本文選題：米力農(nóng)　切入點(diǎn)：艾司洛爾　出處：《南昌大學(xué)》2016年博士論文

【摘要】：目的:觀察β-受體阻滯劑對(duì)膿毒癥相關(guān)心功能不全治療作用并探討可能作用機(jī)制。方法:本研究共分兩部分。第一部分,入選90例符合嚴(yán)重膿毒癥診斷標(biāo)準(zhǔn)且經(jīng)早期目標(biāo)導(dǎo)向治療(EGDT)后心率≥95次/分的患者,將其隨機(jī)分入對(duì)照組(C組)、米力農(nóng)組(M組)和艾司洛爾聯(lián)合米力農(nóng)組(ME組),每組30名患者。C組患者按照感染性休克指南常規(guī)治療,M組患者在C組基本治療基礎(chǔ)上給予米力農(nóng)持續(xù)靜脈泵入,負(fù)荷劑量為30ug/Kg,然后以0.375~0.5ug/Kg·min維持。ME組患者應(yīng)用艾司洛爾持續(xù)靜脈泵入,將患者心率控制在75~94次/分,余治療方案同M組。所有患者在開始治療前及其后第12、24、48、72和96小時(shí)監(jiān)測(cè)患者平均動(dòng)脈壓(MAP)、中心靜脈壓(CVP)及心率(HR)等基礎(chǔ)血流動(dòng)力學(xué)指標(biāo);在開始治療前及其后第12、24、48、72和96小時(shí)采用美國(guó)產(chǎn)I-STAT便攜式血?dú)夥治鰞x檢測(cè)其氧合指數(shù)(PaO2/FiO2)和血乳酸(Lac);在開始治療前及其后第12、24、48、72和96小時(shí)采用脈搏指示連續(xù)心排血量監(jiān)測(cè)(Picco)檢測(cè)患者CI及SVI(每搏指數(shù))等心功能指標(biāo);在開始治療前及其后第24、48、72和96小時(shí)抽取靜脈血,離心后取血漿低溫保存,測(cè)定患者血漿TNF-α、IL-6、HMGB-1、CK-MB、TnI及BNP水平。第二部分,將8-12周雄性C57BL/6J小鼠隨機(jī)分入對(duì)照組(C組)、艾司洛爾組(E組)、脂多糖組(L組)和艾司洛爾+脂多糖組(EL組),每組8只。脂多糖通過(guò)腹腔注射給藥,藥物劑量為6mg/kg;艾司洛爾通過(guò)頸靜脈持續(xù)泵入,劑量為6.7μg/kg/min。L組和EL組實(shí)驗(yàn)動(dòng)物均給予腹腔注射脂多糖,EL組實(shí)驗(yàn)動(dòng)物持續(xù)泵入艾司洛爾,而L組動(dòng)物持續(xù)泵入生理鹽水。E組實(shí)驗(yàn)動(dòng)物給予持續(xù)泵入艾司洛爾及腹腔注射生理鹽水,而C組實(shí)驗(yàn)動(dòng)物給予持續(xù)泵入及腹腔注射生理鹽水。腹腔注射后6小時(shí)采用4導(dǎo)電生理儀經(jīng)頸動(dòng)脈插管檢測(cè)血流動(dòng)力學(xué)指標(biāo),包括心率(HR)、收縮壓(SBP)、舒張壓(DBP)、平均動(dòng)脈壓(MAP);同時(shí)檢測(cè)心功能指標(biāo),包括左室收縮末壓(LVESP)、左室舒張末壓(LVEDP)、左室內(nèi)壓上升最大速率(+dp/dtmax);采用分光光度法檢測(cè)心肌組織caspase-3活性;采用TUNEL法檢測(cè)心肌細(xì)胞凋亡;采用west-blot法檢測(cè)心肌組織Bax、Bcl-2、裂解caspase-3、總P38和JNK及磷酸化P38和JNK蛋白含量。結(jié)果:第一部分,治療前各組患者M(jìn)AP、CVP、HR、PaO2/FiO2及Lac無(wú)明顯差異,治療后各組患者M(jìn)AP、CVP及PaO2/FiO2無(wú)明顯差異。治療12小時(shí)后ME組患者HR顯著低于C組和M組患者,治療48小時(shí)后M組、ME組患者Lac顯著低于C組。治療前各組患者CI及SVI無(wú)明顯差異,治療12小時(shí)后M組、ME組患者CI及SVI顯著高于C組。治療前各組患者血漿TNF-α、IL-6、HMGB-1、CK-MB、TnI及BNP水平無(wú)明顯差異,治療24小時(shí)后ME組患者血漿TNF-α、IL-6、HMGB-1、CK-MB、TnI及BNP顯著低于C組和M組患者。ME組患者28天生存率和96小時(shí)HR達(dá)標(biāo)率顯著高于C組和M組患者。第二部分,腹腔注射脂多糖6小時(shí)后,實(shí)驗(yàn)動(dòng)物HR顯著升高而SBP、DBP及MAP顯著降低,持續(xù)泵入艾司洛爾可以顯著抑制以上作用。腹腔注射脂多糖6小時(shí)后,實(shí)驗(yàn)動(dòng)物L(fēng)VEDP顯著升高而LVESP及+dp/dtmax顯著降低,持續(xù)泵入艾司洛爾可以顯著抑制以上作用。腹腔注射脂多糖導(dǎo)致心肌組織caspase-3活性顯著升高,同時(shí)心肌細(xì)胞凋亡顯著增加;而腹腔注射脂多糖后持續(xù)泵入艾司洛爾可顯著降低心肌組織caspase-3活性,同時(shí)心肌細(xì)胞凋亡顯著減少。腹腔注射脂多糖導(dǎo)致心肌組織Bax、裂解caspase-3、磷酸化P38及JNK蛋白含量顯著升高,而Bcl-2蛋白含量顯著降低;而腹腔注射脂多糖后持續(xù)泵入艾司洛爾可以顯著降低心肌組織Bax、裂解caspase-3、磷酸化P38及JNK蛋白含量,而Bcl-2蛋白含量顯著升高。結(jié)論:1.艾司洛爾聯(lián)合米力農(nóng)可顯著改善嚴(yán)重膿毒癥患者心功能。2.艾司洛爾聯(lián)合米力農(nóng)可顯著減輕嚴(yán)重膿毒癥患者心肌損傷。3.艾司洛爾聯(lián)合米力農(nóng)可顯著抑制嚴(yán)重膿毒癥患者炎癥反應(yīng)。4.艾司洛爾聯(lián)合米力農(nóng)可顯著控制嚴(yán)重膿毒癥患者心率。5.艾司洛爾聯(lián)合米力農(nóng)可顯著降低嚴(yán)重膿毒癥患者死亡率。6.艾司洛爾可顯著改善膿毒癥小鼠心功能。7.艾司洛爾可顯著抑制膿毒癥小鼠心肌細(xì)胞凋亡。8.艾司洛爾可顯著抑制膿毒癥小鼠心肌細(xì)胞JNK及P38通路。9.艾司洛爾改善膿毒癥小鼠心功能可能和其抑制心肌細(xì)胞凋亡作用相關(guān)。
[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?qiáng)纾烽吀鍖朠38鍜孞NK铔嬬櫧鍚噺.緇撴灉:絎竴閮ㄥ垎,娌葷枟鍓嶅悇緇勬?zhèn)ｈ�匨AP,CVP,HR,PaO2/FiO2鍙?qiáng)Lac鏃犳槑鏄懼樊寮，

本文編號(hào)：1724570