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

利多卡因对多器官功能障碍的影响：机制阐明和临床应用

• 批准号: 09671561
• 负责人: MIKAWA Katsuya
• 金额: $ 1.15万
• 依托单位: KOBE UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671561/
• 关键词: Endotoxin; Multiorgan Failure; Local anesthetics; Hyperoxia; ARDS; Neutrophil; リドカイン; 肺障害; 活性酸素

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.

内毒素或脓毒症常常导致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 的发病机制中发挥着关键作用。利多卡因已被证明可以抑制中性粒细胞产生 ROS。我们之前证明利多卡因可有效减轻内毒素引起的急性肺损伤。本研究的第一个目的是使用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干预应用于临床。[实验研究](A)体外我们在存在或不存在利多卡因的情况下测量了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。利多卡因以剂量依赖性方式抑制NOx的产生，但对iNOS mRNA的表达没有影响。(B)体内光镜观察结果显示，利多卡因输注(2 mg/kg/hr)可病理性减轻内毒素引起的急性肺损伤、肾衰竭和肝衰竭。此外，利多卡因可减轻 DIC 的进展。我们还表明，用 2 mg/kg/hr（而非 1 mg/kg/hr）利多卡因预处理可减轻仓鼠脓毒症或高氧引起的膈肌功能障碍，通过收缩曲线和耐力能力进行评估。使用免疫组织化学，我们发现利多卡因减弱了肺泡和支气管上皮细胞中表达的 iNOS 或硝基酪氨酸染色。[临床研究]我们对 5 名被认为有 MODS 风险的成年患者（败血症 1 例、急性胰腺炎 1 例、术后 3 例）施用利多卡因。没有患者出现 MODS。没有观察到不良反应。

项目成果

三川勝也,他: "人工サーファクタント補充療法" 集中治療. 10. 43-54 (1998)

Katsuya Mikawa 等人：“人工表面活性剂替代疗法”强化治疗。10. 43-54 (1998)

Y.Kiyonari, K.Nishina, K.Mikawa, et al.: "Lidocaine attenuates acute lung injury induced by combination of phospholipase A2 and trypsin." Crit Care Med. 27 (in press). (1999)

Y.Kiyonari、K.Nishina、K.Mikawa 等人：“利多卡因可减轻磷脂酶 A2 和胰蛋白酶联合诱导的急性肺损伤。”

K.Nishina, K.Mikawa, Y.Takao, et al.: "Inhaled nitric oxide does not prevent endotoxin-induced lung injury in rabbits." Acta Anaesthesiol Scand. 41. 399-407 (1997)

K.Nishina、K.Mikawa、Y.Takao 等人：“吸入一氧化氮并不能预防兔子内毒素引起的肺损伤。”

K.Nishina, K.Mikawa, Y.Takao, et al.: "ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits" Anesth Analg. 84. 1097-1103 (1997)

K.Nishina、K.Mikawa、Y.Takao 等人：“ONO-5046 是一种弹性蛋白酶抑制剂，可减轻内毒素引起的兔子急性肺损伤”Anesth Analg。

K.Mikawa, H.Akamatsu, K.Nishina, et al.: "Propofol inhibits human neutrophil functions." Anesth Analg. 87. 695-700 (1998)

K.Mikawa、H.Akamatsu、K.Nishina 等人：“异丙酚抑制人类中性粒细胞功能。”