1. Molecular Absorbents Recirculating System (MARS®) “Albumin Dialysis”
Marco Maggiorini
Intensive Care Unit
Department of Internal Medicine
University Hospital Zurich

2. Liver failure - endogenous intoxication
Ongoing
Imbalance of
water-soluble and non-soluble
substances
Toxins:
Bile acids
Bilirubin
Prostacyclins
Nitric oxide
Indol / Phenol-
Metabolites
Toxic fatty acids
Thiols
Digoxin/Diazepam- like subs.
...
Ammonia
Lactate
Further liver damage
via vicious cycle:
necrosis/apoptosis !!!
Brain Function
Kidney Function
Cardiovascular Tone
Bone Marrow Activity

3. Transport of protein bound substances
Plasma albumin
Intracellular transport protein
Biotransformation
Toxin
Bile

4. Accumulation of non-water-soluble substances

5. Accumulation of non water-soluble substances
Albumin binding capacity in liver failure 20 40 60 80
100
120
140
Healthy volunteers Patients with Acute-on-Chronic LF
Albumin binding capacity %
Klammt et al., 3rd ISAD 2001

6. Toxin removal MARS® Therapy water-soluble toxins non water-soluble
Water based human body
Diffusion
Plasma exchange
(unselective)
Binding site related distribution
Filtration
water-soluble
toxins
(free)
non water-soluble
(protein bound)
Balance of water-soluble substances
Balance of protein bound substances
Dialysis
Albumin Dialysis
MARS® Therapy

7. Main indication groups* International MARS Registry
13% Liver failure post LTx
5% LF post liver surgery
5% Others
51% Decompensated chronic liver disease
26% Acute liver failure / dysfunction
* n=287, 51 centers

8. Liver Failure 100% Liver function * Acute on chronic
*critical functioning liver cell mass
years
Liver function
Acute liver failure (5%)
Acute on chronic
liver failure (95%)
100% *
MARS

9. MARS® therapy - currently investigated in
Decompensated chronic liver disease
Acute-on-Chronic Liver Failure
Decompensated end-stage cirrhosis
Acute liver failure / liver dysfunction
Acute liver failure
Acute drug induced cholestasis
Hypoxic liver failure
Liver failure / dysfunction post liver transplantation
Primary graft dysfunction
Primary graft non function
Liver failure / dysfunction post liver surgery
Intractable pruritus in chronic cholestatic syndromes
Multi organ failure

10. The MARS® and PRISMA

11. The MARS® principle

12. The MARS® membrane
Specific polysulfone membrane, which is unique for the MARS-System
Only this special MARS-Membran e allows to remove albumine bound and watersoluble toxins in the same time
Proteins, growth factores and hormons cannot pass the membrane

13. The MARS® membrane

14. The MARS® membrane from the patient Albumin circuit to the patient
Blood circuit

15. The DiaFLUX® filter
Albumin circuit
Dialysate circuit

16. MARS® Absorber cartridges
Activated charcoal column (diaMARS® AC250)
Anion-exchanger resin column (diaMARS® IE 250)

17. Intermittent MARS® treatment strategy
Albumin circuit
600 ml 20% human albumin
Flow ml/min (~ 20% less then blood flow)
Patient circuit
Blood flow ml/min
Dialysate flow intermittent strategy ml/min
Dialysate flow CRRT strategy 2l/h
Duration of treatment
Liver dysfunction: 6-8h MARS®
Liver and renal dysfunction: 6-8h MARS® h CRRT

18. MARS® circuit anticoagulation
Unfractioned heparin
Wash MARS® circuit with 10’000 IU heparin
IU heparin infusion before MARS® filter
ACT optimal range s

19. MARS® associated alteration of coagulation factors
Retrospective analysis of coagulopathy/ bleeding complications observed during 83 consecutive MARS sessions in 21 patients (11 men)
INR  (n=81, p<0.0001)
fibrin D-dimers 1.54  mg/l (n=61, p<0.0001)
platelet counts  50 x 109/l (n=82, p<0.0001)
Fibrinogen  1.6 g/l (n=80, p<0.0001)
Schüppbach et al (sumbitted)

20. MARS® associated alteration of coagulation factors
Retrospective analysis of coagulopathy/ bleeding complications observed during 83 consecutive MARS sessions in 21 patients (11 men)
- median age 46 y.
median 3 sessions/pat.
median duration/session 8 hours.
Schüppbach et al (sumbitted)

21. MARS® associated alteration of coagulation factors
INR
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
NO Bleeding
Bleeding
p=0.001
Platelet Count (x103)
100
200
300
400
500
600
700
p=0.042
Fibrin D-Dimer Concentration (mg/l)
5,0
7,5
10,0
12,5
15,0
17,5
p=0.044
Fibrinogen Concentration (g/l)
4,0
p=0.008
Schüppbach et al (sumbitted)

