Increased intracranial pressure in a porcine model of fulminant hepatic failure using amatoxin and endotoxin.

BACKGROUND/AIMS: The purpose of this study was to develop a clinically relevant porcine model of fulminant hepatic failure (FHF) by means of administration of amatoxin and endotoxin.

METHODS

Pigs were intraportally administered only saline in group 1 (n = 3), 1 microg/kg of lipopolysaccharide (LPS) in group 2 (n = 4), 0.1 mg/kg of alpha-amanitin in group 3 (n = 5), and amanitin plus LPS in group 4 (n = 9).

RESULTS

All the pigs in groups 1 and 2 survived with minimal changes in liver function tests. In contrast to the 60% mortality in group 3, all the pigs in group 4 died within 96 h, with a significant increase in aspartate transaminase at 24 h (9,757 +/- 2,167 IU/I). In addition, they demonstrated severe metabolic disorders, such as serum lactate accumulation, hypoglycemia, coagulopathy, plasma amino acid imbalance, and hyperammonemia. The intracranial pressure significantly increased to 17.8 +/- 2.5 mmHg immediately before death. Reversal of FHF in these pigs following orthotopic liver transplantation confirmed that the toxicity is liver-specific and that the graft liver is unaffected.

CONCLUSIONS

This porcine model of FHF induced by a combination of amanitin and LPS will be of much use in the development of new therapies for human FHF.