Central Nervous System Effects of Intrathecal Muscle Relaxants in Rats
Central Nervous System Effects of Intrathecal Muscle Relaxants in Rats
复制标题
鞘内注射肌肉松弛剂对大鼠中枢神经系统的影响
DOI：
10.1213/00000539-199306000-00020
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发表时间：
1993
影响因子：
5.7
通讯作者：
Ronald D. Miller
中科院分区：
文献类型：
--
作者：
J. Szenohradszky;A. Trevor;P. Bickler;J. Caldwell;M. Sharma;I. Rampil;Ronald D. Miller
&NA;当静脉注射足够的时间和剂量时，神经肌肉阻滞药物最终可以进入脑脊液（CSF）。为了研究脑脊液中神经肌肉阻滞药物的潜在药理学后果，通过鞘内输注这些药物在大鼠中建立了模型。将插管立体定向地植入麻醉的雄性 Sprague-Dawley 大鼠（250-300 g）的侧脑室中。几天后，在未麻醉的大鼠中研究了阿曲库铵 (0.804 μmol/mL)、泮库溴铵 (0.172 μmol/mL) 和维库溴铵 (21.978 μmol/mL) 的脑室内输注 (5 μL/min) 的影响。这些大鼠（每组 n = 6 只）在药物输注期间表现出剂量依赖性过度兴奋，在阿曲库铵、泮库溴铵和维库溴铵的阈值剂量（平均）分别为 0.12、0.26 和 0.065 ± 0.010 和 3.32 μmol/kg 时发生癫痫发作。其他研究人员确定，阿曲库铵、泮库溴铵和维库溴铵在大鼠中的神经肌肉 ED50（产生 50% 抽搐张力抑制所需的静脉剂量）分别为 0.408、0.115 和 0.352 μmol/kg。因此，癫痫阈剂量与这些药物作为神经肌肉阻滞药物的效力无关。根据这些数据，在大约 1/100、1/10 和 1/5 的每种药物导致癫痫发作的累积剂量的亚癫痫剂量范围内研究中枢神经系统效应（每个剂量 n = 5）。在 1/100 的癫痫剂量时，出现运动活动减少和立毛现象。在癫痫剂量的1/10至1/5时，会出现焦躁、颤抖、四肢张开和全身颤抖。我们还证明，在癫痫发作阈剂量下，阿曲库铵、泮库溴铵和维库溴铵的浓度与脑脊液中的浓度相似，会导致体外大鼠皮质脑切片中细胞内钙的增加，这表明癫痫发作活动的可能机制。我们得出的结论是，直接注射到脑脊液中的神经肌肉阻滞药物会引起剂量依赖性中枢神经系统兴奋和癫痫发作。尽管物种和可能的剂量差异阻碍了任何临床应用，但我们认为，大鼠身上的这些结果表明，神经肌肉阻滞药物对接受这些药物几天的患者可能产生的中枢神经系统影响值得探索。 （麻醉分析 1993；76：1304‐9）
&NA; When given for a sufficient time and dose intravenously, neuromuscular blocking drugs eventually can enter the cerebrospinal fluid (CSF). To study the potential pharmacologic consequences of neuromuscular blocking drugs in the CSF, a model was developed in the rat by using an intrathecal infusion of these drugs. A cannula was stereotaxically implanted in a lateral cerebral ventricle of anesthetized male Sprague‐Dawley rats (250‐300 g). Several days later, the effects of an intraventricular infusion (5 μL/min) of atracurium (0.804 μmol/mL), pancuronium (0.172 μmol/mL), and vecuronium (21.978 μmol/mL) were studied in unanesthetized rats. These rats (n = 6 in each group) exhibited dose‐dependent hyperexcitability during drug infusion, with seizures occurring at threshold doses of (mean), 0.12, 0.26, and 0.065 ± 0.010 and 3.32 μmol/kg of atracurium, pancuronium, and vecuronium, respectively. The neuromuscular ED50 (intravenous dose required to produce a 50% depression of twitch tension) in rats determined by other investigators are 0.408, 0.115, and 0.352 μmol/kg for atracurium, pancuronium, and vecuronium, respectively. Therefore, seizure threshold doses were not related to the potencies of these drugs as neuromuscular blocking drugs. Based on these data, central nervous system effects were studied over the subseizure dose range approximating 1/100, 1/10, and 1/5 of the cumulative dose causing seizures for each drug (n = 5 for each dose). At 1/100 of seizure dose, decreased locomotor activity and piloerection occurred. At 1/10 to 1/5 of seizure dose, agitation, shivering, splayed limbs, and whole body shaking resulted. We have demonstrated also that at concentrations similar to those in the CSF at seizure threshold doses, atracurium, pancuronium, and vecuronium produce increases in intracellular calcium in rat cortical brain slices in vitro, suggesting a possible mechanism for seizure activity. We conclude that neuromuscular blocking drugs injected directly into the CSF cause dose‐dependent central nervous system excitation and seizures. Although species and possible dosage differences prevent any clinical applications, we propose that these results in rats indicate that possible central nervous system effects of neuromuscular blocking drugs in patients receiving these drugs for several days deserves exploration. (Anesth Analg 1993;76:1304‐9)