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

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

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

Accumulation of non-water-soluble substances

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

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

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

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

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

The MARS® and PRISMA

The MARS® principle

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

The MARS® membrane ® ®

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

The DiaFLUX® filter Albumin circuit Dialysate circuit

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

Intermittent MARS® treatment strategy Albumin circuit 600 ml 20% human albumin Flow 150-250 ml/min (~ 20% less then blood flow) Patient circuit Blood flow 150-250 ml/min Dialysate flow intermittent strategy 300-500 ml/min Dialysate flow CRRT strategy 2l/h Duration of treatment Liver dysfunction: 6-8h MARS® Liver and renal dysfunction: 6-8h MARS® + 16-18h CRRT

MARS® circuit anticoagulation Unfractioned heparin Wash MARS® circuit with 10’000 IU heparin 200-800 IU heparin infusion before MARS® filter ACT optimal range 150-180 s

MARS® associated alteration of coagulation factors Retrospective analysis of coagulopathy/ bleeding complications observed during 83 consecutive MARS sessions in 21 patients (11 men) INR 1.7  1.8 (n=81, p<0.0001) fibrin D-dimers 1.54  2.46 mg/l (n=61, p<0.0001) platelet counts 68  50 x 109/l (n=82, p<0.0001) Fibrinogen 1.9  1.6 g/l (n=80, p<0.0001) Schüppbach et al (sumbitted)

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)

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)

MARS® associated alteration of coagulation factors pre-treatment values of bleeding vs. non-bleeding sessions bleeding non-bleeding median INR 2.1 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. 1.38 (p=0.044) Schüppbach et al (sumbitted)

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

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 120-150) in 17 FFP given in 37 MARS treatments (17 patients)

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 120-150 s

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

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

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

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

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 120-150) in 17 FFP given in 37 MARS treatments (17 patients) Before 30 min. Within 1h of end

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

MARS® associated alteration of coagulation factors Safety considerations Anticoagulation regimen: Prostaglandin I2 is preferred (transitory platelets inhibition) Add heparin if necessary (ACT 120-150 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

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

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