摘要
目的:体外循环造成的全身性炎症反应及肺的缺血再灌注会造成严重肺的损伤,CPB术后患者的肺功能不同程度下降。因此围术期的肺保护具有重要的意义。山莨菪碱具有抗炎及防护器官缺血再灌注损害的作用,本课题主要研究山莨菪碱对体外循环炎症因子的影响及对肺损伤的保护作用。
方法:24例择期首次行心脏瓣膜置换术患者,ASA分级Ⅱ~Ⅳ级、年龄、体重的差异无显著性。所有患者均无肝肾功能障碍;左室射血分数大于40%;血常规基本正常;无慢性支气管炎、支气管哮喘、青光眼、前列腺肥大;近期无肺部感染及接受类固醇激素治疗等。随机分为山莨菪碱组(A组)和对照组(C组),每组12例。A组按0.8mg/kg的山莨菪碱于转流开始加入预充液中,经转机进入体内。C组用等量生理盐水代替山莨菪碱,用法同A组,麻醉方案两组相同。分别于诱导切皮前(T_1)、转流30min(T_2)、停CPB1小时(T_3)、4小时(T_4)、24小时(T_5)抽取动脉血,肝素抗凝,测定红细胞压积和动脉血气分析,余血立即以2000r/min高速离心,取上层血浆,置入-20℃冰箱内保存。根据试剂盒说明采用放射免疫法测定血浆TNF-α、IL-6浓度。按公式:RI=[P(A-a)DO_2]/PaO_2=[(Pb-PH_2O)×FiO_2-PaCO_2-PaO_2]/PaO_2计算。Pb为大气压(760mmHg),PH_2O为室温下饱和水蒸气压(47mmHg)。
结果:两组患者年龄、性别、体重、转流时间、主动脉阻断时间差异无统计学意义(P>0.05)。两组间血浆IL-6、TNF-α水平和RI值在体外循环前T_1时差异无统计学意义(P>0.05)。C组T_(2-5)各时点TNF-α、IL-6均高于T_1(P<0.05),A组T_(2-5)各时点TNF-α、IL-6浓度明显低于C组同时点值(P<0.05),T_3、T_4各时点C组的RI较T_1和A组同时点显著增高(P<0.05)。RI与IL-6、TNF-α呈正相关,相关系数r分别为0.70和0.67(P<0.01)。
结论:山莨菪碱能有效地抑制体外循环心脏直视手术围术期促炎细胞因子的释放,因而能减轻体外循环引起的急性炎症反应,从而改善肺功能。
Objective: The purpose of this study was to investigate the effect of anisodamine on lung injury during cardiopulmonary bypass.
Methods: Twenty four patients scheduled for elective valve replacement under cardiopulmonary bypass, which had no significant difference existed between two groups in ASA grade, age and body height,no signs of liver function failure and renal failure; left ventricle ejection fraction exceed 40%; blood routine examination is normal probably; no history of chronic bronchitis, bronchial asthma, glaucoma and prostatauxe; no pulmonary infection or receiving hormone in these days, were randomly divided into two groups of 12 patients each. In the experimental group, the patients received anisodamine 0.8mg/kg by adding into the primary solution at the beginning of by-pass,with control group received normal saline instead of anisodamine. Blood samples were taken from radial artery for determination of IL-6 and TNF-αconcentrations and blood gas analysis before operation(T_1) , 30min after initiation of cpb(T_2) , 1h(T_3) , 4h(T_4) and 24h(T_5) after cpb. Respiratory index was calculated at T_1, T_3, T_4.
Results: The age, sex ratio, body weight, time of cpb and time of blocking aorta had no significant difference in both groups(P>0.05) . The plasma levels of TNF-α,IL-6 and respiratory index had no significant difference in both groups at T_1(P>0.05) . In control group the plasma levels of TNF-α,IL-6 were significantly higher than the baseline values during and after cpb(P<0.05) .TNF-α, IL-6 concentrations and respiratory index were significantly higher in control group than in experimental group after cpb(P<0.05) .Respiratory index was positively correlated with plasma concentration of TNF-αand IL-6.The "r" were 0.70 and 0.67(P<0.01) .
