Influence of Hypovolemia on the Pharmacokinetics and the Electroencephalographic Effect of Etomidate in the Rat1

  1. Peter De Paepe1,
  2. Frans M. Belpaire1,
  3. Gert Van Hoey2,
  4. Paul A. Boon1 and
  5. Walter A. Buylaert3
  1. 1Heymans Institute of Pharmacology (P. De P., F.M.B.), Electroencephalography Laboratory, Department of Neurology (P.A.B.), 2Department of Electronics and Information Systems (G. Van H.), and 3Department of Emergency Medicine (W.A.B.), University of Ghent, Medical School, Ghent, Belgium

    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.

    Footnotes

    • Send reprint requests to: Dr. Peter De Paepe, Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail:Peter.DePaepe{at}rug.ac.be

    • ↵1 This work was supported by University of Ghent Research Foundation Grants 011D0296 and 01104495.

    • Abbreviations:
      EEG
      electroencephalographic
      AMP
      amplitude per second
      MAP
      mean arterial blood pressure
      HR
      heart rate
      keo
      first-order rate equilibrium constant
      T1/2keo
      equilibrium half-life
      E0
      baseline effect
      Emax
      maximal activation of the electroencephalographic effect
      ECm
      concentration required to produce maximal electroencephalographic activation
      EC50
      concentration required to obtain 50% activation of the electroencephalographic effect
      ECb
      concentration required to produce the baseline effect between maximal electroencephalographic activation and maximal electroencephalographic inhibition
      • Received December 24, 1998.
      • Accepted April 15, 1999.
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    1. JPET September 1, 1999 vol. 290 no. 3 1048-1053
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