血管活性药物对脓毒血症微循环障碍的影响

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， 80m 的微动脉收缩,【Proc Natl Acad Sci U S A 2000;97:97539758】【Baker CH, Sutton ET. (1993). Arteriolar endothelium-dependent vasodilation occurs during endotoxin. shock. Am J Physiol 264:H1118H1123.】,毛细血管灌注数量降低 微血栓形成红细胞、白细胞变形降低、内皮肿胀毛细血管表面积微静脉内皮屏障功能障碍毛细血管渗漏(蛋白、液体)PMN组织内浸润,Aird WC.Blood 2003; 101:376577,不同时间点微循环状态 不一相同时间点不同器官微循环状态不一,微循环障碍表现形式：时间-空间上的异常,调整血管节律的活性物质,受体激动剂去甲肾上腺素:收缩阻力血管随着剂量增加，MAP升高，但FCD(vessels/mm2, )降低,【Arnaldo Dubin.Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study. Critical Care 2009, 13:R92 (doi:10.1186/cc7922)】,收缩血管的活性物质,毛细血管流量指数,MAP逐渐由60、70、80升至90mmHg，去甲肾由0.18 g/kg/min逐渐加至0.41 g/kg/min全身氧输送、皮肤PtO2 、皮肤微血管红细胞流量显著升高MAP升高并不增加FCD和舌下微循环血流指数大鼠小肠肌层FCD下降至25-60%，联合多巴酚丁胺，FCD正常乳酸有升高趋势,【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia2010110:2 (547-554) 】【The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock. Critical care medicine200937:6 (1961-1966) 】。,去甲肾的应用改善微循环灌注呈剂量依赖性; 建议65mmHg后，再增加MAP ，可导致微循环障碍,SB:125ml/h逐渐增加至500ml/h,去氧肾上腺素大鼠小肠肌层FCD下降至25-60%肾、内脏、皮肤及肢体血流减少肠系膜上静脉内的血乳酸显著升高,【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia2010110:2 (547-554) 】,和受体兴奋剂肾上腺素大样本RCT，与去甲肾对MAP影响无差异，28-d和90-d死亡率无差异第一个24h，见心动过速、乳酸酸中毒和增加胰岛素用量 严重收缩小肠肌层血管，加剧微循环障碍！不建议应用,【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia2010110:2 (547-554) 】【Myburgh JA, Higgins A, Jovanovska A, et al., CAT Study investigators. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008; 34:22262234.】,多巴胺：中等以上剂量，受体和1 激动剂多巴胺提高MAP可保护肠道粘膜微循环大鼠小肠肌层FCD无显著改变显著增加SMA血流；其乳酸浓度不高 增加心率以及心脏负性事件发生率高于去甲肾,【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia2010110:2 (547-554) 】,V1、V2受体激动剂垂体后叶素收缩全身和局部微循环消除低血压、降低液体积聚和逆转毛细血管渗漏冠脉血管收缩致心排量降低等内脏血管过度收缩引起缺血坏死,【Torgersen C, et al. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial. Intensive Care Med. 2010;36:5765.】,脓毒血症时状态机体缺乏AVP感染性休克需0.067 U/min(4IU/h)方恢复至近正常水平特点激动两个受体的作用相似，选择性差半衰期是6min、作用维持30-60min,【Torgersen C, et al. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial. Intensive Care Med. 2010;36:5765.】,特利加压素(Terlipressin)V1a收缩血管为主要作用降低毛细血管渗漏、逆转低血压半衰期6小时，疗效2-10小时持续缓慢静推(1.3g/kg/h)，最大剂量是2g/kg/h 负性心血管作用，需多巴酚丁胺抵消,【Ertmer C. Current place of vasopressin analogues in the treatment of septic shock. Curr Infect Dis Rep 2008;10:362367.】【Ryckwaert F.Terlipressin, a provasopressin drug exhibits direct vasoconstrictor properties: consequences on heart perfusion and performance. Crit Care Med 2009;37:876881. 】,血管加压素的应用建议在儿茶酚胺抵抗时再给予应用剂量：恢复生理水平精氨酸加压素的剂量 0.03 0.067 U/min(4IU/h)特利加压素， 1.3g/kg/h，最大剂量是2g/kg/h,缩血管物质的作用提高MAP，储备毛细血管前灌注压力降低体液积聚和逆转毛细血管渗漏恢复毛细血管灌注负性作用皮肤、内脏阻力血管和微循环过度收缩心脏负性作用,扩张血管的活性物质,NO供体硝酸甘油(NTG)：改善微循环灌注，但褒贬不一主要扩张静脉和微小动脉降低肺动脉压、恢复组织灌注和提高生存率扩容稳定后，硝酸甘油并不能改善微循环，甚至对存活率有负性作用,【Lamontagne F, Meade M, Ondiveeran HK, et al. Nitric oxide donors in sepsis: a systematic review of clinical and in vivo preclinical data. Shock 2008;30:653659.】,【Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: A double-blind randomized placebo controlled trial. Crit Care Med 2010; 38:93100.】,60天存活率也显著降低,NTG ,2mg 持续静推30分钟，然后23.5h持续2mg/h。维持MAP60mmHg,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 al: 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 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 Anesthesia. 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 counteracts 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 flow 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 microvascular 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,【Secchi 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 intestinal microvascular blood flow and leukocyte activation in a sepsis model in rats. Crit