1、毛恩强上海交通大学医学院附属瑞金医院外科ICU,外源性血管活性物质在Sepsis微循环障碍中的作用与地位,微循环的构成，见下图,微循环的构成，见下图,脓毒血症时微循环特点微小动脉血管节律异常，成低反应性压力-血流自动调节丧失儿茶酚胺和血管紧张素的缩血管作用降低(主导)依赖内皮的扩血管作用丧失(大脑除外)80m 的微动脉扩张，60mmHg,死亡率升高的原因NTG不是NO前体长期应用，血管收缩占主导(儿茶酚胺、加压素、醛固酮和肾素水平升高)NTG打开线粒体的渗透转运孔致其产生的氧自由基漏出线粒体的衰竭与NTG的高死亡率相关,【Parker JD, Farrell B, Fenton T, et a
2、l: Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation 1991; 84:23362345.】【Gori T, Daiber A, Di Stolfo G, et al: Nitroglycerin causes mitochondrial reactive oxygen species production: In vitro mechanistic insights. Can J Cardiol 2007; 23:990992】,L-精氨酸大
3、循环稳定后应用改善微循环血流单用即可改善微循环紊乱联合血管加压素对改善微循环有叠加效应,Nakajima Y, Baudry N, Duranteau J, et al. Effects of vasopressin, norepinephrine and L-arginine on intestinal microcirculation in endotoxemia. Crit Care Med 2006; 34:17521757】【De Backer D. L-arginine and vasopressor agents: when antagonists have unexpected
4、 synergistic effects. Crit Care Med 2006; 34:18471849.】,受体兴奋剂多培沙明 有很强2-受体兴奋作用， 1和DA1、DA2较弱显著扩张动脉血管，能增加心肌、肾脏、肝脏、骨骼肌的血流量，降低心脏后负荷心肌收缩力加强，心率加快，并有轻微排钠利尿作用；0.5ug/kg/min开始应用,Effects of Dopamine, Dobutamine, and Dopexamine on Microcirculatory Blood Flow in the Gastrointestinal Tract during Sepsis and Anesth
5、esia. Anesthesiology 2004; 100:118897,受体阻断药物受体阻断药，酚妥拉明和酚苄明解除去甲肾导致的微血管过度收缩M受体阻断药:山莨菪碱、东崀菪碱、盐酸戊乙喹醚(阻断M1、M3)解除毛细血管前括约肌痉挛抑制PAF-1和TF的激活,【Effects of penehyclidine hydrochloride on the splanchnic perfusion of patients with septic shock. Chinese Critical Care Medicine200820:3 (183-186) 】【Anisodamine counter
6、acts lipopolysaccharide-induced tissue factor and plasminogen activator inhibitor-1 expression in human endothelial cells: Contribution of the NF-B pathway. J Vas Res200138:1 (13-19),抗氧化剂：Vit C恢复依赖内皮的血管节律(舒张和收缩)血管舒张作用(NO)抑制iNOS活性增加eNOS的活性抑制内皮细胞内的NADPH酶活性阻止NO氧化,【Septic impairment of capillary blood f
7、low requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med 2008; 36:23552362】【 Delayed ascorbate bolus protects against maldistribution of microvas
8、cular blood flow in septic rat skeletal muscle. Crit Care Med 2005; 33:18231828.】,同时收缩与扩张血管的活性物质,收缩血管作用提高儿茶酚胺的敏感性去甲肾上腺素和血管紧张素,【Lehr1 HA. Eur J Med Res 2006;11: 516-526】【Nualart FJ. J Biol Chem 2003; 278:10128101331】,增加氧摄取的活性物质,降低PMN与内皮的粘附多巴酚丁胺主要兴奋1、对2及受体作用相对弱增加心脏指数和全身血流抑制PMN粘附到血管内皮或促进内皮完整性增加微循环血流,【S
9、ecchi A, Ortanderl JM, Schmidt W, et al. Effects of dobutamine and dopexamine on hepatic micro- and macrocirculation during experimental endotoxemia: an intravital microscopic study in the rat. Crit Care Med 2001; 29:597600.】 【Birnbaum J, Klotz E, Spies CD, et al. Effects of dopexamine on the intest
10、inal microvascular blood flow and leukocyte activation in a sepsis model in rats. Crit Care 2006; 10:R117.】,Vit C封闭内皮细胞、降低PMN粘附、降低微血栓形成降低毛细血管渗漏减少液体复苏的液体量改善组织水肿缩短毛管和细胞的距离,Crit Care Med. 2005;33(8):1823-8.,抗凝 降低微血栓形成增加FCD人重组活化蛋白C不能降低28天死亡率显著增加出血率APC用于脓毒血症的疗效仍不确定AT ，显著出血,Human recombinant activated pro
11、tein C for severe sepsis.Cochrane database of systematic reviews (Online)2011;4 (CD004388),肝素降低微血栓抑制PMN激活和粘附早期治疗剂量应用可显著提高生存率5-15IU/kg/h，INR控制1.5,Early intravenous unfractionated heparin and mortality in septic shock. Crit Care Med 2008;36(11):2973-2979,如何应用外源性血管活性物质,感染性休克早期部分微循环关闭是机体自我保护(代偿机制)液体复苏为主要措施避免应用扩张微循环物质,微循环关闭失代偿，阻力血管扩张和微循环持续关闭可转为微循环障碍感染性休克应用缩血管药物保证大循环稳定，即达到微循环前灌注压同时应用保护内皮物质抗凝药物，早期采取普通肝素,恢复接近生理状态的血管节律(平衡点)一旦出现不能自行打开的微循环则加用扩血管药物缩血管和扩血管药物联合应用,外源性血管活性物质的选择(生理替代)选择生理状态下存在的类似物恢复和保持生理状态下的水平尽快停止外源性活性物质,Thanks,