Conclusion: This results show that anisodamine can effectively suppress the production of the cytokine during cpb, so reduce the systemic inflammatory response and protect respiratory function.
引文
[1] Ng CS, Wan S, Yim AP, et al. Pulmonary dysfunction after cardiac surgery. Chest, 2002, 121(4): 1269-1277
[2] Paparella D, Yau TM, Young E. Cardiopulmonary bypass indued inflammation: pathophysiology and treatment. Eur J Cardiothorac Surg, 2002, 21(2): 232~244
[3] 陈群,曾因明.亚低温复合山莨菪碱对脑缺血再灌注期间羟自由基的影响.中华麻醉学杂志,1999,19(8):509-510
[4] 唐望先,刘晓斌,邵菊芳,等.山莨菪碱对急性肾缺血-再灌注损伤的保护机制.中华实验外科杂志,1997,14(5):304-305
[5] 胡森,盛志勇.山莨菪碱对肠缺血-再灌注大鼠肠粘膜血流量的影响.中国危重病急救医学,2001,13(11):678~680
[6] 董满库,崔彦,王平,等.山莨菪碱对肝脏缺血再灌注损伤的保护作用.中华器官移植杂志,2002,23(1):16~18
[7] 周代星,钟强,李政,等.山莨菪碱对全脑缺血再灌流后脑线粒体损伤的保护作用.中华急诊医学杂志,2003,12(3):176~178
[8] 容俊芳,温进坤,等.山莨菪碱、旋覆花素、苦碟子对过度训练致急性心肌损伤大鼠的影响.中华麻醉学杂志,2007,27(1):79~83
[9] 管用东,黄雄庆,陈秉学,等.山莨菪碱对ARDS的氧输送及血流动力学改变的作用.中华麻醉学杂志,1996,16(5):263~265
[10] 梁继河,朱云喜,李琦,等.山莨菪碱对创伤性肺损伤防治作用的实验研究.中华创伤杂志,1998,14(5):284~287
[11] 李娟,李俊,等.盐酸戊乙奎醚预先给药对大鼠内毒素性急性肺损伤的影响.中华麻醉学杂志,2007,27(1):70~74
[12] 尹文,梁继河,虎晓岷,等.山莨菪碱对创伤性急性肺损伤细胞因子及其mRNA表达的影响.中华实验外科杂志,2000,17(1):75~76
[13] 刘凤,于小玲,董晓青,等.油酸型急性呼吸窘迫综合征血清及肺组织促炎症细胞因子变化及山莨菪碱干预的实验研究.中国病理生理杂志,2002,18(8):959~961
[14] Wang LZ, liu YQ, Cui YH, et al. Effects of dexamethasone, cyproheptadine, anisodamine, and dinoprostone on TNF alpha production in endotoxic shock. Acta Pharmacologica Sinica, 1999, 20(2): 171~174
[15] Zhang HM, Ou ZL, Yamamoto T. Anisodarnine inhibits shiga toxin type 2-mediated tumor necrosis factor-alpha production in vitro and in vivo. Exp Biol Med, 2001, 226(6): 597~604
[16] Nakagawa S, Kushiya K, Taneike I, Imanishi K, Uchiyama T, Yamamoto T.Specific inhibitory action of anisodamine against a staphylococcal superantigenic toxin, toxic shock syndrome toxin 1 (TSST-1), leading to down-regulation of cytokine production and blocking of TSST-1 toxicity in mice. Clin Diagn Lab Immunol, 2005, 12(3): 399~408
[17] 李功宋,李佳春主编.体外循环灌注学[M].第一版,北京:人民军医出版社,1992:178~185
[18] Sganga G, Siegel JH, Coleman B, et al. The physiologic meaning of the respiratory index in various types of critical illness. Circ Shock, 1985, 17(3): 179~193
[19] 龚非力主编.医学免疫学[M].北京:科学出版社,2000:68~90
[20] Asschert JG, Vellenga E, Ruiters MH, et al. Regulation of spontaneous and TNF/IFN-induced 1L-6 expression in two human ovarian-carcinoma cell lines. Int J Cancer, 1999, 82(2): 244~249
[21] Belcher JD, Marker PH, Weber JP, et al. Activated monocytes in sickle Cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood, 2000, 96(7): 2451~2459
[22] 肖锡俊,章崇杰,赵宗蓉,等.体外循环致先天性心脏病手术患者血液细胞因子水平的变化.中国胸心血管外科临床杂志,1998,5(1):14~17
[23] Dauber IM, Parsons PE, Welsh CH, et al. Peripheral bypass-induced pulmonary and coronary vascular injury. Association with increased levels of tumor necrosis factor. Circulation, 1993, 88(2): 726~735
