Walker Suellen M, Malkmus Shelle, Eddinger Kelly, Steinauer Joanne, Roberts Amanda J, Shubayev Veronica I, Grafe Marjorie R, Powell Susan B, Yaksh Tony L
Department of Anesthesiology, University of California San Diego, CA, USA; Developmental Neurosciences Department, UCL Great Ormond Street Institute of Child Health and Department of Anaesthesia and Pain Medicine, Great Ormond St Hospital Foundation Trust, London, United Kingdom.
Department of Anesthesiology, University of California San Diego, CA, USA.
Neurotoxicology. 2022 Jan;88:155-167. doi: 10.1016/j.neuro.2021.11.010. Epub 2021 Nov 18.
Spinally-administered local anesthetics provide effective perioperative anesthesia and/or analgesia for children of all ages. New preparations and drugs require preclinical safety testing in developmental models. We evaluated age-dependent efficacy and safety following 1 % preservative-free 2-chloroprocaine (2-CP) in juvenile Sprague-Dawley rats. Percutaneous lumbar intrathecal 2-CP was administered at postnatal day (P)7, 14 or 21. Mechanical withdrawal threshold pre- and post-injection evaluated the degree and duration of sensory block, compared to intrathecal saline and naive controls. Tissue analyses one- or seven-days following injection included histopathology of spinal cord, cauda equina and brain sections, and quantification of neuronal apoptosis and glial reactivity in lumbar spinal cord. Following intrathecal 2-CP or saline at P7, outcomes assessed between P30 and P72 included: spinal reflex sensitivity (hindlimb thermal latency, mechanical threshold); social approach (novel rat versus object); locomotor activity and anxiety (open field with brightly-lit center); exploratory behavior (rearings, holepoking); sensorimotor gating (acoustic startle, prepulse inhibition); and learning (Morris Water Maze). Maximum tolerated doses of intrathecal 2-CP varied with age (1.0 μL/g at P7, 0.75 μL/g at P14, 0.5 μL/g at P21) and produced motor and sensory block for 10-15 min. Tissue analyses found no significant differences across intrathecal 2-CP, saline or naïve groups. Adult behavioral measures showed expected sex-dependent differences, that did not differ between 2-CP and saline groups. Single maximum tolerated in vivo doses of intrathecal 2-CP produced reversible spinal anesthesia in juvenile rodents without detectable evidence of developmental neurotoxicity. Current results cannot be extrapolated to repeated dosing or prolonged infusion.
椎管内给予局部麻醉药可为各年龄段儿童提供有效的围手术期麻醉和/或镇痛。新的制剂和药物需要在发育模型中进行临床前安全性测试。我们评估了幼年Sprague-Dawley大鼠在给予1%无防腐剂的2-氯普鲁卡因（2-CP）后年龄依赖性的疗效和安全性。在出生后第（P）7、14或21天经皮腰椎鞘内注射2-CP。与鞘内注射生理盐水和未处理的对照组相比，注射前后的机械性撤针阈值评估了感觉阻滞的程度和持续时间。注射后1天或7天的组织分析包括脊髓、马尾和脑切片的组织病理学，以及腰段脊髓神经元凋亡和胶质细胞反应性的定量分析。在P7鞘内注射2-CP或生理盐水后，在P30至P72之间评估的结果包括：脊髓反射敏感性（后肢热潜伏期、机械阈值）；社交接近（新奇大鼠与物体）；运动活动和焦虑（有明亮中心的旷场试验）；探索行为（竖毛、探洞）；感觉运动门控（听觉惊吓、前脉冲抑制）；以及学习（莫里斯水迷宫）。鞘内2-CP的最大耐受剂量随年龄而异（P7时为1.0 μL/g，P14时为0.75 μL/g，P21时为0.5 μL/g），并产生10-15分钟的运动和感觉阻滞。组织分析发现鞘内2-CP组、生理盐水组或未处理组之间无显著差异。成体行为测量显示出预期的性别依赖性差异，2-CP组和生理盐水组之间无差异。鞘内注射单次最大耐受剂量的2-CP可在幼年啮齿动物中产生可逆的脊髓麻醉，且未检测到发育性神经毒性的证据。目前的结果不能外推至重复给药或长时间输注。
