本文選題：膿毒癥 + 心律失常　； 參考：《大連醫(yī)科大學(xué)》2015年博士論文

【摘要】：目的本研究分析膿毒癥時(shí)新發(fā)生心律失常的誘因、主要類型及對(duì)預(yù)后的影響；研究膿毒癥心功能障礙時(shí)中性粒細(xì)胞明膠酶相關(guān)載脂蛋白在血及尿中的改變以及在膿毒癥心肌損害中的診斷價(jià)值；探討膿毒癥心肌線粒體損傷、NLRP3炎癥小體活化致心功能障礙的機(jī)制,以及不同劑量烏司他丁干預(yù)治療對(duì)心功能的影響。方法第一部分收集2012年12月至2014年4月ICU內(nèi)共748例患者的臨床資料,應(yīng)用SPSS統(tǒng)計(jì)軟件分析心律失常的誘因、主要類型及對(duì)預(yù)后的影響。第二部分留取膿毒癥患者入院4小時(shí)內(nèi)血及尿標(biāo)本,患者及正常對(duì)照組血標(biāo)本立即送檢化驗(yàn)?zāi)X鈉肽(BNP)。通過(guò)實(shí)時(shí)定量PCR法檢測(cè)心功能不全組、非心功能不全組及健康對(duì)照組外周血單個(gè)核細(xì)胞NGAL的mRNA表達(dá),采用ELISA方法檢測(cè)心功能不全組、非心功能不全組及健康對(duì)照組血漿中及尿中NGAL的蛋白表達(dá),比較組間差異。第三部分雄性清潔Wistar大鼠65只,分為空白對(duì)照組、假手術(shù)組、盲腸結(jié)扎穿孔組、烏司他丁干預(yù)組,制作大鼠膿毒癥模型,分別給予小劑量及大劑量烏司他丁干預(yù)治療。造模48小時(shí)后觀察各組大鼠左室心肌病理學(xué)及超微結(jié)構(gòu)改變；ELISA法檢測(cè)各組大鼠外周血中肌鈣蛋白I(cTnI).B型腦鈉肽(BNP).TNF-α和IL-1β的變化；通過(guò)RT-PCR檢測(cè)左室心肌細(xì)胞中NLRP3和caspase-1的mRNA表達(dá),Western blot法檢測(cè)各組左室心肌細(xì)胞中NLRP3和caspase-1蛋白的表達(dá),比較組間差異。結(jié)果第一部分ICU內(nèi)心律失常的發(fā)生率為18.85%,心律失常的主要危險(xiǎn)因素包括年齡、急診手術(shù)、膿毒癥、急性呼吸窘迫綜合征、心血管疾病和電解質(zhì)紊亂、機(jī)械通氣、應(yīng)用血管活性藥物、入ICU時(shí)較高的APACHE Ⅱ評(píng)分。膿毒癥是主要危險(xiǎn)因素(43.26%),房顫是膿毒癥患者最常見的心律失常。膿毒癥新發(fā)生心律失常組患者的病死率為29.50%,而無(wú)心律失常組13.66%(p0.01),膿毒癥存活患者中心律失常組患者的ICU住院天數(shù)明顯長(zhǎng)于無(wú)心律失常組(17.10±9.30 vs11.25±5.50,p0.01)。第二部分非心功能不全組、心功能不全組與對(duì)照組相比血及尿中NGAL mRNA及蛋白表達(dá)均有顯著性差異,P0.05；心功能不全組與非心功能不全相比血中NGAL mRNA表達(dá)無(wú)顯著性差異,P0.05：血中及尿中蛋白表達(dá)有顯著性差異,P0.05。第三部分膿毒癥大鼠血清中cTnI、BNP、TNF-α、IL-1 β均明顯升高；組織學(xué)檢測(cè)發(fā)現(xiàn),CLP組大量心肌細(xì)胞水腫、壞死、炎性細(xì)胞浸潤(rùn)及線粒體水腫、結(jié)構(gòu)破壞。免疫組化顯示膿毒癥模型中大鼠心肌NLRP3和caspase-1均表達(dá)增強(qiáng),實(shí)時(shí)定量PCR技術(shù)及免疫印跡技術(shù)顯示NLRP3和caspase-1的mRNA及蛋白表達(dá)均增強(qiáng),且與cTnI、BNP、TNF-α、IL-1β水平相關(guān)。小劑量UTI干預(yù)組及大劑量UTI干預(yù)組心肌損傷標(biāo)志物水平、炎癥介質(zhì)水平、組織病變程度、NLRP3和caspase-1的mRNA表達(dá)及蛋白表達(dá)均比CLP組改善,且大劑量UTI干預(yù)組的病理改變輕,NLRP3和caspase-1的mRNA表達(dá)及蛋白表達(dá)弱于小劑量UTI干預(yù)組。結(jié)論1.膿毒癥是ICU內(nèi)心律失常發(fā)生的主要危險(xiǎn)因素,房顫是膿毒癥誘發(fā)的心律失常的主要類型,心律失常增加了ICU患者的ICU住院天數(shù)及死亡風(fēng)險(xiǎn)。2.膿毒癥患者血BNP升高,心功能不全時(shí)血中BNP升高更明顯。膿毒癥患者存在血及尿NGAL升高,心功能不全時(shí)血中NGAL升高更明顯,且與BNP成正相關(guān),NGAL可做為心肌損害的標(biāo)記物,與其他心臟標(biāo)記物聯(lián)合應(yīng)用。3.膿毒癥時(shí)大鼠心肌組織結(jié)構(gòu)改變,線粒體損傷,心肌標(biāo)志物水平與炎癥介質(zhì)水平升高,膿毒癥可導(dǎo)致心肌損傷。膿毒癥時(shí)大鼠心肌NLRP3炎癥小體活化、caspase-1蛋白增加,NLRP3炎癥小體的活化參與了膿毒癥導(dǎo)致的大鼠心肌損害。烏司他丁對(duì)膿毒癥心肌損害具有保護(hù)作用且大劑量烏司他丁治療效果更明顯,其機(jī)制可能與烏司他丁抑制TNF-α、IL-1β等炎癥介質(zhì)的釋放、下調(diào)NLRP3小體活化導(dǎo)致的下游級(jí)聯(lián)反應(yīng)有關(guān)。
[Abstract]:Objective to analyze the causes, main types and prognosis of cardiac arrhythmia in sepsis, study the changes of neutrophilic gelatinase related apolipoprotein in blood and urine and the diagnostic value in sepsis myocardial damage during sepsis, and explore the myocardial mitochondrial damage and NLRP3 inflammation in sepsis. The mechanism of cardiac dysfunction by small body activation and the effect of different doses of ulinastatin on cardiac function. Methods the first part collected the clinical data of 748 patients in ICU from December 2012 to April 2014, and applied the SPSS statistical software to analyze the causes of arrhythmia, the main types and the effect on the prognosis. The second part retained the sepsis. The blood and urine specimens of the patients were admitted to the hospital for 4 hours, the patients and the normal control group were immediately tested for brain natriuretic peptide (BNP). The mRNA expression of NGAL in the peripheral blood mononuclear cells in the non cardiac insufficiency group and the healthy control group was detected by real-time quantitative PCR method, and the ELISA method was used to detect the heart dysfunction group, and the non cardiac insufficiency was detected by the ELISA method. The protein expression of NGAL in the plasma and urine of the control group and the healthy control group was compared. Third male Wistar rats were divided into blank control group, sham operation group, cecum ligation and perforation group, ulinastatin group, and the rat model of sepsis was made, and a small dose and large dose of Ulinastatin were given for 48 hours. The changes of left ventricular myocardium and ultrastructure of