Liver Failure/Cirrhosis/Portal Hypertension

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L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure†‡

  1. Lars Marius Ytrebø1,§,*,
  2. Rune Gangsøy Kristiansen1,
  3. Hanne Mæhre2,
  4. Ole Martin Fuskevåg3,
  5. Trine Kalstad4,
  6. Arthur Revhaug4,
  7. María Jover Cobos5,
  8. Rajiv Jalan6,¶,*,
  9. Christopher F. Rose7,*

Article first published online: 18 FEB 2009

DOI: 10.1002/hep.22917

Issue

Hepatology

Hepatology

Volume 50, Issue 1, pages 165–174, July 2009

Additional Information

How to Cite

Ytrebø, L. M., Kristiansen, R. G., Mæhre, H., Fuskevåg, O. M., Kalstad, T., Revhaug, A., Cobos, M. J., Jalan, R. and Rose, C. F. (2009), L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology, 50: 165–174. doi: 10.1002/hep.22917

Author Information

  1. 1

    Department of Anesthesiology, University Hospital of North Norway and University of Tromsø, Norway

  2. 2

    Institute of Marine Biotechnology, University of Tromsø, Norway

  3. 3

    Department of Clinical Pharmacology, University Hospital of North Norway and University of Tromsø, Norway

  4. 4

    Department of Digestive Surgery, University Hospital of North Norway and University of Tromsø, Norway

  5. 5

    Unit for Clinical Management of Digestive Diseases-CIBERehd, Hospital Universitario de Valme, Seville, Spain

  6. 6

    Liver Failure Group, Institute of Hepatology, University College London Medical School, UK

  7. 7

    Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada

  1. §

    fax: +47 776 26192

  2. fax: +44 207 3800405

*Department of Anesthesiology, University Hospital of North Norway and University of Tromsø, N-9038 Tromsø, Norway

  1. †

    Potential conflict of interest: University College London has filed for patents surrounding the use of L-Ornithine and Phenylacetate/Phenylbutyrate for the treatment of hepatic encephalopathy, which has been licensed to Ocera Therapeutics.

  2. ‡

    See Editorial on Page 3

Publication History

  1. Issue published online: 23 JUN 2009
  2. Article first published online: 18 FEB 2009
  3. Accepted manuscript online: 18 FEB 2009 12:00AM EST
  4. Manuscript Accepted: 9 FEB 2009
  5. Manuscript Received: 6 MAY 2008

Funded by

  • Norwegian Research Council
  • Helse Nord
  • Fonds de Recherche en Santé du Quebec (FRSQ, Canada)
  • University College London Business

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Abstract

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 μmol/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 (r2 = 0.36,P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 ± 0.6 μmol/L in ALF + OP-treated pigs versus 0.5 ± 0.04 μmol/L in ALF + saline-treated pigs (P< 0.001).Conclusion: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. (HEPATOLOGY 2009;50:165–174.)

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