22. MARS® associated alteration of coagulation factors
pre-treatment values of bleeding vs. non-bleeding sessions
bleeding non-bleeding
median INR vs. 1.6 (p=0.001)
platelet count (x109/l) 40 vs. 68 (p=0.042)
plasma fibrinogen (g/l) 0.8 vs. 2.0 (p=0.008)
fibrin D-dimer (mg/l) 5.75 vs (p=0.044)
Schüppbach et al (sumbitted)

23. Univariate/Multivariate analysis of factors associated with bleeding
* Independent predictors in multivariate analysis
Schüppbach et al (sumbitted)

24. MARS® associated alteration of coagulation factors
Faybik et. al Crit Care 2006, 10 R24
61 MARS treatment in 33 patients
PG I2 in all + Heparin (ACT ) in 17
FFP given in 37 MARS treatments (17 patients)

25. MARS® circuit anticoagulation
Prostacyclin I2 (Epoprostenol)
Rational: Reversible inhibition of platelet activation by decreasing the expression of platelet fibrinogen receptor and P-selectin, and reduction of the heterotypic platelet-leukocyte aggregation.
Prior to treatment: up-titration (1ng/kg/min) to reach 5 ng/kg/min within 30 min.
Treatment start: 3-5ng/kg/min before MARS® filter
Ev. add heparin to reach an ACT between s

26. Thromboelastography (TEG®)
Normal thromboelastograph
R = reaction time; K = coagulation time;  = angle alpha = cloth growth;
MA = maximal amplitude

27. Thromboelastography (TEG®)
Normal trace
Hyper-coagulable trace
Hyper-fibrinolytic trace
Hypo-coagulable trace
Substitution of Factor VIIa
Improvement in terms of a shortened CT, and increased  angle and MCF can be seen postinfusion

28. Thromboelastography (TEG®)
Variable (n)
Time TEG reaches mm
Coagulation
R (3-13 mm)
2 mm
Initial fibrin formation
Factors, inhibitors activity
K (1-9 mm)
20 mm
Clot firmness
Factors, fibrinogen, platelets
Angle  (55-62 mm)
Slope R to K
Rate of clot growth
Platelets and factors on platelet surface
MA (45-53 mm) -
Strength of the clot
Function of platelets and plasma factors
CL30 (100%)
Clot lyses
Clot index (CI) (-3 to 3 mm)
Hypo/hyper coagul. state

29. Modified thromboelastography (TEG®)
Variable (n)
Coagulation Inhibitor
Coagulation
R (3-13 mm) -
Initial fibrin formation
Factors, inhibitors activity
RHEP
Heparinase
= R - (R+Hpase)
Effect of endogeneous/ exogeneous heparin
MA (45-53 mm)
Strength of the clot
Function of platelets and plasma factors
MAPLT
GP iib/IIIa inhib. (abciximab)
= MA - (MA+ abciximab)
Contribution of platelets

30. Thromboelastography (TEG®)
Faybik et. al Crit Care 2006, 10 R24
(45-53 mm)
(9-13 mm)
(1-9 mm)
(55-62 degree)
(-3/+3)
(100%)
61 MARS treatment in 33 patients
PG I2 in all + Heparin (ACT ) in 17
FFP given in 37 MARS treatments (17 patients)
Before
30 min.
Within 1h of end

31. Thromboelastography (TEG®)
Faybik et. al Crit Care 2006, 10 R24
(45-53 mm)
(9-13 mm)
(1-9 mm)
(55-62 degree)
Patients with FFP administration in 37 (46%) MARS treatments (17/33 patients) later than 30 min
Before
30 min.
Within 1h of end
FFP

32. MARS® associated alteration of coagulation factors
Safety considerations
Anticoagulation regimen:
Prostaglandin I2 is preferred (transitory platelets inhibition)
Add heparin if necessary (ACT s)
Monitoring:
TEG preferred to standard coagulation parameters
Substitution with FFP in high risk patients
Contraindication:
Overt DIC
Fibrinogen < 1.0 g/l
Platelet < 30’000 /µl

33. MARS® associated alteration of coagulation factors
TEG in Patients at high risk of bleeding
Doria et al. Clin Transp 2004, 18:365

34. MARS® associated alteration of coagulation factors
Safety considerations
Patients at high risk of bleeding
Platelets < 50’000 /µl
TEG reaction time > 800 s
TEG constant time > 1500 s
TEG  angle < 30 degree
TEG maximal amplitude < 45 mm
Doria et al. Clin Transp 2004, 18:365