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. 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

4. 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

5. 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

6. 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

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
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

10. 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

11. 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

12. 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

13. 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

14. Vascular Access and Anticoagulation for MARS™

15. 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

16. 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

17. 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.

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. 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

21. 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

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

23. Anticoagulation Regional Citrate Systemic Heparin
Goal Circuit iCal mmol/L
Goal Patient iCal mmol/L
Risk for
Hypocalcemia
Alkalosis
Hypernatremia
Systemic Heparin
Goal ACT sec
Patient anticoagulated
Risk of bleeding
Risk for HIT

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. 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

27. 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

28. Prescribing Pediatric MARS™

29. Choosing QB for Pediatric MARS™
Choose blood flow rate (QB) of 3-5ml/kg/min, or:
0-10 kg: ml/min
11-20kg: ml/min
21-50kg: ml/min
>50kg: ml/min
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. Characteristics of the Ideal MARS™ Solution
Physiological
Reliable
Inexpensive
Easy to prepare
Simple to store
Quick to the bedside
Widely available
Fully compatible

32. 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

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

34. 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: , 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.

35. 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 )

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**
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.

38. 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;
Hessel et.al. Cost-effectiveness of MARS in patients with acute-on-chronic liver failure. Gastroenterol Hepatol 2010; 22:
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

39. 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

40. 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:
Schaefer et.al. MARS dialysis in children with cholestatic pruritus. Pediatr Nephrol 2012; 27:

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