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

Outline Hepatic Dialysis- Liver Support MARS™ Rationale Indications Technical Aspects Future Directions

Hepatic Failure 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

Hepatic Failure 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

History Two main approaches to liver support Non-biological: Filtration of potentially harmful molecules Hybrid Biological artificial support: hepatic cells in a synthetic framework Stadlbauer and Jalan. Acute Liver Failure: liver support Therapies Current Opin in Crit Care. 2007; 13:215-21

MARS™ MARS™ Flux Filter ADSORPTION COLUMNS DIALYSIS DiaFlux Filter The system consists of a blood circuit, an albumin circuit, and a classic ‘renal’ circuit. Blood is dialysed across an albumin Impregnated high-flux dialysis membrane; 600 ml of 25% human albumin in the albumin circuit acts as the dialysate. Albumin-bound toxins in blood are released to the membrane. These are subsequently picked up by albumin in the dialysate, which then undergoes hemodialysis/hemofiltration if required. The albumin dialysate is subsequently cleansed via passage across two sequential adsorbent columns containing activated charcoal and anion exchange resin. Blood Circuit 20-25% Albumin Circuit Dialysis Circuit Patient

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

Albumin Bound Toxins Removed During MARS Therapy Water Soluble Substances Removed During MARS Therapy Aromatic Amino Acids Bilirubin Bile Acids Copper Middle and Short Chain Fatty Acids Nitric Oxide (S-Nitrosothiol) Protoporphyrin Ammonia Creatinine Tryptophan Tumor Necrosis Factor Alpha Urea IL-6 Spectrum of substances removed based on clinical and animal experimental data sets

Substances Not Removed During MARS™ 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 This is in contrast to Plasmapheresis, in which the patient’s serum is replaced by Albumin and/or FFP

Rationale 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 The rationale for supportive therapy and extracorporeal systems is to provide an environment facilitating recovery, to prolong the window of opportunity for LT as a Bridge to LT or sometimes to allow waiting for the native liver recovery as a bridge to liver recovery Liver transplantation is required most of the time

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

Technical Aspects Filters : Flow Rates : Anticoagulation: 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 pCRRT Rome 2010

Vascular Access and Anticoagulation for MARS™

Why Do We Need Vascular Access? 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

Access Considerations 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 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 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.

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

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

Summary: Vascular Access for Pediatric MARS™ 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

MARS™Anticoagulation 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

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

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

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)

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

Citrate Specific Issues 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

Summary: Anticoagulation for Pediatric MARS™ 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

Prescribing Pediatric MARS™

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

Solutions for Pediatric MARS™: Dialysis Fluids and Replacement Fluids

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

Purpose of MARS™ solutions 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

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

Benefits of MARS 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 Patients in advanced liver failure demonstrate a Hyperdynamic Circulation, which many propose is secondary to increased serum Nitric Oxide content in this patient population. Indeed, MARS has shown to remove Nitric Oxide from the circulation and may even decrease total body nitric oxide production.

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

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** In acute liver failure, it seemed to us that MARS treatment is able to provide a slight improvement or at least a stabilization of the hepatic encephalopathy. Moreover, this allows us to better control the fluid balance of the children in this severe situation. Finally, this treatment allowed us to bridge 12 children to liver transplantation. However, sthis system has some technical limitations. Because the size of the membrane is too large, the hemodynamic tolerance was poor in infants. Consequently, they required fluid bolus and inotropic drugs. The better tolerance observed when we combined the miniMARS membrane with a haemodiafiltration machine suggests that it would be interesting to develop a miniPRISMARS system. The most interesting impact of the MARS therapy was observed for children with acute-on chronic LF and those with refractory pruritus. Our observation of chronic use of MARS suggests that improving the pruritus and its consequences, the quality of life and the nutrional status of the child was improved. However this therapy is very expensive and require a long term haemodialysis catheter so that we reserved this treatment for the children with the most severe diseases, particularly when they have an associated renal failure and when they are registered on liver transplantation list.

Cost Benefit Positive benefit in terms of health cost reductions using MARS Kantola et.al. Cost-utility of MARS treatment in ALF. World Journal of Gastroenter 2010; 16; 2227-34 Hessel et.al. Cost-effectiveness of MARS in patients with acute-on-chronic liver failure. Gastroenterol Hepatol 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. Ther Apher Dial 2009; 13; 393-8

Non-Biological artificial support 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

Future Horizons 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

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