Hepatic Failure and Hemofiltration
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Hepatic Failure and Hemofiltration Timothy E Bunchman Professor Pediatric Nephrology & Transplantation. Outline. Hepatic Failure-definition(s) Indications-when do we use them? What are hepatic support therapies Recent Literature. Hepatic Failure.

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Hepatic Failure and HemofiltrationTimothy E BunchmanProfessor Pediatric Nephrology & Transplantation


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Outline

  • Hepatic Failure-definition(s)

  • Indications-when do we use them?

  • What are hepatic support therapies

  • Recent Literature


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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 failure, death


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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


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    Indications

    • Bridge to liver transplantation

    • Bridge to allow sufficient time for hepatic regeneration

    • Improve clinical stability of patient


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    What & Why are they?

    • Two main approaches to liver support

      • Non-biological

        • Filtration of potentially harmful molecules

      • Hybrid Biological artificial support (hepatic cells in a synthetic framework)


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    Non-Biological Filtration Techniques

    • Hemofiltration:

      • First attempt (hemodialysis) 1956 Kiley et al (Proc. Soc. Exp. Biol. Medical 1956)

      • Noted Hemodialysis improved clinical (4/5-patients) neurological function, didn’t change outcome though


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    Non-Biological Filtration Techniques

    • Hemofiltration:

    • CRRT support can buy time, help prevent further deterioration/complication and allow

      • Potential recovery of functional critical cell mass

      • Management of precipitating events that lead to decompensated disease

      • Bridge to liver transplantation


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    CVVHD for NH4 Bridge to Hepatic Transplantation

    Successful Liver

    Transplantation

    NH4

    micromoles/L

    Time

    (days)


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    Non-Biological Filtration Techniques

    • Hemofiltration:

    • CRRT may not improve overall outcome of liver failure- provide stability and prolongs life in the setting of hepatic failure

    • Primary applications include use in control of elevated ICP in fulminant hepatic failure (Davenport Lancet 1991:2:1604)

    • Management of Cerebral Edema through middle molecule removal- reversal of Coma (Matsubara et.al. Crit Care Med1990:8:1331)


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    Hepatic Failure-Role of CRRT

    • Others:

      • Fluid Balance

      • Nutritional support

      • Uremic Clearance


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    Non-Biological Filtration Techniques

    • Hemoperfusion:

      • Historically Charcoal gave rise to current cartridge chambers in use today

      • PolyAcryloNitrile-Initially noted to remove substances up to 15000Da (initial study) found clinical but not statistical survival improvement

        • Issues:

          • Non-specific removal of growth factors

          • Reactivity with the membranes


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    Non-Biological Filtration Techniques

    • Hemoperfusion:

      • Development of Resin Exchange Columns:

        • Amberlite- removal of cytokines, bilirubin, bile acids

        • Polymixin-endotoxin removal

        • Hydrophilic Membranes- for removal NH4, phenols and fatty acids

        • Downside- also effective at removing leucocytes and platelets


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    Non-Biological Filtration Techniques

    • Plasma Exchange:

      • Allows removal of hepatic toxins with replacement with equivalent volume of Fresh Frozen Plasma

      • Improved clinical response but no significant increase in survival rates

      • In general- get limited toxin removal and high FFP replacement volumes are required over time- costly


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    Non-Biological Filtration Techniques

    • Molecular Adsorbents Recycling System (MARS)

      • Commercially available-premise based on filtering out albumin bound toxins

      • Uses albumin-enriched dialysate combined with a charcoal filter and an ion exchange resin

      • Utilizes existing Renal Dialysis Machinery along with the MARS device


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    Non-Biological Filtration Techniques

    • Albumin dialysis pumps the blood out of the body and into a plastic tube filled with hollow fibers made of a membrane that has been coated with albumin.

    • On one side of the fiber's membrane is the blood; on the other, a dialysis solution containing more albumin.


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    Non-Biological Filtration Techniques

    • The toxins on the albumin in the patient's blood are attracted to the albumin on the membrane, which is "stickier" because it has more room for molecules to attach.

    • Then, the albumin on the membrane passes the toxins along to the albumin in the solution as it flows by.


