预防性口服布洛芬治疗早产儿动脉导管未闭及其对NT-proBNP、ET-1、PGE2的影响

发布时间：2018-06-03 04:09

  本文选题：早产儿 + 动脉导管未闭　； 参考：《山东大学》2014年博士论文

【摘要】：研究背景 1、动脉导管未闭的的发病率及发生机制 动脉导管未闭(PDA)是早产儿生后早期重要的并发症之一。胎龄越小、出生体重越低越易发生。生后第4天,胎龄30周以上的早产儿有10%动脉导管仍持续开放,而胎龄小于30周的早产儿则可达65%。另有报道,胎龄低于28周的早产儿需药物或手术治疗PDA者约占60-70%。出生体重低于1500g的极低出生体重(VLBW)儿中,30%动脉导管持续开放。而出生体重低于1000g的超低出生体重(ELBW)儿和胎龄小于27周的极早产儿绝大多数在整个新生儿期动脉导管均持续开放,其中60%发生有症状性PDA,需药物或手术治疗。 动物实验和临床研究均表明PDA可增加早产儿的死亡率和严重并发症的发生率。因此,对于早产儿,特别是VLBW儿和ELBW儿,绝大部分新生儿专家认为,应积极干预PDA以降低并发症的发生率及婴幼儿死亡率。 胎儿期动脉导管持续开放,联结肺动脉与降主动脉。胎儿期动脉导管主要是由低氧和高前列腺素水平来维持开放的,前列腺素主要包括前列腺素E2(PGE2)和前列环素(PGl2)。足月儿生后氧分压明显上升,PGE2、PGI2水平明显下降,导致动脉导管平滑肌细胞收缩,功能性关闭。而高氧诱发动脉导管关闭的重要通路之一即为内皮素通路。高氧可导致由动脉导管产生的血管收缩物质—内皮素1(ET-1)释放。但目前ET-1在动脉导管关闭中的具体作用尚有争议。 2、动脉导管未闭的药物治疗 早产儿对高氧介导的动脉导管关闭通路不敏感。相对而言,早产儿对于PGE2、NO通路更为敏感。因此,早于1976年就有学者提出应用非选择性环氧化酶抑制剂,抑制前列腺素的产生,来提高早产儿PDA的关闭率。目前,静脉用吲哚美辛已被公认为药物治疗早产儿PDA的经典方案。 吲哚美辛可显著降低早产儿肾、肠系膜灌注及脑血流,可导致肾功损伤、少尿等不良反应。近年来,布洛芬作为另一非选择性环氧化酶抑制剂受到越来越多的重视。研究表明,静脉用布洛芬治疗早产儿PDA同样有效,而且少尿、肾功损伤等不良反应较吲哚美辛减少。但对于用药的时间尚存在较大争议。有学者认为ELBW儿预防性应用布洛芬PDA关闭率较高,且副作用无明显增加。另外一些研究则显示预防性应用布洛芬可致肠穿孔等近期并发症增加,且增加了不必要的药物暴露。因此是否应采用预防性应用布洛芬需进一步研究。 另外布洛芬静脉制剂价格较贵,且目前国内尚无布洛芬静脉制剂,因此口服布洛芬成为一种可能的替代选择。近年来陆续有关于口服布洛芬治疗早产儿PDA的研究报道,但多数研究局限性较大,存在如样本量较小,非双盲研究,未作到随机化等缺陷,所以目前大多数新生儿专家仍对口服布洛芬持否定态度。目前需要更多的研究来进一步证实口服布洛芬的是否有效、是否安全。 3、动脉导管未闭的监测 研究表明早产儿动脉导管有较高的自发性关闭率,因此有学者提出过度的干预可能增加不必要的药物暴露率,主张仅给予限制液体等基础治疗,而不给予药物干预。但是鉴于早产儿生后早期合并PDA可明确增加死亡率,因此,我们认为,严格筛选病例,积极寻找预测PDA发生和发展的有效指标,显然是更为稳妥的方法。 心脏超声作为PDA诊断的金标准,具有不可替代的优势。