L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure.
Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a combination of L-ornithine and phenylacetate (OP) would synergistically reduce toxic levels of ammonia by (1) L-ornithine increasing glutamine production (ammonia removal) through muscle glutamine synthetase and (2) phenylacetate conjugating with the ornithine-derived glutamine to form phenylacetylglutamine, which is excreted into the urine. The aims of this study were to determine the effect of OP on arterial and extracellular brain ammonia concentrations as well as ICP in pigs with ALF (induced by liver devascularization). ALF pigs were treated with OP (L-ornithine 0.07 g/kg/hour intravenously; phenylbutyrate, prodrug for phenylacetate; 0.05 g/kg/hour intraduodenally) for 8 hours following ALF induction. ICP was monitored throughout, and arterial and extracellular brain ammonia were measured along with phenylacetylglutamine in the urine. Compared with ALF + saline pigs, treatment with OP significantly attenuated concentrations of arterial ammonia (589.6 +/- 56.7 versus 365.2 +/- 60.4 mumol/L [mean +/- SEM], P= 0.002) and extracellular brain ammonia (P= 0.01). The ALF-induced increase in ICP was prevented in ALF + OP-treated pigs (18.3 +/- 1.3 mmHg in ALF + saline versus 10.3 +/- 1.1 mmHg in ALF + OP-treated pigs;P= 0.001). The value of ICP significantly correlated with the concentration of extracellular brain ammonia (r(2) = 0.36,P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 +/- 0.6 micromol/L in ALF + OP-treated pigs versus 0.5 +/- 0.04 micromol/L in ALF + saline-treated pigs (P< 0.001).


CONCLUSIONS
L-Ornithine and phenylacetate act synergistically to successfully attenuate increases in arterial ammonia, which is accompanied by a significant decrease in extracellular brain ammonia and prevention of intracranial hypertension in pigs with ALF.
Ytrebø
Lars Marius
LM
Department of Anesthesiology, University Hospital of North Norway and University of Tromsø, Norway. larsmy@fagmed.uit.no
Kristiansen
Rune Gangsøy
RG
Maehre
Hanne
H
Fuskevåg
Ole Martin
OM
Kalstad
Trine
T
Revhaug
Arthur
A
Cobos
María Jover
MJ
Jalan
Rajiv
R
Rose
Christopher F
CF
D000641:Ammonia / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001158:Arteries; D001921:Brain / Q000378:metabolism*; D004338:Drug Combinations; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism*; D019586:Intracranial Hypertension / Q000209:etiology* / Q000517:prevention & control*; D017114:Liver Failure, Acute / Q000150:complications* / Q000378:metabolism*; D009952:Ornithine / Q000494:pharmacology* / Q000627:therapeutic use*; D010648:Phenylacetates / Q000494:pharmacology* / Q000627:therapeutic use*; D013552:Swine
D004338:Drug Combinations; D010648:Phenylacetates; D000641:Ammonia; D009952:Ornithine; C025136:phenylacetic acid