婴幼儿心内直视围术期血流动力学变化及与血浆亚硝基硫醇水平的相关性
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摘要
一氧化氮(NO)在调控氧化还原信号和心血管功能调节中发挥重要作用。外源性NO在体内的半衰期很短,限制了它的生物学作用的有效性和持续性。除了经典NO激活依赖环鸟苷酸(cGMP)通路外,目前较多热点研究发现NO通过非依赖cGMP的途径发挥作用,其调节细胞功能是通过NO与蛋白质亲核巯基翻译后修饰发生亚硝基化反应(S-nitrosylation)介导,生成蛋白质亚硝基硫醇(S-nitrosothiols, RSNO,分子通式为R-S-N=O)而实现的。Stamler等在1992年提出硫醇类物质是NO的储存体的学说。Gabor等通过对中性pH条件下RSNO形成和降解的速率研究证明RSNO的形式有助于NO的储存。NO可以和硫醇类物质的巯基以共价键的方式结合形成RSNO,它的性质相对稳定。RSNO是蛋白、多肽或硫醇的巯基亚硝基化的产物,在体内广泛存在,有些以游离的形式存在,有些作为蛋白结构的一部分存在。
蛋白S-亚硝基化不仅导致蛋白质结构与功能变化,而且防止这些巯基发生进一步不可逆的氧化/硝基化修饰。许多蛋白质巯基一旦硝基化后,蛋白质的活性被增强或抑制,这是机体的一种重要的翻译后修饰方式,从而介导NO的广泛功能。RSNO既担任第二信使又作为效应器发挥NO的核心作用。S-亚硝基化的机制帮助解释NO在心血管系统的广泛影响,与信号传导密切相关的蛋白包括离子通道蛋白、受体蛋白G蛋白以及核调节蛋白都含有巯基基团,转硝基化反应调节细胞信号传递,参与发挥NO对心血管系统的所有重大作用。
活性氧簇(reactive oxygen species, ROS)与活性氮簇(reactive nitrogen species, RNS)的失衡与心血管疾病和功能密切相关。ROS与RNS通过化学相互作用水平或协同作用于靶蛋白,交互调节信号通路。氧自由基攻击生物组织中的多不饱和脂肪酸(polyunsaturated fatty acid, PUFA),引发脂质过氧化作用,形成脂质过氧化物丙二醛(malondialdehyde, MDA)等。脂质过氧化作用不仅可以将活性氧ROS转化成活性化学剂,而且可以通过链式或链式支链反应,放大活性氧的作用。各种抗氧化机制如过氧化物歧化酶(superoxide dismutase, SOD)具有防止这种类型的损伤的作用。氧化/硝化失衡反映在心脏(黄嘌呤氧化酶)、血管(NADPH氧化酶)、红细胞(血红蛋白氧化酶)的氧化活性增加,抑制内源性基于NO信号通路,促进心血管功能衰竭。对黄嘌呤氧化酶的靶向治疗能够逆转大鼠扩张型心肌病的重塑。因此,恢复NO/氧化还原平衡提供了一个潜在有效改善心血管功能的方法。
本课题选取婴幼儿先天性心脏病(先心病)体外循环心内直视手术病人,包括室间隔缺损不合并肺动脉高压(VSD组)、室间隔缺损合并肺动脉高压(VSD+PH组)、法乐四联症(TOF组),研究围术期血流动力学的变化规律,以及围术期血浆NO/cGMP通路分子和RSNO活性、氧化应激水平,并分析NO/cGMP通路分子和RSNO活性以及氧化应激水平与血流动力学的相关性,探讨蛋白质亚硝基化／氧化应激平衡与先心病心内直视围术期心血管功能调节的分子机制关系。
第一部分脉波指示剂连续心排血量法(PiCCO)测定婴幼儿心内直视围术期血流动力学变化
目的：
1.临床应用PiCCO方法研究和探索婴幼儿先天性心脏病围术期血流动力学的变化。
2.明确VSD、VSD+PH、TOF,患者在体外循环心内直视围术期各自的血流动力学特点,为指导临床正确判断和有效治疗提供更为客观、直接的理论依据。方法：
1.研究对象的选择：
前瞻性研究,连续选取浙江大学附属儿童医院2009年8月-2010年6月期间经体外循环心内直视手术的0-3岁先天性心脏病(先心病)患儿30例为研究对象。入选标准：<3岁；男女不限；诊断为法乐四联症(10例)、室间隔缺损(20例)；根据术前心超及术中体外循环前测定肺动脉压力将室间隔缺损病人分入：室间隔缺损组(mPAP≤25mmHg)、室间隔缺损合并肺动脉高压组(mPAP>25mmHg)。排除标准：严重凝血功能异常；股动脉穿刺和热稀释导管置入禁忌症；对术后存在残余心内分流及心脏严重瓣膜功能不全等可能对本研究结果有影响者不列入本研究范围。麻醉诱导后经颈内静脉置入中心静脉导管和经股动脉置入热稀释导管供测定血流动力学参数用；术中置入左房和肺动脉测压管以进行左房压力和肺动脉压力监测,并计算肺循环阻力。
2.PiCCO测定方法
所有患儿均在麻醉诱导后常规行经颈内静脉置入中心静脉导管,作为热稀释测量的冷生理盐水注入端。置入3F PiCCO动脉热稀释导管(PV2013L07,德国Pulsion医疗系统公司)作为血压监测和心指数等测定。连接PiCCO plus循环监测仪(德国Pulsion公司),将PiCCO热稀释导管温度接口与监测仪血温传感电缆连接,压力接口经压力传感器(PV8015)与监测仪压力传感电缆连接；同时将监测仪的注入温度感受装置(PV4046)连接至中心静脉导管外接端。输入患者体重、身高、中心静脉压等信息,进行动脉压力调零。
PiCCO测定仪连续测定术后0h、4h、8h、12h、24h、48h、72h共7个时间点血流动力学监测,每个时间点均测量3次,取平均值。记录数据包括平均动脉压(MAP)、心率(HR)、心指数(CI)、全身血管阻力指数(SVRI)、肺循环阻力指数(PVRI)、全心舒张末期容积指数(GEDVI)、胸腔内血容量指数(ITBVI)、血管外肺水指数(EVLWI)、肺血管通透性指透性指数(PVPI)。
3.pHi测定方法
自动空气张力法测定导管(Tonometric catheter,8F,芬兰)为一双腔导管,其中一腔与其顶端的硅胶气囊(CO2可自由弥散进入)相通,可与Datex Ohmeda监护仪的PgCO2测定模块(芬兰)相连,用于测定PgCO2;另一腔与胃腔相通,用于胃肠减压引流或抽取胃液。
4.监测记录术后0h、4h、8h、12h、24h、48h、72h各时间点的LAP、CVP、胃黏膜pHi、PAP、PVRI;记录和计算术后0h、4h、8h、12h、24h、48h、72h各时间点的血管活性药评分(inotropic score):(计算公式：多巴胺±1x多巴酚丁胺+10x米力农±100x肾上腺素,药物剂量单位ug/kg/min)。
5.检测术前、术后4h、24h、48h、72h各时点的血浆CKMB活性、CKMB质量、肌钙蛋白水平。
6.术后病程和临床转归
(1)记录术后0h、4h、8h、12h、24h、48h、72h各时间点的血浆乳酸水平和PaO2/FiO2。
(2)并发症的发生：低心排、心律失常、反应性肺高压、肺高压危象、毛细渗漏综合征、肺不张、胸腔积液、大出血、感染、气胸、无创CPAP应用、二次插管等。
(3)记录呼吸机机械通气应用时间、ICU入住天数、术后住院天数、总住院天数。结果：
1.入选研究病人的基本资料
(1)VSD组患者10人,其中男5例,女5例,年龄15.6+3.2月,体重9.9±1kg；VSD+PH组患者10人,其中男8例,女2例,年龄11.4±3.2月,体重7.1±0.8kg；TOF组患者10例,其中男5例,女5例,年龄13.6±2.8月,体重8.7±0.9kg。
(2)三组病人年龄无显著性差异(P>0.05)；VSD组和TOF组病人的体重显著高于VSD+PH组(P<0.05),而VSD组体重与TOF组无显著差异(P>0.05)；VSD组患者的体外循环时间、主动脉阻断时间、机械通气时间、ICU入住天数、总住院天数、术后住院天数均显著短于VSD+PH组和TOF组(P<0.05),而VSD+PH组患者的体外循环时间、主动脉阻断时间、机械通气时间、ICU入住天数、总住院天数、术后住院天数与TOF组患者无显著差异(P>0.05)。
(3)并发症的总发生率：VSD+PH组为21例次,TOF组为13例次,VSD组为7例次。
2.本研究显示先心病VSD、VSD+PH、TOF组患者血浆CKMB活性、CKMB质量、肌钙蛋白均于体外循环心内直视术后4h达到最高值,后逐渐下降恢复。3组患者术前血浆CKMB活性、CKMB质量、肌钙蛋白水平均无显著性差异(P>0.05),TOF组患者术后CKMB活性、CKMB质量、肌钙蛋白水平显著高于VSD组,而VSD+PH组患者术后肌钙蛋白水平也显著高于VSD组,提示相比VSD组,TOF组和VSD+PH组患者心内直视术后心肌受损的程度较重。Spearman等级相关检验分析显示CKMB活性、CKMB质量、肌钙蛋白呈正相关,并与SVRI、PVRI、血管活性药评分、乳酸等存在正相关,与CI、ITBVI、GEDVI、PaO2/FiO2存在负相关。
3.TOF组病人术后早期心指数显著下降,以术后8h-12h为最低,术后24h以后显著好转。TOF组病人在术后0h、4h、8h、12h、24h、48h的CI均低于VSD组(P<0.05)和VSD+PH组(P>0.05),同时TOF组患者术后4h、8h、12h、24h、48h的SVRI显著高于VSD组(P<0.05),TOF组和VSD+PH组病人的需要的血管活性药物用量显著比VSD组大(P<0.05),TOF组术后Oh、12h、24h的乳酸水平显著高于VSD组(P<0.05)。
4.所有3组患者术后各时点的mPAP和PVRI与术前比较均无显著性差异(P>0.05)；组间比较显示VSD+PH组患者术前和术后的mPAP和PVRI均显著高于VSD组和TOF组同时点的水平(P<0.05),而TOF组和VSD组患者术后同一时点的nPAP和PVRI间均无显著性差异(P>0.05)。Spearman等级相关检验分析显示PVRI与PAP、SVRI、肌钙蛋白、CVP正相关,与CI、ITBVI、GEDVI、pHi、PaO2/FiO2负相关。
5.TOF组患者术后早期ITBVI和GEDVI显著低于VSD组(P<0.05),VSD+PH组术后12h的ITBVI和GEDVI显著低于VSD组(P<0.05)。与术后Oh相比,VSD组患者术后12h的ITBVI和GEDVI显著增加恢复(P<0.05),TOF组术后24h的ITBVI和GEDVI开始显著增加(P<0.05),VSD+PH组病人ITBVI于术后48h显著增加恢复(P<0.05)。
6.与术后Oh相比,仅VSD组患者在术后4hEVLWI显著下降(P<0.05),而VSD组其余时间点以及VSD+PH组、TOF组的各时点EVLWI无显著性差异(P>0.05)；组间比较显示术后48h时,VSD+PH组EVLWI显著高于TOF组(P<0.05),而TOF组EVLWI显著高于VSD组(P<0.05)。VSD组在术后24h和48h的PVPI显著低于术后0h(P<0.05),组间比较VSD组术后24h和48h的PVPI显著低于VSD+PH组和TOF组(P<0.05),同一时点VSD+PH组和TOF组的PVPI之间无显著性差异(P>0.05)。Spearman等级相关检验分析还显示EVLWI与PVPI正相关,EVLWI随ITBVI和GEDVI增加而增加,负性影响PaO2/FiO2。而PVPI与CI负相关,肺血管通透性增加,使ITBVI和GEDVI减少,也负性影响PaO2/FiO2。
结论：
1.TOF和VSD+PH组比VSD组病人在心内直视术后心肌受损的程度较重,与心指数下降、循环阻力增加、组织灌注差、血管活性药用量增大等密切相关。
