Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis
Article first published online: 30 DEC 2003
Copyright © 2001 American Association for the Study of Liver Diseases
Volume 34, Issue 2, pages 249–254, August 2001
How to Cite
Chung, C., Gottstein, J. and Blei, A. T. (2001), Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology, 34: 249–254. doi: 10.1053/jhep.2001.26383
- Issue published online: 30 DEC 2003
- Article first published online: 30 DEC 2003
- Manuscript Accepted: 21 MAY 2001
- Manuscript Received: 23 FEB 2001
- Veterans Administration Research Service and the Stephen B. Tips Memorial Fund at Northwestern Memorial Hospital.
Patients with fulminant hepatic failure (FHF) die with brain edema, exhibiting an increased cerebral blood flow (CBF) at the time of cerebral swelling. Mild hypothermia prevents brain edema in experimental models and in humans with FHF, an effect associated with normalization of CBF. To study the effects of alterations of CBF on the development of brain edema, we administered intravenous (IV) indomethacin to rats receiving an ammonia infusion after portacaval anastomosis. This model predictably develops brain edema and a marked increase in CBF at 3 hours of infusion. Brain water was measured with the gravimetry technique; CBF was monitored with both laser Doppler flowmetry and radioactive microspheres, whereas intracranial pressure (ICP) was monitored with a cisterna magna catheter. Coadministration of indomethacin prevented the increase in CBF seen with ammonia alone (110 ± 19% vs. −2 ± 9%) as well as the increase in brain water (80.86 ± 0.12% vs. 80.18 ± 0.06%) and the increase in ICP. Plasma ammonia and brain glutamine levels were markedly elevated in the ammonia-infused group and unaffected by indomethacin. However, ammonia uptake by the brain was significantly reduced by indomethacin. Levels of 6-keto-PGF1α, a stable metabolite of prostacyclin, were reduced in the cerebrospinal fluid (CSF) of indomethacin-treated animals. As with mild hypothermia, avoiding cerebral vasodilatation with indomethacin will prevent the development of brain edema in this hyperammonemic model. Cerebral vasoconstriction reduces cerebral ammonia uptake and, if selective to the brain, may be of benefit in FHF.