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Is time to peak effect of neuromuscular blocking agents dependent on dose? Testing the concept of buffered diffusion

Published online by Cambridge University Press:  01 July 2008

J. H. Proost ,
M. C. Houwertjes  and
J. M. K. H. Wierda
J. H. Proost*
Affiliation:
University of Groningen, University Medical Center Groningen, Department of Anaesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
M. C. Houwertjes
Affiliation:
University of Groningen, University Medical Center Groningen, Department of Anaesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
J. M. K. H. Wierda
Affiliation:
University of Groningen, University Medical Center Groningen, Department of Anaesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
*
Correspondence to: Johannes H. Proost, Department of Anaesthesiology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. E-mail: j.h.proost@rug.nl; Tel: +31 50 3613633; Fax: +31 50 3613763
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Summary

Background and objectives

For neuromuscular blocking agents, an inverse relationship between potency and time to peak effect has been observed. To test the hypothesis that this relationship is due to buffered diffusion, we investigated the influence of dose on time to peak effect. Pharmacokinetic–pharmacodynamic simulations were performed to support the expected relationships between potency, dose, peak effect and time to peak effect.

Methods

Pigs (20–28 kg body weight) were anaesthetized with ketamine and midazolam, followed by pentobarbital and fentanyl intravenously. Neuromuscular block was measured by stimulating the peroneal nerve supramaximally at 0.1 Hz and measuring the response of the tibialis anterior muscle mechanomyographically. After an initial dose to establish the individual ED90 of a neuromuscular blocking agent (rocuronium, vecuronium, pipecuronium or d-tubocurarine), five different doses of the same compound were administered to each animal, aiming at 20%, 40%, 60%, 75% or 90% block, in a random order. Doses were given 45 min after complete recovery of the twitch response.

Results

For rocuronium and pipecuronium, time to peak effect increased with dose, whereas dose did not affect time to peak effect of vecuronium and d-tubocurarine. Simulations predict that time to peak effect decreases with dose if buffered diffusion is taken into account.

Conclusions

The results suggest that buffered diffusion does not play a dominant role in the time to peak effect of neuromuscular blocking agents. Therefore it is unlikely that the observed inverse relationship between potency and time to peak effect of neuromuscular blocking agents in the clinical range is due to buffered diffusion.

Keywords

NEUROMUSCULAR BLOCKING AGENTSPHARMACOKINETICSPHARMACODYNAMICSSWINE
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 25 , Issue 7 , July 2008 , pp. 572 - 580
Copyright
Copyright © European Society of Anaesthesiology 2008

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