2.ITBVI和GEDVI在婴幼儿先心病术后较CVP更能准确反映心脏前负荷的变化,对于先心术后的患儿尤其是危重症者的补液治疗有很好的指导意义。
3.TOF组和VSD组术后同时点的mPAP和PVRI间无显著性差异。
4.术后48h VSD+PH组的EVLWI以VSD+PH组最高,其次TOF组,VSD组最低,EVLWI与PVPI正相关,与心脏前负荷正相关,与氧合水平负相关。
第二部分婴幼儿心内直视围术期血浆NO/cGMP通路分子与亚硝基硫醇和氧化应激变化及与血流动力学的相关性
目的：
1.明确先心病VSD、VSD+PH、TOF病人心内直视围术期血浆NO/cGMP通路分子和RSNO水平变化。
2.明确先心病VSD、VSD+PH、TOF病人心内直视围术期氧化应激水平变化。
3.研究先心病心内直视围术期血浆RSNO水平与NO/cGMP通路分子活性和氧化应激水平的变化规律及其相关性。
4.统计分析先心病心内直视围术期血浆RSNO水平和血流动力学指标的相关性,探讨蛋白质亚硝基化/氧化失衡与先心病心内直视围术期心血管功能调节的分子机制关系
方法：
1.研究对象的选择
见第一部分。
2.血标本的采集
对满足入选标准的先心病手术患儿,在1)术前；2)术后4h；3)术后24h；4)术后48h；5)术后72h五个时点分别采集同一部位静脉血标本3m1,用肝素钠(每1ml血内含肝素钠10u)抗凝,血标本采集后立即在4℃,以3000转/分速度离心10分钟,将血浆与红细胞分离后避光液氮或-80℃保存。
3.分别测定各组各时点血浆RSNO, cGMP,亚硝酸盐/硝酸盐(NO2-/NO3-), MDA, SOD水平。
4.实验结果的矫正
为排除体外循环血液稀释对血浆各测定值的影响和结果偏差,作者采用红细胞压积(Hct)来数学矫正各血浆测定值,包括各组、各时点的血浆RSNO, cGMP,NO2-/NO3-,MDA,SOD值。
5.实验结果的统计学处理
矫正的实验数据用均数±标准误表示。数据经正态性检验符合非正态分布；组内前后比较采用配对符号检验；组间两两比较采用秩和检验；应用Spearman等级相关检验分析血浆RSNO、cGMP、NO2-/NO3-、MDA、SOD水平间的相关性；以P<0.05为差异有显著性意义,在SPSS for windows 15.0统计软件上完成。
结果：
1.先心病体外循环心内直视围术期血浆RSNO水平的变化
VSD、VSD+PH、TOF组病人的血浆RSNO水平的趋势均为术后4h最高,逐渐下降。组内比较：相比术前,VSD组术后4h的RSNO显著升高(190±21 pA vs129±16 pA,P<0.05),VSD+PH组和TOF组各时点的RSNO无显著差异(P>0.05)；组间比较结果显示：3组间在各同一时点的血浆RSNO水平均无显著性差异(P>0.05)。
2.围术期血浆cGMP水平的变化
3组患者的血浆cGMP趋势均于术后24h最高,逐渐下降。组内比较：与术前比,VSD组cGMP各时点无显著差异(P>0.05),VSD+PH组术后4h的cGMP显著降低(7.1±0.9 pmol/ml vs 8.3±0.9 pmol/ml, P<0.05),TOF组术后4h的cGMP也显著下降(5.6±0.8 pmol/ml vs 7.9±0.8 pmol/ml,P<0.05)；组间比较：TOF组术后4h的cGMP显著低于VSD组(5.6±0.8 pmol/ml vs 8.6±1.0 pmol/ml,P<0.05)。
3.围术期血浆NO2-/NO3-含量的变化
血浆NO2-/NO3-术后下降至24小时达最低点,后逐渐回升。组内比较：与术前相比,VSD组术后24h、48h、72h的NO2-/NO3-显著降低(P<0.05),VSD+PH组术后24h、72h的NO2-/NO3-显著下降(P<0.05),TOF组术后24h、48h、72h的NO2-/NO3-均显著下降(P<0.05)；组间比较：各组患者各时点的NO2-/NO3-水平间均无显著性差异(P>0.05)。
4.围术期血浆MDA的变化
组内比较：与术前比较,VSD组患者血浆MDA水平于术后4h、72h显著增高(P<0.05),VSD+PH组患者各时点血浆MDA水平无显著性差异(P>0.05),TOF组患者各时点血浆MDA水平无显著性差异(P>0.05)；组间比较显示VDS+PH组患者术前血浆MDA显著高于TOF组(3.3±0.7 nmol/ml vs 1.6±O.4nmol/ml,p<0.05)。
5.围术期血浆SOD的变化
组内比较：与术前比较,TOF组患者术后4h血浆SOD水平显著下降(67±8 U/ml vs 89±5 U/ml,P<0.05),VSD组和VSD+PH组患者各时点血浆SOD水平比较无显著性差异(P>0.05)；组间比较：VSD+PH组术后4h血浆SOD水平显著高于TOF组(87±8 U／ml vs 67±8 U/ml,p<0.05)。
6.围术期血浆RSNO水平与NO/cGMP通路分子水平的相关性
(1)Spearman等级相关检验分析所有病人所有时点的血浆RSNO水平与其他血浆NO/cGMP通路分子(cGMP、NO2-/NO3-)、氧化应激(MDA、SOD)水平的相关性：
1)血浆RSNO水平与血浆cGMP水平存在正相关,相关系数r=0.22,P=0.0078；
2)血浆RSNO水平与血浆MDA水平存在正相关,相关系数r=0.35,P<0.0001；
3)血浆cGMP水平与血浆MDA水平呈正相关,相关系数r=0.22,P=0.0059。
(2)Spearman等级相关检验分析各组病人血浆RSNO水平与cGMP、NO2-/NO3-、MDA、SOD水平相关性：
1)VSD组：血浆RSNO水平与cGMP水平存在正相关(相关系数=0.45,P=0.0015),血浆RSNO水平与MDA水平正相关(相关系数=0.42,P=0.0026),血浆cGMP水平与MDA水平正相关(相关系数=0.31,P=0.03)；
2)VSD+PH组：血浆RSNO水平与MDA水平正相关(相关系数=0.49,P=0.0004),血浆cGMP水平与SOD水平正相关(相关系数=0.37,P=0.0091)；
3)TOF组：无相关性(P>0.05)。
7.围术期血浆RSNO水平与血液动力学的相关性
(1)Spearman等级相关检验分析显示3组先心病患者在心内直视围术期所有时点的血浆RSNO水平和各个血流动力学指标间无显著意义的相关性。
(2)分别比较VSD组、VSD+PH组、TOF组病人的围术期血浆RSNO水平和各个血流动力学指标的关系,组内不分时点,结果显示：
1)VSD组：血浆RSNO水平与PVRI负相关(相关系数r=-0.66,P=0.0052)。
2)VSD+PH组：血浆RSNO水平与CI负相关(相关系数r=-0.37,P=0.0230)。
3)TOF组：血浆RSNO水平与各血流动力学指标无相关性。
(3)组内分时点,分别比较VSD组、VSD+PH组、TOF组病人的围术期血浆RSNO水平和各个血流动力学指标的关系：
1)VSD组：①术后Oh：血浆RSNO水平与pHi正相关(相关系数r=0.52,P=0.027)；②术后4h：血浆RSNO水平与血流动力学指标无相关；③术后24h：血浆RSNO水平与血流动力学指标无相关；④术后48h：血浆RSNO水平与血流动力学指标无相关；⑤术后72h：血浆RSNO水平与PVPI(相关系数r=0.58,P=0.022)正相关。
2)VSD+PH组：①术后Oh：血浆RSNO水平与血流动力学指标无相关；②术后4h：血浆RSNO水平与血流动力学指标无相关；③术后24h：血浆RSNO水平与mPAP(相关系数r=-0.91,P=0.011)负相关；④术后48h：血浆RSNO水平与血流动力学指标无相关；⑤术后72h：血浆RSNO水平与血流动力学指标无相关。
3)TOF组：①术后Oh：血浆RSNO水平与pHi(相关系数r=0.94,P=0.005)正相关；②术后4h：血浆RSNO水平与血流动力学指标无相关；③术后24h：血浆RSNO水平与CKMB活性(相关系数r=-0.67,P=0.05)负相关；④术后48h：血浆RSNO水平与血流动力学指标无相关；⑤术后72h：血浆RSNO水平与PVPI(相关系数r=0.76,P=0.031)正相关。
结论：
1.VSD、VSD+PH、TOF组患者心内直视术后早期均存在NO/cGMP通路抑制,其中VSD+PH和TOF组患者的抑制程度重于VSD组患者。
2.心内直视围术期血浆RSNO水平与血浆NO/cGMP通路分子活性、氧化应激水平呈正相关的线性关系。
3.血浆RSNO参与调节婴幼儿心内直视围术期心脏功能和肺血管张力改变等,发挥重要的心血管胜利作用。
全文结论
1.TOF和VSD+PH组比VSD组病人在心内直视术后心肌受损的程度较重,与心指数下降、循环阻力增加、组织灌注差、血管活性药用量增大等密切相关。
2.ITBVI和GEDVI在婴幼儿先心病术后较CVP更能准确反映心脏前负荷的变化,对于先心病危重症者的补液治疗有很好的指导意义。
3.TOF组和VSD组术后同时点的mPAP和PVRI间无显著性差异。
4.术后48h VSD+PH组的EVLWI以VSD+PH组最高,其次TOF组,VSD组最低,EVLWI与PVPI正相关,与心脏前负荷正相关,与氧合水平负相关。
5.VSD、VSD+PH、TOF组病人心内直视术后早期均存在NO/cGMP通路的抑制,其中VSD+PH组和TOF组病人的抑制程度重于VSD组病人。
6.心内直视围术期血浆RSNO水平与血浆NO/cGMP通路分子活性、氧化应激水平呈正相关的线性关系。
7.RSNO参与调节婴幼儿心内直视围术期心脏功能和肺血管张力改变,发挥重要的心血管生理作用。
Nitric oxide (NO) plays an important role in the regulation of cardiovascular function. The half-life of NO is very short, limiting its biological effects. In addition to the classic NO activation of the cGMP-dependent pathway, NO can also regulate cell function through protein S-nitrosylation, a redox dependent, thiol-based, reversible posttranslational protein modification that involves attachment of an NO moiety to a nucleophilic protein sulfhydryl group. Stamler and colleagues identified thiols as the storage substance for NO in 1992. Gabor proved that RSNO help to store NO from his study of the formation and degradation rate of RSNO under neutral pH.
