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ω-3多不饱和脂肪酸对体外循环心脏手术围术期炎性因子的影响

发布时间:2018-08-11 19:39
【摘要】:背景体外循环(Cardiopulmonary bypass,CPB)技术是心脏手术得以顺利开展的重要辅助措施之一。然而对患者来说,体外循环不同于机体自身的生理性循环,体外循环这种非生理模式,会导致全身炎症反应综合征(systemic inflammatory response syndrom,SIRS)的发生。失控的炎症反应可导致体外循环术后心肺、肝、肾、脑等重要脏器功能不全,显著增加患者的致死率和致残率。外科手术的创伤、血液直接暴露于异物表面、缺血-再灌注损伤(Ischemia-Reperfusion Injury, IRI)、肠道细菌移位所致内毒素血症、温度变化等因素均可激活体内中性粒细胞、单核细胞、内皮细胞及血小板等多种细胞成分,激活血液中的补体系统、内源性凝血和外源性凝血系统和纤溶系统,引起多种与炎症反应有关的生物活性物质的释放,并形成难以控制的的炎症瀑布效应,使得机体炎性反应失控而形成全身炎症反应综合征。近年大量研究资料表明,在体外循环心脏直视手术期间,对全身炎症反应起核心作用的炎性介质主要有肿瘤坏死因子-α (Tumor Necrosis Factor,TNF-α)、白介素1(Interleukin-1,IL-1)、白介素-6(Interleukin-6,IL-6)、白介素-8(Interleukin-8,IL-8)、白介素-10(Interleukin-10,IL-10)等。其中,较为重要的是白介素系统。IL-1、IL-6和IL-8是促炎介质,IL-10是抗炎介质。有报道,IL-6血浆水平在体外循环开始后即刻升高,2小时后出现第一次高峰,5-6小时降至术前水平,12-18小时出现第二次高峰,48小时后降至术前水平;IL-10血浆水平在升主动脉开放后逐渐升高,90分钟后达到高峰,体外循环结束后4小时基本恢复至术前水平。适量的抗炎介质有助于控制炎症进展,恢复内环境稳定,但是机体过度的抗炎反应也会产生免疫抑制,即代偿性抗炎反应综合征(compensatory anti-inflammatory response syndrome,CARS)。SIRS的产生和发展是一个极其复杂的级联过程,在体外循环所致SIRS的发生发展过程中,SIRS的严重程度主要是由下游促炎细胞因子(主要为IL-6、IL-8)和抗炎细胞因子(主要为IL-10)的平衡状态决定。随着医学技术的进步,临床上已有多种行而有效的方法用来减轻体外循环所致的炎症反应,如应用具有生物相容性的涂层材料、搏动灌注模式、使用白细胞滤器及超滤装置、使用皮质类固醇激素、乌司他丁、磷酸二酯酶抑制剂、单克隆抗体等。Omega-3多不饱和脂肪酸(ω-3Polyunsaturated Fatty Acids,ω-3PUFAs)主要包括a-亚麻酸(α-Linolenic Acid, ALA)、二十碳五烯酸(Eicosapentaenoic Acid,EPA)和二十二碳六烯酸(Docosahexaenoic Acid,DHA)。在自然界,Omega-3多不饱和脂肪酸主要来源于水生浮游植物合和深海鱼类。陆地的动植物几乎不含Omega-3多不饱和脂肪酸。研究证明Omega-33多不饱和脂肪酸可通过以下途径调节机体炎症与免疫反应:(1)通过影响花生四烯酸(Arachidonic Acid,AA)的代谢而产生效应。(2)通过改变细胞膜的流动性产生抗炎效应。(3)作用于某些炎症、免疫介质产生效应。(4)通过作用于细胞信号转导和基因表达而产生抗炎调节免疫效应等。近年来,Omega-3多不饱和脂肪酸的心脏保护作用引起了越来越多的重视。Mc Guinness等发现,兔的心肌缺血再灌注模型中,ω-3多不饱和脂肪酸预处理可诱导心肌细胞HSP的大量表达,缩小心肌梗死面积。Charman等发现体外循环术前有计划地给予病人服用鱼油(主要成分为Omega-3多不饱和脂肪酸),可以减轻体外循环手术带来的心肌损伤。亦有研究报道,Omega-3多不饱和脂肪酸可以减少心肌耗氧量,减少心肌缺血再灌注时氧化应激及钾离子的丢失,从而起到保护心肌作用。大规模的临床试验证明每日摄入500mg到1000mg的多不饱和脂肪酸可显著的减少心血管事件的发生几率。目前在临床上,重点添加Omega-3多不饱和脂肪酸的的第一种治疗型脂肪乳剂:Omega-3鱼油脂肪乳剂问世并应用于临床,在脓毒症、全身炎症反应综合症、严重创伤、头颅、腹部等外科大手术后的重症患者的治疗上取得较好的疗效。然而作为创伤大、炎症因子释放量大、风险高的体外循环下心脏直视手术的抗炎治疗方法中,补充Omega-3鱼油脂肪乳在国内外的研究报道尚不多见。目的观察Omega-3鱼油脂肪乳对体外循环心脏手术围术期全身炎症反应的影响方法30例体外循环心脏手术患者随机分为Omega-3鱼油脂肪乳组(15例)和空白对照组(15例)。Omega-3鱼油脂肪乳组于麻醉诱导后给予Omega-3鱼油脂肪乳0.2g/kg;空白对照组于麻醉诱导后给予等量生理盐水。记录患者术前一般情况:年龄、性别、身高、体重和既往史,术中情况:手术时间、体外循环时间、升主动脉阻断时间、术中出血量,术后情况:引流量、术后拔除气管插管时间、抗生素使用时间、重症监护病房停留时间、术后住院时间、总输血量;另外,分别于T1:麻醉诱导后,T2"升主动脉阻断后30分钟,T3:升主动脉阻断后1小时,T4:升主动脉开放后30分钟,T5-升主动脉开放后1小时,T6手术后6小时:T7:手术后12小时,T8:手术后24小时,T9:手术后48小时,T10-手术后72小时等10个时间点采集血液样本检测血浆白细胞介素-6、白细胞介素-10浓度水平。结果1.两组患者在年龄(实验组49.8±8.7岁,对照组49.4±11.9岁)、性别(实验组男性46.7%,对照组男性40%)、身高(实验组162.5±11.4cm,对照组159.6-+9.7cm)、体重(实验组66.6±13.5kg,对照组61.1±11.6kg)、既往史等方面,均无统计学差异,P0.05。2.两组患者在手术时间(实验组249.2±44.8min,对照组241.1+37.4min)、体外循环时间(实验组95.5±53.7min,对照组95.3-+31.4min)、升主动脉阻断时间(实验组69.8±44.Omin,对照组68.2±28.1min)、术中出血量(实验组800±185.9m1,对照组741.4±288.3m1)均无统计学差异,P0.05。3.两组患者在术后引流量(实验组598.8±162.5m1,对照组687.3±276.7m1)、术后拔除气管插管时间(实验组12.8±5.3h,对照组12.1±5.1h)、抗生素使用时间(实验组3.4±1.2d,对照组3.5±1.5d)、ICU停留时间(实验组2.8±0.8d,对照组3.2±0.9d)、术后住院时间(实验组14.7±1.5d,对照组18.6±7.9d)、总输血量(实验组741.6±698.6m1,对照组492.9±503.Oml),上述结果均无统计学差异,P0.05。4.