left ventricular myocardium were observed in each group, and the changes of I (cTnI).B type natriuretic peptide (BNP).TNF- alpha and IL-1 beta in peripheral blood were detected by ELISA. The mRNA expression of NLRP3 and caspase-1 in left ventricular myocytes was detected by RT-PCR. The expression of pase-1 protein was compared between groups. Results the incidence of arrhythmia in part one ICU was 18.85%. The main risk factors for arrhythmia were age, emergency operation, sepsis, acute respiratory distress syndrome, cardiovascular disease and electrolyte disorder, mechanical ventilation, vasoactive drugs, and higher APACHE II evaluation at ICU. Sepsis is the main risk factor (43.26%). Atrial fibrillation is the most common arrhythmia in patients with sepsis. The fatality rate of patients with sepsis new arrhythmia group is 29.50%, while no arrhythmia group is 13.66% (P0.01). The number of ICU hospitalization days in the patients with central arrhythmia group of sepsis surviving patients is significantly longer than that of the non cardiac arrhythmia group (17.10 + 9.30 vs11.). 25 + 5.50, P0.01). There were significant differences in the expression of NGAL mRNA and protein in the blood and urine compared with the control group in the second part of non cardiac insufficiency group, P0.05. There was no significant difference in the expression of NGAL mRNA in the heart function group and the non cardiac insufficiency, P0.05: the protein expression in the blood and urine was significantly different, P0.05. The serum levels of cTnI, BNP, TNF- a, and IL-1 beta in the third part of the sepsis rats were significantly increased. Histological examination revealed that a large number of cardiac myocytes were edema, necrosis, inflammatory cell infiltration and mitochondrial edema and structural damage in CLP group. Immunohistochemistry showed that the expression of NLRP3 and caspase-1 in the myocardium of rats in the sepsis model was enhanced, and the real-time quantitative PCR technology and immunity were quantified. The expression of mRNA and protein in NLRP3 and caspase-1 were enhanced and related to the levels of cTnI, BNP, TNF- alpha and IL-1 beta. The level of myocardial damage markers in the small dose UTI intervention group and the large dose UTI intervention group, the level of the inflammatory mediators, the degree of tissue lesion, the NLRP3 and caspase-1 mRNA expression and protein expression were better than those of the group. The pathological changes of the intervention group were light. The expression and protein expression of NLRP3 and caspase-1 were weaker than the small dose UTI intervention group. Conclusion 1. sepsis is the main risk factor for arrhythmia in ICU. Atrial fibrillation is the main type of arrhythmia induced by sepsis. Arrhythmia increases the number of ICU hospitalization days and death risk.2. sepsis in ICU patients. The increase of blood BNP in the patients and the increase of BNP in the blood were more obvious in the patients with cardiac insufficiency. The increase of blood and urine NGAL in the patients with sepsis and the increase of NGAL in the blood were more obvious when the heart function was incomplete, and it was positively related to BNP, and NGAL could be used as a marker of myocardial damage, and the structure of the myocardium in the rats with.3. sepsis was combined with other cardiac markers. Injury, the level of myocardial markers and the level of inflammatory mediators, sepsis can lead to myocardial injury. The activation of NLRP3 inflammatory bodies in the myocardium of sepsis, the increase of Caspase-1 protein, and the activation of NLRP3 inflammatory corpuscle involved in the myocardial damage caused by sepsis. The effect of the therapy is more obvious. The mechanism may be related to the release of Ulinastatin to inhibit the release of TNF- a, IL-1 beta and other inflammatory mediators, and down the downstream cascade reaction caused by the activation of NLRP3 corpuscle.
【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R459.7

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