LOCAL ANESTHETIC NEUROTOXICITY IN THE SPINAL CORD

局部麻醉剂对脊髓的神经毒性

• 批准号: 3476889
• 负责人: MICHAEL W KALICHMAN
• 金额: $ 6.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3476889
• 关键词: Schwann cells; X ray spectrometry; anesthesia complication; antioxidants; autoradiography; cerebrospinal fluid pressure; drug administration routes; electrophysiology; epidural anesthesia; histopathology; laboratory rat; local anesthetics; membrane permeability; neural conduction; neuropharmacology; neurotoxins; peripheral nervous system; peripheral nervous system disorders; radiotracer; subarachnoid space

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.

局部麻醉药奈沙卡因-CE的硬膜外给药 （2-氯普鲁卡因）是最近报告的长期持久的共同因素 区域麻醉后的神经功能缺损。 随后的审查 临床文献以及大量的实验研究 未能区分神经损伤是否应归因于部分或全部 局部麻醉剂，奈沙卡因抗氧化剂，或无意中 大剂量硬膜外给药进入脊髓蛛网膜下腔 空间 在没有证据的情况下， 关于所观察到的损伤的机制的信息。 使用大鼠坐骨神经模型，申请人已经证明， 麻醉诱导的周围神经损伤是由最初的 神经束膜鞘的通透性增加，随后降低 神经血流，正常高渗神经内膜液的稀释， 神经内膜压力增加，雪旺细胞和神经损伤 纤维损伤 在脊髓中， 屏障系统的渗透性，损伤引起的流体积聚，以及 以前未考虑组织液化学的变化 任何中枢神经系统毒性模型;因此， 重要的是，在坐骨神经的研究扩展到测试 局麻药脊髓毒性假说 给药是由间质环境的变化介导的 影响结构和功能。 特别是神经损伤 可能是次要的，以改变保护屏障系统和 营养性血流受损。 商业局部麻醉制剂将首先使用 电生理功能的定量测量， 确定硬膜外和蛛网膜下腔途径的相对毒性， 局 神经传导速度和不应期将 确定的背根和微丝。 使用此款 功能缺陷，局部麻醉剂，药物载体的毒性，以及 将测试注射体积。 后续实验将提供 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 液 这些实验将量化屏障渗透率的变化 （辣根过氧化物酶的渗透），血流量（用 可扩散示踪剂）、神经内膜液电解质（用能量可视化 色散X射线光谱法）和流体压力。