Intravenous administration of high-dose pentobarbital has been proposed as a treatment for elevated intracranial pressure refractory to other measures in brain-injured patients. The purpose of this clinical study was to examine the pharmacokinetics of high-dose continuous intravenous infusion of pentobarbital in this critical care setting. Six patients received a 25-34 mg/kg intravenous loading dose followed by a 1-3 mg/kg/h continuous infusion for 61-190 hours. Dosing rates were adjusted based on the patient's clinical status. The mean clearance was 0.72 ml/min/kg, with a volume of distribution (Vd) of 1.03 L/kg and a terminal half-life of 19.1 h. Considerable variation in individual patient parameters was observed. In addition, a change in clearance was suggested in patients requiring a longer infusion duration.