实验组患者血浆白介素-6(IL-6)水平分别是:T1(麻醉诱导后,6.81±0.20pg/ml)、T2(升主动脉阻断后30分钟,10.66±1.61pg/ml)、T3(升主动脉阻断后1小时,29.16±4.73pg/m1)、T4(升主动脉开放后30分钟,101.02±7.61pg/ml)、 T5(升主动脉开放后1小时,182.38±11.73pg/ml)、T6(手术后6小时,86.91±14.49pg/ml)、T7(手术后12小时,43.08±10.26pg/ml)、T8(手术后24小时,8.21±1.66pg/ml)、T9(手术后48小时,6.71±0.16pg/m1)、T10(手术后72小时,6.50±0.17pg/ml),其中T2至T8时间点IL-6血浆水平较术前比均有显著统计学差异,P0.01;对照组患者血浆白介素-6(IL-6)水平分别是:T1(麻醉诱导后,6.71±0.16pg/ml)、T2(升主动脉阻断后30分钟,15.80±1.54pg/ml)、T3(升主动脉阻断后1小时,53.43±5.15pg/ml)、T4(升主动脉开放后30分钟,130.62±9.83pg/ml、T5(升主动脉开放后1小时,207.9±16.21pg/ml、T6(手术后6小时,132.91±15.21pg/ml)、T7(手术后12小时,98.58±10.17pg/ml)、T8(手术后24小时,29.57±9.42pg/ml)、T9(手术后48小时,11.14±3.2pg/ml)、T10(手术后72小时,6.71±0.16pg/m1),其中T2至T9时间点IL-6血浆水平较术前比均有显著统计学差异,P0.01;实验组血浆IL-6水平低于对照组,有显著统计学差异,P0.01。5.实验组患者血浆白介素-10(IL-10)水平分别是:T1(麻醉诱导后,21.88±4.14pg/ml)、T2(升主动脉阻断后30分钟,59.58±11.93pg/ml)、T3(升主动脉阻断后1小时,262.34±20.99pg/ml)、T4(升主动脉开放后30分钟,390.27±1.09pg/ml)、T5(升主动脉开放后1小时,299.32±41.63pg/ml)、T6(手术后6小时,115.66±21.06pg/ml)、T7(手术后12小时,63.64±13.29pg/ml)、T8(手术后24小时,52.11±9.67pg/ml)、T9(手术后48小时,30.03±7.05pg/ml)、T10(手术后72小时,19.29±5.36pg/ml),其中T2至T9时间点IL-10血浆水平较术前比均有显著统计学差异,P0.01;对照组患者血浆白介素-10(IL-10)水平分别是:T1(麻醉诱导后,13.14±0.60pg/ml)、T2(升主动脉阻断后30分钟,49.93±6.44pg/ml)、T3(升主动脉阻断后1小时,150.05±17.70pg/ml)、T4(升主动脉开放后30分钟,303.53±34.72pg/ml)、T5(升主动脉开放后1小时,206.58±30.22pg/ml)、T6(手术后6小时,89.42±12.95pg/ml)、T7(手术后12小时,44.45±14.65pg/ml)、T8(手术后24小时,23.36±7.37pg/ml)、T9(手术后48小时,18.89±6.14pg/ml)、T10(手术后72小时,12.73±0.44pg/ml),其中T2至T9时间点IL-10血浆水平较术前比均有显著统计学差异,P0.01,T10时间点IL-10血浆水平较术前比有统计学差异,P0.05;实验组血浆IL-10水平高于对照组,有显著统计学差异,P0.01。结论在体外循环心脏手术中,0mega-3鱼油脂肪乳能够有效的降低围术期白细胞介素-6水平、提高白细胞介素-10水平;没有明显增加围术期出血量;但对患者的ICU停留时间、住院时间等未见明显影响。
[Abstract]:BACKGROUND Cardiopulmonary bypass (CPB) is one of the most important assistant measures for successful cardiac surgery. However, for patients, CPB is different from the physiological circulation of the body itself. This non-physiological mode of CPB can lead to systemic inflammatory response syndrome (SI). Out-of-control inflammation can lead to cardiopulmonary, liver, kidney, brain and other important organ dysfunction after cardiopulmonary bypass, significantly increasing mortality and disability. Surgical trauma, direct blood exposure to foreign body surfaces, ischemia-Reperfusion Injury (IRI), intestinal bacterial translocation caused by endotoxin blood Symptoms, temperature changes and other factors can activate the body's neutrophils, monocytes, endothelial cells and platelets and other cellular components, activating the complement system in the blood, endogenous and exogenous coagulation system and fibrinolysis system, causing a variety of inflammatory response-related release of bioactive substances, and the formation of uncontrollable inflammation In recent years, a large number of studies have shown that tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play a central role in systemic inflammatory response during open heart surgery. Interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and so on. Among them, the more important is the interleukin system. IL-1, IL-6 