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Cerebral edema is a potentially life-threatening complication of acute liver failure, the syndrome of abrupt loss of liver function in a patient with a previously healthy liver. Although the prevalence of cerebral edema appears to be decreasing, patients with rapidly progressive (hyperacute) liver failure, such as after acetaminophen overdose, remain at highest risk. In severe cases of cerebral edema, intracranial hypertension develops and leads to brain death after brainstem herniation or to anoxic brain injury and permanent neurologic impairment. Intracranial hypertension in patients with acute liver failure often can be temporarily controlled by manipulating body position, increasing the degree of sedation, and increasing blood osmolarity through pharmacologic means. However, these maneuvers often postpone, but do not eliminate, the risk of brainstem herniation unless orthotopic liver transplantation or spontaneous liver regeneration follows in short order. To buy time, the induction of therapeutic hypothermia (core temperature 32°C-35°C) has been shown to effectively bridge patients to transplant. Similar to the experience in patients with cerebral edema after other neurologic insults, hypothermia reduces cerebral edema and intracranial hypertension in patients with acute liver failure by decreasing splanchnic ammonia production, restoring normal regulation of cerebral hemodynamics, and lowering oxidative metabolism within the brain. Hypothermia may also ameliorate the degree of liver injury. Hypothermia has not been adequately studied for its safety and theoretically may increase the risk of infection, cardiac dysrhythmias, and bleeding, all complications independently associated with acute liver failure. Therefore, although an ample body of experimental and human data provides a rationale for the use of therapeutic hypothermia in patients with acute liver failure, multicenter, randomized, controlled clinical trials are needed to confirm that hypothermia secures brain viability and improves survival without causing harm.