Hepatic Failure, intoxication and Hemofiltration Timothy E Bunchman Professor Pediatric Nephrology

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Hepatic Failure, intoxication 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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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, didnt
  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 199121604)
• Management of Cerebral Edema through middle
  molecule removal- reversal of Coma (Matsubara
  et.al. Crit Care Med199081331)

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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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Hepatic Support Devices
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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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What is the recent literature?
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Artificial Liver Support System
Du et al, Transpl Proc 37, 4359-4364, 2005
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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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Intoxication

• INTRODUCTION
• 2.2 million reported poisonings (1998) 67 in
  pediatrics
• Approximately 0.05 required extracorporeal
  elimination
• Primary prevention strategies for acute
  ingestions have been designed and implemented
  (primarily with legislative effort) with a
  subsequent decrease in poisoning fatalities

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• Poison Management
• DECONTAMINATION/TREATMENT OPTIONS FOR OVERDOSE
• Standard Airway, Breathing and Circulatory
  measures take precedent
• Oral Charcoal
• Bowel Cleansing Regimens
• Antidotes IV or PO when applicable
• IV Hydration

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• Extracorporeal Methods
• Peritoneal Dialysis
• Hemodialysis
• Hemofiltration
• Charcoal hemoperfusion
• Considerations
• Volume of Distribution (Vd)/compartments
• molecular size
• protein/lipid binding
• solubility

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ELIMINATION
I N P U T
Distribution
Re-distribution
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• GENERAL PRINCIPLES
• kinetics of drugs are based on therapeutic not
  toxic levels (therefore kinetics may change)
• choice of extracorporeal modality is based on
  availability, expertise of people the
  properties of the intoxicant in general
• Each Modality has drawbacks
• It may be necessary to switch modalities during
  therapy (combined therapies inc endogenous
  excretion/detoxification methods)

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• INDICATIONS
• gt48 hrs on vent
• ARF
• Impaired metabolism
• high probability of significant
  morbidity/mortality
• progressive clinical deterioration

• INDICATIONS
• severe intoxication with abnormal vital signs
• complications of coma
• prolonged coma
• intoxication with an extractable drug

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• PERITONEAL DIALYSIS
• 1st done in 1934 for 2 anuric patients after
  sublimate poisoning (Balzs et al Wien Klin Wschr
  193447851 )
• Allows diffusion of toxins across peritoneal
  membrane from mesenteric capillaries into
  dialysis solution within the peritoneal cavity
• limited use in poisoning (clears drugs with low
  Mwt., Small Vd, minimal protein binding those
  that are water soluble)
• alcohols, NaCl intoxications, salicylates

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• HEMODIALYSIS
• optimal drug characteristics for removal
• relative molecular mass lt 500
• water soluble
• small Vd (lt 1 L/Kg)
• minimal plasma protein binding
• single compartment kinetics
• low endogenous clearance (lt 4ml/Kg/min)
• (Pond, SM - Med J Australia 1991 154 617-622)

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• Intoxicants amenable to Hemodialysis
• vancomycin (high flux)
• alcohols
• diethylene glycol
• methanol
• lithium
• salicylates

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Ethylene Glycol IntoxicationRx with Hemodialysis
Mg/ml (gt 30 mg/ml toxic)
Duration of Rx (hrs)
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Vancomycin clearance High efficiency dialysis
membrane
Rx
Rx
Rx
Rebound
Rebound
Vanc level (mic/dl)
Time of therapy
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High flux hemodialysis for Carbamazine
Intoxication
Rx
Mic/ml
Hrs from time of ingestion
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Albumin Hemofiltration

• Serum half-life (hr) Valproic Acid
• Total Unbound Total
• Baseline 10.3 10.0 SievingCoefficient
  
• CVVHD 7.7 4.5 0.12
• CVVHD 4.0 3.0 0.32
• Albumin

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Carbamazine Clearance
Natural Decay
Clearance with Albumin Dialysis
Askenazi et al, Pediatrics 2004
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L i m E q / L
CVVHD following HD for Lithium poisoning
HD started
Li Therapeutic range 0.5-1.5 mEq/L
CVVHD started
CT-190 (HD) Multiflo-60 both patients BFR-pt 1
200 ml/min HD CVVHD -pt 2 325
ml/min HD 200 ml/min CVVHD PO4 Based
dialysate at 2L/1.73m2/hr
Hours
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Conclusion

• Hepatic Support Devices are still in their
  infancy
• Use of CVVH with or without albumin may be
  equally effective for hepatic support or for
  intoxications
• Future research in this area is on going
• OLT only definitive Rx of ALF