and IL-8 are pro-inflammatory mediators, IL-10 is anti-inflammatory mediators. It has been reported that the plasma level of IL-6 increases immediately after the start of extracorporeal circulation, the first peak occurs 2 hours later, and 5-6 is small. IL-10 plasma levels gradually increased after aortic opening, reached a peak after 90 minutes, and basically returned to preoperative level after cardiopulmonary bypass 4 hours. Appropriate amount of anti-inflammatory mediators can help control inflammation and restore internal environment stability. Excessive anti-inflammatory response also produces immunosuppression, i.e. compensatory anti-inflammatory response syndrome (CARS). The production and development of SIRS is an extremely complex cascade process. The severity of SIRS is mainly caused by downstream pro-inflammatory cells during the development of SIRS induced by extracorporeal circulation. The balance of factors (mainly IL-6, IL-8) and anti-inflammatory cytokines (mainly IL-10) is determined. With the advancement of medical technology, there are many effective and practical methods to alleviate inflammation induced by cardiopulmonary bypass, such as the application of biocompatible coating materials, pulsatile perfusion patterns, the use of leukocyte filters and ultrafiltration packages. Omega-3 polyunsaturated fatty acids (_-3PUFAs) mainly include a-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (Docosa acid, EPA). In nature, Omega-3 polyunsaturated fatty acids are mainly derived from aquatic phytoplankton and deep-sea fishes. Almost no Omega-3 polyunsaturated fatty acids are found in terrestrial plants and animals. Studies have shown that Omega-33 polyunsaturated fatty acids can regulate inflammation and immune responses through the following pathways: (1) Arachidonic acid (Arachidonic A) Cid, AA metabolic effects. (2) through the change of cell membrane fluidity produced anti-inflammatory effects. (3) action on certain inflammation, immune mediators produced effects. (4) through the role of cell signal transduction and gene expression to produce anti-inflammatory regulatory immune effects. Mc Guinness et al. found that omega-3 polyunsaturated fatty acid preconditioning could induce the expression of HSP in myocardial cells and reduce the size of myocardial infarction. Charman et al. found that fish oil (mainly Omega-3 polyunsaturated fatty acid) could be given to patients before cardiopulmonary bypass in a planned manner. Studies have also reported that Omega-3 polyunsaturated fatty acids can reduce myocardial oxygen consumption, reduce oxidative stress and loss of potassium ions during myocardial ischemia-reperfusion, and thus protect the myocardium. Large-scale clinical trials have shown that daily intake of polyunsaturated fatty acids ranging from 500 mg to 1000 mg is significant. The first therapeutic fat emulsion, Omega-3 Fish Oil Fatty Emulsion, has been developed and used clinically in critically ill patients after major surgical operations such as sepsis, systemic inflammatory