Comparative Neurotoxicity of Stereoisomers and Racemic Bupivacaine Administered Intrathecally in the Rat

本研究的目的是利用大鼠模型比较R(+)、S(-)和消旋布比卡因对大鼠功能和形态的影响。方法：83只雄性SD大鼠经动物研究委员会批准，在鞘内植入32g导管，随机分为4组，分别鞘内注入1%R(+)布比卡因(n=22)、1%S(n=24)、1%消旋布比卡因(n=13)和生理盐水(n=13)，每次2小时。动物在输液后第4天和第7天用甩尾试验评估持续性感觉损害。尾部近端、中端和远端的甩尾潜伏期被平均并换算为%MPE=[(药物后潜伏期-基线潜伏期)/(截止基线潜伏期)]x 100。输液后7天处死动物。神经根在圆锥体尾侧12 mm处切开。每个神经束的损伤评分为0~2(0=正常和轻度，1=中度，2=重度)。每个横断面的损伤评分计算为幻灯片中存在的所有束状物的平均值。使用Kruskal-Wallis检验和Mann-Whitney检验对这些数据进行比较。结果：在输注4天后评估时，三个布比卡因组均未出现感觉功能障碍。然而，三个布比卡因组的组织学损伤仍然存在，尤其是S(-)或外消旋布比卡因造成的损伤明显大于R(+)布比卡因。结论：鞘内注射R(+)布比卡因产生的神经毒性低于S(-)或外消旋布比卡因。我们应该观察鞘内注射左旋布比卡因的神经毒性潜力。

The aim of this study was to compare the functional and morphologic effects of intrathecally administered R(+), S(-), and racemic bupivacaine using a rat model.Methods : With approval from our Committee on Animal Research, 83 male Sprague-Dawly rats were implanted with 32-gauge intrathecal catheters, and ramdomly divided into four groups to receive a single 2-hr intrathecal infusion (1μl/min) of 1 % R(+) bupivacaine (n = 22), 1 % S(-) bupivacaine (n = 24), 1 % racemic bupivacaine (n = 24), or normal saline (n = 13). Animals were assessed for persistant sensory impairment 4 and 7 days after infusion using the tail-flick test. Tail flick latencies at the proximal, mid, and distal portions of the tail were averaged and converted to % MPE = [(post-drug latency - baseline latency)/(cut-off - baseline latency)] x 100. Animals were sacrificed 7 days after infusion. The nerve roots were sectioned 12 mm caudal to the conus. Each nerve fascicle was assigned an injury score of 0-2 (0 = nomal and mild, 1 = moderate, 2 = sever). The injury score of each cross-section was calculated as the average of all fascicles present in the slide. These data were compared using the Kruskal-Wallis test and Mann-Whitney test.Results : When assessed 4 days after infusion, sensory dysfunction did not appeare in three bupivacaine-treated groups. However, histologic damage remained in three bupivacaine-treated groups ; especially injury by S(-) or racemic bupivacaine was significantly greater than by R(+) bupivacaine.Conclusions : R(+) bupivacaine administered intrathecally has a lower potential for producing neurotoxicity than does S(-) or racemic bupivacaine. We should observe the neurotoxic potential of intrathecally administered levobupivacaine.