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    Non-Biological Filtration Techniques

    • Meanwhile, smaller toxin molecules that don't stick to albumin flow through the membrane's tiny pores into the less-concentrated dialysis solution.

    • The patient's own albumin, too large to fit through the membrane's pores, returns to the body with the blood.



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    Hybrid Biological artificial support

    • Rooted in Cross Circulation Studies- using Dogs and Human subjects & Porcine, Baboon extracorporeal liver perfusion

    • Conceptually: liver function-including synthesis and homeostasis are replaced by hepatocytes in an exogenous environment

      • Peritoneal placement of hepatocytes

      • Extracorporeal perfusion (cells in synthetic frame)


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    Hybrid Biological artificial support

    • Implantation: (using coated microcarrier beads)

      • Within liver resulted in cell aggregation and portal hypertension

      • Within peritoneum/spleen (animal models)

      • Benefits: relatively simple to do

      • Problems: delayed onset of function (less useful in Acute Hepatic Failure), Lose function over time-need re-implantation (animal studies), require immunosuppresion


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    Hybrid Biological artificial support

    • Implantation: (using coated microcarrier beads)

      • Problems: Human pilot (Bilir et al. Liver Transplantation 2000,6,32-40)

      • 8 patients transplanted- no survivors, 3/8 showed some neuro improvement


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    Hybrid Biological artificial support

    • Extracorporeal Bioartificial Liver Support Devices:

      • Extracorporeal systems that combine hepatocytes in a plastic cartridge and semi-permeable membrane

      • Problems: 1) maintaining cell viability and numbers

        2) Membrane type and structure

        3) cell mass and type of hepatocyte


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    Hybrid Biological artificial support

    • Extracorporeal Bioartificial Liver Support Devices:

      • Types:

        • HepatAssist 2000

        • ELAD (extracorporeal liver assist device)

        • BLSS (bioartificial liver support system)

        • MELS (Modular extracorporeal liver system)

        • LiverX2000 system

        • AMC-BAL (academic medical centre) Chamuleau


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    Hybrid Biological artificial support

    • All of these therapies combine replacement hepatocytes (human, porcine, immortalized, inducible) within a structured meshwork fiber

    • Each has a different cell mass and nourishment system for the cells

    • Several provide charcoal columns for toxin removal, and/or albumin dialysate along with the ability to add in a dialysis unit


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    Hybrid Biological artificial support

    • Most are in Phase I/II clinical trials

    • Initial studies have been mixed with respect to outcomes (end points differ between studies)

    • Data just starting to emerge on these devices


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    Hybrid 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

      • Possibility of introducing viruses with live cell use

      • Need to standardize end points in these studies



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    Artificial Liver Support System

    Du et al, Transpl Proc 37, 4359-4364, 3005


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    MARS

    • N = 116

    • Bili drop 23-12 mg/dl

    • NH4 drop 238-115 microgms/dl

    • Lactate drop 3.48 – 1.76 mmol/L

    • Creatinine drop 2.4-1.2 mg/dl

    • No comment on survival, bridge to Tx

      • Novelli et al, Trans Proc 37, 2557-2559, 2005


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    ARF and Liver Failure

    • 66 patients with ARF and LF Rx with CVVH

    • 26 – OLT with 9.5 avg CVVH days, ICU and Hospital mortality of 15% and 23%

    • 40 – no OLT 5 avg CVVH days, ICU and Hospital mortality of 63% and 70%

      • Naka et al, ISAO, 27 949-955, 2004


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    Device Review

    • Review of all devices to date (semi meta-analysis)

    • Conclusion = Hepatic support systems use is not justified as an ongoing support but may be best use for OLT bridge

      • Wigg & Padbury, J Gastro & Hepatol 20: 1807-1816, 2005


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    PCRRT 4 Abstract

    • Ringe et al

      • 8 children Rx with Single Pass albumin hemofiltration (SPAD)

      • Improvement in Hepatic Encephalopathy

      • Stable hemodynamics


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    Conclusion

    • Hepatic Support Devices are still in their infancy

    • Use of CVVH with or without albumin may be “equally” effective

    • Future research in this area is on goin

    • OLT only definitive Rx of ALF


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