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LOCAL ANESTHETIC NEUROTOXICITY IN THE SPINAL CORD

局部麻醉剂对脊髓的神经毒性

基本信息

批准号：
3476892
负责人：
MICHAEL W KALICHMAN
金额：
$ 7.8万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-04-01 至 1993-06-30
项目状态：
已结题

项目摘要

The administration of epidural doses of the local anesthetic NESACAINE-CE (2-chloroprocaine) was the common factor in recent reports of long-lasting neurological deficits following regional anesthesia. Subsequent reviews of the clinical literature as well as numerous experimental studies have failed to discriminate if nerve injury should be attributed to some or all local anesthetics, the NESACAINE antioxidant, or the inadvertent administration of large epidural doses into the spinal cord subarachnoid space. It is not possible to explain these inconsistencies in the absence of information about the mechanisms of the observed injury. Using a rat sciatic nerve model, the applicant has demonstrated that local anesthetic-induced peripheral nerve injury is mediated by an initial increase in permeability of the perineurial sheath, followed by decreased nerve blood flow, dilution of normally hypertonic endoneurial fluid, increased endoneurial fluid pressure, injury of Schwann cells, and nerve fiber injury. In spinal cord the possible interactions between altered permeability of barrier systems, injury-induced fluid accumulation, and changes in interstitial fluid chemistry have not been considered previously for any model of central nervous system toxicity; therefore, it is important that studies in the sciatic nerve be extended to test the hypothesis that spinal cord toxicity following local anesthetic administration is mediated by changes in the interstitial environment affecting both structure and function. Specifically, neurological injury might be secondary to alterations in protective barrier systems and a compromise of nutritive blood flow. Commercial local anesthetic preparations will first be tested using quantitative measures of electrophysiological function in order to determine the relative toxicity of the epidural and subarachnoid routes of administration. Nerve conduction velocity and refractory periods will be determined for both dorsal roots and microfilaments. Using this model of functional deficit, the toxicity of local anesthetics, drug vehicles, and injection volume will be tested. Subsequent experiments will provide functional and structural evidence for corresponding changes in nerve fibers, the dura mater barrier, spinal cord blood flow, and interstitial fluid. These experiments will quantify changes in barrier permeability (penetration of horseradish peroxidase), blood flow (measured with a diffusible tracer), endoneurial fluid electrolytes (visualized with energy dispersive x-ray spectrometry), and fluid pressure.

硬膜外剂量局麻药NESACAINE-CE的应用 (2-氯普鲁卡因)是最近报道的长期持续的共同因素区域麻醉后的神经功能障碍。随后对以下内容进行审查临床文献以及大量的实验研究都表明未能区分神经损伤是否应归因于部分或全部局麻药，NESACAINE抗氧化剂，或无意中大剂量硬膜外注射入脊髓蛛网膜下腔太空。在缺席的情况下，无法解释这些不一致之处关于观察到的损伤机制的信息。使用大鼠坐骨神经模型，申请人已经证明了局部麻醉诱导的周围神经损伤是由最初的神经鞘通透性增加，随后降低神经血流，稀释正常的高渗神经内膜液，神经内液压力升高、雪旺细胞和神经损伤纤维损伤。在脊髓中，改变之间可能的相互作用屏障系统的渗透性、损伤引起的液体堆积以及间质液体化学的变化以前没有被考虑过任何模型的中枢神经系统毒性；因此，它是重要的是要扩大对坐骨神经的研究，以测试局麻药致脊髓毒性假说给药是由间质环境的变化调节的同时影响结构和功能的。具体地说，神经损伤可能是次要的，因为防护屏障系统和营养血流受损。商业局部麻醉制剂将首先进行测试，使用电生理功能的定量测量测定硬膜外途径和蛛网膜下腔途径的相对毒性行政管理。神经传导速度和不应期对背根和微丝都有测定。使用此模型功能缺陷，局麻药，药物载体的毒性，以及将测试注射体积。随后的实验将提供神经相应变化的功能和结构证据纤维、硬脑膜屏障、脊髓血流量和间质流体。这些实验将量化屏障渗透性的变化。 (辣根过氧化物酶的穿透)，血流量(用可扩散示踪剂)，神经内液电解质(用能量可视化色散X射线光谱分析)和流体压力。