β-受体阻滞剂治疗脓毒症相关心功能不全的临床与基础研究

发布时间：2018-04-09 03:10

  本文选题：米力农　切入点：艾司洛尔　出处：《南昌大学》2016年博士论文

【摘要】：目的:观察β-受体阻滞剂对脓毒症相关心功能不全治疗作用并探讨可能作用机制。方法:本研究共分两部分。第一部分,入选90例符合严重脓毒症诊断标准且经早期目标导向治疗(EGDT)后心率≥95次/分的患者,将其随机分入对照组(C组)、米力农组(M组)和艾司洛尔联合米力农组(ME组),每组30名患者。C组患者按照感染性休克指南常规治疗,M组患者在C组基本治疗基础上给予米力农持续静脉泵入,负荷剂量为30ug/Kg,然后以0.375~0.5ug/Kg·min维持。ME组患者应用艾司洛尔持续静脉泵入,将患者心率控制在75~94次/分,余治疗方案同M组。所有患者在开始治疗前及其后第12、24、48、72和96小时监测患者平均动脉压(MAP)、中心静脉压(CVP)及心率(HR)等基础血流动力学指标;在开始治疗前及其后第12、24、48、72和96小时采用美国产I-STAT便携式血气分析仪检测其氧合指数(PaO2/FiO2)和血乳酸(Lac);在开始治疗前及其后第12、24、48、72和96小时采用脉搏指示连续心排血量监测(Picco)检测患者CI及SVI(每搏指数)等心功能指标;在开始治疗前及其后第24、48、72和96小时抽取静脉血,离心后取血浆低温保存,测定患者血浆TNF-α、IL-6、HMGB-1、CK-MB、TnI及BNP水平。第二部分,将8-12周雄性C57BL/6J小鼠随机分入对照组(C组)、艾司洛尔组(E组)、脂多糖组(L组)和艾司洛尔+脂多糖组(EL组),每组8只。脂多糖通过腹腔注射给药,药物剂量为6mg/kg;艾司洛尔通过颈静脉持续泵入,剂量为6.7μg/kg/min。L组和EL组实验动物均给予腹腔注射脂多糖,EL组实验动物持续泵入艾司洛尔,而L组动物持续泵入生理盐水。E组实验动物给予持续泵入艾司洛尔及腹腔注射生理盐水,而C组实验动物给予持续泵入及腹腔注射生理盐水。腹腔注射后6小时采用4导电生理仪经颈动脉插管检测血流动力学指标,包括心率(HR)、收缩压(SBP)、舒张压(DBP)、平均动脉压(MAP);同时检测心功能指标,包括左室收缩末压(LVESP)、左室舒张末压(LVEDP)、左室内压上升最大速率(+dp/dtmax);采用分光光度法检测心肌组织caspase-3活性;采用TUNEL法检测心肌细胞凋亡;采用west-blot法检测心肌组织Bax、Bcl-2、裂解caspase-3、总P38和JNK及磷酸化P38和JNK蛋白含量。结果:第一部分,治疗前各组患者MAP、CVP、HR、PaO2/FiO2及Lac无明显差异,治疗后各组患者MAP、CVP及PaO2/FiO2无明显差异。治疗12小时后ME组患者HR显著低于C组和M组患者,治疗48小时后M组、ME组患者Lac显著低于C组。治疗前各组患者CI及SVI无明显差异,治疗12小时后M组、ME组患者CI及SVI显著高于C组。治疗前各组患者血浆TNF-α、IL-6、HMGB-1、CK-MB、TnI及BNP水平无明显差异,治疗24小时后ME组患者血浆TNF-α、IL-6、HMGB-1、CK-MB、TnI及BNP显著低于C组和M组患者。ME组患者28天生存率和96小时HR达标率显著高于C组和M组患者。第二部分,腹腔注射脂多糖6小时后,实验动物HR显著升高而SBP、DBP及MAP显著降低,持续泵入艾司洛尔可以显著抑制以上作用。腹腔注射脂多糖6小时后,实验动物LVEDP显著升高而LVESP及+dp/dtmax显著降低,持续泵入艾司洛尔可以显著抑制以上作用。腹腔注射脂多糖导致心肌组织caspase-3活性显著升高,同时心肌细胞凋亡显著增加;而腹腔注射脂多糖后持续泵入艾司洛尔可显著降低心肌组织caspase-3活性,同时心肌细胞凋亡显著减少。腹腔注射脂多糖导致心肌组织Bax、裂解caspase-3、磷酸化P38及JNK蛋白含量显著升高,而Bcl-2蛋白含量显著降低;而腹腔注射脂多糖后持续泵入艾司洛尔可以显著降低心肌组织Bax、裂解caspase-3、磷酸化P38及JNK蛋白含量,而Bcl-2蛋白含量显著升高。结论:1.艾司洛尔联合米力农可显著改善严重脓毒症患者心功能。2.艾司洛尔联合米力农可显著减轻严重脓毒症患者心肌损伤。3.艾司洛尔联合米力农可显著抑制严重脓毒症患者炎症反应。4.艾司洛尔联合米力农可显著控制严重脓毒症患者心率。5.艾司洛尔联合米力农可显著降低严重脓毒症患者死亡率。6.艾司洛尔可显著改善脓毒症小鼠心功能。7.艾司洛尔可显著抑制脓毒症小鼠心肌细胞凋亡。8.艾司洛尔可显著抑制脓毒症小鼠心肌细胞JNK及P38通路。9.艾司洛尔改善脓毒症小鼠心功能可能和其抑制心肌细胞凋亡作用相关。
[Abstract]:Objective: To observe the effect of beta blockers on sepsis associated with dysfunction of therapeutic effect and to explore the possible mechanism. Methods: This study consists of two parts. The first part, 90 patients with severe sepsis and by early goal-directed therapy (EGDT) after the heart rate more than 95 BPM patients will they were divided into control group (C group), milrinone group (M group) and esmolol combined milrinone group (ME group), 30 patients in each group.C patients with septic shock for routine treatment, patients in group M group C were given