Brain edema sufficient to cause
intracranial hypertension and brain herniation remains a major cause of mortality in
acute liver failure (ALF). Studies in experimental animal models of ALF suggest a role for
ammonia in the pathogenesis of both
encephalopathy and
brain edema in this condition. As part of a series of studies to evaluate the therapeutic efficacy of
ammonia-lowering agents, groups of rats with ALF caused by hepatic devascularization were treated with
L-ornithine-L-aspartate (OA), an agent shown previously to be effective in reducing blood
ammonia concentrations in both experimental and human
chronic liver failure. Treatment of rats in ALF with infusions of OA (0.33 g/kg/h, intravenously) resulted in normalization of plasma
ammonia concentrations and in a significant delay in onset of severe
encephalopathy. More importantly, brain water content was significantly reduced in OA-treated rats with ALF. These protective effects of OA were accompanied by increased plasma concentrations of several
amino acids including
glutamate,
gamma-aminobutyric acid (
GABA),
taurine, and
alanine, as well as the
branched-chain amino acids,
leucine,
isoleucine, and
valine. Increased availability of
glutamate following OA treatment provides the substrate for the major
ammonia-removal mechanism (
glutamine synthetase). Plasma (but not cerebrospinal fluid)
glutamine concentrations were increased 2-fold (P <.02) in OA-treated rats, consistent with increased muscle
glutamine synthesis. Direct measurement of
glutamine synthetase activities revealed a 2-fold increase following OA treatment. These findings demonstrate a significant
ammonia-lowering effect of OA together with a protective effect on the development of
encephalopathy and
brain edema in this model of ALF.