Bissinger U, Nigrovic V
Universitütsklinik für Anaesthesiologie und Transfusionsmedizin, Abteilung Anaesthesiologie, Tübingen, Germany.
Eur J Clin Pharmacol. 1997;52(1):71-5. doi: 10.1007/s002280050251.
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).
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.
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.
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.
本研究旨在通过模拟描述非去极化肌松药（NDMRs）的真实血浆浓度随时间的连续变化情况。与通过外推血浆浓度对作用时间进程进行的标准药代动力学分析不同，推导得出的曲线应反映出最初血浆浓度为零，随后出现一个或多个峰谷循环。我们希望研究血浆浓度的初始延迟和早期振荡对达到峰值但未达最大的神经肌肉阻滞（NMB）起效时间的影响。假设的NDMRs在人体中被假定呈现出与报道的犬吲哚菁绿血浆浓度模式相似的早期动脉血浆浓度模式（一个初始延迟期以及随后的峰谷）。
使用两种血浆浓度衰减速度分别非常快或非常慢的假设性NDMRs进行模拟。通过一个额外的双指数衰减正弦函数，对NDMRs血浆浓度的多指数函数施加延迟和振荡。静脉推注NDMRs与血浆浓度首次升高之间的时间固定为0.2分钟。正如在犬身上对吲哚菁绿进行实验观察到的那样，振荡仅限于注射后的第一分钟。假设NDMRs根据速率常数和浓度梯度从血浆扩散进入和离开肌肉的间质空间。假设NDMRs可从间质空间自由进入受体，并使用希尔方程计算神经肌肉阻滞。
通过假定的衰减正弦函数能很好地模拟推注NDMRs后第一分钟内的延迟以及峰谷血浆浓度。无论是基于振荡的多指数函数还是外推的多指数函数计算，达到峰值亚最大NMB的时间和等效剂量都相似。两种模拟均表明，血浆浓度的快速初始衰减与峰值NMB的起效略快以及等效剂量略高有关。
考虑NDMRs血浆浓度的早期振荡对模拟的作用时间进程的影响，与通过外推多指数函数模拟的结果相比几乎没有变化。
