EXTRACORPOREAL LIVER SUPPORT – A BALANCING ACT BETWEEN EFFICIENCY AND BIOCOMPATIBILITY

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

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).

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

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

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.

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

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

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

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

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

Pore size

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

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

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

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

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

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

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.

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.

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

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

Anticoagulation Citrate vs Heparin

Anticoagulation Citrate vs Heparin  Lost of thrombocytes & leucocytes

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.

Thanks Karin Ute Jens Claudia