Protein S-nitrosylation not only leads to changes in protein structure and function, and prevent further irreversible thiol oxidation/nitration modification. Once protein is S-nitrosylated, the activity of protein is enhanced or inhibited, which is an important post-translational modification, mediating a wide range of functions by NO. RSNO serves as second messenger and effector as well, and plays a central role of NO. The s-nitrosylation mechanism help explain the wide range of NO effects in the cardiovascular system. The signal transduction proteins including ion channel proteins, G protein receptor proteins, and nuclear regulatory proteins contain sulfhydryl groups, transfering of thiols between proteins play a major role in regulating cell signaling involved in NO activity on the cardiovascular system.
ROS (reactive oxygen species, ROS) and reactive nitrogen clusters (reactive nitrogen species, RNS) disequilibrium is closely related cardiovascular disease. ROS and RNS have chemical interactions or synergistic effects on the target protein of the signal pathway. Free radicals attack the polyunsaturated fatty acids (PUFA) in the tissue, inducing lipid peroxidation, and formation of malondialdehyde (MDA) etc. A variety of antioxidant mechanisms, such as superoxide dismutase (SOD) can prevent this type of injury. NO/redox disequilibrium reflected as the increased oxidation activity in the heart (xanthine oxidase), vascular (NADPH oxidase), red blood cells (hemoglobin oxidase), inhibit endogenous NO-based signaling pathways and promote cardiovascular failure. Remodeling of dilated cardiomyopathy can be reversed by targeted therapy of xanthine oxidase in rats. Therefore, the resumption of NO/redox balance offers a potentially effective method of maintaining cardiovascular function.
The infants and young children with congenital heart disease (CHD) undergoing open-heart surgery, including ventricular septal defect without pulmonary hypertension (VSD group), ventricular septal defect with pulmonary hypertension (VSD+PH group) and Tetralogy of Fallot (TOF group) were included in our study. We evaluated the activity of perioperative plasma NO/cGMP pathway and RSNO and oxidative stress levels, as well as the perioperative hemodynamics. This study is to identify the changes and relationship between perioperative plasma RSNO levels and hemodynamics in infants and young children with CHD undergoing open-heart syrgery. A better understanding of the mechanism regulating protein S-nitrosylation and its role in cardioprotection will provide us new therapeutic opportunities and targets for interventions in cardiovascular diseases.
Part I Perioperative hemodynamic changes in infants and young children undergoing open-heart surgery
Aim:
1. The clinical application of PiCCO in evaluating the hemodynamic changes in infants and young children after open-heart surgery.
2. To analyze the respective hemodynamic characteristics in different types of congenital heart disease after open-heart surgery.
Methods:
1. Design and patients
This is a prospective study. Consecutive 30 cases of 0-3 years old pediatric patients with congenital heart disease undergoing open heart surgery from August 2009 to June 2010 were included in this study. There were 10 cases with Tetralogy of Fallot,10 cases with VSD and pulmonary hypertension, and 10 cases with VSD without pulmonary hypertension. Exclusion criteria include severe coagulopathy, contraindications for femoral artery thermodilution catheterization, postoperative residual shunt and severe cardiac valve insufficiency, which may have impact on the results of this study.
2. PiCCO determination of hemodynamics
PiCCO analyzer continuously measured hemodynamic data on 0h,4h,8h,12h,24h, 48h,72h after operation, including mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), dedicated end-diastolic volume index (GEDVI), intrathoracic blood volume index (ITBVI), extravascular lung water index (EVLWI), the permeability of pulmonary vascular permeability index (PVPI).
3. pHi measurement methods:tonometric catheter was connected to determine PgCO2
pHi=7.40-log PgCO2/PaCO2
4. LAP, CVP, gastric pHi, PAP, PVRI were measured and recorded on 0h,4h,8h, 12h,24h,48h,72h after surgery; inotropic score was calculated and recorded on 0h,4h, 8h,12h,24h,48h,72h after surgery:inotropic score=1x Dobutamine+1x Dopamine+ 10x Milrinone+100x epinephrine.
5. Plasma CKMB activity, CKMB mass, troponin were tested before surgery, and on 4h,24h,48h,72h after syrgery.
6. Postoperative course and clinical outcome
(1) Plasma lactate levels and PaO2/FiO2 were record on 0h,4h,8h,12h,24h,48h, 72h after surgery.
(2) Complications were recorded, such as low cardiac output syndrome, arrhythmia, pulmonary hypertension and crisis, capillary leak syndrome, atelectasis, pleural effusion, bleeding, infection, pneumothorax, non-invasive CPAP, re-intubation, etc.
