摘要目的 探讨脂肪乳预先给药对罗哌卡因致大鼠神经毒性及半数致死剂量的影响,并与传统抗惊厥药咪达唑仑及丙泊酚相比较.方法 (1)将120只(雌雄各半)SD大鼠按性别以数字随机法分为4组,即对照组(C),脂肪乳组(L),咪达唑仑组(M)和丙泊酚组(P).在腹腔注射罗哌卡因前,对照组先静脉缓推10 ml/kg生理盐水;L组先静脉缓推脂肪乳10 ml/kg;M组先静脉缓推生理盐水,剂量为10 ml/kg×体质量-应注射咪达唑仑体积,再注射咪达唑仑0.23 mg/kg;P组先静脉缓推生理盐水,剂量为10 ml/kg×体质量-应注射丙泊酚体积,再注射丙泊酚4 ml/kg,然后各组再于腹腔注射罗哌卡因44 mg/kg.以出现肢体抽搐为惊厥标准.观察其致惊厥率.并于大鼠惊厥发作时采集血液测血罗哌卡因浓度,记录从给药完毕到惊厥发作时间.(2)将100只SD雄鼠编号,用序贯法测4组罗哌卡因LD50.根据预实验结果选择各组罗哌卡因的剂量范围,按等比例0.85分为6个剂量亚组,各组预先给药方法和剂量同(1).结果 对照组惊厥率为43.3％,LD50(C)=64.39 mg/kg,致惊厥时平均血罗哌卡因浓度为(1.65±0.30) μg/kg;脂肪乳组惊厥率为70.0％,LD50(L) =55.45mg/kg,平均血药浓度为(3.45±0.26)μg/kg;咪达唑仑组惊厥率为0％,LD50(M)=88.40 mg/kg;丙泊酚惊厥率组为13.3％,LD50(P) =90.20 mg/kg,平均血药浓度为1.73 ±0.14 μg/kg.与对照组比,脂肪乳组惊厥率升高,半数致死量降低,两组间差异有统计学意义(P＜0.05).咪达唑仑组与丙泊酚组惊厥率降低,LD50升高,与对照组相比差异有统计学意义(P＜0.05).脂肪乳组的血药浓度最高,与对照组比差异有统计学意义(P ＜0.001).丙泊酚组血药浓度与对照组之间差异无统计学意义(P =0.895).各组大鼠出现惊厥时间差异无统计学意义(P＞0.05).结论 咪达唑仑与丙泊酚有神经毒性预防作用,并能提高罗哌卡因半数致死剂量.脂肪乳加重了罗哌卡因神经毒性并且降低其半数致死剂量.预先给予脂肪乳预防局部麻醉药物中毒反应有潜在风险.

abstractsObjective To assess the effects of lipid on ropivacaine-induced convulsion and LD50 in rats and compare with those of the traditional anticonvulsants midazolam and propofol.Methods Protocol 1:A total of 120 SD rats (60 males,60 females),weighing 200-300 g,were randomly assigned into 4 groups with equal males and females:lipid (L),midazolam (M) and propofol (P) and control (C).Rats were pretreated with 10 ml/kg lipid intravenously in group L,saline and 0.23 mg/kg madazolam (10 ml/kg in volume) sequentially in group M,saline and 4 mg/kg propofol (10 ml/kg in volume) in group P and saline 10 ml/kg in group C.Then ropivacaine 44 mg/kg (0.75％) was injected intraperitoneally into each rat.The convulsion rate in each group and the time of convulsion after ropivacaine injection were observed.Meanwhile,the plasma concentration of ropivacaine at the time of convulsion was measured.Protocol 2:Additional 100 male SD rats were used for the measurements of ropivacaine LDS0 with different pretreatments including lipid,midozolam,propofol and saline through the up-and-down method.Rats were randomly assigned into 4 groups similarly as protocol 1.The doses of ropivacaine in each group were determined according to our pilot study and 6 dosage levels with the same interval ratio 8.5 was applied in each group.The doses of these pretreatment drugs and administration methods were similarly as protocol 1.Results The convulsion rate after 44 mg/kg ropivaeaine ip injection was 43.3％ in group C,0％ in group M,13.3％ in group P and 70％ in group L.Lipid increased the convulsion rate significantly.The plasma concentration of ropivacaine at the time of convulsion was 1.65 ±0.30 μg/kg in group C,1.73 ±0.14 μg/kg in group P and 3.45±0.26 μg/kg in group L.The LD50 of ropivacaine in group C was 64.39 mg/kg,88.40 mg/kg in group M and 90.20 mg/kg in group P and 55.45 mg/kg in group L.Conclusions Midazolam and propofol not only decrease the convulsion rate of ropivacaine,but also increase its LD50.Lipid not only increases the convulsion rate of ropivacaine,but also decreases its LD50.The application of lipid for the prevention of local anesthetic toxicity has potential risks.