Gambús P L, Schnider T W, Minto C F
Departamento de Anestesiología, Ciutat Sanitària i Universitària de Bellvitge, Barcelona.
Rev Esp Anestesiol Reanim. 1998 Oct;45(8):317-25.
To estimate the optimum dosing regimen and delivery system for remifentanil, a new opioid, using computer simulations based on information from pharmacokinetic and pharmacodynamic models available for fentanyl, alfentanil and remifentanil, as well as from clinical trials of fentanyl and alfentanil.
We estimated the site concentration ranges likely to be needed to blunt response to anesthetic or surgical stimuli and to recover from spontaneous ventilation. Dosing guidelines for remifentanil, fentanyl and alfentanil were estimated for three methods of administration (bolus, bolus + variable continuous infusion or constant continuous infusion). To that end, the time course of opioid concentration was simulated for hypothetical balanced anesthesia lasting 60 min. We then studied the number of boluses, the number of infusion rate steps, time taken to reach the terapeutic threshold, and time from turning off the infusion until reaching a concentration compatible with spontaneous ventilation.
The estimated "effect site" concentration ranges for remifentanil were 6 to 10 ng.ml-1 during intubation; 4 to 6 ng.ml-1 during cutaneous incision; 4 to 7 ng.ml-1 for maintenance; and less than 2.5 ng.ml-1 for recovery of spontaneous ventilation. Simulated bolus administration indicated that 21 boluses of remifentanil, 4 boluses of fentanyl and 7 boluses of alfentanil were needed during one hour. The therapeutic threshold was reached within the first minute with remifentanil, within 2 minutes with fentanyl and within 1 min with alfentanil. Time until recovery of spontaneous ventilation was 7 min with remifentanil, 22 min with fentanyl and 14 min with alfentanil. In the simulation of bolus plus variable infusion, the initial bolus of remifentanil was 100 micrograms, the infusion rate for induction and maintenance was 25 micrograms.min-1 and the maintenance rate was 15 micrograms.min-1. The initial bolus of fentanyl was 300 micrograms, the infusion rate for induction and maintenance was 5 micrograms.min-1. The initial bolus of alfentanil was 2,000 micrograms, the infusion rate for induction was 200 micrograms.min-1 and the maintenance rates were 75 and 25 micrograms.min-1. The therapeutic threshold was reached in 1 min with remifentanil, in 2 min with fentanyl and within 1 min with alfentanil. Spontaneous ventilation was recovered 4 min after turning off the infusion of remifentanil, 4 min afterwards with fentanyl and 6 min afterwards with alfentanil. The simulated constant infusion rate for remifentanil of 15 micrograms.min1 (8 micrograms.min-1 for fentanyl and 75 micrograms.min-1 for alfentanil) allowed the therapeutic threshold to be reached in 10 min with remifentanil, in 22 min with fentanyl and in 17 min with alfentanil. Recovery of spontaneous ventilation occurred 5 min after closure of the infusion pump with remifentanil (24 min with fentanyl and 17 min with alfentanil).
Information from pharmacokinetic and pharmacodynamic models allows us to establish the effect site concentration ranges for remifentanil and determine the ideal administration technique for this drug. The simulation also allows us to compare the properties of remifentanil to those of other common opioids such as fentanyl and alfentanil. The results are fairly consistent with clinical evidence, demonstrating the power of pharmacokinetic and pharmacodynamic models for rationally establishing opioid dosing guidelines.
利用基于芬太尼、阿芬太尼和瑞芬太尼的药代动力学与药效学模型信息以及芬太尼和阿芬太尼的临床试验数据进行计算机模拟，估算新型阿片类药物瑞芬太尼的最佳给药方案和给药系统。
我们估算了可能需要的作用部位浓度范围，以抑制对麻醉或手术刺激的反应并恢复自主通气。针对三种给药方法（单次推注、单次推注 + 可变持续输注或持续恒速输注）估算了瑞芬太尼、芬太尼和阿芬太尼的给药指南。为此，模拟了持续60分钟的假想平衡麻醉期间阿片类药物浓度的时间进程。然后我们研究了推注次数、输注速率变化步数、达到治疗阈值所需时间以及从停止输注到达到与自主通气相容浓度的时间。
瑞芬太尼的估算“效应部位”浓度范围在插管期间为6至10 ng.ml-1；皮肤切开期间为4至6 ng.ml-1；维持期间为4至7 ng.ml-1；自主通气恢复时小于2.5 ng.ml-1。模拟单次推注给药表明，1小时内需要21次瑞芬太尼推注、4次芬太尼推注和7次阿芬太尼推注。瑞芬太尼在第1分钟内达到治疗阈值，芬太尼在2分钟内，阿芬太尼在1分钟内。瑞芬太尼恢复自主通气的时间为7分钟，芬太尼为22分钟，阿芬太尼为14分钟。在单次推注加可变输注的模拟中，瑞芬太尼的初始推注量为100微克，诱导和维持的输注速率为25微克·分钟-1，维持速率为15微克·分钟-1。芬太尼的初始推注量为300微克，诱导和维持的输注速率为5微克·分钟-1。阿芬太尼的初始推注量为2000微克，诱导的输注速率为200微克·分钟-1，维持速率为75和25微克·分钟-1。瑞芬太尼在1分钟内达到治疗阈值，芬太尼在2分钟内，阿芬太尼在1分钟内。停止输注瑞芬太尼后4分钟恢复自主通气，芬太尼在4分钟后，阿芬太尼在6分钟后。模拟的瑞芬太尼持续输注速率为15微克·分钟-1（芬太尼为8微克·分钟-1，阿芬太尼为75微克·分钟-1），瑞芬太尼在10分钟内达到治疗阈值，芬太尼在22分钟内，阿芬太尼在17分钟内。停止输注泵后，瑞芬太尼5分钟恢复自主通气（芬太尼为24分钟，阿芬太尼为17分钟）。
药代动力学和药效学模型信息使我们能够确定瑞芬太尼的效应部位浓度范围，并确定该药物理想的给药技术。模拟还使我们能够将瑞芬太尼的特性与其他常用阿片类药物如芬太尼和阿芬太尼的特性进行比较。结果与临床证据相当一致，证明了药代动力学和药效学模型在合理制定阿片类药物给药指南方面的作用。
