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BJA Advance Access originally published online on June 24, 2005
British Journal of Anaesthesia 2005 95(3):367-371; doi:10.1093/bja/aei179
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: journal.permissions@oupjournals.org

Development of acute tolerance to the EEG effect of propofol in rats{dagger}

H. Ihmsen*, M. Schywalsky, A. Tzabazis and H. Schwilden

Klinik für Anästhesiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstrasse 12, 91054 Erlangen, Germany

* Corresponding author. E-mail: Harald.Ihmsen{at}kfa.imed.uni-erlangen.de

Background. A previous study in rats with propofol suggested the development of acute tolerance to the EEG effect. The aim of this study was to evaluate acute tolerance by means of EEG-controlled closed-loop anaesthesia as this approach allows precise determination of drug requirement to maintain a defined drug effect.

Methods. Ten male Sprague–Dawley rats [weight 402 (40) g, mean (SD)] were included in the study. The EEG was recorded with occipito-occipital needle electrodes and a modified median frequency (mMEF) of the EEG power spectrum was used as a pharmacodynamic control parameter. The propofol infusion rate was controlled by a model-based adaptive algorithm to maintain a set point of mMEF=3 (0.5) Hz for 90 min. The performance of the closed-loop system was characterized by the prediction error PE=(mMEF–set point)/set point. Plasma propofol concentrations were determined from arterial samples by HPLC.

Results. The chosen set point was successfully maintained in all rats. The median (SE) and absolute median values of PE were –5.0 (0.3) and 11.3 (0.2)% respectively. Propofol concentration increased significantly from 2.9 (2.2) µg ml–1 at the beginning to 5.8 (3.8) µg ml–1 at 90 min [mean (SD), P<0.05]. The cumulative dose increased linearly, with a mean infusion rate of 0.60 (0.16) mg kg–1 min–1. The minimum value of the mean arterial pressure during closed-loop administration of propofol was 130 (24) mm Hg, compared with a baseline value of 141 (12) mm Hg.

Conclusions. The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.

{dagger} Presented in part at the Euroanaesthesia meeting, Lisbon, Portugal, June 5–8, 2004.


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H. Ihmsen, K. Naguib, G. Schneider, H. Schwilden, J. Schuttler, and E. Kochs
Teletherapeutic drug administration by long distance closed-loop control of propofol
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[Abstract] [Full Text] [PDF]

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Propofol tolerance - young male
jithesh appukutty
British Journal of Anaesthesia, 28 Sep 2007 [Full text]
Re: Propofol tolerance - young male
Harald Ihmsen
British Journal of Anaesthesia, 5 Oct 2007 [Full text]

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