RESEARCH OF THE MECHANISM OF GENEKRAL ANESTHESIA-PHARMACOKINETICS OF ANESTHETICS IN THE BRAIN AND ITS RELATION TO ANESTHETIC EFFECT

背景：局麻药通过抑制脑内神经元活动发挥中枢神经系统（CNS）毒性，而肾上腺素增加静脉给药局麻药的中枢神经系统毒性。综上所述，脑内局麻药细胞外浓度的增加可能与中枢神经系统毒性的增加直接相关。作者检验了肾上腺素通过增加大脑细胞外浓度增强利多卡因中枢神经系统毒性的假设。方法：采用清醒自主呼吸大鼠模型。雄性Sprague-Dawley大鼠20只，静脉滴注利多卡因（3 mg × kg × min， C组）或利多卡因加肾上腺素（3 mg × kg × min, 2 mg × kg × min， E组），持续10 min（每组10只）。检测肾上腺素对惊厥时血浆中总利多卡因（蛋白结合和非蛋白结合）和非蛋白结合利多卡因剂量和浓度的影响。用微透析法定量测定脑伏隔核细胞外利多卡因浓度。结果：E组惊厥剂量显著低于C组（22.4+/-5.5 vs. 27.9+/-3.1 mg/kg， P<0.05）。E组未结合利多卡因的总浓度和血浆浓度-时间曲线下面积均显著高于c组。E组伏隔核细胞外利多卡因浓度与血浆未结合部分浓度相当，也显著高于c组。结论：同时给予肾上腺素可显著增强静脉注射利多卡因对中枢神经系统的毒性。大脑中细胞外浓度的增加可能与这一机制有关。

BACKGROUND : 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. METHODS : 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. RESULTS : 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. CONCLUSIONS : 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.