The Relationship Between Functional Sciatic Nerve Block Duration and the Rate of Release of Lidocaine from a Controlled-Release Matrix
The Relationship Between Functional Sciatic Nerve Block Duration and the Rate of Release of Lidocaine from a Controlled-Release Matrix
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DOI：
10.1213/ane.0b013e3181dd2690
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发表时间：
2010-07-01
影响因子：
5.7
通讯作者：
Strichartz, Gary
中科院分区：
文献类型：
--
作者：
Gerner, Peter;Wang, Chi-Fei;Strichartz, Gary
背景：围手术期和术后需要长时间的神经阻滞。这种阻滞的持续时间与局部麻醉剂释放的速度之间的关系对于开发局部给药系统以优化阻滞持续时间是很重要的。方法：在1个系列（OSB-L）中加入一定量的释放速度调节剂，改变利多卡因的浓度。在另一个系列（OST-R）中，释放速度调节剂在利多卡因含量保持不变的情况下变化。体外释放动力学测量，并与体内抗痛觉和运动阻滞效应持续时间相关，当该制剂植入大鼠坐骨神经旁。在平行研究中，给予不同处方的慢释利多卡因的大鼠采用4%多聚甲醛心内灌注固定，并取神经肌肉组织进行组织病理学分析。结果：在本研究中，我们证明了影响功能性神经阻滞，即坐骨神经相关纤维脉冲阻滞的最重要变量是利多卡因释放率。对于OSB-L配方（利多卡因浓度分别为1.875%、3.75%、7.5%和15%，恒定释放率调节剂为5%），运动阻滞和伤害性阻滞在50%回收率下的平均体外释放率分别为0.91 +/- 0.28和1.75 +/- 0.61 mg/h。对于OST-R配方（16%利多卡因，释放率调节剂浓度分别为1.875%、3.75%、7.5%和15%），运动阻滞和伤害性阻滞在50%回收率下的平均体外释放率分别为2.33 +/- 1.39和4.34 +/- 1.09 mg/h。OSB-L剂型的阻滞持续时间随初始利多卡因浓度的增加呈剂量依赖性增加，而OST-R剂型的释放速率调节剂浓度与阻滞持续时间呈非单调关系。植入后24小时、3、5、7天和4周的组织病理学研究显示，炎症反应的程度与利多卡因含量相关，但仅限于植入材料周围的结缔组织和肌肉。尽管观察到这些炎症反应，所有动物的伤害和运动阻滞功能恢复到正常的植入前值。结论：增加初始利多卡因含量成比例地增加功能性坐骨神经阻滞的持续时间。然而，降低释放率本身并不会使块持续时间成比例地增加。相反，似乎有一个最佳的，中间释放率达到阻滞的最大持续时间。（Anesth Analg 2010;111:221-9）
BACKGROUND: Nerve blocks of long duration are often desirable in perioperative and postoperative situations. The relationship between the duration of such blocks and the rate at which a local anesthetic is released is important to know for developing a localized drug delivery system that will optimize block duration.METHODS: Lidocaine concentration was varied in 1 series of formulations (OSB-L) containing a constant amount of release rate modifier. In another series (OST-R), the release rate modifier was varied while the lidocaine content was held constant. Release kinetics were measured in vitro and correlated to the in vivo duration of antinociceptive and motor block effects when the formulation was implanted next to the rat sciatic nerve. In parallel studies, rats receiving different formulations of slow-release lidocaine were fixed by intracardiac perfusion with 4% paraformaldehyde and nerve-muscle tissue taken for histopathological analysis.RESULTS: In this study, we have demonstrated that the most important variable for effecting functional nerve block, i.e., the blockade of impulses in the relevant fibers of the sciatic nerve, is the rate of lidocaine release at that time. For the OSB-L formulations (lidocaine concentrations of 1.875%, 3.75%, 7.5%, and 15% at a constant release rate modifier of 5%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 0.91 +/- 0.28 and 1.75 +/- 0.61 mg/h, respectively. For the OST-R formulations (16% lidocaine with release rate modifier concentrations of 1.875%, 3.75%, 7.5%, and 15%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 2.33 +/- 1.39 and 4.34 +/- 1.09 mg/h, respectively. The OSB-L formulations showed a dose-dependent increase in block duration proportional to an increase in initial lidocaine concentration, whereas the OST-R formulations showed a nonmonotonic relationship between release rate modifier concentration and block duration. The histopathological studies at 24 hours, 3, 5, or 7 days, and 4 weeks after the implantation revealed inflammatory reactions with degrees correlated with lidocaine content, but limited to the connective tissue and muscle immediately surrounding the implanted material. Despite these observed inflammatory reactions, nociceptive and motor block function returned to normal, preimplantation values in all animals.CONCLUSIONS: Increasing initial lidocaine content proportionately increased the duration of functional sciatic nerve block. However, decreasing the release rate per se does not give a proportional increase in block duration. Instead, there seems to be an optimal, intermediate release rate for achieving the maximum duration of block. (Anesth Analg 2010;111:221-9)