Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis

Abstract

Brain edema, leading to intracranial hypertension and brain herniation, is a major cause of death in fulminant liver failure. Astrocyte swelling is a prominent neuropathological feature in experimental fulminant liver failure. It has been postulated that the osmotic effects of glutamine, generated in astrocytes from ammonia and glutamate in a reaction catalyzed by glutamine synthetase, could mediate brain swelling. Normal rats and rats that received a portacaval anastomosis were infused with ammonium acetate or a sodium acetate control; brain water in cerebral cortex was measured with the gravimetry method, intracranial pressure by means of a cisterna magna catheter and cortical amino acids using high-performance liquid chromatography. Although brain edema was detected in both groups receiving ammonia, it was of a greater magnitude in portacaval anastomosis rats (80.94% + 0.17% vs. 80.24% + 0.09%, p < 0.01), resulting in the development of intracranial hypertension. When portacaval anastomosis rats were infused with ammonium acetate and pretreated with 150 mg/kg methionine-sulfoximine, an inhibitor of glutamine synthetase activity, brain edema was ameliorated and intracranial pressure did not rise. A dose-dependent reduction in brain glutamine levels was seen with increasing doses of methionine-sulfoximine; however, brain edema did not decrease beyond the 150 mg/kg dose, suggesting that the increase in brain water was not solely a result of glutamine accumulation. We conclude that brain edema of a magnitude that results in intracranial hypertension is more likely to develop in rats after portacaval anastomosis receiving a continuous ammonia infusion. The osmotic effects of glutamine appear to mediate, but only in part, the increase in brain water seen in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital

“…This finding is in full accordance with the literature where data showed that only plasma concentrations of ammonia above $2 mmol/L are associated with increased ICP and CBF in naïve rats [18]. Moreover, in rats with portacaval anastomosis and a plasma ammonia concentration maintained close to 1 mmol/L, ICP and CBF start to increase after more than 150 min [19][20][21][22][23], a much more protracted delay than that we observed in rats with moderate hyperammonemia and given LPS.…”

Contribution of Extracellular Glutamine as An Anaplerotic Substrate to Neuronal Metabolism: A Re-Evaluation by Multinuclear NMR Spectroscopy in Primary Cultured Neurons

“…This may have important implications in hyperammonemic syndromes such as Hepatic Encephalopathy (HE) due to ALF. The principal cause of mortality in HE is brain edema, leading to increased intracranial pressure and subsequently brain herniation (40,41). It has been suggested for long that astrocyte swelling due to the increased intracellular osmolarity by glutamine accumulation is the major reason responsible for brain edema in HE due to ALF.…”

Acute liver failure: current management and future prospects

“…Ammonia related brain edema is possibly the first event [51]. CBF autoregulation is lost in patients with ALF resulting in cerebral hyperemia [40,52].…”