High doses of thiopental were administered to 12 patients over a prolonged period to control elevated intracranial pressure secondary to severe head injury with ischaemic brain damage. Dosage rates ranged from 1.47 to 4.81 mgsol;kgsol;h, total doses from 186.3 to 745.3 mgsol;kg, and the time-course of therapy from 60 to 189 hours. Thiopental was assayed in plasma by a specific high-pressure liquid chromatography (HPLC) method with ultraviolet detection. Steady-state plasma concentrations (Css) averaged 31.07 plusmn; 12.6 mgsol;L and corresponding steady-state clearance was 1.64 plusmn; 0.44 mlsol;minsol;kg. Data analysis was performed for each patient covering all the dosages upon the total thiopental concentration-time curve according to a one-compartment open model. A better fit was obtained with a Michaelis-Menten elimination model than with a linear model. The Michaelis-Menten constant (Km) averaged 12.9 plusmn; 8.65 mgsol;L and the ratio Csssol;Km ranged from 0.697 to 8.29. Enzymatic saturation was about 50percnt; for Csssol;Km ratios near to 1 and was up to 89percnt; for higher ratios. During thiopental treatment, steady-state clearance as well as enzymatic saturation did not show a noticeable intraindividual variability. The maximum rate of metabolism (Vm) averaged 158.2 plusmn; 58.6 mgsol;h and the mean volume of distribution was 4.45 plusmn; 2.72 Lsol;kg. Below plasma levels of 5 to 10 mgsol;L, the data appeared to approach a final first-order decline with a mean elimination half-life of 14.3 plusmn; 11.7 hours. Km, Vm, enzymatic saturation and elimination half-life of the terminal phase were not correlated with the total dose normalised to bodyweight. A delayed elimination is a clinical implication of nonlinear kinetics that may lengthen the time required to distinguish between the effect of thiopental and head injury on the EEG.
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