(3) The duration of mechanical ventilation, ICU stay, hospital stay were recorded and compared between groups.
Results:
1. The patients'demographics
(1) There were 10 patients in VSD group with an age of 15.6±3.2 months and a weight of 9.9±1kg; There were 10 patients in VSD+PH group with an age of 11.4±3.2 months and a weight of 7.1±0.8kg; There were 10 patients in TOF group with an age of 13.6±2.8 months and a weight of 8.7±0.9kg.
(2) There was no significant difference of age among the three groups (P>0.05); the body weight of patients in VSD group and the TOF group was significantly higher than that of VSD+PH group (P<0.05); the cardiopulmonary bypass time, aortic clamping time was significantly shorter in VSD group than in VSD+PH and TOF group (P<0.05); the duration of mechanical ventilation, ICU stay, hospital stay was significantly shorter in VSD group than in VSD+PH and TOF group (P<0.05).
2. The CKMB activity, CKMB mass, troponin levels were significantly higher in TOF and VSD+PH group than that of VSD group. Spearman correlation analysis showed CKMB activity, CKMB mass, troponin was positively correlated with SVRI, PVRI, inotropic score, lactate and negatively correlated with CI, ITBVI, GEDVI, PaO2/FiO2.
3. The cardiac index in TOF patients decreased significantly to the lowest nadir on 8h-12h after surgery, and was significantly improved on 24h after surgery. The CI of TOF group was significantly lower than the VSD group accopanied with significantly higher SVRI and inotropic score as well as higher lactate levels.
4. VSD+PH group of patients have significantly higher mPAP and PVRI than that of VSD and TOF group, while the mPAP and PVRI of TOF group showed no significant difference with the VSD group.
5. The GEDVI and ITBVI was significantly lower in TOF and VSD+PH group than VSD group during the early postoperative period.
6. The EVLWI was significantly higher in VSD+PH group than TOF group at 48h after surgery, whereas the EVLWI was significantly higher in TOF group than VSD group.
Conclusions:
1. The patients in TOF and the VSD+PH group showed more severe myocardial damage than in VSD group patients, with decreased CI, increased SVRI, poor tissue perfusion, higher inotropic score.
2. The GEDVI and ITBVI was significantly lower in TOF and VSD+PH group than in VSD group in the early period after surgery.
3. VSD+PH group of patients have significantly higher mPAP and PVRI than that of VSD and TOF group, while the mPAP and PVRI of TOF group showed no significant difference with the VSD group.
4. The EVLWI was significantly higher in VSD+PH group than TOF group at 48h after surgery, whereas the EVLWI was significantly higher in TOF group than VSD group.
5. Spearman rank correlation test also showed a positive correlation between EVLWI and PVPI. There was a positive correlation between EVLWI and ITBVI and GEDVI, and a negative correlation with PaO2/FiO2. The PVPI was negatively correlated with CI, ITBVI and GEDVI decreased with the increased pulmonary vascular permeability, and showed a negative effect on PaO2/FiO2.
PartⅡThe perioperative activity of plasma NO/cGMP pathway and nitrosothiols and oxidative stress with hemodynamics in infants and young children undergoing open-heart surgery
Aim:
1. To identify the activity of perioperative NO/cGMP pathway and plasma nitrosothiols in infants and young children undergoing open-heart surgery.
2. To identify the activity of perioperative oxidative stress levels in infants and young children undergoing open-heart surgery.
3. To evaluate the relationship between plasma nitrosothiols and NO/cGMP pathway and redox activity in infants and young children undergoing open-heart surgery.
4. Statistical analysis of perioperative plasma RSNO levels and hemodynamic data in infants and young children with congenital heart disease undergoing open-heart surgery, to underly the molecular mechanisms of protein nitrosylation/oxidation balance in regulating cardiovascular function in infants and young children undergoing
open-heart surgery.
Methods:
1. Design and patients Same as partⅠ.
2. The collection of blood samples
Blood samples were collected on:1) before surgery; 2) 4h post-op; 3) 24h post-op; 4) 48h post-op; 5) 72h post-op; 3ml blood samples (per lml of blood containing heparin 10u) were collected, and instant centrifugated at 4℃,3000 r/min for 10 minutes. Plasma was separated and stored in liquid nitrogen and light protected. The blood was drawn before diet to avoid its impact on nitrite and nitrate.
3. Plasma RSNO, cGMP, NO2-/NO3-, MDA, SOD levels were measured.
4. The mathmatic correction of the experimental data Corrected value= measured value x preoperative HCT/sample HCT
5. Statistical analysis
The corrected experimental data were expressed as mean±standard error. A paired sign test was used to compare between groups. Spearman rank correlation test was used to evaluate the correlations between plasma RSNO, cGMP, NO2-/NO3-, MDA, SOD levels. P<0.05 was of significant difference. These statistical analyses were completed by the 15.0 statistical software SPSS for windows.
Results:
1. The 4h post-op plasma RSNO level were significantly higher compared with preoperative RSNO level in VSD group (190±21 pA VS 129±16 pA, P<0.05). There were no significant differences of the plasma RSNO levels between other groups as well as all other time points (P>0.05).
2. Four hours after operation, the cGMP levels were significantly lower in VSD+ PH and TOF group than in VSD group(p<0.05).
3. Plasma NO2-/NO3- levels were significantly decreased after operation in 3 groups.
4. Plasma MDA levels were significantly increased in VSD group at 4h after operation; preoperatively, the plasma MDA levels were significantly higher in VSD+ PH group than in TOF group (P<0.05).
5. Plasma SOD levels were significantlydecreased in TOF group at 4h after operation, and were significantly lower than VSD+PH group.
6. The relationship between perioperative plasma nitrosothiols and NO/cGMP pathway activity and redox levels:
(1) Spearman rank correlation test of plasma RSNO levels of all patients at all time point with NO/cGMP pathway activity (cGMP, NO2-/NO3-) and redox molecular level (MDA, SOD):
1) There was a positive correlation between plasma RSNO and cGMP levels, the correlation coefficient r=0.22, P=0.0078.
2) Plasma RSNO levels positively correlated with plasma MDA level, the correlation coefficient r=0.35, P=0.0001.
3) cGMP levels in plasma were positively correlated with MDA levels, the correlation coefficient r=0.22, P=0.0059.
(2) Spearman rank correlation test of plasma RSNO levels of all time point with NO/cGMP pathway activity and redox molecular level (MDA, SOD) in each group:
1) VSD Group:there is a positive correlation between plasma RSNO and cGMP levels (correlation coefficient=0.45, P=0.0015); RSNO levels were positively correlated with MDA level (correlation coefficient=0.42, P=0.0026); cGMP levels were positively correlated with MDA level (correlation coefficient-0.31,P=0.03).
2) VSD+PH group:plasma RSNO level and MDA level positively correlated (correlation coefficient= 0.49, P= 0.0004), plasma SOD levels were positively correlated with cGMP levels (correlation coefficient=0.37, P=0.0091).
3) There was no correlations in TOF group (P>0.05).
7. The relationship between perioperative plasma nitrosothiols and hemodynamics:
(1) Spearman rank correlation test showed that among 3 groups of congenital heart disease undergoing open-heart surgery for all time points, the plasma RSNO levels showed no significant correlation with all the hemodynamic data.
(2) Regardless of time point, we compared the relationship between plasma RSNO levels and hemodynamic data in VSD, VSD+PH, TOF group respectively, the results showed:
1) VSD group:plasma RSNO levels were negatively correlated with PVRI (correlation coefficient r=-0.66, P=0.0052).
2) VSD+PH group:plasma RSNO levels were negatively correlated with CI (correlation coefficient r=-0.37, P=0.0230).
3) TOF group:there was no significant correlation between plasma RSNO levels and hemodynamic data.
(3) We compared the relationship between plasma RSNO levels and hemodynamic data in VSD, VSD+PH, TOF group of patients in different time points, the results showed:
1) VSD group:①0h post-op:plasma RSNO levels positively correlated with pHi (correlation coefficient r=0.52, P=0.027);②4h post-op:plasma RSNO levels showed no correlation with the hemodynamics;③24h post-op:plasma RSNO levels showed no correlation with the hemodynamics;④48h post-op:plasma RSNO levels showed no correlation with the hemodynamics;⑤72h post-op:plasma RSNO levels positively correlated with PVPI (correlation coefficient r=0.58, P=0.022).
2) VSD+PH group:①0h post-op:plasma RSNO levels showed no correlation with the hemodynamics;②4h post-op:plasma RSNO levels showed no correlation with the hemodynamics;③24h post-op:plasma RSNO levels negatively correlated with mPAP (correlation coefficient r=-0.91, P=0.011);④48h post-op:plasma RSNO levels showed no correlation with the hemodynamics;⑤72h post-op:plasma RSNO levels showed no correlation with the hemodynamics.
3) TOF group:①0h post-op:plasma RSNO levels positively correlated with pHi (correlation coefficient r=0.94, P=0.005);②4h post-op:plasma RSNO levels showed no correlation with the hemodynamics;③24h post-op:plasma RSNO levels negatively correlated with CKMB activity (correlation coefficient r=-0.67, P=0.05);④48h post-op:plasma RSNO levels showed no correlation with the hemodynamics;⑤72h post-op:plasma RSNO levels positively correlated with PVPI (correlation coefficient r =0.76, P=0.031).
