Molecular Absorbents Recirculating System (MARS®)

“Albumin Dialysis”

Marco MaggioriniIntensive Care Unit

Department of Internal Medicine

University Hospital Zurich

Toxins:• Bile acids• Bilirubin• Prostacyclins• Nitric oxide• Indol / Phenol-• Metabolites• Toxic fatty acids• Thiols• Digoxin/Diazepam-

like subs.• ...• Ammonia• Lactate

Further liver damagevia vicious cycle:necrosis/apoptosis !!!

• Brain Function• Kidney Function• Cardiovascular Tone• Bone Marrow Activity

Liver failure - endogenous intoxication

Ongoing Ongoing

ImbalanceImbalance ofof water-solublewater-soluble and and non-soluble non-soluble substancessubstances

Transport of protein bound substances

Plasma albumin

Intracellular transport protein Biotransformation

Toxin

Bile

Accumulation of non-water-soluble substances

Klammt et al., 3rd ISAD 2001

Albumin binding capacity in liver failure

0

20

40

60

80

100

120

140

Healthy volunteers Patients with Acute-on-Chronic LF

Alb

um

in b

ind

ing

cap

acit

y

%

Accumulation of non water-soluble substances

MARS® Therapy

Balance of water-solublesubstances

Balance ofprotein bound

substances

Dialysis Albumin Dialysis

Water based human body

Diffusion

Plasma exchange(unselective)

Binding siterelated distribution

Filtration(unselective)

water-solubletoxins

(free)

non water-solubletoxins

(protein bound)

Toxin removal

* n=287, 51 centers

51% Decompensated chronic liver disease

26% Acute liver failure / dysfunction

13% Liver failure post LTx

5% LF post liver surgery

5% Others

Main indication groups*International MARS Registry

*critical functioning liver cell mass years

Liv

er f

un

ctio

n

Acute liver failure (5%)

Acute on chronicliver failure (95%)

100%

*

MARS

MARS

Liver Failure

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

®®

The MARS® membrane

The MARS® membrane

from the patient

to the patient

AlbuminAlbumincircuitcircuit

Blo

od

cir

cuit

Blo

od

cir

cuit

The DiaFLUX® filterA

lbu

min

cir

cuit

Alb

um

in c

ircu

it Dialysate circu

itD

ialysate 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 heparinWash 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

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

1 2

INR

Prior MaximalduringMARS

p<0.0001

0

100

200

300

400

500

1 2

Platelets(x109/l)

Prior MinimalduringMARS

p<0.0001

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

1 2

Fibrinogen(g/l)

Prior MinimalduringMARS

p<0.0001

0

5

10

15

20

1 2

Fibrin D-Dimers

(mg/l)

Prior MaximalduringMARS

p<0.0001

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

pre-treatment values of bleeding vs. non-bleeding sessions

bleeding non-bleedingmedian 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

Odds Ratio

95% Confidence Limits

Lower Upper

p-value

INR* 6.591 1.611 26.958 0.005

Fibrin D-Dimer Level (mg/l)* 1.252 1.016 1.542 0.033

Activated Partial Thromboplastin Time (sec)

1.013 0.999 1.028 0.096

Platelet Count (x109/l) 0.981 0.956 1.007 0.056

Plasma Fibrinogen Concentration (g/l) 0.195 0.056 0.676 0.003

Circulatory Support (no vasopressors) 0.131 0.025 0.683 0.007

Age (<50 years)* 0.121 -3.762 -0.464 0.005

* 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 patientsPG I2 in all + Heparin (ACT 120-150) in 17FFP 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 patientsPG I2 in all + Heparin (ACT 120-150) in 17FFP 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)

(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 considerationsPatients 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