Paul Boon

Influence of hypovolemia on the pharmacokinetics and the electroencephalographic effect of propofol in the rat.

BackgroundHypovolemia decreases the dose requirement for anesthetics, but no data are available for propofol. As it is impossible to study this in patients, a rat model was used in which the influence of hypovolemia on the pharmacokinetics and pharmacodynamics of propofol was investigated. MethodsAnimals were randomly allocated to either a control (n = 9) or a hypovolemia (n = 9) group, and propofol was infused (150 mg · kg−1 · h−1) until isoelectric periods of 5 s or longer were observed in the electroencephalogram. The changes observed in the electroencephalogram were quantified using aperiodic analysis and used as a surrogate measure of hypnosis. The righting reflex served as a clinical measure of hypnosis. ResultsThe propofol dose needed to reach the electroencephalographic end point in the hypovolemic rats was reduced by 60% (P < 0.01). This could be attributed to a decrease in propofol clearance and in distribution volume. Protein binding was similar in both groups. To investigate changes in end organ sensitivity during hypovolemia, the electroencephalographic effect versus effect–site concentration relation was studied. The effect–blood concentration relation was biphasic, exhibiting profound hysteresis in both hypovolemic and control animals. Semiparametric minimization of this hysteresis revealed similar equilibration half-lives in both groups. The biphasic effect–concentration relation was characterized by descriptors showing an increased potency of propofol during hemorrhage. The effect–site concentration at the return of righting reflex was 23% (P < 0.01) lower in the hypovolemic animals, also suggesting an increased end organ sensitivity. ConclusionsAn increased hypnotic effect of propofol occurs during hypovolemia in the rat and can be attributed to changes in both pharmacokinetics and end organ sensitivity.

Relationship Between Etomidate Plasma Concentration and EEG Effect in the Rat

AbstractPurpose. The effect-plasma concentration relationship of etomidate was studied in the rat using electroencephalographic changes as a pharmacodynamic parameter.nMethods. Etomidate was infused (50 mg/kg/h) in chronically instrumented rats (n = 6) until isoelectric periods of 5 s or longer were observed in the electroencephalogram (EEG). The EEG was continuously recorded during the experiment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signal were quantified using aperiodic analysis in the 2.5−7.5 Hz frequency band. The return of the righting reflex was used as another parameter of anesthesia.nResults. A mean dose of 8.58 ± 0.41 mg/kg needed to be infused to reach the end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clearance, volume of distribution at steady-state and elimination half-life averaged 93 ± 6 ml/min/kg, 4.03 ± 0.24 l/kg and 59.4 ± 10.7 min respectively. The EEG effect-plasma concentration relationship was biphasic exhibiting profound hysteresis. Semi-parametric minimization of this hysteresis revealed an equilibration half-life of 2.65 ± 0.15 min, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. The effect-site concentration at the return of the righting reflex was 0.44 ± 0.03 μg/ml.nConclusions. The results of the present study show that the concentration-effect relationship of etomidate can be characterized in individual rats using aperiodic analysis in the 2.5−7.5 Hz frequency band of the EEG. This characterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.

Tolerance to the hypnotic and electroencephalographic effect of gamma-hydroxybutyrate in the rat: pharmacokinetic and pharmacodynamic aspects

Tolerance to gamma‐hydroxybutyrate (GHB) has been suggested in illicit users and has been described for the hypnotic effect in the rat. The aim of this study was to investigate whether tolerance is also observed for the EEG effect, and whether the EEG can give insight into the pharmacodynamic aspects of GHB tolerance. In three series of experiments, rats were pre‐treated with either the GHB precursor gamma‐butyrolactone (GBL) or saline intraperitoneally twice daily. In the first series, a reduction in sleeping time was observed in the GBL pre‐treated rats compared with controls. In the second series, a fast infusion of GHB (300 mg kg−1 over 5 min) was given after 10 days pre‐treatment. The GHB plasma concentration‐time curves showed a slightly faster decrease in GHB concentration in the GBL pre‐treated rats, suggesting a small induction of the GHB metabolism (Vmax = 2882 ± 457 μg min−1 kg−1 vs 2205 ± 315 μg min−1 kg−1, P<0.01). In contrast to controls, GBL pre‐treated rats did not lose righting reflex. In the third series, a slow infusion of 480 mg kg−1 h−1 was given after 7 days pre‐treatment, which allowed fitting a sigmoid Emax model to the EEG amplitude versus GHB plasma concentration curve. This showed reduced end‐organ sensitivity to GHB in the GBL pre‐treated rats (EC50 (concentration required to obtain 50% depression of the baseline effect) = 653 ± 183 μg mL−1 vs 323 ± 68 μg mL−1, P < 0.001). In conclusion, chronic pre‐treatment with gamma‐butyrolactone in the rat results in a reduced sleeping time and this tolerance is reflected by the EEG. This can mainly be explained by reduced end‐organ sensitivity.