Conclusions:
1. There was transient NO/cGMP pathway inhibition in VSD, VSD+PH, TOF group of patients early after open heart surgery.
2. This study shows that plasma RSNO levels has a positive linear relationship with NO/cGMP pathway and oxide stress.
3. Plasma RSNO plays an important role in regulating perioperative heart function and pulmonary vascular resistance in infants and young children with congenital heart disease undergoing open-heart surgery.
蛋白S-亚硝基化不仅导致蛋白质结构与功能变化,而且防止这些巯基发生进一步不可逆的氧化/硝基化修饰。许多蛋白质巯基一旦硝基化后,蛋白质的活性被增强或抑制,这是机体的一种重要的翻译后修饰方式,从而介导NO的广泛功能。RSNO既担任第二信使又作为效应器发挥NO的核心作用。S-亚硝基化的机制帮助解释NO在心血管系统的广泛影响,与信号传导密切相关的蛋白包括离子通道蛋白、受体蛋白G蛋白以及核调节蛋白都含有巯基基团,转硝基化反应调节细胞信号传递,参与发挥NO对心血管系统的所有重大作用。
活性氧簇(reactive oxygen species, ROS)与活性氮簇(reactive nitrogen species, RNS)的失衡与心血管疾病和功能密切相关。ROS与RNS通过化学相互作用水平或协同作用于靶蛋白,交互调节信号通路。氧自由基攻击生物组织中的多不饱和脂肪酸(polyunsaturated fatty acid, PUFA),引发脂质过氧化作用,形成脂质过氧化物丙二醛(malondialdehyde, MDA)等。脂质过氧化作用不仅可以将活性氧ROS转化成活性化学剂,而且可以通过链式或链式支链反应,放大活性氧的作用。各种抗氧化机制如过氧化物歧化酶(superoxide dismutase, SOD)具有防止这种类型的损伤的作用。氧化/硝化失衡反映在心脏(黄嘌呤氧化酶)、血管(NADPH氧化酶)、红细胞(血红蛋白氧化酶)的氧化活性增加,抑制内源性基于NO信号通路,促进心血管功能衰竭。对黄嘌呤氧化酶的靶向治疗能够逆转大鼠扩张型心肌病的重塑。因此,恢复NO/氧化还原平衡提供了一个潜在有效改善心血管功能的方法。
本课题选取婴幼儿先天性心脏病(先心病)体外循环心内直视手术病人,包括室间隔缺损不合并肺动脉高压(VSD组)、室间隔缺损合并肺动脉高压(VSD+PH组)、法乐四联症(TOF组),研究围术期血流动力学的变化规律,以及围术期血浆NO/cGMP通路分子和RSNO活性、氧化应激水平,并分析NO/cGMP通路分子和RSNO活性以及氧化应激水平与血流动力学的相关性,探讨蛋白质亚硝基化／氧化应激平衡与先心病心内直视围术期心血管功能调节的分子机制关系。
第一部分脉波指示剂连续心排血量法(PiCCO)测定婴幼儿心内直视围术期血流动力学变化
目的：
1.临床应用PiCCO方法研究和探索婴幼儿先天性心脏病围术期血流动力学的变化。
2.明确VSD、VSD+PH、TOF,患者在体外循环心内直视围术期各自的血流动力学特点,为指导临床正确判断和有效治疗提供更为客观、直接的理论依据。方法：
1.研究对象的选择：
前瞻性研究,连续选取浙江大学附属儿童医院2009年8月-2010年6月期间经体外循环心内直视手术的0-3岁先天性心脏病(先心病)患儿30例为研究对象。入选标准：<3岁；男女不限；诊断为法乐四联症(10例)、室间隔缺损(20例)；根据术前心超及术中体外循环前测定肺动脉压力将室间隔缺损病人分入：室间隔缺损组(mPAP≤25mmHg)、室间隔缺损合并肺动脉高压组(mPAP>25mmHg)。排除标准：严重凝血功能异常；股动脉穿刺和热稀释导管置入禁忌症；对术后存在残余心内分流及心脏严重瓣膜功能不全等可能对本研究结果有影响者不列入本研究范围。麻醉诱导后经颈内静脉置入中心静脉导管和经股动脉置入热稀释导管供测定血流动力学参数用；术中置入左房和肺动脉测压管以进行左房压力和肺动脉压力监测,并计算肺循环阻力。
2.PiCCO测定方法
所有患儿均在麻醉诱导后常规行经颈内静脉置入中心静脉导管,作为热稀释测量的冷生理盐水注入端。置入3F PiCCO动脉热稀释导管(PV2013L07,德国Pulsion医疗系统公司)作为血压监测和心指数等测定。连接PiCCO plus循环监测仪(德国Pulsion公司),将PiCCO热稀释导管温度接口与监测仪血温传感电缆连接,压力接口经压力传感器(PV8015)与监测仪压力传感电缆连接；同时将监测仪的注入温度感受装置(PV4046)连接至中心静脉导管外接端。输入患者体重、身高、中心静脉压等信息,进行动脉压力调零。
PiCCO测定仪连续测定术后0h、4h、8h、12h、24h、48h、72h共7个时间点血流动力学监测,每个时间点均测量3次,取平均值。记录数据包括平均动脉压(MAP)、心率(HR)、心指数(CI)、全身血管阻力指数(SVRI)、肺循环阻力指数(PVRI)、全心舒张末期容积指数(GEDVI)、胸腔内血容量指数(ITBVI)、血管外肺水指数(EVLWI)、肺血管通透性指透性指数(PVPI)。
3.pHi测定方法
自动空气张力法测定导管(Tonometric catheter,8F,芬兰)为一双腔导管,其中一腔与其顶端的硅胶气囊(CO2可自由弥散进入)相通,可与Datex Ohmeda监护仪的PgCO2测定模块(芬兰)相连,用于测定PgCO2;另一腔与胃腔相通,用于胃肠减压引流或抽取胃液。
4.监测记录术后0h、4h、8h、12h、24h、48h、72h各时间点的LAP、CVP、胃黏膜pHi、PAP、PVRI;记录和计算术后0h、4h、8h、12h、24h、48h、72h各时间点的血管活性药评分(inotropic score):(计算公式：多巴胺±1x多巴酚丁胺+10x米力农±100x肾上腺素,药物剂量单位ug/kg/min)。
5.检测术前、术后4h、24h、48h、72h各时点的血浆CKMB活性、CKMB质量、肌钙蛋白水平。
6.术后病程和临床转归
(1)记录术后0h、4h、8h、12h、24h、48h、72h各时间点的血浆乳酸水平和PaO2/FiO2。
(2)并发症的发生：低心排、心律失常、反应性肺高压、肺高压危象、毛细渗漏综合征、肺不张、胸腔积液、大出血、感染、气胸、无创CPAP应用、二次插管等。
(3)记录呼吸机机械通气应用时间、ICU入住天数、术后住院天数、总住院天数。结果：
1.入选研究病人的基本资料
(1)VSD组患者10人,其中男5例,女5例,年龄15.6+3.2月,体重9.9±1kg；VSD+PH组患者10人,其中男8例,女2例,年龄11.4±3.2月,体重7.1±0.8kg；TOF组患者10例,其中男5例,女5例,年龄13.6±2.8月,体重8.7±0.9kg。
(2)三组病人年龄无显著性差异(P>0.05)；VSD组和TOF组病人的体重显著高于VSD+PH组(P<0.05),而VSD组体重与TOF组无显著差异(P>0.05)；VSD组患者的体外循环时间、主动脉阻断时间、机械通气时间、ICU入住天数、总住院天数、术后住院天数均显著短于VSD+PH组和TOF组(P<0.05),而VSD+PH组患者的体外循环时间、主动脉阻断时间、机械通气时间、ICU入住天数、总住院天数、术后住院天数与TOF组患者无显著差异(P>0.05)。
(3)并发症的总发生率：VSD+PH组为21例次,TOF组为13例次,VSD组为7例次。
2.本研究显示先心病VSD、VSD+PH、TOF组患者血浆CKMB活性、CKMB质量、肌钙蛋白均于体外循环心内直视术后4h达到最高值,后逐渐下降恢复。3组患者术前血浆CKMB活性、CKMB质量、肌钙蛋白水平均无显著性差异(P>0.05),TOF组患者术后CKMB活性、CKMB质量、肌钙蛋白水平显著高于VSD组,而VSD+PH组患者术后肌钙蛋白水平也显著高于VSD组,提示相比VSD组,TOF组和VSD+PH组患者心内直视术后心肌受损的程度较重。Spearman等级相关检验分析显示CKMB活性、CKMB质量、肌钙蛋白呈正相关,并与SVRI、PVRI、血管活性药评分、乳酸等存在正相关,与CI、ITBVI、GEDVI、PaO2/FiO2存在负相关。
3.TOF组病人术后早期心指数显著下降,以术后8h-12h为最低,术后24h以后显著好转。TOF组病人在术后0h、4h、8h、12h、24h、48h的CI均低于VSD组(P<0.05)和VSD+PH组(P>0.05),同时TOF组患者术后4h、8h、12h、24h、48h的SVRI显著高于VSD组(P<0.05),TOF组和VSD+PH组病人的需要的血管活性药物用量显著比VSD组大(P<0.05),TOF组术后Oh、12h、24h的乳酸水平显著高于VSD组(P<0.05)。
4.所有3组患者术后各时点的mPAP和PVRI与术前比较均无显著性差异(P>0.05)；组间比较显示VSD+PH组患者术前和术后的mPAP和PVRI均显著高于VSD组和TOF组同时点的水平(P<0.05),而TOF组和VSD组患者术后同一时点的nPAP和PVRI间均无显著性差异(P>0.05)。Spearman等级相关检验分析显示PVRI与PAP、SVRI、肌钙蛋白、CVP正相关,与CI、ITBVI、GEDVI、pHi、PaO2/FiO2负相关。
5.TOF组患者术后早期ITBVI和GEDVI显著低于VSD组(P<0.05),VSD+PH组术后12h的ITBVI和GEDVI显著低于VSD组(P<0.05)。与术后Oh相比,VSD组患者术后12h的ITBVI和GEDVI显著增加恢复(P<0.05),TOF组术后24h的ITBVI和GEDVI开始显著增加(P<0.05),VSD+PH组病人ITBVI于术后48h显著增加恢复(P<0.05)。
6.与术后Oh相比,仅VSD组患者在术后4hEVLWI显著下降(P<0.05),而VSD组其余时间点以及VSD+PH组、TOF组的各时点EVLWI无显著性差异(P>0.05)；组间比较显示术后48h时,VSD+PH组EVLWI显著高于TOF组(P<0.05),而TOF组EVLWI显著高于VSD组(P<0.05)。VSD组在术后24h和48h的PVPI显著低于术后0h(P<0.05),组间比较VSD组术后24h和48h的PVPI显著低于VSD+PH组和TOF组(P<0.05),同一时点VSD+PH组和TOF组的PVPI之间无显著性差异(P>0.05)。Spearman等级相关检验分析还显示EVLWI与PVPI正相关,EVLWI随ITBVI和GEDVI增加而增加,负性影响PaO2/FiO2。而PVPI与CI负相关,肺血管通透性增加,使ITBVI和GEDVI减少,也负性影响PaO2/FiO2。
结论：
1.TOF和VSD+PH组比VSD组病人在心内直视术后心肌受损的程度较重,与心指数下降、循环阻力增加、组织灌注差、血管活性药用量增大等密切相关。
2.ITBVI和GEDVI在婴幼儿先心病术后较CVP更能准确反映心脏前负荷的变化,对于先心术后的患儿尤其是危重症者的补液治疗有很好的指导意义。
3.TOF组和VSD组术后同时点的mPAP和PVRI间无显著性差异。
4.术后48h VSD+PH组的EVLWI以VSD+PH组最高,其次TOF组,VSD组最低,EVLWI与PVPI正相关,与心脏前负荷正相关,与氧合水平负相关。
