High-dose pentobarbital infusion has been advocated as an effective adjunct in controlling persistent intracranial hypertension after severe head trauma in patients refractory to conventional therapy. Pentobarbital disposition was assessed in 10 adults with severe nonpenetrating head injury after an intravenous loading dose of sodium pentobarbital, 10 mg/kg, infused over 1 hour, followed by a continuous infusion at 0.5 to 3.0 mg/kg/hr provided the cerebral perfusion pressure remained greater than 50 torr. Pharmacokinetic parameters of volume of distribution at steady state (Vss), total body clearance (CL), and t1/2 for the patients with trauma were statistically compared with similar estimates reported for seven adult subjects without head injury. On discontinuation of the pentobarbital infusion, serum concentrations in the patients followed a monoexponential decline with a mean (+/- SD) t1/2 and Vss that were significantly less than values reported for the control subjects (15.6 +/- 3.9 vs. 22.3 +/- 4.0 hours and 44.0 +/- 11.7 vs. 63.4 +/- 15.2 L, respectively). However, there was no significant difference between the mean pentobarbital CL of the patients (2.0 +/- 0.7 L/hr) and the subjects (2.0 +/- 0.4 L/hr). To our knowledge this is the first report on the disposition, elimination, and intrasubject variability of high-dose pentobarbital infusion in adult patients with head trauma.