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Molecular Adsorbent Recirculating System
Patrick Brophy MD
Director Pediatric Nephrology, University of Iowa Children’s
Hospital
Outline
• Hepatic Dialysis- Liver Support
• MARS™
• Rationale
• Indications
• Outcomes
• 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
Stadlbauer and Jalan. Acute Liver Failure: liver support TherapiesCurrent Opin in Crit Care. 2007; 13:215-21
MARS™MARS™ Flux Filter
ADSORPTION COLUMNS
DIALYSISDiaFlux Filter
Patient BloodCircuit
20-25% AlbuminCircuit
DialysisCircuit
MARS Flux Filter
Kapoor D., Journal of Gastroenterology and Hepatology, 2002
pCRRT Rome 2010
Technical Aspects• 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
Albumin Bound Toxins Removed During MARS Therapy
• Aromatic Amino Acids• Bilirubin• Bile Acids• Copper• Middle and Short Chain
Fatty Acids• Nitric Oxide (S-
Nitrosothiol)• Protoporphyrin
Water Soluble Substances Removed During MARS Therapy
• Ammonia• Creatinine• Tryptophan• Tumor Necrosis Factor
Alpha• Urea• IL-6
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
12
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
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
Intoxications leading to Acute Liver Failure
• Exogenous:– Acetaminophen– Amanita Toxin
• Endogenous: – Inborn Error Metabolism– Wilson disease, neonatal hemochromatosis
• Removal of inflammatory Toxins– Sepsis/SIRS– MOSFSee appendix for references
Multiple studies have shown MARS to be an effective therapy in these types of toxin induced ALF
Acute Liver Failure
0
0,2
0,4
0,6
0,8
1
0 5 10 15 20 25 30
treatment days
cum
ula
tive
su
rviv
al
MARS(n=8) HDF(n=5)
p = 0,0123
Acute Liver Failure
Data -2000-2009 PICU at Pédiatriques Hôpital Femme Mère Enfant, Lyon, France: Dr. E Javouhey- presented ppCRRT meeting 2010
Weight Kg
Age month
Liver disease
Underlying disase
Indication Transplantation Outcome
1 9 10 Biliary atresia Graft dysfunction
ALF Living donor Severe disabilities
2 7 7 Fulminant hepatitis
Cystic fibrosis
ALF Cadaveric Donor Died
3 9,5 28 Biliary cirrhosis End stage renal failure
AoCLF Liver-Kidney Alive
4 13 36 Byler disease Chronic graft rejection
RP Living donor Alive
5 6,3 9 Biliary atresia Biliary Cirrhosis
AoCLF/RP Cadaveric Donor Alive
6 50 166 Wilson disease ALF Living donor Alive 7 55 180 Biliary atresia Chronic graft
rejection RP Living donor Alive
8 37 189 Fulminant hepatitis
Graft Dysfunction
RP Living donor Alive
9 6,8 6 Fulminant hepatitis
ALF Living donor Alive
10 20 139 Wilson disease ALF Cadaveric Donor Alive 11 30 135 Wilson disease ALF Cadaveric Donor Alive 12 50 181 Wilson disease
Priamary graft dysfunction
ALF
Cadaveric donor X2
Alive
Acute on Chronic Liver Failure
• 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
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
Hepatic Encephalopathy
Endogenous Benzodiazepine
LIVER FAILURE MARS
Ammonia
Nitric Oxide
Fischer Index
Glutamine Glutamate
Loss of CerebralAuto-regulation
IntracranialHypertension
CerebralEdema
CerebralIschemia
Herniation
Benefits of MARS• Improvement in Hepatic Encephalopathy
Hassanein T., Hepatology 46: 1853-1862, 2007
Tolerance and efficacy Tolerance Efficacy Weight
kg Age
month Indication Hemodynamic Transfusion Neurological Pruritus Humor
9 10 ALF Moderate Yes (+/-)
7 7 ALF Bad No NA
ALF
6,8 6 ALF Bad Yes NA
9,5 28 AoCLF Good No Yes Yes Yes 13 36 RP Good No Yes Yes Yes
6,3 9 AoCLF/RP Good Yes Stable Stable NA 55 180 RP Good No Yes Yes Yes
AoCLF/RP
37 189 RP Good No Yes Yes Yes
50 166 ALF Good Yes Stable Wilson disease 20 139 ALF Good Yes NA
30 135 ALF Good Yes Sable, no EH 50 181 ALF
Graft dysfunction
Good Atrial
tachycardia
yes Yes
Data -2000-2009 PICU at Pédiatriques Hôpital Femme Mère Enfant, Lyon, France: Dr. E Javouhey- presented ppCRRT meeting 2010
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
Cost Benefit
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 HorizonsHuge 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
Appendix