第二部分婴幼儿心内直视围术期血浆NO/cGMP通路分子与亚硝基硫醇和氧化应激变化及与血流动力学的相关性
目的：
1.明确先心病VSD、VSD+PH、TOF病人心内直视围术期血浆NO/cGMP通路分子和RSNO水平变化。
2.明确先心病VSD、VSD+PH、TOF病人心内直视围术期氧化应激水平变化。
3.研究先心病心内直视围术期血浆RSNO水平与NO/cGMP通路分子活性和氧化应激水平的变化规律及其相关性。
4.统计分析先心病心内直视围术期血浆RSNO水平和血流动力学指标的相关性,探讨蛋白质亚硝基化/氧化失衡与先心病心内直视围术期心血管功能调节的分子机制关系
方法：
1.研究对象的选择
见第一部分。
2.血标本的采集
对满足入选标准的先心病手术患儿,在1)术前；2)术后4h；3)术后24h；4)术后48h；5)术后72h五个时点分别采集同一部位静脉血标本3m1,用肝素钠(每1ml血内含肝素钠10u)抗凝,血标本采集后立即在4℃,以3000转/分速度离心10分钟,将血浆与红细胞分离后避光液氮或-80℃保存。
3.分别测定各组各时点血浆RSNO, cGMP,亚硝酸盐/硝酸盐(NO2-/NO3-), MDA, SOD水平。
4.实验结果的矫正
为排除体外循环血液稀释对血浆各测定值的影响和结果偏差,作者采用红细胞压积(Hct)来数学矫正各血浆测定值,包括各组、各时点的血浆RSNO, cGMP,NO2-/NO3-,MDA,SOD值。
5.实验结果的统计学处理
矫正的实验数据用均数±标准误表示。数据经正态性检验符合非正态分布；组内前后比较采用配对符号检验；组间两两比较采用秩和检验；应用Spearman等级相关检验分析血浆RSNO、cGMP、NO2-/NO3-、MDA、SOD水平间的相关性；以P<0.05为差异有显著性意义,在SPSS for windows 15.0统计软件上完成。
结果：
1.先心病体外循环心内直视围术期血浆RSNO水平的变化
VSD、VSD+PH、TOF组病人的血浆RSNO水平的趋势均为术后4h最高,逐渐下降。组内比较：相比术前,VSD组术后4h的RSNO显著升高(190±21 pA vs129±16 pA,P<0.05),VSD+PH组和TOF组各时点的RSNO无显著差异(P>0.05)；组间比较结果显示：3组间在各同一时点的血浆RSNO水平均无显著性差异(P>0.05)。
2.围术期血浆cGMP水平的变化
3组患者的血浆cGMP趋势均于术后24h最高,逐渐下降。组内比较：与术前比,VSD组cGMP各时点无显著差异(P>0.05),VSD+PH组术后4h的cGMP显著降低(7.1±0.9 pmol/ml vs 8.3±0.9 pmol/ml, P<0.05),TOF组术后4h的cGMP也显著下降(5.6±0.8 pmol/ml vs 7.9±0.8 pmol/ml,P<0.05)；组间比较：TOF组术后4h的cGMP显著低于VSD组(5.6±0.8 pmol/ml vs 8.6±1.0 pmol/ml,P<0.05)。
3.围术期血浆NO2-/NO3-含量的变化
血浆NO2-/NO3-术后下降至24小时达最低点,后逐渐回升。组内比较：与术前相比,VSD组术后24h、48h、72h的NO2-/NO3-显著降低(P<0.05),VSD+PH组术后24h、72h的NO2-/NO3-显著下降(P<0.05),TOF组术后24h、48h、72h的NO2-/NO3-均显著下降(P<0.05)；组间比较：各组患者各时点的NO2-/NO3-水平间均无显著性差异(P>0.05)。
4.围术期血浆MDA的变化
组内比较：与术前比较,VSD组患者血浆MDA水平于术后4h、72h显著增高(P<0.05),VSD+PH组患者各时点血浆MDA水平无显著性差异(P>0.05),TOF组患者各时点血浆MDA水平无显著性差异(P>0.05)；组间比较显示VDS+PH组患者术前血浆MDA显著高于TOF组(3.3±0.7 nmol/ml vs 1.6±O.4nmol/ml,p<0.05)。
5.围术期血浆SOD的变化
组内比较：与术前比较,TOF组患者术后4h血浆SOD水平显著下降(67±8 U/ml vs 89±5 U/ml,P<0.05),VSD组和VSD+PH组患者各时点血浆SOD水平比较无显著性差异(P>0.05)；组间比较：VSD+PH组术后4h血浆SOD水平显著高于TOF组(87±8 U／ml vs 67±8 U/ml,p<0.05)。
6.围术期血浆RSNO水平与NO/cGMP通路分子水平的相关性
(1)Spearman等级相关检验分析所有病人所有时点的血浆RSNO水平与其他血浆NO/cGMP通路分子(cGMP、NO2-/NO3-)、氧化应激(MDA、SOD)水平的相关性：
1)血浆RSNO水平与血浆cGMP水平存在正相关,相关系数r=0.22,P=0.0078；
2)血浆RSNO水平与血浆MDA水平存在正相关,相关系数r=0.35,P<0.0001；
3)血浆cGMP水平与血浆MDA水平呈正相关,相关系数r=0.22,P=0.0059。
(2)Spearman等级相关检验分析各组病人血浆RSNO水平与cGMP、NO2-/NO3-、MDA、SOD水平相关性：
1)VSD组：血浆RSNO水平与cGMP水平存在正相关(相关系数=0.45,P=0.0015),血浆RSNO水平与MDA水平正相关(相关系数=0.42,P=0.0026),血浆cGMP水平与MDA水平正相关(相关系数=0.31,P=0.03)；
2)VSD+PH组：血浆RSNO水平与MDA水平正相关(相关系数=0.49,P=0.0004),血浆cGMP水平与SOD水平正相关(相关系数=0.37,P=0.0091)；
3)TOF组：无相关性(P>0.05)。
7.围术期血浆RSNO水平与血液动力学的相关性
(1)Spearman等级相关检验分析显示3组先心病患者在心内直视围术期所有时点的血浆RSNO水平和各个血流动力学指标间无显著意义的相关性。
(2)分别比较VSD组、VSD+PH组、TOF组病人的围术期血浆RSNO水平和各个血流动力学指标的关系,组内不分时点,结果显示：
1)VSD组：血浆RSNO水平与PVRI负相关(相关系数r=-0.66,P=0.0052)。
2)VSD+PH组：血浆RSNO水平与CI负相关(相关系数r=-0.37,P=0.0230)。
3)TOF组：血浆RSNO水平与各血流动力学指标无相关性。
(3)组内分时点,分别比较VSD组、VSD+PH组、TOF组病人的围术期血浆RSNO水平和各个血流动力学指标的关系：
1)VSD组：①术后Oh：血浆RSNO水平与pHi正相关(相关系数r=0.52,P=0.027)；②术后4h：血浆RSNO水平与血流动力学指标无相关；③术后24h：血浆RSNO水平与血流动力学指标无相关；④术后48h：血浆RSNO水平与血流动力学指标无相关；⑤术后72h：血浆RSNO水平与PVPI(相关系数r=0.58,P=0.022)正相关。
2)VSD+PH组：①术后Oh：血浆RSNO水平与血流动力学指标无相关；②术后4h：血浆RSNO水平与血流动力学指标无相关；③术后24h：血浆RSNO水平与mPAP(相关系数r=-0.91,P=0.011)负相关；④术后48h：血浆RSNO水平与血流动力学指标无相关；⑤术后72h：血浆RSNO水平与血流动力学指标无相关。
3)TOF组：①术后Oh：血浆RSNO水平与pHi(相关系数r=0.94,P=0.005)正相关；②术后4h：血浆RSNO水平与血流动力学指标无相关；③术后24h：血浆RSNO水平与CKMB活性(相关系数r=-0.67,P=0.05)负相关；④术后48h：血浆RSNO水平与血流动力学指标无相关；⑤术后72h：血浆RSNO水平与PVPI(相关系数r=0.76,P=0.031)正相关。
结论：
1.VSD、VSD+PH、TOF组患者心内直视术后早期均存在NO/cGMP通路抑制,其中VSD+PH和TOF组患者的抑制程度重于VSD组患者。
2.心内直视围术期血浆RSNO水平与血浆NO/cGMP通路分子活性、氧化应激水平呈正相关的线性关系。
3.血浆RSNO参与调节婴幼儿心内直视围术期心脏功能和肺血管张力改变等,发挥重要的心血管胜利作用。
全文结论
1.TOF和VSD+PH组比VSD组病人在心内直视术后心肌受损的程度较重,与心指数下降、循环阻力增加、组织灌注差、血管活性药用量增大等密切相关。
2.ITBVI和GEDVI在婴幼儿先心病术后较CVP更能准确反映心脏前负荷的变化,对于先心病危重症者的补液治疗有很好的指导意义。
3.TOF组和VSD组术后同时点的mPAP和PVRI间无显著性差异。
4.术后48h VSD+PH组的EVLWI以VSD+PH组最高,其次TOF组,VSD组最低,EVLWI与PVPI正相关,与心脏前负荷正相关,与氧合水平负相关。
5.VSD、VSD+PH、TOF组病人心内直视术后早期均存在NO/cGMP通路的抑制,其中VSD+PH组和TOF组病人的抑制程度重于VSD组病人。
6.心内直视围术期血浆RSNO水平与血浆NO/cGMP通路分子活性、氧化应激水平呈正相关的线性关系。
7.RSNO参与调节婴幼儿心内直视围术期心脏功能和肺血管张力改变,发挥重要的心血管生理作用。
Nitric oxide (NO) plays an important role in the regulation of cardiovascular function. The half-life of NO is very short, limiting its biological effects. In addition to the classic NO activation of the cGMP-dependent pathway, NO can also regulate cell function through protein S-nitrosylation, a redox dependent, thiol-based, reversible posttranslational protein modification that involves attachment of an NO moiety to a nucleophilic protein sulfhydryl group. Stamler and colleagues identified thiols as the storage substance for NO in 1992. Gabor proved that RSNO help to store NO from his study of the formation and degradation rate of RSNO under neutral pH.
