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
0
100
200
300
400
500
600
700
800
1 2 4 6 8 10 12 14 16
NH
4m
icro
mol
es/L
Time(days)
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
0
100
200
300
400
500
600
700
800
900
0 2 4 6
Pt 1Pt 2
Duration of Rx (hrs)
Mg/
ml
(> 3
0 m
g/m
l tox
ic)
Vancomycin clearance High efficiency dialysis
membrane
0
50
100
150
200
250
0 3 12 15 27 30
Pt 1Pt 2
Time of therapy
Van
c le
vel
(m
ic/d
l)
Rx Rx Rx
Rebound Rebound
0
5
10
15
20
25
30
35
0 5 10 15 20 25 30 35 40
CBZ level(nl < 12)
High flux hemodialysis for Carbamazine Intoxication
Rx
Hrs from time of ingestion
Mic
/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
0
1
2
3
4
5
6Pt #1Pt #2
Hours
Li
mEq/ L
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