Hepatic resections are complex surgical procedures harboring a significant risk for complications. In line with the continued development of liver surgery, hepatic resections tend to be more complex and extensive, with to this associated enhanced risk for post-hepatectomy liver failure (PHLF). Despite these improvements in outcome after major liver resection, PHLF remains one of the most serious and fatal complication of major liver resection occurring in up to 8 % of the cases.

1. Is there ”a life-future” in (on) MARS?

2. 0
50
100
150
200
250
300
2008 2009 2010 2011 2012 2015
171
208
219
236
246
300
no
The annual number of liver resections at Center for Digestive
Diseases, Karolinska University Hospital, Stockholm, Sweden

3. Liver regeneration
Portal Vein Embolization and two stage hepatectomy

4. Liver regeneration
In situ Split or ALPPS
Operation 1
Operation 2
1 week later
Alvarez, J Gastrointest Surg 2012

5. Schadde E, et al Surgery. 2015 Apr;157(4):676-89
Liver regeneration
Monosegment ALPPS hepatectomy – extending resectability by rapid hypertrophy

6. Tygstrup et al, Liver failure and quantitative liver function tests. In
R.Williams (ed): Artificial Liver Support, 1975
I
II
III
A loss of functional liver cell mass below
a critical level results in acut liver failure
Rational for acute liver disease
Survival limit
Rational liver support system
Regeneration limit
The dynamics of liver damage

7. • Post-hepatectomy liver failure (PHLF) has been identified as a
major risk factor leading to increased morbidity and mortality.
• The incidence of PHLF varies largely between 0-30%.
• PHLF is the main reason behind postoperative deaths related
to liver surgery (reported figures ranging from 18 to75%).
Liver dialysis in PHLF – the background

8. The “50-50 Criteria” on Postoperative Day 5
Patients:
5 years (1998 – 2002), 775 elective liver resections, 60% major
resections, prospective database
In-hospital death occurred in 26 patients (3.4%)
8
Prediction of posthepatectomy liver failure (PHLF)
Balzan et al, Ann Surg 2005;242: 824–829

9. The “50-50 Criteria” on Postoperative Day 5
Patients:
5 years (1998 – 2002), 775 elective liver resections, 60% major resections,
prospective database
In-hospital death occurred in 26 patients (3.4%)
Resulted in the proposal:
• PT (prothrombin ratio) <50% and SB (serum bilirubin) >50 μmol/L on POD 5
(the 50-50 criteria) were simple, early, and accurate predictors of mortality
after hepatectomy ( more than 50% mortality rate! )
Balzan et al, Ann Surg 2005;242: 824–829
Prediction of posthepatectomy liver failure (PHLF)

10. According to the International Study Group of Liver Surgery (ISGLS)
Grade:
A PHLF resulting in abnormal laboratory parameters but requiring no
change in the clinical management of the patient.
B PHLF resulting in a deviation from the regular clinical
management but manageable without invasive treatment.
C PHLF resulting in a deviation from the regular clinical
management and requiring invasive treatment.
• If INR or serum bilirubin concentrations are increased preoperatively, PHLF is
defined by an increasing INR (decreasing prothrombin time) and increasing
serum bilirubin concentration on or after postoperative day 5 (compared with
the values of the previous day)
Rahbari et al, Surgery 2011;149:713-24
Prediction of posthepatectomy liver failure (PHLF)

11. MARS (Molecular Absorbent Recirculating System)
Blood circuit Albumin circuit Dialysate circuit

12. Effect of MARS on encephalopathy
Range of HE
Range of HE
Time (weeks)
0 1 2 3 4 5
Hepaticencephalopathygrade
0
1
2
3
4
p<0,01
ECAD: 0-3 0-3* 0-3 0-3 0-3
Control: 0-2 0-4 1-4 * 0-4 * 0-4*
SMT
SMT + MARS
Heemann et al., Hepatology 2002; 36: 949-958

13. Mitzner et al., Liver Transpl 2000, 6: 277-86
MARS in HRS – bridge to transplantation
0
0,2
0,4
0,6
0,8
1
0 5 10 15 20 25 30
hospital days
cumulativesurvival
SMT + MARS(n=8)
SMT + HDF(n=5)
p = 0,0123

