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

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.

Pharmacokinetics of high-dose thiopental in pediatric patients with increased intracranial pressure.

This study was conducted on 10 pediatric patients in whom intracranial hypertension stemming from head injury was reduced by high-dose thiopental administered for a prolonged period. All children showed a favorable recovery of their neurological functions. The total dose normalized to body weight averaged 335 +/- 135 mg/kg, and the mean treatment duration was 93.0 +/- 37.1 h. Data analysis was modeled for each patient to cover all the doses on the whole plasma thiopental concentration-time curve, according to a one-compartment open model. A better fit was obtained using a linear model rather than a Michaelis-Menten elimination model. Model selection was guided by evaluation of the minimum objective function, the weighted residuals, and the Akaike criterion. Thiopental pharmacokinetic parameters in pediatric patients were compared with those determined in an adult control group with similar total doses and durations of treatment. No significant difference was found between the two groups in spite of a 33% decrease of the elimination half-life in children (11.7 +/- 5.7 h) compared with adults (17.5 +/- 9.03 h). The mean values obtained were 2.42 and 2.19 ml/min/kg for total clearance and 2.18 and 2.90 L/kg for Vd in pediatric and adult groups, respectively. The linear regression of pharmacokinetic parameters in terms of age was not significant. When high doses of thiopental were administered over a prolonged period, the pharmacokinetic parameters computed for pediatric patients did not differ from those obtained in adults.

Variability of thiopental clearance in routine critical care patients.

Thiopental was administered to neurosurgical patients as a drug for cerebral protection for up to 9 days either by continuous infusion (seven subjects) or repeated intravenous bolus (nine subjects). The efficient levels of thiopental measured at steady state ranged between 5 and 63 mg.l-1. Steady-state clearance evidenced considerable interindividual variability. Overall mean plasma clearance was lower than 1 ml.min-1.kg-1 for one subjects, ranged between 1 and 2 ml.min-1.kg-1 for six subjects, between 2 and 3 ml.min-1.kg-1 for seven subjects and was up to 5 ml.min-1,kg-1 for one subject. Extreme values for apparent daily clearance were 0.268 ml.min-1.kg-1 and 5.40 ml.min-1.kg-1. Daily intersubject CV gradually increased from day to day, increasing from 37% on day 1 to 51% on day 7. During the treatment for seven subjects, variations were minimal and clearance was considered to be constant; the maximum variation of clearance expressed as a percentage of the initial value was lower than 21% over a period longer than 3 days. For the other subjects, clearance was not stable with time. A decrease in clearance was evidenced for four subjects over a period of 7 days and more; the maximum variation of clearance was greater than -35%. An increase in clearance was noted for three subjects after 2 days of treatment; the maximum variation of clearance was greater than +44%. Evaluation of clearance at steady state made it possible to analyse interindividual variability and its clinical implications.

Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients.

Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three-compartment model and linear kinetics. After a single iv bolus, the mean initial volume of distribution (V1) was 0.481 l.kg-1, and the steady-state volume of distribution (Vss) was 2.16 l.kg-1. The distribution (t1/2 alpha) and elimination (t1/2 beta) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml.min-1.kg-1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CVintra) as it was between patients (CVinter). The steady-state trough plasma concentration (Cmin obs) ranged from 4.8 to 30 mg.l-1 (mean 16.0 mg.l-1 and median 14.3 mg.l-1). Peak concentrations (Cmax obs) ranged from 8.35 to 45 mg.l-1 (25.4 mg.l-1, and median 23.3 mg.l-1). The values of V1 and Vss were similar to those obtained after a single dose. For V1, the mean was 0.333 l.kg-1. The mean Vss was 2.68 l.kg-1, with a CVintra of 12.6 to 56% and a CVinter of 13.2%. A shorter distribution half-life t1/2 alpha was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t1/2 beta and the mean residence time became longer due to a decrease in clearance. For t1/2 beta the mean value was 16.3 h. The mean MRT was 21.9 h, CVintra 9.19 to 48.5%, and the CVinter 35.3%. The mean clearance was 2.16 ml.min-1.kg-1, CVintra 7.28 to 25.5%, and the CVinter 20.4%. This value is 50% lower than after a single dose. Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.

[Evoked brain stem potentials in cases of traumatic coma of: value in determining the degree of brain stem dysfunction (author's transl)]. / Etude des potentiels évoqués du tronc cérébral dans les comas traumatiques: intérêt pour la d'etermination des niveaux de dysfonctionnement du tronc cérébral.

Auditory brainstem potentials were recorded in 22 comatose patients in whom the level of brainstem dysfunction was defined by the clinical assessment of brainstem reflexes and posture. The patients with cortico-subcortical or diencephalic levels showed normal brainstem potentials. The other patients showed a relationship between the abnormalities of the different components of the brainstem potentials and the clinical levels of brainstem dysfunction caused by the rostro-caudal evolution. Alteration of wave V seemed to be related to a midbrain dysfunction, alteration of wave III to a pontine dysfunction and alteration of waves I and II to a lower brainstem dysfunction.

[Action of dibencozide on nitrogen metabolism in immediate and long-term postoperative resuscitation]. / Action du dibencozide sur le métabolisme azoté en réanimation aiguë et chronique.

The catabolic orientation of the immediate post-aggression phase is aggravated in neurosurgery by the almost routine prescription of corticosteroids. This emphasises the value of any treatment which might limit this orientation. The authors report their experience with the use of dibencozide, with its known facilitating action upon nitrogen assimilation, in the absence of any side effects.

[The effect of gamma-OH on cerebral metabolism and blood flow in human patients (author's transl)]. / Action du gamma-OH sur le métabolisme et le début cérébral en clinique humaine.

The effects of gamma-OH on cerebral blood flow (CBF) and metabolism were analysed in 10 neurosurgical patients, 15 min after a 60 mg/kg injection, both blood flow and oxygen consumption demonstrates a disconnection between blood flow and metabolism which appears an advantage and hence the interest in using this agent in anaesthesia and neurosurgical intensive care. 1 h40 min later no rebound effect was found; the metabolic reduction persisted whereas the CBF had returned to its resting level. Under gamma-OH CO2 production does not parallel O2 consumption and this could be interpreted as a sign that glucose-6-phosphate is metabolising via pentose.