Hypermagnesemia does not prevent intracranial hypertension and aggravates cerebral hyperperfusion in a rat model of acute hyperammonemia

Abstract

Intravenous infusion of magnesium sulfate prevents seizures in patients with eclampsia and brain edema after traumatic brain injury. Neuroprotection is achieved by controlling cerebral blood flow (CBF), intracranial pressure, neuronal glutamate release, and aquaporin-4 (Aqp4) expression. These factors are also thought to be involved in the development of brain edema in acute liver failure. We wanted to study whether hypermagnesemia prevented development of intracranial hypertension and hyperperfusion in a rat model of portacaval anastomosis (PCA) and acute hyperammonemia. We also studied whether hypermagnesemia had an influence on brain content of glutamate, glutamine, and aquaporin-4 expression. The study consisted of three experiments: The first was a dose-finding study of four different dosing regimens of magnesium sulfate (MgSO 4 ) in healthy rats. The second involved four groups of PCA rats receiving ammonia infusion/vehicle and MgSO 4 /saline. The effect of MgSO 4 on mean arterial pressure (MAP), intracranial pressure (ICP), CBF, cerebral glutamate and glutamine, and aquaporin-4 expression was studied. Finally, the effect of MgSO 4 on MAP, ICP, and CBF was studied, using two supplementary dosing regimens. In the second experiment, we found that hypermagnesemia and hyperammonemia were associated with a significantly higher CBF (P < 0.05, twoway analysis of variance [ANOVA]). Hypermagnesemia did not lead to a reduction in ICP and did not affect the brain content of glutamate, glutamine, or Aqp-4 expression. In the third experiment, we achieved higher P-Mg but this did not lead to a significant reduction in ICP or CBF. Conclusion: Our results demonstrate that hypermagnesemia does not prevent intracranial hypertension and aggravates cerebral hyperperfusion in rats with PCA and hyperammonemia. (HEPATOLOGY 2011;53:1986-1994 A cute liver failure (ALF) is a condition with a substantial mortality rate because of a high risk of multiple organ failure. Of special interest are the cerebral complications in ALF that in the most severe cases can progress to cerebral edema, intracranial hypertension, and ultimately cerebral incarceration. The genesis for these cerebral complications is among other factors related to persistent hyperammonemia, 1,2 systemic inflammation, 2,3 and electrolyte disturbances 4 and is associated with cerebral hyperperfusion and loss of autoregulation of the cerebral blood flow (CBF). 5The complex and multifactorial nature has made the understanding of the pathogenesis of brain edema difficult. Both the therapeutic and prophylactic strategies related to brain edema in ALF are few and limited in efficacy. During surges of high intracranial pressure (ICP), intervention with mannitol, hypertonic saline, hyperventilation, hypothermia, and indomethacin has demonstrated a temporary beneficial effect on intracranial hypertension. 6,7 Recently, ammonia-lowering therapy with the compound of L-ornithine and phenylacetate has shown promising data in animal studies, 8 but no human data have yet been publishe...

Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage

“…In vasogenic cerebral oedema, AQP4 plays an important role in improving oedema, which was confirmed by the significantly reduced rate of resolution of cerebral oedema in AQP4 knockout cells ( Papadopoulos et al, 2004 ; Tourdias et al, 2011 ). Progressive cerebral oedema leads to increased ICP and malignant intracranial hypertension and subsequently to cerebral ischemia and neuronal necrosis ( Bjerring et al, 2011 ; Halstead and Geocadin, 2019 ). Therefore, the early management of cerebral oedema after SAH is vitally important in improving the prognosis of patients with SAH, especially those with poor-grade aneurysmal SAH.…”