response syndrome, severe trauma, head and abdomen. However, as an anti-inflammatory therapy for open heart surgery under cardiopulmonary bypass, supplementation of Omega-3 fish fat emulsion is rare. Objective To observe the effect of Omega-3 fish fat emulsion on systemic inflammation during cardiopulmonary bypass. Methods Thirty patients undergoing cardiac surgery under cardiopulmonary bypass were randomly divided into Omega-3 fish oil fat emulsion group (15 cases) and control group (15 cases). Omega-3 fish oil fat emulsion group was given 0.2g/kg after anesthesia induction, and the blank control group was given the same amount of saline after anesthesia induction. Age, sex, height, weight and previous history, intraoperative conditions: operative time, cardiopulmonary bypass time, ascending aortic occlusion time, intraoperative bleeding volume, postoperative conditions: drainage, postoperative tracheal intubation time, antibiotic use time, ICU stay time, postoperative hospital stay, total blood transfusion; in addition, T1: anesthesia: anesthesia After induction, blood samples were collected at 30 minutes after T2 "ascending aorta occlusion, 1 hour after T3: ascending aorta occlusion, 30 minutes after T4: ascending aorta opening, 1 hour after T5 - ascending aorta opening, 6 hours after T6: T7: 12 hours after operation, 24 hours after T8: operation, 48 hours after T9: operation, 72 hours after T10 - operation, and 10 time points for blood testing. Plasma interleukin-6 and interleukin-10 levels. results 1. two groups of patients in the age (experimental group 49.8 + 8.7 years old, control group 49.4 + 11.9 years old), sex (experimental group male 46.7%, control group male 40%), height (experimental group 162.5 + 11.4 cm, control group 159.6 - + 9.7 cm), weight (experimental group 66.6 + 13.5 kg, control group 61.1 + 11.6 kg), past history and so on. There was no significant difference between the two groups (P 0.05.2). The operative time (249.2 + 44.8 min in experimental group, 241.1 + 37.4 min in control group), cardiopulmonary bypass time (95.5 + 53.7 min in experimental group, 95.3 - + 31.4 min in control group), ascending aorta occlusion time (69.8 + 44.Omin in experimental group, 68.2 + 28.1 min in control group), intraoperative bleeding volume (800 + 185.9 M1 in experimental group, 741.4 + 1.4 min in control group). There was no significant difference in 288.3 M1 between the two groups (P 0.05.3). The postoperative drainage volume (experimental group 598.8 [162.5 m1], control group 687.3 [276.7 m1]), time of tracheal intubation (experimental group 12.8 [5.3 h], control group 12.1 [5.1 h]), antibiotic use time (experimental group 3.4 [1.2 d], control group 3.5 [1.5 d]), ICU stay time (experimental group 2.8 [0.8], control group 3.2 [2] days]. There was no significant difference in the above results (P 0.05.4). The plasma levels of interleukin-6 (IL-6) in the experimental group were T1 (6.81+0.20pg/ml after anesthesia induction), T2 (30 minutes after ascending aorta occlusion, 10 minutes). 