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M olecular A dsorbent R ecirculating S ystem

M olecular A dsorbent R ecirculating S ystem. Patrick Brophy MD Director Pediatric Nephrology, University of Iowa Children’s Hospital. Outline. Hepatic Dialysis- Liver Support MARS™ Rationale Indications Outcomes Future Directions.

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M olecular A dsorbent R ecirculating S ystem

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  1. Molecular Adsorbent Recirculating System Patrick Brophy MD Director Pediatric Nephrology, University of Iowa Children’s Hospital

  2. Outline • Hepatic Dialysis- Liver Support • MARS™ • Rationale • Indications • Outcomes • Future Directions

  3. Definition: Loss of functional liver cell mass below a critical level results in liver failure (acute or complicating a chronic liver disease) Results in: hepatic encephalopathy & coma, jaundice, cholestasis, ascites, bleeding, renal injury, death HepaticFailure

  4. Production of Endogenous Toxins & Drug Metabolic Failure Bile Acids, Bilirubin, Prostacyclins, NO, Toxic fatty acids, Thiols, Indol-phenol metabolites These toxins cause further necrosis/apoptosis and a vicious cycle Detrimental to renal, brain and bone marrow function; results in poor vascular tone HepaticFailure

  5. History Stadlbauer and Jalan. Acute Liver Failure: liver support Therapies Current Opin in Crit Care. 2007; 13:215-21

  6. MARS™ MARS™ Flux Filter ADSORPTION COLUMNS DIALYSIS DiaFlux Filter Blood Circuit 20-25% Albumin Circuit Dialysis Circuit Patient

  7. MARS Flux Filter Kapoor D., Journal of Gastroenterology and Hepatology, 2002

  8. pCRRT Rome 2010 Filters : MARS™ flux : 2m2 ECV = 150 ml + lines, 600ml 20% Alb MARSMini™: 0.6m2 ECV = 56ml + lines, 500ml 20% Alb *** (not Available in US) PRISMARS™ 1 kit = $ 2700 (USD) Flow Rates : Blood flow rate: 4-10 ml/kg/min Albumin dialysate Flow Rate = BFR UFR : 2000ml/h/1.73m2 in CVVH or in CVVHDF mode Anticoagulation: No anticoagulation Heparin (5 U/kg/h) Citrate Technical Aspects

  9. Albumin Bound Toxins Removed During MARS Therapy Water Soluble Substances Removed During MARS Therapy Ammonia Creatinine Tryptophan Tumor Necrosis Factor Alpha Urea IL-6 • Aromatic Amino Acids • Bilirubin • Bile Acids • Copper • Middle and Short Chain Fatty Acids • Nitric Oxide (S-Nitrosothiol) • Protoporphyrin

  10. Clotting Factors (Factor VII 50,000 Daltons) Improvement in Factor VII levels after repeated treatments in small studies Immunoglobulin G (150,000 Daltons) Hormone binding proteins Albumin Substances Not Removed During MARS™

  11. To provide an environment facilitating recovery- isolated or as a component of MOSF Therapy To prolong the window of opportunity for LTx : Bridge to Transplantation To allow waiting for the native liver recovery: Bridge to recovery Rationale

  12. Intoxications (US ***) Acute Liver Failure (ALF) Hepatorenal Syndrome Acute on Chronic Liver Failure (AoCLF) Hepatic Encephalopathy Refractory Pruritus in Liver Failure Sepsis / SIRS / MODS Indications

  13. Exogenous: Acetaminophen Amanita Toxin Endogenous: Inborn Error Metabolism Wilson disease, neonatal hemochromatosis Removal of inflammatory Toxins Sepsis/SIRS MOSF See appendix for references Multiple studies have shown MARS to be an effective therapy in these types of toxin induced ALF Intoxications leading to Acute Liver Failure

  14. Improvement in native liver function? Increased avoidance of liver transplant in adult patients with fulminate hepatic failure Camus, C., TherApher Dial 2009 Dec, 13(6): 549-55 Improvement in survival: 67% survival in MARS group at 7 days 25% survival in MARS group at 30 days 0% survival in control group at 7 days Mitzner SR., Liver Transpl 6: 277-286, 2000 Acute Liver Failure

  15. Acute Liver Failure Data -2000-2009 PICU at Pédiatriques Hôpital Femme Mère Enfant, Lyon, France: Dr. E Javouhey- presented ppCRRT meeting 2010

  16. Increased Survival 24 adult patients with AoCLF 92% 30 day survival in MARS group 50% 30 day survival in control group Heemann U., Hepatology 36: 949-958, 2002 Acute on Chronic Liver Failure

  17. Improvement in Hemodynamic Stability Increased systemic vascular resistance Increased mean arterial pressure Decreased portal venous pressure in AoCLF Improvement in renal blood flow (RBF) Laleman W., Critical Care 10:R108, 2006 Schmidt LE., Liver Transpl 9: 290-297, 2003 Kapoor D., Journal of Gastroenterology and Hepatology 2002, 17: S280 – 86, 2002 Mitzner SR., J Am Soc Nephrol 12: S75-82, 2006 Benefits of MARS

  18. Hepatic Encephalopathy LIVER FAILURE MARS Fischer Index Ammonia Loss of Cerebral Auto-regulation Nitric Oxide Endogenous Benzodiazepine Cerebral Ischemia Glutamine Glutamate Herniation Cerebral Edema Intracranial Hypertension

  19. Improvement in Hepatic Encephalopathy Benefits of MARS Hassanein T., Hepatology 46: 1853-1862, 2007

  20. Tolerance and efficacy Data -2000-2009 PICU at Pédiatriques Hôpital Femme Mère Enfant, Lyon, France: Dr. E Javouhey- presented ppCRRT meeting 2010

  21. Risks • Hemodynamic Instability • Has been seen primarily in children weighing < 10kg also undergoing hemodialysis • Overall improvement with continued therapy • Thrombocytopenia • Bleeding Complications • Transfusion of Blood Products

  22. Cost Benefit • Positive benefit in terms of health cost reductions using MARS • Kantolaet.al. Cost-utility of MARS treatment in ALF. World Journal of Gastroenter 2010; 16; 2227-34 • Hesselet.al. Cost-effectiveness of MARS in patients with acute-on-chronic liver failure. GastroenterolHepatol 2010; 22: 213-20 • Positive impact on reduction of Pharmacy utilization (albumin)- compared to SPAD • Drexler et. al. Albumin dialysis MARS: impact of albumin dialysate concentration on detoxification efficacy. TherApher Dial 2009; 13; 393-8

  23. Issues: Still don’t understand the complexity of the liver and the causes of hepatic encephalopathy/coma May be removing both good (growth factors-for liver regeneration) and bad substances Need to standardize end points in these studies Multicenter RCTs are desperately required in Pediatrics Non-Biological artificial support

  24. Huge potential Impact on critical care & Transplantation Potential for managing patients chronically as an outpatient with intractable pruritus- High impact on quality of life: Leckie et.al. Outpatient albumin dialysis for Cholestatic patients with intractable pruritus Aliment Pharmacol Ther 2012; 35: 696-714 Schaefer et.al. MARS dialysis in children with cholestatic pruritus. Pediatr Nephrol 2012; 27: 829-34 Future Horizons

  25. Thank You • Pediatric Dialysis Staff • Mary Lee Neuberger • Critical Care physicians/Nursing • Pharmacy

  26. Appendix

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