[24] 杨国栋.莨菪碱类药物治疗感染性休克的药理基础。中华内科杂志,1985,24:171~173
[25] 杨国栋.微循环障碍与莨菪类药的临床应用[M].2版.北京:人民卫生出版社,1999:346~352
[26] 徐兴祥,孙耕耘,钱桂生.急性肺损伤大鼠白细胞变形性变化及山莨菪碱影响.中华结核和呼吸杂志,1998,21(10):598~600
[27] 王奇,朱朗标,等.山莨菪碱对体外循环心脏手术后白细胞变形力的影响.中华胸心血管外科杂志,1998,14(6):348~349
[28] Mercurio F, Manning AM. Multiple signals converging on NF-kappaB. Curr Opin Cell Bioi, 1999, 11(2): 226~232
[29] Goebeler M, Gillitzer R, Kilian K, et al. Multiple signaling pathways regulate NF-kappaB-dependent transcription of the monocyte chemoattractant protein-1 gene in primary endothelial cells. Blood, 2001, 97(1): 46~55
[30] Sizemore N, Lemer N, Dombrowski N, et al. Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B(NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem, 2002, 277(6): 3863-3869
[31] Senftleben U, Karin M.The IKK/NF-kappaB pathway. Crit Care Med, 2002, 30(1): S18-S26
[32] 陈祥仪,严仪昭,西品香,等.山莨菪碱(654-2)可具有肾上腺皮质激素样作用.中国医学科学院学报,1985,7(6):348~349
[33] Gong JH, Renz H, Sprenger H, et al. Enhancement of tumor necrosis factor-alpha gene expression by low doses of prostaglandin E2 and cyclic GMP. Immunobiology, 1990, 182(1): 44~55
[34] 葛磊,肖献忠,等.山莨菪碱对H_2O_2所致内皮细胞凋亡的保护及其分子机制.对NF-κB/I-κB信号转导通路的影响.中国病理生理杂志,2000,16(10):969-972
[35] 郭振辉,洪新,毛宝龄,等.山莨菪碱对核因子-κB活化的抑制作用.第三军医大学学报,2000,22(6):545-548
[36] 袁静,尹文,张远强,等.失血性休克肺组织IKB激酶-β表达及山莨菪碱干预研究.中华实验外科杂志,2003,20(61:548~549
[1] 胡盛寿,孙晓刚,郭加强,等.2261例二尖瓣及主动脉瓣联合瓣膜置换术临床结果随访.中华胸心血管外科杂志,2002,18(1):11~13
[2] Ng CS, Wang S, Yim AP, et al. Pulmonary dysfunction after cardiac surgery. Chest, 2002, 121(4): 1269~1277
[3] Tanaka K. Specific inhibition of thrombin activity during cardiopulmonary bypass reduces ischemia-reperfusion injury of the lung. Fukuoka Igaku Zasshi, 2001, 92(1): 7~20
[4] Steinberg JB, Kapelanski DP, Olson JD, et al. Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg, 1993, 106: 1008~1016
[5] Cremer J, Martin M, Redl H, et al. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg, 1996, 61(6): 1714~1720
[6] Asimakopoulos G. The inflammatory response to CPB: the role of leukocyte flit ration. Perfusion, 2002, 17: 7~10
[7] Stefanou DC, Gourlay T, Asimakopoulos G, et al. Leucodepletion during cardiopulmonary bypass reduces blood transfusion and crystalloid requirements. Perfusion, 2001, 16(1): 51~58
[8] Azzolina A, Bongiovanni A, Lampiasi N. Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cell. Biochim Biophys Acta, 2003, 1643(1-3): 75~83
[9] Glanemann M, Strenziok R, Kuntze R, et al. Ischemic preconditioning and methylprednisolone both equally reduce hepatic ischemia/reperfusion injury. Surgery, 2004, 135(2): 203~214
[10] 于洋,蒋树林,刘艳萍,等.体外循环中抗肿瘤坏死因子抗体的肺保护作用.中华胸心血管外科杂志,2003,19(3):159~161
[11] De Santo LS, Romano G, Amarelli C, et al. Surgical repair of acute type A aortic dissection: continuous pulmonary perfusion retrograde cerebral perfusion prevents lung injury in a pilot study. J Thorac Cardiovasc Surg, 2003, 126(3): 826~831
