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

The influence of hypovolemia (removal of 30% of the blood volume) on the ph armacokinetics and pharmacodynamics of etomidate was investigated in the ra t. Chronically instrumented animals were randomly allocated to either a con trol (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 el ectroencephalogram. The changes observed in the electroencephalogram were q uantified 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 asa clinical measure of hypnosis. The etomidate dose that had to be infused to reach the electroencephalographic endpoint was almost 40% lower (p < .01) i n the hypovolemic animals than in the control animals. This difference coul d be attributed to a decrease in clearance (-20%; p =.06) and distribution volume (-30%; p < .01) of etomidate. Protein binding was similar in both gr oups. To investigate changes in end organ sensitivity during hypovolemia, t he electroencephalographic effect-versus-effect-site concentration relation ship was studied. The effect-plasma concentration relationship was biphasic , exhibiting Profound hysteresis in both hypovolemic and control animals. S emiparametric minimization of this hysteresis revealed similar equilibrium half-lives in both groups, and the biphasic effect-concentration relationsh ip was characterized nonparametrically by descriptors. With these descripto rs, a slightly increased potency of etomidate during hemorrhage was observe d. The concentration at the return of righting reflex was 16% (p < .05) low er in the hypovolemic animals. In conclusion, an increased hypnotic effect of etomidate was observed during hypovolemia that is mainly attributed to p harmacokinetic changes. Our data also suggest a small increase in central n ervous system sensitivity for etomidate in hypovolemic animals.