M olecular A dsorbent R ecirculating S ystem: Practical Issues

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

2. Outline • Hepatic Dialysis- Liver Support • MARS™ • Rationale • Indications • Technical Aspects • 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

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. 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

14. Vascular Access and Anticoagulation forMARS™

15. Access function is crucial for therapy Flows obtained will affect adequacy of blood flow for dose delivered and can affect MARS™-circuit life Downtime from clotted circuits or access is time off therapy Why Do We Need Vascular Access?

16. Low resistance Resistance ~ 8lη/2r4 So, the biggest and shortest catheter should be best Vessel size French ~ 3 x diameter of vessel Bedside ultrasound nearly universal SVC is bigger than femoral vein Access Considerations

17. Internal Jugular Very accessible Large caliber (SVC) Great flows Low recirculation rate Risk for Pneumothorax Cardiac monitoring may take precedence Femoral Usually accessible Smaller than SVC Flows may be diminished by: Abdominal pressures Patient movement Risk for retroperitoneal hemorrhage Higher recirculation rate Access Considerations • Subclavian: Many feel current double lumen vas cath are too stiff to make the turn into the SVC and I don’t personally use them. Although they are used in some centers. • Better for bigger kids likely.

18. 376 Patients • 1574 circuits • Femoral 69% • IJ 16% • Sub-Clavian 8% • Not Specified 7%

19. Circuit Survival Curves by French Size of Catheter 5Fr Demise Hackbarth R et al: IJAIO December 2007

20. Put in the largest and shortest catheter when possible Caveat: short femoral catheters have been shown to have high rate of recirc in adult patients. (Little et al. AJKD 2000;36:1135-9) The IJ site is preferable (over femoral) when clinical situation allows Avoid 5Fr Catheters Summary: Vascular Access for Pediatric MARS™

21. Another crucial step in delivering the prescribed dose (reducing downtime) Critically ill patients are at risk for both increased and decreased clot formation simultaneously Especially relevant & controversial in ALF MARS™Anticoagulation

22. Calcium is necessary for each event in the cascade. Heparin acts in conjunction with ATIII on thrombin and F IX, FX, FXII

23. Systemic Heparin Goal ACT 180-240 sec Patient anticoagulated Risk of bleeding Risk for HIT Regional Citrate Goal Circuit iCal 0.3-0.4mmol/L Goal Patient iCal 1.1-1.4 mmol/L Risk for Hypocalcemia Alkalosis Hypernatremia Anticoagulation

24. 138 Patients in multicenter registry study • 442 circuits • Circuit survival time evaluated for three anticoagulation strategies • Heparin (52% of circuits) • Regional citrate (36% of circuits) • No anticoagulation (12% of circuits)

25. Brophy PD et al. Nephrol Dial Transplant. 2005;20:1416-21 • Mean circuit survival (42 and 44 hr) were not different for Hep vs Citrate, but both longer than no anticoagulation (27 hr) • At 60 hr, 69% of Hep and Citrate circuits were functional, but only 28% of the no-anticoagulation circuits • In this analysis circuit survival was not affected by the access size • Citrate group had no bleeding complications, 9 Heparin patients with bleeding

26. Alkalosis 1 mmol Citrate to 3 mmol HCO3 High-bicarbonate solutions may exacerbate (35 mEq/L) Hypernatremia Tri-Sodium Citrate infusion Hypocalcemic Citrate Toxicity Incomplete clearance of citrate, usually due to liver dysfunction Rising total calcium, decreasing iCal Citrate Specific Issues

27. Heparin or citrate is better than no anticoagulation (even in liver failure, DIC, etc) Citrate has fewer bleeding complications Circuit survival means less downtime hence more delivered therapy Pick institutional strategy and learn to use it well Summary: Anticoagulation for Pediatric MARS™

28. Prescribing Pediatric MARS™

29. 0-10 kg: 25-50ml/min 11-20kg: 80-100ml/min 21-50kg: 100-150ml/min >50kg: 150-180ml/min Choosing QB for Pediatric MARS™ Choose blood flow rate (QB) of 3-5ml/kg/min, or: Albumin Dialysate flow rate must equal QB (minimum of 100 ml/min for US presently)

30. Solutions for Pediatric MARS™:Dialysis Fluids and Replacement Fluids

31. Physiological Reliable Inexpensive Easy to prepare Simple to store Quick to the bedside Widely available Fully compatible Characteristics of the Ideal MARS™ Solution

32. Provide safe and consistent metabolic control To be adaptive to the choice of therapy – convection vs. diffusion vs. combined modality- this is relevant on the dialysis side Purpose of MARS™ solutions

33. Solutions needed to maximize clearance Pharmacy made solutions give greatest flexibility but have increased risks/costs Several industry-made solutions Summary: MARS™ Solutions

34. 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

35. 17 year-old Hispanic male with high-risk pre-B ALL Chemotherapeutic treatment was modified due to previous delayed Methotrexate (MTX) clearance Admitting serum creatinine 0.64 mg/dl 24 hours post MTX infusion: Serum creatinine: 2 mg/dl MTX level: 226 mol/L (Normal<5 mol/L ) Combined CRRT/MARS MTX Intoxication

36. Combined CRRT/MARS MTX Intoxication Start CRRT 76.6 mol/L MARS Started STOP MARS 0.39 mol/L

37. 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 • DRUG Clearance**

38. 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

39. 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

40. 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

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