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;25:918-22AOCLF n=8

Effect of IV Colloid on bilirubin level prior to liver supportBilirubin measured; baseline, post colloid (10 ml/kg 6% HAES solution)

Bilirubin Fall p

Baseline to post-colloid 18% (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 improvement70 enrolled GCS 6/15Sedation 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 HE34% in MARS group19% in SMT group (p=0.044)

Variable SMT SMT+MARS PHRS (n (%)) 45 (52.9 %) 37 (52.1 %) NSEncephalopathy ≥ grade II (n (%))

37 (43.5 %) 28 (39.4 %) NS

SOFA score (n=95) 7.7 (3.3) 8.1 (2.8) NSGCS (n=140) 13 (3) 13 (4) NSBilirubin (mg/dl) 27.0 (12.3) 26.8 (11.8) NSAlbumin (g/L) 28.1 (9.9) 27.3 (6.3) NSSerum creatinine 2.27 (2.07) 2.50 (2.20) NSINR 1.78 (0.33) 1.74 (0.31) NSHematocrit 29.3 (6.0) 28.4 (4.8) NSLeucocytes 15.6 (11.0) 16 (9.6) NSPlatelet count 120.3 (72.3) 130.9 (75.2) NS

MELD > 20 (n(%)) 59 (69.4 %) 58 (81.7 %) P=0.078SBP (n (%)) 6 (7.1 %) 12 (16.9 %) P=0.055

Table 1: Baseline characteristics (per protocol)

SMT +MARSSMT

302520151050

1.0

0.8

0.6

0.4

0.2

0.0

Overall 28 days mortality: SMT: 39.3 % SMT + MARS: 41.4 %

Overall 28 days mortality: SMT: 40 % SMT + MARS: 41.2 %

302520151050

1.0

0.8

0.6

0.4

0.2

0.0

SMT +MARSSMT

ITT population PP population

10Confidential

Log-rank test: p=0.79 Log-rank test: p=0.88

• reduces toxins• improves hepatic coma• improves hemodynamic instability

RELIEF (MARS) study n=185Fall 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 21Diff.~10%

reduces toxinseffective 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;159:522-531.

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

Ann Intern Med. 2013;159:522-531.

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 surgery10 &24 hrs) Annonymized assessment of surgery

Transplant International ISSN 2007