSA: 66% SMT: 63% Diff. ~ 3 %, NS Day 90 SMT+FPSA : 47% SMT: 38% Diff. ~ 9%, NS Day 21 Diff.~10% reduces toxins effective in certain sub-groups GASTROENTEROLOGY 2012;142:782–789

LIVER TRANSPLANTATION 21:369–380, 2015 Willem S. Lexmond, Case series : no difference in MARS vs non- MARS treated patients

Pierre Bourgoin Pediatr Nephrol (2014) 29:901–908 Haemodynamics unstable in mini mars Rx (0.6 m2 – prime volume 172 vs 2.1 and 275 ml) Cut point 25 kg

Nephrol Dial Transplant (2011) 26: 3633–3639

Superior efficay of PE / HD vs MARS in ALF cases

Wai et al 2006

FULMAR (Saliba et al) Prospective, controlled, randomized parallel group trial – Total number of patients: 102 (ITT) – Main etiology of ALF due to Acetaminophen (38%) SMT = 19, MARS=20 Comparison of SMT versus SMT + MARS Indication ALF, with indication for liver transplantation 68/102 patients transplanted – 41% of acetaminophen group Ann Intern Med. 2013;159:

Median 16 hours from wait list to Tx Median number Rx 1 (0-7)

Ann Intern Med. 2013;159:

Sauer et al Hepatology 2004;39:1048

Can J Gastroenterol Vol 26 No 11 November 2012

Risks vs benefits All studies have appeared safe Antimicrobial clearance Coagulation –How to anticoaguate the circuit –Improved coagulation System functioning –Deteriorating coagulation –Fall in fibrinogen, platelets Intravascular haemolysis Doria et al Clinical Transplantation 2004;18:365 SPAD and Wilsons

Journal of Hepatology 2015 Jalan et al

Didier M. Payen Intensive Care Med April 2015 Abdominal peritonitis Lower (82),upper (32) and biliary (6) X 2 treatments post surgery 10 &24 hrs) Annonymized assessment of surgery

Transplant International ISSN 2007