14. Albumin Dialysis With a Noncell Artificial Liver Support Device in Patients With Acute Liver Failure
A Randomized, Controlled Trial
Salibas et al 2013
6 month patient survival (ITT analysis)

15. Albumin Dialysis With a Noncell Artificial Liver Support Device in Patients With Acute Liver Failure
A Randomized, Controlled Trial
Salibas et al 2013
Cumulative probability of transplantation

16. Heemann et al., Hepatology 2002, 36: 949-958
MARS in cholestatic liver failure
0
0,2
0,4
0,6
0,8
1
0 10 20 30
Cumulativesurvival
Hospital days
SMT
SMT + MARS
p<0.05

17. Molecular Adsorbent Recirculating System as Artificial Support
Therapy for Liver Failure: A Meta-Analysis
Vaid et al 2012

18. mortality
Molecular Adsorbent Recirculating System as Artificial Support
Therapy for Liver Failure: A Meta-Analysis
VAID et al 2012

19. Extracorporeal Albumin Dialysis With the Molecular Adsorbent Recirculating System in
Acute-on-Chronic Liver Failure (ACLF ): The RELIEF Trial
Banares et al 2013

20. Cumulative probability of 28-day transplant-free survival
ITT analysis PP analysis
Extracorporeal Albumin Dialysis With the Molecular Adsorbent Recirculating System in
Acute-on-Chronic Liver Failure (ACLF ): The RELIEF Trial
Banares et al 2013

21. Before After
100
200
300
400
500
600
700
800
900
Bilirubin decreased from 537 (324-877) to 351 (228-512) µmol/l; p<0,05
Bilirubin (µmol/l)
Schmidt et al., Liver Transpl 2001, 7: 709-12
Effect of MARS on excretory capacity
Bilirubin

22. SMT MARS plus SMT
Bileacidchangefrombaseline
(µmol/l)
(Baseline) Hospital day
-300
-200
-100
0
100
200
196 + 107 245 + 91
Baseline
p<0,05*
p<0,05*
1 7 14 21 28
n.s.
p<0,05*
p<0,05*
MARS
treatments
Stange et al., J Hepatology 2001; 34 S1: 45 A1289
Effect on MARS on excretory capacity
Bile Acids

23. 0
10
20
30
40
50
60
70
prothrombinactivity(%)
p < 0,01
MARS
pre treatment
MARS
post treatment
HDF
pre treatment
HDF
post treatment
Mitzner et al., Liver Transpl 2000, 6: 277-86
E¤ffect of MARS on Liver Synthesis Capacity
Coagulopathy

24. Further studies are needed to explore whether organ support and patient
survival could be improved using ;
• A more intensive treatment
• A higher dosage
• Different schedules
• More appropriate patient selection
• Production of new prototypes with greater detoxification capacity
• Above all properly designed and targeted clinical trials.
The MARS wishlist

25. Tygstrup et al, Liver failure and quantitative liver function tests. In
R.Williams (ed): Artificial Liver Support, 1975
I
II
III
A loss of functional liver cell mass below
a critical level results in acut liver failure
Rational for acute liver disease
Survival limit
Rational liver support system
Regeneration limit
The potential benefit of MARS in PHLF

26. MARS in PHLF - clinical practice
Gilg et al 2015

27. MARS in PHLF - clinical practice
Gilg et al 2015

28. • Compared to earlier reports, we identified 4/9 survivors
with primary PHLF after MARS treatment
• Surviving patients were treated early after hepatectomy
and more frequent than non-survivors
• No obvious complications related to MARS were
observed
• Prospective studies are needed to evaluate the value of
MARS in the PHLF situation
MARS in PHLF - clinical practice
Gilg et al 2015

29.  To asses safety and feasibility of MARS
treatment in the PHLF situation
Early MARS® treatment in post-hepatectomy liver failure –a
prospective phase I study
S. Gilg, E. Sparrelid, L. Saraste, L. Lundell, C. Strömberg, B. Isaksson
Centre for Digestive Diseases, Karolinska University Hospital Stockholm Sweden

