EFFECTS OF LIDOCAINE ON MULTIPLE ORGAN DYSFUNCTION : ELUCIDATION OF MECHANISM AND CLINICAL APPLICATION

内毒素或败血症常引起多器官功能障碍综合征（MODS），包括急性肺损伤。中性粒细胞被认为通过释放活性氧（ROS）在MODS的发病机制中起关键作用。利多卡因已被证明可以抑制中性粒细胞产生ROS。我们先前证明利多卡因对内毒素引起的急性肺损伤有效。本研究的第一个目的是通过实验模型评估利多卡因预处理对内毒素/脓毒症诱导的MODS的影响。第二个目的是确定利多卡因减弱MODS的机制。最终目的是将这种药理学干预应用于临床环境。[实验研究](A)体外实验我们测量了在利多卡因存在或不存在的情况下，Raw 264培养细胞中NOx（亚硝酸盐+硝酸盐）的产生和iNOS（诱导型一氧化氮合酶）的表达。利多卡因抑制一氧化氮的产生呈剂量依赖性，但对iNOS mRNA的表达无影响。(B) vivoLight显微镜检查结果显示，利多卡因输注（2mg /kg/hr）在病理上减轻了内毒素引起的急性肺损伤、肾功能衰竭和肝功能衰竭。此外，利多卡因可减缓DIC的进展。我们还表明，用利多卡因2 mg/kg/hr而不是1 mg/kg/hr预处理，可以通过收缩特征和耐力来评估仓鼠败血症或高氧引起的膈功能障碍。免疫组化结果显示，利多卡因可减弱肺泡和支气管上皮细胞中iNOS或硝基酪氨酸的表达。【临床研究】我们对5例被认为有MODS危险的成人患者（脓毒症1例，急性胰腺炎1例，术后3例）给予利多卡因。没有患者发生MODS。未观察到不良反应。

Endotoxin or sepsis often causes multiple organ dysfunction syndrome (MODS) including acute lung injury. Neutrophils are thought to play a pivotal role in the pathogenesis of MODS through the release of reactive oxygen species (ROS). Lidocaine has been shown to inhibit production of ROS by neutrophils. We previously demonstrated that lidocaine is effective for attenuating acute lung injury induced by endotoxin. The first aim of this study was to assess the effect of pretreatment with lidocaine on endotoxin/sepsis- induced MODS using experimental models. The second aim was to determine the mechanism underlying attenuation of MODS by lidocaine. The final aim was to apply this pharmacological intervention to clinical settings.[Experimental Study](A) in vitroWe measured NOx (nitrite + nitrate) production and expression of iNOS (inducible nitric oxide synthase) in Raw 264 cultured cell in the presence or absence of lidocaine. Lidocaine inhibited NOx production in a dose-dependent manner, but had no effect on expression of iNOS mRNA.(B) in vivoLight microscopic findings revealed that lidocaine infusion (2 mg/kg/hr) pathologically attenuated acute lung injury, renal failure, and hepatic failure induced by endotoxin. Furthermore, lidocaine attenuated progression of DIC.We have also shown that pre-treatment with lidocaine 2 mg/kg/hr but not 1 mg/kg/hr attenuated diaphragmatic dysfunction induced by sepsis or hyperoxia in hamsters assessed by contractile profiles and endurance capacity. Using immunohistochemistry we found that lidocaine attenuated stains of iNOS or nitrotyrosine expressed in alveolar and bronchial epithelial cells.[Clinical Study]We administered lidocaine to 5 adult patients (sepsis 1, acute pancreatitis 1, postoperation 3) who were thought to be at risk for MODS.No patients developed MODS.No adverse effects were observed.