[12] 魏波,刘迎龙,于存涛,等.肺动脉灌注低温肺保护液抑制肺内实质细胞凋亡的研究.中华外科杂志,2004,42(4):227~229
[13] Eren S, Esme H, Balci AE, et al. The effect of aprotinin on ischemia-reperfusion injury in an in situ normothermic ischemic lung model. Eur J Cardiothorac Surg, 2003, 23(1): 60~65
[14] Cheifetz IM, Cannon ML, Craig DM, et al. Liquid ventilation improves pulmonary function and cardiac output in a neonatal swine model of cardiopulmonary bypass. J Thorac cardiovasc Surg, 1998, 115(3): 528~535
[15] Ucar G, Topaloglu E, Burak Kandilci H, et al. Elevated semicarbazide-sensitive amine oxidase (SSAO) activity in lung with ischemia-reperfusion injury: protective effect of ischemic preconditioning plus SSAO inhibition. Life Sci, 2005, 78(4): 421~427
[16] Hattori R, Otani H, et al. Pharmacological preconditioning with resveratrol: role of nitric oxide. Am J Physiol Heart Circ Physio1, 2002, 282(6): H1988~1995
[17] Miki T, Cohen MV, Downey JM. Opioid receptor contributes to ischemic preconditioning throung protein kinase C activation in rabbits. Mol Cell Biochem, 1998, 186(1-2): 3~12
[18] Loubani M, Galinanes M. Long-term administration of nicorandil abolishes ischemic and pharmacologic preconditioning of the humen myocardium: role of mitochondrial adenosine triphosphate-dependent potassium channels. J Thorac Cardiovasc Surg, 2002, 124(4): 750~757
[19] 张涛,张峰,周勇安,等.缺血预处理对肺缺血再灌注损伤中细胞因子生成的影响.中华外科杂志,2003,41(7):545~547
[20] De Vroege R, van Oeveren W, et al. The impact of heparin-coated cardio-pulmonary bypass circuits on pulmonary function and the release of inflammatory mediators. Anesth Analg, 2004, 98(6): 1586~1594
[21] De Vroege R, Huybregts R, van Oeveren W, et al. The impact of heparin-coated circuits on hemodynamics during and after cardiopulmonary bypass. Artif Organs, 2005, 29(6): 490~497
[22] Baufreton C, Jansen PG, Le Besnerais P, et al. Heparin coating with aprotinin reduce blood activation during coronary artery operations. Ann Thorac Surg, 1997, 63(1): 50~56
[23] Patel AN, Sutton SW, Livingston S, et al. Clinical benefits of leukocyte filtration during valve surgery. Am J Surg, 2003, 186 (6): 636~639
[24] 章晓华,张希,肖学钧,等.白细胞过滤对肺保护作用的临床研究.中国胸心血管外科临床杂志,2006,4(2):68~71
[25] Scholz M, Cinatl J, et al. First efficacy and safety results with the antibody containing leukocyte inhibition module in cardiac surgery patients with neutrophil hyperactivity. ASAIO J, 2005, 51(2): 144~147
[26] Huang H, Yao T, Wang W, et al. Combination of balanced ultrafiltration with modified ultrafiltration attenuates pulmonary injury in patients undergoing open heart surgery. ChinMed J, 2003, 116(10): 1504~1507
