Transcript Hepatic Support Therapies - Pediatric Continuous Renal

Hepatic Failure, intoxication and
Hemofiltration
Timothy E Bunchman
Professor Pediatric Nephrology &
Transplantation
Outline
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Hepatic Failure-definition(s)
Indications-when do we use them?
What are hepatic support therapies
Recent Literature
Hepatic Failure
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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
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Production of Endogenous Toxins &
Drug metabolic Failure
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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
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Bridge to liver transplantation
Bridge to allow sufficient time for
hepatic regeneration
Improve clinical stability of patient
Non-Biological Filtration
Techniques
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Hemofiltration:
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First attempt (hemodialysis) 1956 Kiley et
al (Proc. Soc. Exp. Biol. Medical 1956)
Noted Hemodialysis improved clinical (4/5patients) neurological function, didn’t
change outcome though
Non-Biological Filtration
Techniques
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Hemofiltration:
CRRT support can buy time, help prevent further
deterioration/complication and allow
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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
800
700
micromoles/L
NH4
600
Successful Liver
Transplantation
500
400
300
200
100
0
1
2
4
6
8
Time
(days)
10
12
14
16
Non-Biological Filtration
Techniques
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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)
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Management of Cerebral Edema through
middle molecule removal- reversal of Coma
(Matsubara et.al. Crit Care Med1990:8:1331)
Hepatic Failure-Role of CRRT
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Others:
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Fluid Balance
Nutritional support
Uremic Clearance
Non-Biological Filtration
Techniques
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Hemoperfusion:
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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
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Issues:
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Non-specific removal of growth factors
Reactivity with the membranes
Non-Biological Filtration
Techniques
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Hemoperfusion:
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Development of Resin Exchange Columns:
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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
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Plasma Exchange:
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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
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Molecular Adsorbents Recycling System
(MARS)
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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
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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
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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
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Meanwhile, smaller toxin molecules that
don't stick to albumin flow through the
membrane's tiny pores into the lessconcentrated 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
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Extracorporeal Bioartificial Liver Support
Devices:
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Types:
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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
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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
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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
N
+ ALSS
- ALSS
338
312
30 day survival 48%
37%
Decrease in
71%
encephalopathy
OLT
31/338
52%
0
Du et al, Transpl Proc 37, 4359-4364, 2005
MARS
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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
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Novelli et al, Trans Proc 37, 2557-2559, 2005
ARF and Liver Failure
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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%
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Naka et al, ISAO, 27 949-955, 2004
Device Review
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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
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Wigg & Padbury, J Gastro & Hepatol 20:
1807-1816, 2005
PCRRT 4 Abstract
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Ringe et al
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8 children Rx with Single Pass albumin
hemofiltration (SPAD)
Improvement in Hepatic Encephalopathy
Stable hemodynamics
Intoxication
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INTRODUCTION
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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
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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
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Peritoneal Dialysis
Hemodialysis
Hemofiltration
Charcoal hemoperfusion
Considerations
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Volume of Distribution (Vd)/compartments
molecular size
protein/lipid binding
solubility
PHARMOCOKINETIC COMPARTMENTS
ELIMINATION
I
N
P
U
T
Distribution
Re-distribution
kidney
blood
Peripheral
liver
GI Tract
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GENERAL PRINCIPLES
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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
 >48 hrs on vent
 ARF
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Impaired
metabolism
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high probability of
significant
morbidity/mortality
 progressive clinical
deterioration
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INDICATIONS
 severe intoxication
with abnormal vital
signs
 complications of
coma
 prolonged coma
 intoxication with an
extractable drug
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PERITONEAL DIALYSIS
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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
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HEMODIALYSIS
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optimal drug characteristics for removal:
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relative molecular mass < 500
water soluble
small Vd (< 1 L/Kg)
minimal plasma protein binding
single compartment kinetics
low endogenous clearance (< 4ml/Kg/min)
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(Pond, SM - Med J Australia 1991; 154: 617-622)
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Intoxicants amenable to Hemodialysis
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vancomycin (high flux)
alcohols
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diethylene glycol
methanol
lithium
salicylates
Ethylene Glycol Intoxication
Rx with Hemodialysis
900
800
700
600
500
400
300
Pt 1
Pt 2
200
100
0
0
2
4
Duration of Rx (hrs)
6
Vancomycin clearance
High efficiency dialysis
membrane
250
Rx
Rx
Rx
200
Rebound
Rebound
150
Pt 1
Pt 2
100
50
0
0
3
12
15
Time of therapy
27
30
High flux hemodialysis for
Carbamazine Intoxication
Rx
35
30
Mic/ml
25
20
CBZ level
(nl < 12)
15
10
5
0
0
5
10
15
20
25
30
Hrs from time of ingestion
35
40
Albumin Hemofiltration
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Serum half-life (hr) Valproic Acid
Total Unbound
Total
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Baseline 10.3
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CVVHD
7.7
4.5
0.12
CVVHD
+Albumin
4.0
3.0
0.32
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10.0
SievingCoefficient*
Carbamazine Clearance
Clearance with
Albumin Dialysis
Askenazi et al, Pediatrics 2004
Natural
Decay
CVVHD following HD for Lithium poisoning
L 6
i
HD started
5
CVVHD started
m 4
E
q 3
/
2
L
Pt #1
Pt #2
Li Therapeutic range
0.5-1.5 mEq/L
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
1
0
Hours
24
12
6
5
0
Conclusion
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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