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 non-depolarizing muscle relaxants (NDMRs) as a continuous function of time. In contrast to standard pharmacokinetic analysis of the time course of action via extrapolated plasma concentrations, the derived curve was to reflect zero plasma concentration initially and one or more cycles of peaks and troughs subsequently. We desired to study the influence of the initial delay and the early oscillations in the plasma concentrations on the time to onset of peak but submaximal neuromuscular block (NMB). Hypothetical NDMRs were postulated to display in humans a pattern of early arterial plasma concentrations similar to the reported pattern of indocyanine green plasma concentrations in dogs (an initial delay period and subsequent peaks and troughs).


METHODS
Two hypothetical NDMRs with either a very rapid or a slow decay in plasma concentrations were used for the simulations. A delay and oscillations were imposed on a multiexponential function for the plasma concentrations of the NDMRs by an additional, biexponentially dampened sinusoid function. The time between intravenous bolus administration of the NDMRs and the first rise in plasma concentrations was fixed at 0.2 min. As experimentally observed with indocyanine green in dogs, the oscillations were limited to the first minute after injection. The NDMRs were simulated to diffuse from plasma into and out of the 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 block was calculated using the Hill equation.


RESULTS
The delay and the peak and trough plasma concentrations during the first minute after bolus injection of the NDMRs were simulated well by the postulated dampened sinusoidal function. The times to peak submaximal NMB and the equieffective doses were similar whether calculated on the basis of oscillatory or extrapolated multiexponential functions. Both simulations demonstrated that a rapid initial decay of the plasma concentrations is associated with a slightly faster onset of peak NMB and a slightly higher equieffective dose.


CONCLUSIONS
Consideration of early oscillations in the plasma concentrations of a NDMR barely alters the simulated time course of action from that simulated by an extrapolated multiexponential function.
Bissinger
U
U
Universitütsklinik für Anaesthesiologie und Transfusionsmedizin, Abteilung Anaesthesiologie, Tübingen, Germany.
Nigrovic
V
V
D000818:Animals; D001158:Arteries; D004396:Coloring Agents / Q000493:pharmacokinetics; D003198:Computer Simulation; D004285:Dogs; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D007208:Indocyanine Green / Q000493:pharmacokinetics; D003473:Neuromuscular Nondepolarizing Agents / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D004396:Coloring Agents; D003473:Neuromuscular Nondepolarizing Agents; D007208:Indocyanine Green