Evaluation of spinal toxicity and long-term spinal reflex function after intrathecal levobupivaciane in the neonatal rat.
Evaluation of spinal toxicity and long-term spinal reflex function after intrathecal levobupivaciane in the neonatal rat.
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DOI：
10.1097/aln.0b013e31828fc7e7
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发表时间：
2013-07
期刊：
影响因子：
8.8
通讯作者：
Walker SM
中科院分区：
文献类型：
--
作者：
Hamurtekin E;Fitzsimmons BL;Shubayev VI;Grafe MR;Deumens R;Yaksh TL;Walker SM
所有年龄段的儿童都可使用轴神经麻醉。局部麻醉剂在某些成人模型中产生剂量依赖性毒性，但发育中的脊髓也可能对药物诱导的细胞凋亡敏感。在出生后的啮齿动物中，我们研究了鞘内注射左旋布比卡因对神经病理学和长期感觉运动结果的影响。出生后第3天（P3）或P7天的大鼠幼崽接受鞘内注射左布比卡因2.5mg/kg（0.5%）或生理盐水。评估机械性退缩阈值和运动阻滞。脊髓组织分析包括：24小时的细胞凋亡计数（活化的半胱天冬酶-3，Fluoro-Jade C）; 7天时的神经胶质反应性;以及24小时和7天时脊髓和马尾的组织病理学。通过后肢退缩阈值、对阈上刺激的肌电图反应和步态分析评估年轻成人（P35）的长期脊髓功能。鞘内左旋布比卡因在P3和P7产生脊髓麻醉。在脊髓或马尾神经中未观察到细胞凋亡或组织病理学变化增加。在P3生理盐水组中，活化半胱天冬酶-3（腰髓切片平均值±SEM 6.1±0.3）和Fluoro-Jade C（12.1±1.2）计数高于P7，但左布比卡因没有改变（P=0.62和P=0.11，双尾Mann-Whitney检验）。在P35时，P3或P7左布比卡因或生理盐水组之间的机械退缩阈值、热退缩潜伏期和肌电图反射反应没有差异（单因素ANOVA与Bonferroni比较）。P3时鞘内注射布比卡因未改变步态。单剂量鞘内注射0.5%左旋布比卡因不会增加新生大鼠幼仔的细胞凋亡或产生脊髓毒性。本研究提供了与新生儿使用轴索局部麻醉相关的临床前安全性数据。
Neuraxial anesthesia is utilized in children of all ages. Local anesthetics produce dose-dependent toxicity in certain adult models, but the developing spinal cord may also be susceptible to drug-induced apoptosis. In postnatal rodents, we examined effects of intrathecal levobupivacaine on neuropathology and long-term sensorimotor outcomes. Postnatal day 3 (P3) or P7 rat pups received intrathecal levobupivacaine 2.5mg/kg (0.5%) or saline. Mechanical withdrawal thresholds and motor block were assessed. Spinal cord tissue analysis included: apoptosis counts (activated-caspase-3, Fluoro-Jade C) at 24 h; glial reactivity at 7 days; and histopathology in cord and cauda equina at 24 h and 7 days. Long-term spinal function in young adults (P35) was assessed by hindlimb withdrawal thresholds, electromyography responses to suprathreshold stimuli, and gait analysis. Intrathecal levobupivacaine produced spinal anesthesia at P3 and P7. No increase in apoptosis or histopathological change was seen in the cord or cauda equina. In the P3 saline group, activated-caspase-3 (mean±SEM per lumbar cord section 6.1±0.3) and Fluoro-Jade C (12.1±1.2) counts were higher than at P7, but were not altered by levobupivacaine (P=0.62 and P=0.11, two-tailed Mann-Whitney test). At P35, mechanical withdrawal thresholds, thermal withdrawal latency and electromyographic reflex responses did not differ across P3 or P7 levobupivacaine or saline groups (one way ANOVA with Bonferroni comparisons). Intrathecal bupivacaine at P3 did not alter gait. Single dose intrathecal levobupivacaine 0.5% did not increase apoptosis or produce spinal toxicity in neonatal rat pups. This study provides preclinical safety data relevant to neonatal use of neuraxial local anesthesia.