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Received April 1, 1997; accepted August 5, 1997
Purpose. In patients with severe head injuries receiving long-term infusion for reducing intracranial pressure, a decline in concentrations was apparent following attainment of an initial steady state. This could be explained by an increased rate of elimination. An adequate modeling of the plasma disposition curves was used to demonstrate clearly the metabolic induction.
Methods. The concentration-time data of 17 patients were fit by a one compartment pharmacokinetic model in which the decline of plasma concentration during infusion was due to an increase in the clearance rate of thiopental following a latency period. This time-dependent clearance model provided estimates of initial and final clearance rates.
Results. This study demonstrated that large interindividual variations were observed during the course of the thiopental time-dependent pharmacokinetics. Depending on the patient, one or two steps of induction occurred. The mean initial and final clearance rates were 1.22 ± 0.82 mL/min/kg and 10.5 ± 23 mL/min/kg. The latency period for the first induction averaged 69 ± 56 h. For 6 subjects, the rate of thiopental metabolism continued to change with time and there was a second step of induction.
Conclusions. Induction of thiopental metabolism occur within therapeutic ranges, but it was not established that attainment of individual limits in dosing rate, total dose, or treatment duration occur in the process. Thus, monitoring is needed for achievement of a target plasma concentration.
KEY WORDS: thiopental; long term infusion; time-dependent clearance model; critically ill patients.
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INTRODUCTION
Patients with head injuries, receiving high-dose infusion of thiopental over a prolonged period to decrease elevated intracranial pressure (ICP) were studied. The pharmacokinetics of high-dose thiopental have been described using a first-order (1-3) or a Michaelis-Menten elimination.(2-6) However, for some patients these models were inappropriate, i.e., a gradual decline in plasma concentration was observed although the infusion rate was unchanged. This could be explained by an increased rate of elimination indicating that thiopental induced its own metabolism. In a previously published study, a large intraindividual variability in clearance values was observed (7). Since thiopental is completely metabolized before excretion with a low hepatic extraction ratio (8), enzyme activity is the rate limiting step of elimination.
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