Multiple estimates of EC(50).

Abstract

Medical College of Ohio, Toledo, Ohio. vnigrovic@mco.eduTo the Editor:—I read with great interest the report by Bergeron et al. 1on the concentration–effect relationship of cisatracurium. One of the findings of the study is the dependence of EC50(the concentration of cisatracurium in the effect compartment at half-maximal neuromuscular block) on the bolus dose of cisatracurium. This finding contradicts basic pharmacologic principles. Nondepolarizing muscle relaxants produce neuromuscular block (NMB) by binding to the postsynaptic receptors at the motor end plates. Increasing concentrations of muscle relaxants produce increasing levels of NMB, and there is only one set of concentration–NMB data pairs for a specific muscle and a given muscle relaxant. Therefore, only one concentration corresponds to the half-maximal NMB. However, the authors present several estimates of EC50, each as a function of the dose and the method of analysis. Multiple estimates of EC50might be due to the experimental design or to the methods of analysis. First, multiple estimates might be due to a complete NMB observed by the investigators with large doses of cisatracurium (1.5 × ED95to 6 × ED95). A complete NMB is compatible with any concentration of cisatracurium in the effect compartment that is higher than the concentration just sufficient to produce 100% NMB. Since the dependency of NMB on the muscle relaxant concentration is the prerequisite for pharmacodynamic simulations, this prerequisite was not fulfilled in the study. Alternatively, the methods of analysis might not be adequate. Since the pharmacokinetic parameters were dose independent, one has to question the methods of obtaining the estimates of pharmacodynamic parameters. If these provide several (“statistically different”) estimates for the conceptually single value of EC50, then the pharmacodynamic methods might not be appropriate. That multiple estimates of EC50were reported previously for vecuronium 2might be due to the use of identical pharmacodynamic methods; it constitutes neither the proof that the methods are correct nor that the estimates represent real values. To paraphrase, if three methods of determination of sodium in plasma yield three estimates of the sodium concentration, the methods should be questioned before accepting the finding that sodium is present in plasma in three concentrations. Similarly, if the pharmacodynamic methods yield different estimates of EC50, the results contradict the accepted pharmacologic principles and need to be reexamined.