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Hepatic Failure and Hemofiltration Timothy E Bunchman Professor Pediatric Nephrology & Transplantation

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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

outline
Outline
  • Hepatic Failure-definition(s)
  • Indications-when do we use them?
  • What are hepatic support therapies
  • Recent Literature
hepatic failure
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
hepatic failure4
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
indications
Indications
  • Bridge to liver transplantation
  • Bridge to allow sufficient time for hepatic regeneration
  • Improve clinical stability of patient
what why are they
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)
non biological filtration techniques
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
non biological filtration techniques8
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
cvvhd for nh4 bridge to hepatic transplantation
CVVHD for NH4 Bridge to Hepatic Transplantation

Successful Liver

Transplantation

NH4

micromoles/L

Time

(days)

non biological filtration techniques10
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)
hepatic failure role of crrt
Hepatic Failure-Role of CRRT
  • Others:
    • Fluid Balance
    • Nutritional support
    • Uremic Clearance
non biological filtration techniques12
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
non biological filtration techniques13
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
non biological filtration techniques14
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
non biological filtration techniques15
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
non biological filtration techniques16
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.
non biological filtration techniques17
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.
non biological filtration techniques18
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.
hybrid biological artificial support
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)
hybrid biological artificial support23
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
hybrid biological artificial support24
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
hybrid biological artificial support25
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

hybrid biological artificial support26
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
hybrid biological artificial support27
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
hybrid biological artificial support28
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
hybrid biological artificial support29
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
artificial liver support system
Artificial Liver Support System

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

slide32
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
arf and liver failure
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
device review
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
pcrrt 4 abstract
PCRRT 4 Abstract
  • Ringe et al
    • 8 children Rx with Single Pass albumin hemofiltration (SPAD)
    • Improvement in Hepatic Encephalopathy
    • Stable hemodynamics
conclusion
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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