Hepatic Failure, intoxication and Hemofiltration

Timothy E BunchmanProfessor Pediatric

Nephrology & Transplantation

Outline Hepatic Failure-definition(s) Indications-when do we use them? What are hepatic support therapies Recent Literature

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 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 Bridge to liver transplantation

Bridge to allow sufficient time for hepatic regeneration

Improve clinical stability of patient

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 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

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Successful Liver Transplantation

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 Others:

Fluid Balance Nutritional support Uremic Clearance

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 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 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 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 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 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 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.

Hepatic Support Devices

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 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 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

What is the recent literature?

Artificial Liver Support System

+ ALSS - ALSS

N 338 312

30 day survival

48% 37%

Decrease in encephalopathy

71% 52%

OLT 31/338 0

Du et al, Transpl Proc 37, 4359-4364, 2005

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 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 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 Ringe et al

8 children Rx with Single Pass albumin hemofiltration (SPAD)

Improvement in Hepatic Encephalopathy

Stable hemodynamics

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

Intoxication

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

Extracorporeal Methods Peritoneal Dialysis Hemodialysis Hemofiltration Charcoal hemoperfusion

Considerations Volume of Distribution (Vd)/compartments molecular size protein/lipid binding solubility

PHARMOCOKINETIC COMPARTMENTS

kidney

blood

Peripheral

liver

GI TractDistribution Re-distribution

INPUT

ELIMINATION

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)

INDICATIONS >48 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

PERITONEAL DIALYSIS 1st done in 1934 for 2 anuric patients after

sublimate poisoning (Balzs et al; Wien Klin Wschr 1934;47:851 )

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

HEMODIALYSIS optimal drug characteristics for removal:

relative molecular mass < 500 water soluble small Vd (< 1 L/Kg) minimal plasma protein binding single compartment kinetics low endogenous clearance (< 4ml/Kg/min)

(Pond, SM - Med J Australia 1991; 154: 617-622)

Intoxicants amenable to Hemodialysis vancomycin (high flux) alcohols

diethylene glycol methanol

lithium salicylates

Ethylene Glycol IntoxicationRx with Hemodialysis

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Vancomycin clearance High efficiency dialysis

membrane

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Rebound Rebound

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CBZ level(nl < 12)

High flux hemodialysis for Carbamazine Intoxication

Rx

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/ml

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

Albumin Hemofiltration

Carbamazine ClearanceNatural Decay

Clearance with Albumin Dialysis

Askenazi et al, Pediatrics 2004

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CVVHD following HD for Lithium poisoning

HD started

CVVHD started CT-190 (HD)Multiflo-60both patientsBFR-pt #1 200 ml/minHD & CVVHD -pt # 2 325 ml/minHD & 200 ml/min

CVVHDPO4 Based dialysate at

2L/1.73m2/hr

Li Therapeutic range0.5-1.5 mEq/L

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