[27] Saatvedt K, Lindberg H, Geiran OR, et al. Ultrafiltration after cardiopulmonary bypass in children: effects on hemodynamics, cytokines and complement. Cardicvasc Res, 1996, 31(4): 596~602
[28] Ferguson ND, Frutos-Vivar F, Esteban A, et al. Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress syndrome. Crit Care Med, 2005, 33(1): 21~30
[29] Takeuchi M, Goddon S, Dolhnikoff M, et al. Set positive end-expiration pressure during protective ventilation affects lung injury. Anesthesiology, 2002, 97(3): 682~692
[30] 邢泉生,韩俐,曹倩,等.联合应用外源性肺表面活性物质和改良保护性肺通气策略对婴幼儿体外循环后急性呼吸窘迫综合征的治疗效应.中华实验外科杂志,2003,20:849~851
[31] Giomarelli P, Scolletta S, Borrelli E, et al. Myocardial and lung injury after cardiopulmonary bypass: role of interleukin(IL)-10. Ann Thorac Surg, 2003, 76(1): 117~123
[32] Ege T, Arar C, Canbaz S, et al. The importance of aprotinin and pentoxifylline in preventing leukocyte sequestration and lung injury caused by protamine at the end of cardiopulmonary bypass surgery. Thorac Cardiovasc Surg, 2004, 52(1): 10~15
[33] Hiyama A, Takeda J, Kotate Y, et al. A human urinary protease inhibitor (ulinastatin) inhibits neutrophil extracellular release of elastase during cardiopulmonary bypass. J Cardiothorac Vase Anesth, 1997, 11(5): 580~584
[34] 李李,沈金美,等.乌司他丁对体外循环患者血浆细胞因子水平及呼吸指数的影响.中华麻醉学杂志,2004,24(8):578~581
[35] Jheon S, Lee YM, Sung SW, et al. Pulmonary preservation effect of nitroglycerine in isolated rat lung reperfusion model. Transplant Proc, 2004, 36(7): 1933~1935
[36] Feindt P, Litmathe J, Boeken U, et al. Anticoagulation during extracorporeal circulation under conditions of an ongoing systemic inflammatory response syndrome: effects of heparin. Perfusion, 2005, 20(1): 11~15
[37] Paparella D, AI Radi OO, Meng QH, et al. The effects of high dose heparin on inflammatory and coagulation parameters following cardiopulmonary bypass. Blood Coagul Fibrinolysis, 2005, 16(5): 323~328
[38] 徐兴祥,孙耕耘,钱桂生.急性肺损伤大鼠白细胞变形变化及山莨菪碱影响.中华结核和呼吸杂志,1998,21(10):598~600
[39] 袁静,尹文,张远强,等.失血性休克肺组织IKB激酶-β表达及山莨菪碱干预研,究.中华实验外科杂志,2003,20(6):548~549
[40] 罗勇,李世忠,申树先,等.1,6-二磷酸果糖对体外循环间中性粒细胞的影响.临床麻醉学杂志,2001,8:17~18
[41] Balyasnikova IV, Visintine DJ, Gunnerson HB, et al. Propofol attenuates lung endothelial injury induced by ischemia reperfusion and oxidative stress. Anesth Analg, 2005, 100(4): 929~936
[42] Hoff G, Bauer I, Larsen B, et al. Modulation of endotoxin-stimulated TNF-alpha gene expression by ketamine and propofolin cultured human whole blood. Anaesthesist, 2001, 50(7): 494~499
[43] Rivo J, Zeira E, Galun E, et al. Activation of A3 adenosine receptors attenuates lung injury after in vivo reperfusion. Anaesthesist, 2004,101(5): 1153~1159
[44] Kadoi Y, Saito S, Goto F, et al. Effects of small does of prostaglandin E(1) on systemic hemodynamics and jugular venous oxygen saturation during cardiopulmonary bypass. J Clin Anesth,2001,13(6):417~421