Relationship between gamma‐hydroxybutyrate plasma concentrations and its electroencephalographic effects in the rat

In view of the potential interest in an objective parameter for the depth of coma in intoxications with the recreational drug gamma‐hydroxybutyrate (GHB), we have studied the relationship between the plasma concentrations and the electroencephalographic (EEG) changes induced by GHB in the rat. Fifteen rats randomly received either 150 (n = 3), 200 (n = 6) or 300 mg kg−1 (n = 6) GHB over 5 min, followed by a supramaximal dose of 450 mg kg−1 over 5 min at the end of the experiment. Plasma concentrations were determined with HPLC. The EEG was continuously recorded and the amplitude in the 15.5–30 Hz frequency band was quantified using aperiodic analysis. The plasma concentration‐time profiles were fitted to a two‐compartment model with Michaelis‐Menten elimination. The pharmacokinetic parameters Vmax, Km and the apparent volume of distribution (Vd) proved to be independent of the dose and the mean pooled values were Vmax 2068 ± 140 μg mL−1 kg−1, Km 58 ± 16 μg mL−1 and Vd 476 ± 12 mL kg−1. The EEG amplitude in the 15.5–30 Hz frequency band displayed a monophasic inhibition and the effect‐plasma concentration curve showed hysteresis. This hysteresis between EEG effect and plasma concentrations was minimized by simultaneous calculation of hypothetical effect‐site concentrations and fitting the effect vs effect‐site concentration curve to a sigmoid inhibitory Emax model. The descriptors of this Emax model (Emax, EC50, ke,0, γ and E0) were independent of the dose with an equilibration half‐life t½ke,0 of 5.6 ± 0.3 min (mean value of the pooled results of the 5‐min treatment groups). To investigate the origin of this hysteresis, a dose of 600 mg kg−1 GHB was infused over either 45 or 60 min each in three animals. The hysteresis was much less pronounced with 45 min than with 5 min and was absent with 60‐min infusions. This indicated that the hysteresis was due to a distribution delay between the central compartment and the effect site. This study showed that the concentration‐effect relationship of GHB could be characterized in individual rats using aperiodic analysis in the 15.5–30 Hz frequency band.

Influence of Hypovolemia on the Pharmacokinetics and Electroencephalographic Effect of γ-Hydroxybutyrate in the Rat

Background Hypovolemia alters the effect of propofol in the rat by influencing the pharmacokinetics and the end organ sensitivity. We now studied the effect of hypovolemia on the anesthetic &ggr;-hydroxybutyrate (GHB) because in contrast with propofol it increases blood pressure. Methods Thirty-two rats were randomly assigned to undergo moderate hypovolemia or a control procedure. Each rat received either an infusion of sodium–GHB (390 mg · kg−1 · 5 min−1) or the same volume of an equimolar solution of sodium chloride (6.9%). Plasma samples were taken for GHB assay (high-performance liquid chromatography) and the electroencephalography and blood pressure values were recorded. A two-compartment model with Michaelis–Menten elimination was fitted to the concentration-time data and a sigmoid Emax model to the electroencephalographic effect versus effect site concentration curve allowing the study of the end organ sensitivity. Results Plasma concentration–time curves and the total volume of distribution in hypovolemic and normovolemic rats were comparable with only small but significant differences in central volume of distribution and the intercompartmental clearance. There was no significant difference either in the distribution from the plasma to the brain (ke0) or in the end organ sensitivity (EC50 = 335 ± 76 &mgr;g/ml in control vs. 341 ± 89 &mgr;g/ml in hypovolemic rats). GHB temporarily increased mean arterial pressure in both groups, which cannot be explained by the sodium salt alone. Conclusions Hypovolemia does not influence the overall concentration–time curve of GHB and induces no changes in the electroencephalographic effect of GHB in the rat. This difference with propofol may be due to the fact that it increases blood pressure but also due to its different pharmacokinetic properties.