treatment on the basis of continuous intravenous infusion of milrinone, loading dose 30ug/Kg, 0.375~0.5ug/Kg, min and then to maintain the.ME group were treated with continuous intravenous infusion of esmolol, patients with heart rate control in 75~94 / min, more than treatment with M group. All the patients before the start of treatment and after 12,24,48,72 and 96 hour monitoring patients with mean arterial Pressure (MAP), central venous pressure (CVP) and heart rate (HR) and other basic hemodynamic indexes; before the start of treatment and after 12,24,48,72 and 96 hours using the United States I-STAT portable blood gas analyzer and oxygenation index (PaO2/FiO2) and blood lactate (Lac) before and after treatment; at the beginning of the 12,24,48,72 and 96 hours by pulse indicator continuous cardiac output monitoring (Picco) detection in patients with CI and SVI (stroke index) and heart function index; at the beginning of treatment before and after 24,48,72 and 96 hours of venous blood after centrifugation, plasma cryopreservation, plasma IL-6, TNF- alpha, HMGB-1, CK-MB, and TnI the level of BNP. The second part, the 8-12 week male C57BL/6J mice were randomly divided into control group (C group), esmolol group (E group), LPS group (L group) and esmolol + LPS group (EL group), 8 rats in each group. The lipid polysaccharide administered by intraperitoneal injection dose was 6mg/kg esmolol; In the jugular vein continuously pumped, the dose of 6.7 g/kg/min.L group and EL group of experimental animal were given intraperitoneal injection of LPS, EL Group continued to pump into the experimental animal and animal esmolol, L Group continued to pump into the saline group.E experimental animal continuous infusion of esmolol and given intraperitoneal injection of saline, and group C give the animal continued to pump into and injected with saline. After intraperitoneal injection for 6 hours by 4 electric physiological instrument by carotid artery hemodynamics, including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP); simultaneous detection of cardiac function index, including left ventricular end systolic pressure (LVESP), left ventricular end diastolic pressure (LVEDP), maximum rate of left ventricular pressure rise (+dp/dtmax); spectrophotometry was used to detect the activity of Caspase-3 in myocardial tissue; detection of myocardial cell apoptosis by TUNEL method; west-blot method was used to detect myocardial tissue Ba x,Bcl-2,瑁傝Вcaspase-3,鎬籔38鍜孞NK鍙婄７閰稿寲P38鍜孞NK铔嬬櫧鍚�閲�.缁撴灉:绗�涓�閮ㄥ垎,娌荤枟鍓嶅悇缁勬偅鑰匨AP,CVP,HR,PaO2/FiO2鍙奓ac鏃犳槑鏄惧樊寮，

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