30. 30
Major
hepatectomy
Normal postoperative
course, PLF grade A
post-op day 5,
End observation
Elevated and still rising INR
(>1,7)
and bilirubin (>50 μmol/l) on
post-op day 3
Check for complications
like biliary obstruction,
leakage or bleeding on
post-op day 3
Initiate LD treatment
post-op day 5, in case
of PHLF grade B or C
any day before
Complications detected:
despite treatment of
complications still rising
samples: Start LD
treatment within 48 h after
definitive treatment of the
complication
No complications
detected day 4 and still
rising blood samples:
prepare for LD start on
day 5
Prospective research protocol

31. 31
• Identification of patients
being at risk of fulfilling the
50:50 criteria
• Checking for complications
like infection, thrombosis or
bile leakage
• Bilirubin > 50 μmol/l,
• INR > 1,5 (“50:50” criteria)
• Fulfilling inclusion criteria
 Start MARS POD 5-7
with 5-7 consecutive
treatment cycles
• Major/extended
• hepatectomy
OP POD 3 POD 5
patient selection
Gilg et al 2015

32. Patients screened between December 2012 and may 2015:
206 major/extended hepatectomies
16 ALPPS procedures
12 patients fullfilled inclusion criteria
10 patients included
2 patients not included
(1 suspicion of portal vein thrombosis, 1 resource
problem at ICU)
Gilg et al 2015
Early MARS® treatment in post-hepatectomy liver failure –a
prospective phase I study

33. INR before/after MARS treatment Bilirubin before/after MARS treatment
p=0,028* p=0,016*
*Wilcoxon test
Gilg et al 2016
Early MARS® treatment in post-hepatectomy
liver failure –a prospective phase I study

34. Patient 90 day mortality hospital stay/days Chronic on acute
liver failure
1 0 35 0
2 0 46 0
3 0 35 0
4 0 128 1
5 1 90 1
6 0 20 0
7 0 39 0
8 0 46 1
9 0 24 1
10 0 30 1
Gilg et al 2016
Early MARS® treatment in post-hepatectomy liver failure –
a prospective phase I study

35.  MARS is feasible and safe in primary PHLF
 No complications > 3a according to the Clavien/Dindo classification
occurred related to MARS treatment
 Significant decrease of Plasma Bilirubin and INR after MARS
treatment (in 9/10 patients)
 Immediate effect on hepatic encephalopathy
 Exceptionally low 90-day mortality (1/10)
Gilg et al 2016
Early MARS® treatment in post-hepatectomy
liver failure –a prospective phase I study

36. Major Hepatectomy
POD 3+4 Hepatic encephalophaty + 50:50 rule
Yes No
Randomisation Observation
POD 5-14
SMTMARS+SMT
50:50 rule + Hepatic encephalophaty
Randomisation
Yes No
MARS+SMT SMT

37. MARS treatment + SMT
Start of 1. MARS cycle within 48h from randomization
3 treatment cycles/ 3 consecutive days
2 days observation
3 treatment cycles/ 3 consecutive days
Persistence/recurrence of PHLF PHLF resolved
2 days observation
Persistence/recurrence of PHLF PHLF resolved
3 treatment cycles/ 3 consecutive days

38. Early liver support with MARS in post-hepatectomy liver
failure: a phase III, randomized, multicentre study.
The ELISH Trial
Primary aim
To evaluate the impact of early MARS therapy on 60 day survival
in patients with primary PHLF
Sample size calculation
The overall 60-day mortality rate in the control arm can estimated to be
55%. Based on these data, a global sample size of 44 patients (22 per
treatment arm) will detect an absolute reduction, of 60-day mortality,
amounting to 40 % by MARS treatment with an 80% statistical power
and with a probability of 95 %. A one-way 5% type-I error has been
assumed.

39. Is there ”a life-future” in MARS?
Early liver support with MARS in post-hepatectomy liver
failure: a phase III, randomized, multicentre study.
The ELISH Trial

40. If you see a light in the tunnel – it´s a train!