Population pharmacokinetics of high-dose thiopental in patients with cerebral injuries

Abstract

Thiopental monitoring was performed in 95 critically ill patients hospitalized for neurologic damage, High-dose thiopental was infused during long-term treatment. Total dose of 333 +/- 144 mg/kg (449 +/- 185 mg/kg for females and 302 +/- 113 mg/kg for men) were given in 125 +/- 43 hours. Plasma concentration-time data were analyzed according to a population pharmacokinetic approach with an initial group of 65 patients. Clearance (CL) and central volume of distribution (Vc) were modeled alone and under the influence of demographic covariates, assuming a two-compartment open model with first-order elimination. The final population models were as follows: CL (L/hr) = 11.7.weight (kg).age (yr)/(2136 + age2) and Vc = 1.52.weight (kg) + 44.8. Mean CL and Vc mean population estimates were 8.01 L/hr (133 ml/min or 2.02 ml/min/kg) and 145 L (2.19 L/kg). The predictive performance of the population modeling and parameters was evaluated with a bayesian fitting procedure in an independent validation set of 30 patients with similar physical and clinical characteristics. There was no statistically significant bias or imprecision between measured and predicted thiopental plasma concentrations in this validation group. Moreover, there was a good adequation (r = 0.939) between individual CL values predicted from the population formula and estimated with the bayesian approach.

Heterocyclic Thioureylenes Protect from Calcium-Dependent Neuronal Cell Death

“…Efficient treatment of traumatic brain injury by thiopental requires high doses and a long-termed application of the barbiturate (Russo et al, 1997). In brain tissue, thiopental concentrations may be increased as much as 20-fold compared with plasma concentrations (Yasuda et al, 1993).…”

“…In summary, our study describes a pharmacological approach to protect neurons from cellular damage by drugs of the thioureylene class that are currently used for treatment of hyperthyroidism or induction of anesthesia (Russo et al, 1997;Bartalena et al, 2005). Furthermore, we suggest that neuroprotective therapy must combine both the inhibition of apoptosis and necrosis.…”

Pharmacokinetics of Thiopental Enantiomers during and following Prolonged High-dose Therapy

“…It is well-established that thiopental can show nonlinear (Michaelis-Menten or saturable) kinetics when administered in high doses for prolonged periods. [1][2][3][4][5][6][7][8] The progression from linear to nonlinear conditions coincides with increasing body (and thus hepatic mixed-function oxidase) burden of thiopental.…”

“…Thiopental shows "multicompartment behavior" after intravenous bolus doses and brief infusions; however, as it approaches a steady state after a prolonged infusion, its behavior is described adequately by a single "wellmixed" compartment. 6 For both linear and nonlinear models, Cl ss was defined as the ratio of average thiopental dose rate for the last 12 h of thiopental therapy to average serum concentration measured during this period, during quasi steady state conditions.…”

“…It is well-established that thiopental shows nonlinear Michaelis-Menten pharmacokinetics at high doses. [1][2][3][4][5][6][7][8] Commercially available thiopental, being a racemate (rac-thiopental), is used as an equimolar mixture of R-and S-thiopental enantiomers.ʈ The pharmacokinetics 9,10 and effects 11,12 of R-and S-thiopental differ quantitatively after anesthesia induction doses. However, it is not known whether the nonlinearity of high-dose thiopental pharmacokinetics is an artifact of data analysis because of two drugs being combined or whether the component enantiomers each undergo nonlinear pharmacokinetics.…”