Medical Therapy of Brain Edema in Fulminant Hepatic Failure

Fulminant hepatic failure (FHF), a rare but devastating syndrome of multifactorial etiology, is defined by the appearance of hepatic encephalopathy in patients with acute liver injury.Patients with FHF and deep encephalopathy develop brain edema, a feared complication that can lead to brain herniation and death.Subjects with a short interval between the onset of jaundice and the development of encephalopathy are more likely to develop cerebral swelling.1 Residual neurologic injury may be present even after a successful liver transplantation. 2 For many years, the treatment of brain edema in FHF has been symptomatic.The use of mannitol to remove intracerebral water, 3 mild elevation of the head of the bed to favor venous drainage, 4 or continuous renal replacement methods to lessen the impact of rapid fluid shifts with intermittent dialysis 5 are useful approaches but are inherently limited.They do not address the mechanisms that lead to the development of brain edema.In this issue of HEPATOLOGY, 6 Ellis et al. from London report benefits of phenytoin in the management of patients with FHF, controlling subclinical seizures and noting a reduction in the incidence of brain edema.It is useful to put these results in context, as several new approaches to the medical treatment of brain edema have been proposed; approaches that can be arranged according to the underlying pathophysiologic disturbance. THE SWOLLEN ASTROCYTERepeated observations have shown prominent swelling of this cellular element in experimental FHF.7 Human brain biopsies immediately post-mortem also show this finding.8 Is astrocyte swelling a primary event in the development of brain edema?As glial cells normally play an important role in the maintenance of a stable extracellular volume, 9 it could be argued that the observed swelling is simply an adaptive response to another abnormality.For example, astrocyte swelling can be observed in conditions where the blood-brain barrier is disrupted.To answer this question, studies in both in vitro and in vivo conditions have proven invaluable.Circulating factors implicated in the development of brain edema in FHF will result in swelling of cultured astrocytes as well as inducing brain edema in the experimental animal.