Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study.
OBJECTIVE
In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure.


METHODS
Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure.


RESULTS
The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen.


CONCLUSIONS
The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients.
Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, UK. Electronic address: klee@rvc.ac.uk.
Karla C L
KC
Lee
Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, UK.
Luisa A
LA
Baker
Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, UK.
Giacomo
G
Stanzani
Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, UK.
Hatim
H
Alibhai
Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, UK.
Yu Mei
YM
Chang
Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, UK.
Carolina
C
Jimenez Palacios
Institute of Liver and Digestive Health, Liver Failure Group, University College London Medical School Royal Free Campus, London, UK.
Pamela J
PJ
Leckie
Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, UK.
Paola
P
Giordano
Department of Pathology and Pathogen Biology, The Royal Veterinary College, Hertfordshire, UK.
Simon L
SL
Priestnall
MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Daniel J
DJ
Antoine
MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Rosalind E
RE
Jenkins
MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Christopher E
CE
Goldring
MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
B Kevin
BK
Park
Institute of Liver and Digestive Health, Liver Failure Group, University College London Medical School Royal Free Campus, London, UK.
Fausto
F
Andreola
Intensive Care Unit, Royal Free London NHS Foundation Trust, London, UK.
Banwari
B
Agarwal
Institute of Liver and Digestive Health, Liver Failure Group, University College London Medical School Royal Free Campus, London, UK.
Rajeshwar P
RP
Mookerjee
Institute of Liver and Digestive Health, Liver Failure Group, University College London Medical School Royal Free Campus, London, UK.
Nathan A
NA
Davies
Institute of Liver and Digestive Health, Liver Failure Group, University College London Medical School Royal Free Campus, London, UK.
Rajiv
R
Jalan
D000818:Animals; D004731:Endotoxins / Q000302:isolation & purification*; D005112:Extracorporeal Circulation; D005260:Female; D024243:HMGB1 Protein / Q000097:blood; D017114:Liver Failure, Acute / Q000628:therapy*; D019164:Liver, Artificial; D012709:Serum Albumin / Q000378:metabolism*; D015398:Signal Transduction; D016060:Sorption Detoxification / Q000295:instrumentation*; D013552:Swine; D051197:Toll-Like Receptor 4 / Q000502:physiology
D004731:Endotoxins; D024243:HMGB1 Protein; D012709:Serum Albumin; D051197:Toll-Like Receptor 4
Acetaminophen; Acute liver failure; Albumin; Endotoxin; Extracorporeal liver assist device; Toll-like receptor 4; UCL-LDD