Protein S-nitrosylation not only leads to changes in protein structure and function, and prevent further irreversible thiol oxidation/nitration modification. Once protein is S-nitrosylated, the activity of protein is enhanced or inhibited, which is an important post-translational modification, mediating a wide range of functions by NO. RSNO serves as second messenger and effector as well, and plays a central role of NO. The s-nitrosylation mechanism help explain the wide range of NO effects in the cardiovascular system. The signal transduction proteins including ion channel proteins, G protein receptor proteins, and nuclear regulatory proteins contain sulfhydryl groups, transfering of thiols between proteins play a major role in regulating cell signaling involved in NO activity on the cardiovascular system.
ROS (reactive oxygen species, ROS) and reactive nitrogen clusters (reactive nitrogen species, RNS) disequilibrium is closely related cardiovascular disease. ROS and RNS have chemical interactions or synergistic effects on the target protein of the signal pathway. Free radicals attack the polyunsaturated fatty acids (PUFA) in the tissue, inducing lipid peroxidation, and formation of malondialdehyde (MDA) etc. A variety of antioxidant mechanisms, such as superoxide dismutase (SOD) can prevent this type of injury. NO/redox disequilibrium reflected as the increased oxidation activity in the heart (xanthine oxidase), vascular (NADPH oxidase), red blood cells (hemoglobin oxidase), inhibit endogenous NO-based signaling pathways and promote cardiovascular failure. Remodeling of dilated cardiomyopathy can be reversed by targeted therapy of xanthine oxidase in rats. Therefore, the resumption of NO/redox balance offers a potentially effective method of maintaining cardiovascular function.
The infants and young children with congenital heart disease (CHD) undergoing open-heart surgery, including ventricular septal defect without pulmonary hypertension (VSD group), ventricular septal defect with pulmonary hypertension (VSD+PH group) and Tetralogy of Fallot (TOF group) were included in our study. We evaluated the activity of perioperative plasma NO/cGMP pathway and RSNO and oxidative stress levels, as well as the perioperative hemodynamics. This study is to identify the changes and relationship between perioperative plasma RSNO levels and hemodynamics in infants and young children with CHD undergoing open-heart syrgery. A better understanding of the mechanism regulating protein S-nitrosylation and its role in cardioprotection will provide us new therapeutic opportunities and targets for interventions in cardiovascular diseases.
Part I Perioperative hemodynamic changes in infants and young children undergoing open-heart surgery
Aim:
1. The clinical application of PiCCO in evaluating the hemodynamic changes in infants and young children after open-heart surgery.
2. To analyze the respective hemodynamic characteristics in different types of congenital heart disease after open-heart surgery.
Methods:
1. Design and patients
This is a prospective study. Consecutive 30 cases of 0-3 years old pediatric patients with congenital heart disease undergoing open heart surgery from August 2009 to June 2010 were included in this study. There were 10 cases with Tetralogy of Fallot,10 cases with VSD and pulmonary hypertension, and 10 cases with VSD without pulmonary hypertension. Exclusion criteria include severe coagulopathy, contraindications for femoral artery thermodilution catheterization, postoperative residual shunt and severe cardiac valve insufficiency, which may have impact on the results of this study.
2. PiCCO determination of hemodynamics
PiCCO analyzer continuously measured hemodynamic data on 0h,4h,8h,12h,24h, 48h,72h after operation, including mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), dedicated end-diastolic volume index (GEDVI), intrathoracic blood volume index (ITBVI), extravascular lung water index (EVLWI), the permeability of pulmonary vascular permeability index (PVPI).
3. pHi measurement methods:tonometric catheter was connected to determine PgCO2
pHi=7.40-log PgCO2/PaCO2
4. LAP, CVP, gastric pHi, PAP, PVRI were measured and recorded on 0h,4h,8h, 12h,24h,48h,72h after surgery; inotropic score was calculated and recorded on 0h,4h, 8h,12h,24h,48h,72h after surgery:inotropic score=1x Dobutamine+1x Dopamine+ 10x Milrinone+100x epinephrine.
5. Plasma CKMB activity, CKMB mass, troponin were tested before surgery, and on 4h,24h,48h,72h after syrgery.
6. Postoperative course and clinical outcome
(1) Plasma lactate levels and PaO2/FiO2 were record on 0h,4h,8h,12h,24h,48h, 72h after surgery.
(2) Complications were recorded, such as low cardiac output syndrome, arrhythmia, pulmonary hypertension and crisis, capillary leak syndrome, atelectasis, pleural effusion, bleeding, infection, pneumothorax, non-invasive CPAP, re-intubation, etc.
(3) The duration of mechanical ventilation, ICU stay, hospital stay were recorded and compared between groups.
Results:
1. The patients'demographics
(1) There were 10 patients in VSD group with an age of 15.6±3.2 months and a weight of 9.9±1kg; There were 10 patients in VSD+PH group with an age of 11.4±3.2 months and a weight of 7.1±0.8kg; There were 10 patients in TOF group with an age of 13.6±2.8 months and a weight of 8.7±0.9kg.
