Takahashi Ryota, Oda Yutaka, Tanaka Katsuaki, Morishima Hisayo O, Inoue Koki, Asada Akira
Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Anesthesiology. 2006 Nov;105(5):984-9. doi: 10.1097/00000542-200611000-00020.
Local anesthetics exert central nervous system (CNS) toxicity by inhibiting intracerebral neuronal activity, while epinephrine augments the CNS toxicity of intravenously administered local anesthetics. Viewed together, increases of extracellular concentrations of local anesthetics in the brain may be directly associated with increased CNS toxicity. The authors examined the hypothesis that epinephrine enhances the CNS toxicity of lidocaine by increasing the extracellular concentration in the brain.
An awake, spontaneously breathing rat model was used. Twenty male Sprague-Dawley rats received an intravenous infusion of lidocaine (3 mg x kg x min; group C) or lidocaine with epinephrine (3 mg x kg x min and 2 microg x kg x min, respectively; group E) for 10 min (n = 10 in each group). Effects of epinephrine on the convulsive dose and concentrations of total (protein-bound and unbound) and unbound lidocaine in plasma were examined. Concentrations of extracellular lidocaine in the cerebral nucleus accumbens were quantitatively determined by a microdialysis method.
The convulsive dose of lidocaine was significantly lower in group E than in group C (22.4 +/- 5.5 vs. 27.9 +/- 3.1 mg/kg, respectively; P < 0.05). Overall concentrations and area under the plasma concentration-versus-time curve of unbound lidocaine in group E were significantly higher than those in group C. Concentrations of extracellular lidocaine in the nucleus accumbens in group E were comparable to those of unbound fraction in plasma and were also significantly higher than those in group C.
Concomitant administration of epinephrine significantly enhanced the CNS toxicity of intravenously administered lidocaine. Increased extracellular concentration in the brain would be related to this mechanism.
局部麻醉药通过抑制脑内神经元活动发挥中枢神经系统（CNS）毒性，而肾上腺素会增强静脉注射局部麻醉药的CNS毒性。综合来看，脑内局部麻醉药细胞外浓度的增加可能与CNS毒性增加直接相关。作者检验了肾上腺素通过增加脑内细胞外浓度来增强利多卡因CNS毒性的假设。
使用清醒、自主呼吸的大鼠模型。20只雄性Sprague-Dawley大鼠接受静脉输注利多卡因（3mg·kg⁻¹·min⁻¹；C组）或利多卡因加肾上腺素（分别为3mg·kg⁻¹·min⁻¹和2μg·kg⁻¹·min⁻¹；E组），持续10分钟（每组n = 10）。研究了肾上腺素对惊厥剂量以及血浆中总（蛋白结合和未结合）利多卡因和未结合利多卡因浓度的影响。采用微透析法定量测定伏隔核中细胞外利多卡因的浓度。
E组利多卡因的惊厥剂量显著低于C组（分别为22.4±5.5与27.9±3.1mg/kg；P<0.05）。E组未结合利多卡因的总体浓度和血浆浓度-时间曲线下面积显著高于C组。E组伏隔核中细胞外利多卡因的浓度与血浆中未结合部分的浓度相当，也显著高于C组。
同时给予肾上腺素显著增强了静脉注射利多卡因的CNS毒性。脑内细胞外浓度增加与该机制有关。
