Elimination of methohexitone after long-term, high-dose infusion in patients with critically elevated intracranial pressure

Objective: To determine the plasma elimination of methohexitone in patients with critically elevated intracranial pressure (ICP) who received the drug in high doses for several days. Design: Drug-monitoring study. Setting: Intensive care unit at a university hospital. Patients: Twelve intensive care unit patients with brain injuries who received methohexitone as a final therapeutic approach after routine therapy had proved to be insufficient in controlling critically elevated ICP. Measurements and Main Results: Plasma samples were taken during methohexitone infusion, before cessation, and in distinct, short increments after discontinuation of the infusion. Methohexitone was determined in plasma by reverse-phase high-pressure liquid chromatography and photometric detection. The median duration of infusion of methohexitone was 137 hrs (minimum, 27 hrs; maximum, 445 hrs), with a median infusion rate of 62.5 mu g/kg/min (minimum, 22.5 mu g/kg/min; maximum, 116.2 mu g/kg/min). Plasma concentrations of methohexitone at burst suppression under concomitant analgesic sedation ranged from 1.6 to 17.3 mu g/mL (median, 4.7 mu g/mL). After cessation of methohexitone infusion, the decline of plasma concentrations followed a biexponential function. Clearance rates, volume of distribution at steady state, context-sensitive half-time, and initial and terminal elimination half-times were calculated. Pharmacokinetic data showed remarkable interindividual variability that could not be correlated to the infusion rate, to the duration of the infusion, or to obvious differences in physiology or the disease states of these patients. Even in patients with high plasma concentrations who received the drug for a considerable length of time, the initial decline in plasma concentration was exponential, indicating redistribution. Conclusions: We conclude that the elimination kinetics of methohexitone after long-term, high-dose infusion In critically ill patients with brain injuries may favor the use of methohexitone over thiopentone for controlling critically elevated ICP by allowing for a more timely neurologic examination after cessation.