66 [1.61 pg / ml], T3 (1 hour after aortic occlusion, 29.16 [4.73 pg / m1], T4 (30 minutes after aortic occlusion, 101.02 [7.61 pg / ml], T5 (1 hour after aortic occlusion, 182.38 [11.73 pg / ml]), T6 (6 hours after aortic occlusion, 86.91 [14.49 pg / ml], T7 (12 hours after aortic occlusion, 43.08 [10.26 PG / ml]), T8 (24 hours after aortic occlusion, 18.21 [1.668] pg / ml], T9 (operation). The plasma levels of IL-6 at the time points of T2 to T8 were significantly different from those before operation (P 0.01); the plasma levels of IL-6 in the control group were: T1 (6.71.16 pg/ml after anesthesia induction), T2 (15.80.54 pg/ml 30 minutes after aortic occlusion), T3 (T3) and T1 (6.71.16 pg/ml after anesthesia induction). T4 (30 minutes after aortic occlusion, 130.62+9.83 pg/ml, T5 (1 hour after aortic occlusion, 207.9+16.21 pg/ml, T6 (6 hours after aortic occlusion, 132.91+15.21 pg/ml), T7 (12 hours after aortic occlusion, 98.58+10.17 pg/ml), T8 (24 hours, 29.57+9.42 pg/ml), T9 (11.14+3.2 pg/ml) and T9 (48 hours after aortic occlusion, respectively). The plasma levels of IL-6 in the experimental group were significantly lower than those in the control group (P 0.01.5). The plasma levels of IL-10 in the experimental group were significantly lower than those in the control group (P 0.01.5). T3, T4, T5, T6, T6, T6, 115.66 [21.06pg / ml] 6 hours after aortic occlusion, T7 (12 hours after aortic occlusion, 63.64 [13.29pg / ml], T4 (30 minutes after aortic occlusion, 390.27 [1.09pg / ml]), T5 (1 hour after aortic occlusion, 299.32 [41.63pg / ml], T6 (6 hours after aortic occlusion, 115.66 [21.06pg / ml]), T7 (12 hours after aortic occlusion, 63.64 [13.29pg / ml], T8 (surgery). The plasma levels of IL-10 at the time of T2 to T9 were significantly different from those before operation (P 0.01). The plasma levels of IL-10 in the control group were: T1 (13.14+0.60pg/ml after anesthesia induction), T2 (up) and T9 (up) respectively. Thirty minutes after aortic occlusion, 49.93 [6.44 pg / ml], T3 (1 hour after aortic occlusion, 150.05 [17.70 pg / ml], T4 (30 minutes after aortic occlusion, 303.53 [34.72 pg / ml]), T5 (1 hour after aortic occlusion, 206.58 [30.22 pg / ml]), T6 (6 hours after aortic occlusion, 89.42 [12.95 pg / ml], T7 (12 hours after aortic occlusion, 44.45 [14.65 pg / ml]), T8 (24 hours after aortic occlusion), T8 (small after aorti The plasma levels of IL-10 in the experimental group were higher than those in the control group (P 0.01, P 0.01, P 0.10 time point) and P 0.05. The plasma levels of IL-10 in the experimental group were higher than those in the control group (P 0.05). Conclusion 0 mega-3 fish oil emulsion can effectively reduce the level of interleukin-6 and increase the level of interleukin-10 during the perioperative period, and has no significant effect on the amount of perioperative bleeding, but has no significant effect on the ICU stay time and hospitalization time.
【学位授予单位】:南方医科大学
【学位级别】:硕士
【学位授予年份】:2014
【分类号】:R654.2

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