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

Background: Hypovolemia decreases the dose requirement for anesthetics, but no data are available for propofol, As it is impossible to study this in p atients, a rat model was used in which the influence of hypovolemia on the pharmacokinetics and pharmacodynamics of propofol was investigated. Methods: Animals were randomly allocated to either a control (n = 9) or a h ypovolemia (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 electroen cephalogram. The changes observed in the electroencephalogram were quantifi ed using aperiodic analysis and used as a surrogate measure of hypnosis, Th e righting reflex served as a clinical measure of hypnosis. Results: The 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 o rgan sensitivity during hypovolemia, the electroencephalographic effect ver sus effect-site concentration relation was studied. The effect-blood concen tration relation was biphasic, exhibiting profound hysteresis in both hypov olemic and control animals. Semiparametric minimization of this hysteresis revealed similar equilibration half-lives in both groups. The biphasic effe ct-concentration relation was characterized by descriptors showing an incre ased potency of propofol during hemorrhage. The effect-site concentration a t the return of righting reflex was 23% (P < 0.01)lower in the hypovolemic animals, also suggesting an increased end organ sensitivity. Conclusions An increased hypnotic effect of propofol occurs during hypovole mia in the rat and can be attributed to changes in both pharmacokinetics an d end organ sensitivity.