BACKGROUND AND AIMS: About 20% of patients with acute liver failure (ALF) die from increased intracranial pressure (ICP) while awaiting transplantation. This study evaluates the clinical effects and pathophysiologic basis of hypothermia in patients with ALF and intracranial hypertension that is unresponsive to standard medical therapy. METHODS: Fourteen patients with ALF who were awaiting orthotopic liver transplantation (OLT) and had increased ICP that was unresponsive to standard medical therapy were studied. Core temperature was reduced to 32 degrees C-33 degrees C using cooling blankets. RESULTS: Thirteen patients were successfully bridged to OLT with a median of 32 hours (range, 10-118 hours) of cooling. They underwent OLT with no significant complications related to cooling either before or after OLT and had complete neurologic recovery. ICP before cooling was 36.5 +/- 2.7 mm Hg and was reduced to 16.3 +/- .7 mm Hg at 4 hours, which was sustained at 24 hours (16.8 +/- 1.5 mm Hg) ( P < .0001). Mean arterial pressure and cerebral perfusion pressure increased significantly, and the requirement for inotropes was reduced significantly. Hypothermia produced sustained and significant reduction in arterial ammonia concentration and its brain metabolism, cerebral blood flow, brain cytokine production, and markers of oxidative stress. CONCLUSIONS: Moderate hypothermia is an effective and safe bridge to OLT in patients with ALF who have increased ICP that is resistant to standard medical therapy. Hypothermia reduces ICP by impacting on multiple pathophysiologic mechanisms that are believed to be important in its pathogenesis. A large multicenter trial of hypothermia in ALF is justified.