Schmitt H J, Batz G M, Götz H, Knoll R J, Danner U G, Härtl L M
Institut für Anaesthesiologie, Universität Erlangen-Nürnberg.
Anaesthesist. 1991 Feb;40(2):79-84.
Although the general pharmacokinetics of midazolam (M) are well documented, little is known about the possible effects of a thigh tourniquet on the distribution and elimination of this drug. METHOD. Institutional approval for the study and individual informed consent were obtained. We studied 30 patients (ASA-I) without premedication who electively underwent a surgical procedure of the lower limb. Patients were divided into three groups of 10. The procedure was done in groups I and II with and in group III without tourniquet use. Anesthesia was induced in groups I and II with 0.1 mg/kg M, fentanyl 5 micrograms/kg, alcuronium-dichloride 0.15 mg/kg and etomidate 0.1-0.2 mg/kg i.v. and maintained with enflurane 0.3-1.0 vol.-%. About 20 min after midazolam injection and after exsanguination the tourniquet was applied on the proximal thigh in group I. In group II anesthesia was induced with etomidate 0.2 mg/kg and alcuronium-dichloride 0.15 mg/kg i.v., and maintained about 20 min with enflurane 1.0-1.5 vol.-% until exsanguination and tourniquet application. After this, these patients also received 0.1 mg/kg M and 5 micrograms/kg fentanyl i.v. Through an indwelling arterial line, blood samples were obtained prior to and 2, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165 and 180 min after M injection. Plasma M levels were measured by high-performance liquid chromatography with UV detection. These concentrations were fitted to a two-compartment open model. Comparison between groups was performed using the Kruskal-Wallis test and p less than 0.05 was considered to indicate significance. RESULTS. The groups were all comparable in age and weight, and groups I and II also in duration of thigh ischemia. Midazolam elimination half-time (t beta 1/2) was significantly shorter in group II than in groups III and I (52 min vs 126 min and 139 min; p less than 0.05). Of the calculated distribution volumes (volume of the central compartment, volume in the steady state and volume in the elimination phase), only the volume in the steady state was significantly smaller in group II than in groups III and I (p less than 0.05). Groups III and I did not differ significantly in the computed parameters. The measured initial midazolam mean concentrations in group II were twice those in groups III and I (655 ng/ml vs 323 ng/ml and 332 ng/ml). Since clearance was not significantly different between any two groups, the shorter t beta 1/2 in group II was probably due to the reduced distribution volume. CONCLUSION. These data demonstrate that in the presence of a thigh tourniquet the timing of the injection - before or after application of the tourniquet is of decisive importance. Injection after the application of a tourniquet leads to an higher plasma level and shortens the elimination half-life.
虽然咪达唑仑（M）的一般药代动力学已有充分记载，但关于大腿止血带对该药物分布和消除的可能影响却知之甚少。方法：获得了该研究的机构批准和个人知情同意。我们研究了30例未进行术前用药、择期接受下肢外科手术的患者（ASA - I级）。患者被分为三组，每组10人。第一组和第二组在使用止血带的情况下进行手术，第三组不使用止血带。第一组和第二组静脉注射0.1mg/kg的咪达唑仑、5μg/kg的芬太尼、0.15mg/kg的阿库氯铵和0.1 - 0.2mg/kg的依托咪酯诱导麻醉，并用0.3 - 1.0vol.-%的恩氟烷维持麻醉。在注射咪达唑仑约20分钟后且放血后，第一组在大腿近端应用止血带。第二组静脉注射0.2mg/kg的依托咪酯和0.15mg/kg的阿库氯铵诱导麻醉，并用1.0 - 1.5vol.-%的恩氟烷维持约20分钟，直至放血和应用止血带。在此之后，这些患者也静脉注射0.1mg/kg的咪达唑仑和5μg/kg的芬太尼。通过留置动脉导管，在注射咪达唑仑前以及注射后2、15、30、45、60、75、90、105、120、135、150、165和180分钟采集血样。采用高效液相色谱 - 紫外检测法测定血浆咪达唑仑水平。将这些浓度拟合到二室开放模型。采用Kruskal - Wallis检验进行组间比较，p小于0.05被认为具有统计学意义。结果：三组患者在年龄和体重方面均具有可比性，第一组和第二组在大腿缺血持续时间方面也具有可比性。第二组咪达唑仑消除半衰期（tβ1/2）明显短于第三组和第一组（52分钟对126分钟和139分钟；p小于0.05）。在所计算的分布容积（中央室容积、稳态容积和消除相容积）中，只有第二组的稳态容积明显小于第三组和第一组（p小于0.05）。第三组和第一组在计算参数方面无显著差异。第二组测得的咪达唑仑初始平均浓度是第三组和第一组的两倍（655ng/ml对323ng/ml和332ng/ml）。由于任意两组之间的清除率无显著差异，第二组较短的tβ1/2可能是由于分布容积减小所致。结论：这些数据表明，在使用大腿止血带的情况下，注射时间 - 在止血带应用之前还是之后具有决定性意义。在应用止血带后注射会导致更高的血浆水平并缩短消除半衰期。
