title: Influence of hypovolemia on the pharmacokinetics and the electroencephalographic effect of etomidate in the rat.
abstract: The influence of hypovolemia (removal of 30% of the blood volume) on the pharmacokinetics and pharmacodynamics of etomidate was investigated in the rat. Chronically instrumented animals were randomly allocated to either a control (n = 9) or a hypovolemia (n = 9) group, and etomidate was infused (50 mg/kg/h) until isoelectric periods of 5 s or longer were observed in the electroencephalogram. The changes observed in the electroencephalogram were quantified using aperiodic analysis in the 2.5- to 7.5-Hz frequency band and used as a surrogate measure of hypnosis. The righting reflex was used as a clinical measure of hypnosis. The etomidate dose that had to be infused to reach the electroencephalographic endpoint was almost 40% lower (p <.01) in the hypovolemic animals than in the control animals. This difference could be attributed to a decrease in clearance (-20%; p =.06) and distribution volume (-30%; p <.01) of etomidate. Protein binding was similar in both groups. To investigate changes in end organ sensitivity during hypovolemia, the electroencephalographic effect-versus-effect-site concentration relationship was studied. The effect-plasma concentration relationship was biphasic, exhibiting profound hysteresis in both hypovolemic and control animals. Semiparametric minimization of this hysteresis revealed similar equilibrium half-lives in both groups, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. With these descriptors, a slightly increased potency of etomidate during hemorrhage was observed. The concentration at the return of righting reflex was 16% (p <.05) lower in the hypovolemic animals. In conclusion, an increased hypnotic effect of etomidate was observed during hypovolemia that is mainly attributed to pharmacokinetic changes. Our data also suggest a small increase in central nervous system sensitivity for etomidate in hypovolemic animals.
authors.affiliation: Heymans Institute of Pharmacology, Electroencephalography Laboratory, Department of Neurology, University of Ghent, Medical School, Ghent, Belgium. Peter.DePaepe@rug.ac.be
authors.forename: P
authors.initials: P
authors.lastname: De Paepe
authors.forename: F M
authors.initials: FM
authors.lastname: Belpaire
authors.forename: G
authors.initials: G
authors.lastname: Van Hoey
authors.forename: P A
authors.initials: PA
authors.lastname: Boon
authors.forename: W A
authors.initials: WA
authors.lastname: Buylaert
mesh_terms: D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001810:Blood Volume / Q000502:physiology*; D001831:Body Temperature / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D005045:Etomidate / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012769:Shock / Q000503:physiopathology*
chemical_list: D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D005045:Etomidate