SIMULATION OF THE ONSET OF NEUROMUSCULAR BLOCK BASED ON THE EARLY OSCILLATIONS IN THE ARTERIAL PLASMA-CONCENTRATIONS

Objective: The aim of the study was to describe by simulation the true plasma concentrations of nondepolarizing muscle relaxants (NDMRs) as a continuous function of time. In contrast to standard pharmacokinetic analysis of the time course of action via extrapolated plasma concent rations, the derived curve was to reflect zero plasma concentration in itially and one or more cycles of peaks and troughs subsequently. We d esired to study the influence of the initial delay and the early oscil lations in the plasma concentrations on the time to onset of peak but submaximal neuromuscular block (NMB). Hypothetical NDMRs were postulat ed to display in humans a pattern of early arterial plasma concentrati ons similar to the reported pattern of indocyanine green plasma concen trations in dogs (an initial delay period and subsequent peaks and tro ughs). Methods: Two hypothetical NDMRs with either a very rapid or a s low decay in plasma concentrations were used for the simulations. A de lay and oscillations were imposed on a multiexponential function for t he plasma concentrations of the NDMRs by an additional; biexponentiall y dampened sinusoid function. The time between intravenous bolus admin istration of the NDMRs and the first rise in plasma concentrations was fixed at 0.2 min. As experimentally observed with indocyanine green i n dogs, the oscillations were limited to the first minute after inject ion. The NDMRs were simulated to diffuse from plasma into and out of t he interstitial space of muscles according to a rate constant and the concentration gradient. The NDMRs were postulated to have free access from the interstitial space to the receptors, and the neuromuscular bl ock was calculated using the Hill equation. Results: The delay and the peak and trough plasma concentrations during the first minute after b olus injection of the NDMRs were simulated well by the postulated damp ened sinusoidal function. The times to peak submaximal NMB and the equ ieffective doses were similar whether calculated on the basis of oscil latory or extrapolated multiexponential functions. Both simulations de monstrated that a rapid initial decay of the plasma concentrations is associated with a slightly faster onset of peak NMB and a slightly hig her equieffective dose. Conclusion: Consideration of early oscillation s in the plasma concentrations of a NDMR barely alters the simulated t ime course of action from that simulated by an extrapolated multiexpon ential function.