1. EXTRACORPOREAL LIVER SUPPORT – A BALANCING ACT BETWEEN EFFICIENCY AND BIOCOMPATIBILITY

2. Overview
Extracorporeal Liver Support Systems/targetmolecules
Adsorbent based Systems
Pore size of adsorbents
Use of fractionated plasma vs plasma
Use of citrat vs heparine in extracorporeal systems
Conclusion

3. Liver support systems
The Liver possesses the unique ability to regenerate itself with new healthy tissue. As little as 25% of remaining liver can regenerate into a whole liver again. Acute liver failure: An extracorporeal liver assist device (LAD) is used to detoxify the blood, giving the damaged liver a chance to regenerate. The LAD acts as an organ for the time it takes to regenerate (bride to regeneration). Chronic hepatic failure: No regeneration is possible, the LAD acts as a bridge while waiting for the availability of transplant (bridge to transplantation).

4. Liver support systems
Conventional liver support systems can only partly replace the detoxification part.  Development of bioartificial liver support systems

5. Target toxins for blood purification systems
Water soluble toxins:
Uremic toxins (Dialysis)
NH3/NH4+
Aromatic amino acids
Cytokines
Albumin-bounded toxins:
Bilirubin (product of haemoglobin catabolism)
Bile acids
Aromatic substances like phenol
Middle and short chain fatty acids
Benzodiazepenes
Furancarboxylic acid
Indoyxlsulfate
Para-cresol
Hemodialysis/Hemofiltration
Adsorption

6. Overview of liver support systems
Systems working with Albumin-Dialysis
Molecular Adsorbent recirculating System (MARS)
Singel-pass Albumine Dialysis (SPAD)
Hepa Wash® procedure
 Good biocompatibility but low effectivity regarding albumin bounded toxins.

7. Overview of liver support systems
Systems working with Plasmasorption:
 High detoxification rate but low biocompatibility of adsorbent material.

8. Overview of liver support systems
Bioartificial liver support devices
Used cells:
Hepatoplastoma cells (C3a)
Primary porcine hepatocytes
 Risk of metastatic cells spreading and xenozoonoses

9. Overview of liver support systems
Patient C A B
Blood circuit
Filtrate circuit D E F
A… Bloodpump
B… Centrifugal pump
C… plasma filter
D… Dialyzator
E… Oxygenator
F… encapsulated C3a cells
G… adsorbent microspheres G

10. Adsorption Systems
Haemoperfusion (LDL-Apheresis, Cytosorb™, Torray®, Alteco®,…)
Limitation of particle size
Cell-compatibility material
Easy to use
Low extracorporeal volume
Plasmaperfusion (Bellco®, Prometheus®, …)
High extracorporeal volume
Additional device for plasma separation
Only plasma-compatible material and
conditions are needed
Use of small adsorbent particles  shorter diffusion distance

11. - Adsorbent surface Pore size + specific receptors proteins
peptides
antibody + -
charge
specific receptors
polymer-structure
pore size
proteins

12. Pore size

13. Pore size
 The pores of adsorbents act as molecular sieve!

14. ADSORPTION OF SELECTED ANTIBIOTICS TO RESINS
name
provider
characteristics
Prometh01
Fresenius Medical Care Adsorber Tec GmbH, Austria
PS-DVB based neutral resin, BPa
Prometh02
PS-DVB based matrices with quaternary ammonium cations (anion exchanger), BPa
dia Mars AC 250
Gambro, Sweden
activated charcoal, BPa
Amberchrom® CG161c
Dow Chemical, US
PS-DVB based neutral resin
aBP indicates adsorbers that are commercially used for blood purification

15. ADSORPTION OF SELECTED ANTIBIOTICS TO RESINS
For better drug monitoring during extracorporeal treatment, further investigations have to be performed to determine the clearance rates.

16. Use of fractionated plasma for plasmasorption
No lost of high molecular weight proteins (Fibrinogen, IgG,…)
Pores become clogged faster in whole plasma
Possibility to use none plasma compatibility material (Anion-exchanger)
Fractionated plasma has higher water content  lower hydrophobicity  better adsorption
Plasma circuit

17. Use of fractionated plasma for plasmasorptionB C D
A… Plasma pool with spiked bilirubin
cholic acid
B… roller pump
C… 1 ml adsorbent cartridge
D… Sampling

18. SEM pictures of adsorbents used in plasma vs fractionated plasma
Before treatment
Used in fractionated plasma
Used in whole plasma

19. Anticoagulation Citrate vs Heparin
Most frequently use anticoagulants  dosage is well known
Systemic anticoagulation
Can induce heparin-induced thrombocytopenia (HIT)
Higher risk of bleeding
Reduced effect in patients with lower Anti-thrombin (AT)
Inhibits the anti-inflammatory effect of AT
ASAIO Journal 2012;58:443–44p. PODOLL ET AL.

20. Anticoagulation Citrate vs Heparin
Biocompatible (fewer cell attachment)
Restricted extracorporeal anticoagulant
Can be used when patients have heparin-induced thrombocytopenia (HIT)
Inhibit extracorporeal activation of complement system and inflammation
Filter survival time is much longer with citrate compared to heparin
No systemic anticoagulation  lower risk of internal bleeding
Citrate accumulation (bed citrate clearance)  Acidosis
Intensive Care Med. 2004;30(2):260-5.
Monchi M. et al
96 patient were treated with CVVH with heparin & citrate, dialyzer live time was determined.

21. Anticoagulation Citrate vs Heparin
Run time
240 min
Blood volume
210 ml
Flow rate blood
30 ml/min
Flow rate filtrate
6 ml/min
Sample time
0/15/30/60/120/180/240 min

22. Anticoagulation Citrate vs Heparin
After experiment the filters were washed with 0.9 % NaCl solution and cut with a saw.
6 mM Citrate
3 IU/ml Heparin

23. Anticoagulation Citrate vs Heparin

24. Anticoagulation Citrate vs Heparin
 Lost of thrombocytes & leucocytes

25. Conclusion
Pores of adsorbents act as molecular sieves and prevent the entry of large molecules.
Adsorbents with very large pores lead to uncontrolled adsorption of all plasma proteins.
Adsorbent particles which possess different surface structures and modifications demonstrated, besides toxins which have to be removed, different removal rates for various antibiotics in plasma.
Use of fractionated plasma instead of whole plasma causes higher adsorption rates and better biocompatibility and also the clotting of the nanostructured pores can be hindered.
Citrate anticoagulation effected in longer filter live time and better biocompatibility.

26. Thanks
Karin
Ute
Jens
Claudia