Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis.
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-PGF(1alpha), 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.
Chung
C
C
Hepatology Section and Department of Medicine, VA Chicago Health Care System, Lakeside Division and Northwestern University, Chicago, IL 60611, USA.
Gottstein
J
J
Blei
A T
AT
D015121:6-Ketoprostaglandin F1 alpha / Q000134:cerebrospinal fluid; D000641:Ammonia / Q000097:blood / Q000378:metabolism; D000818:Animals; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000139:chemically induced* / Q000209:etiology* / Q000517:prevention & control; D005973:Glutamine / Q000378:metabolism; D007213:Indomethacin / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D017078:Laser-Doppler Flowmetry; D008297:Male; D011167:Portacaval Shunt, Surgical / Q000009:adverse effects*; D011315:Preventive Medicine / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*
D014662:Vasoconstrictor Agents; D005973:Glutamine; D015121:6-Ketoprostaglandin F1 alpha; D000641:Ammonia; D007213:Indomethacin