(2) There was no significant difference of age among the three groups (P>0.05); the body weight of patients in VSD group and the TOF group was significantly higher than that of VSD+PH group (P<0.05); the cardiopulmonary bypass time, aortic clamping time was significantly shorter in VSD group than in VSD+PH and TOF group (P<0.05); the duration of mechanical ventilation, ICU stay, hospital stay was significantly shorter in VSD group than in VSD+PH and TOF group (P<0.05).
2. The CKMB activity, CKMB mass, troponin levels were significantly higher in TOF and VSD+PH group than that of VSD group. Spearman correlation analysis showed CKMB activity, CKMB mass, troponin was positively correlated with SVRI, PVRI, inotropic score, lactate and negatively correlated with CI, ITBVI, GEDVI, PaO2/FiO2.
3. The cardiac index in TOF patients decreased significantly to the lowest nadir on 8h-12h after surgery, and was significantly improved on 24h after surgery. The CI of TOF group was significantly lower than the VSD group accopanied with significantly higher SVRI and inotropic score as well as higher lactate levels.
4. VSD+PH group of patients have significantly higher mPAP and PVRI than that of VSD and TOF group, while the mPAP and PVRI of TOF group showed no significant difference with the VSD group.
5. The GEDVI and ITBVI was significantly lower in TOF and VSD+PH group than VSD group during the early postoperative period.
6. The EVLWI was significantly higher in VSD+PH group than TOF group at 48h after surgery, whereas the EVLWI was significantly higher in TOF group than VSD group.
Conclusions:
1. The patients in TOF and the VSD+PH group showed more severe myocardial damage than in VSD group patients, with decreased CI, increased SVRI, poor tissue perfusion, higher inotropic score.
2. The GEDVI and ITBVI was significantly lower in TOF and VSD+PH group than in VSD group in the early period after surgery.
3. VSD+PH group of patients have significantly higher mPAP and PVRI than that of VSD and TOF group, while the mPAP and PVRI of TOF group showed no significant difference with the VSD group.
4. The EVLWI was significantly higher in VSD+PH group than TOF group at 48h after surgery, whereas the EVLWI was significantly higher in TOF group than VSD group.
5. Spearman rank correlation test also showed a positive correlation between EVLWI and PVPI. There was a positive correlation between EVLWI and ITBVI and GEDVI, and a negative correlation with PaO2/FiO2. The PVPI was negatively correlated with CI, ITBVI and GEDVI decreased with the increased pulmonary vascular permeability, and showed a negative effect on PaO2/FiO2.
PartⅡThe perioperative activity of plasma NO/cGMP pathway and nitrosothiols and oxidative stress with hemodynamics in infants and young children undergoing open-heart surgery
Aim:
1. To identify the activity of perioperative NO/cGMP pathway and plasma nitrosothiols in infants and young children undergoing open-heart surgery.
2. To identify the activity of perioperative oxidative stress levels in infants and young children undergoing open-heart surgery.
3. To evaluate the relationship between plasma nitrosothiols and NO/cGMP pathway and redox activity in infants and young children undergoing open-heart surgery.
4. Statistical analysis of perioperative plasma RSNO levels and hemodynamic data in infants and young children with congenital heart disease undergoing open-heart surgery, to underly the molecular mechanisms of protein nitrosylation/oxidation balance in regulating cardiovascular function in infants and young children undergoing
open-heart surgery.
Methods:
1. Design and patients Same as partⅠ.
2. The collection of blood samples
Blood samples were collected on:1) before surgery; 2) 4h post-op; 3) 24h post-op; 4) 48h post-op; 5) 72h post-op; 3ml blood samples (per lml of blood containing heparin 10u) were collected, and instant centrifugated at 4℃,3000 r/min for 10 minutes. Plasma was separated and stored in liquid nitrogen and light protected. The blood was drawn before diet to avoid its impact on nitrite and nitrate.
3. Plasma RSNO, cGMP, NO2-/NO3-, MDA, SOD levels were measured.
4. The mathmatic correction of the experimental data Corrected value= measured value x preoperative HCT/sample HCT
5. Statistical analysis
The corrected experimental data were expressed as mean±standard error. A paired sign test was used to compare between groups. Spearman rank correlation test was used to evaluate the correlations between plasma RSNO, cGMP, NO2-/NO3-, MDA, SOD levels. P<0.05 was of significant difference. These statistical analyses were completed by the 15.0 statistical software SPSS for windows.
Results:
1. The 4h post-op plasma RSNO level were significantly higher compared with preoperative RSNO level in VSD group (190±21 pA VS 129±16 pA, P<0.05). There were no significant differences of the plasma RSNO levels between other groups as well as all other time points (P>0.05).
2. Four hours after operation, the cGMP levels were significantly lower in VSD+ PH and TOF group than in VSD group(p<0.05).
3. Plasma NO2-/NO3- levels were significantly decreased after operation in 3 groups.
4. Plasma MDA levels were significantly increased in VSD group at 4h after operation; preoperatively, the plasma MDA levels were significantly higher in VSD+ PH group than in TOF group (P<0.05).
5. Plasma SOD levels were significantlydecreased in TOF group at 4h after operation, and were significantly lower than VSD+PH group.
6. The relationship between perioperative plasma nitrosothiols and NO/cGMP pathway activity and redox levels:
(1) Spearman rank correlation test of plasma RSNO levels of all patients at all time point with NO/cGMP pathway activity (cGMP, NO2-/NO3-) and redox molecular level (MDA, SOD):
1) There was a positive correlation between plasma RSNO and cGMP levels, the correlation coefficient r=0.22, P=0.0078.
2) Plasma RSNO levels positively correlated with plasma MDA level, the correlation coefficient r=0.35, P=0.0001.
3) cGMP levels in plasma were positively correlated with MDA levels, the correlation coefficient r=0.22, P=0.0059.
(2) Spearman rank correlation test of plasma RSNO levels of all time point with NO/cGMP pathway activity and redox molecular level (MDA, SOD) in each group:
1) VSD Group:there is a positive correlation between plasma RSNO and cGMP levels (correlation coefficient=0.45, P=0.0015); RSNO levels were positively correlated with MDA level (correlation coefficient=0.42, P=0.0026); cGMP levels were positively correlated with MDA level (correlation coefficient-0.31,P=0.03).
2) VSD+PH group:plasma RSNO level and MDA level positively correlated (correlation coefficient= 0.49, P= 0.0004), plasma SOD levels were positively correlated with cGMP levels (correlation coefficient=0.37, P=0.0091).
3) There was no correlations in TOF group (P>0.05).
7. The relationship between perioperative plasma nitrosothiols and hemodynamics:
(1) Spearman rank correlation test showed that among 3 groups of congenital heart disease undergoing open-heart surgery for all time points, the plasma RSNO levels showed no significant correlation with all the hemodynamic data.
(2) Regardless of time point, we compared the relationship between plasma RSNO levels and hemodynamic data in VSD, VSD+PH, TOF group respectively, the results showed:
1) VSD group:plasma RSNO levels were negatively correlated with PVRI (correlation coefficient r=-0.66, P=0.0052).
2) VSD+PH group:plasma RSNO levels were negatively correlated with CI (correlation coefficient r=-0.37, P=0.0230).
3) TOF group:there was no significant correlation between plasma RSNO levels and hemodynamic data.
(3) We compared the relationship between plasma RSNO levels and hemodynamic data in VSD, VSD+PH, TOF group of patients in different time points, the results showed:
1) VSD group:①0h post-op:plasma RSNO levels positively correlated with pHi (correlation coefficient r=0.52, P=0.027);②4h post-op:plasma RSNO levels showed no correlation with the hemodynamics;③24h post-op:plasma RSNO levels showed no correlation with the hemodynamics;④48h post-op:plasma RSNO levels showed no correlation with the hemodynamics;⑤72h post-op:plasma RSNO levels positively correlated with PVPI (correlation coefficient r=0.58, P=0.022).
2) VSD+PH group:①0h post-op:plasma RSNO levels showed no correlation with the hemodynamics;②4h post-op:plasma RSNO levels showed no correlation with the hemodynamics;③24h post-op:plasma RSNO levels negatively correlated with mPAP (correlation coefficient r=-0.91, P=0.011);④48h post-op:plasma RSNO levels showed no correlation with the hemodynamics;⑤72h post-op:plasma RSNO levels showed no correlation with the hemodynamics.
3) TOF group:①0h post-op:plasma RSNO levels positively correlated with pHi (correlation coefficient r=0.94, P=0.005);②4h post-op:plasma RSNO levels showed no correlation with the hemodynamics;③24h post-op:plasma RSNO levels negatively correlated with CKMB activity (correlation coefficient r=-0.67, P=0.05);④48h post-op:plasma RSNO levels showed no correlation with the hemodynamics;⑤72h post-op:plasma RSNO levels positively correlated with PVPI (correlation coefficient r =0.76, P=0.031).
Conclusions:
1. There was transient NO/cGMP pathway inhibition in VSD, VSD+PH, TOF group of patients early after open heart surgery.
2. This study shows that plasma RSNO levels has a positive linear relationship with NO/cGMP pathway and oxide stress.
3. Plasma RSNO plays an important role in regulating perioperative heart function and pulmonary vascular resistance in infants and young children with congenital heart disease undergoing open-heart surgery.
引文
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