多数研究认为左室(LV)径、左房主动脉根部直径比(LA/AO)和动脉导管(DA)直径可作为预测PDA是否需干预的指标。不过,超声诊断自身存在很大的局限性。因心脏超声设备昂贵,且需专门技术人员操作,在国内基层医院很难做到对早产儿PDA的床头超声追踪筛查。因此,将心脏超声作为唯一预测和监测治疗反应的指标,难度较大。临床上迫切需要寻找一些相对简便,且经济安全的指标来作为替代。 近年来,有学者致力于研究能够预测动脉导管发生及转归的生物学指标,其中较受关注的有B型钠尿肽(BNP)、氨基末端B型钠尿肽(NT-proBNP)、心房利钠肽(ANP)等,但相应的研究不多,且尚无明确的结论。 研究目的 1、探讨预防性口服布洛芬治疗早产儿PDA的有效性,及其疗效是否优于常规治疗性口服。 2、监测口服布洛芬后早产儿外周血中NT-proBNP、ET-1. PGE2的变化,寻找可用于预测PDA发生及监测治疗反应的生物学指标。 研究方法 设计前瞻性双盲随机对照试验。2011年7月至12月,山东省立医院新生儿科收治的胎龄小于36周的早产儿,共103人。随机分为三组,预防性治疗组于生后24小时内口服第一剂布洛芬(10mg/kg),各间隔24小时后口服第二、三剂布洛芬(5mg/kg)。常规治疗组于生后第3天行超声检查,证实存在PDA的患儿给予相同剂量的布洛芬口服。安慰剂组自生后24小时始口服等量的5%葡萄糖,间隔时间、疗程与预防性治疗组相同。生后24小时内、第3天,第7天分别行心脏超声检查,并抽外周血查NT-proBNP、ET-1、PGE2水平及肾功、血常规、C反应蛋白,并监测有无不良反应。 结果 1、三组患儿基本资料无显著性差异(P0.05),生后24小时内的超声检查指标无显著性差异(P0.05)； 2、预防性治疗组较安慰剂组生后第7天动脉导管关闭率明显增加,有显著性差异(97.14%对78.38%,P0.05)。但与常规治疗组相比,差异不显著(97.14%与87.10%,P0.05)。而常规治疗组与安慰剂组间相比关闭率亦明显上升,但统计学上无显著性差异(87.10%对78.38%,P0.05)。 3、三组间不良反应统计学上无差异(P0.05)。 4、动脉导管自发性闭合的早产儿生后24小时内的导管直径明显小于未自发性闭合者,两者间差异明显(0.11±0.06对0.19±0.06,P0.05)。 5、早产儿外周血NT-proBNP水平随日龄增加而下降。生后第3天、第7天预防性治疗组较安慰剂组明显下降,有统计学差异(13.27±8.29对19.41±10.69,9.98±4.14对13.85±7.19,均P0.05)。 6、三组早产儿生后7天内ET-1水平无明显变化,三组间无差异。 7、动脉导管自发性闭合的早产儿生后24小时内的ET-1水平低于未能自发性闭合者,两者间差异明显(16.74±6.50对20.65±4.61,P0.05)。 8、早产儿外周血中PGE2水平随日龄增加而下降,但三组间无差异(P0.05)。 结论 1、预防性口服布洛芬可提高早产儿PDA的关闭率,且不良反应未增加。 2、预防性口服布洛芬与常规治疗性口服布洛芬相比,无明显优势。 3、生后24小时内的动脉导管直径可作为预测早产儿PDA发生的指标之一。 4、预防性口服布洛芬治疗后NT-proBNP水平明显下降,提示可作为观察早产儿PDA治疗后反应的生物学指标,此为国内外首次报道。 5、早产儿生后24小时内的血浆ET-1水平,可作为有前途的预测PDA发生的生物学指标之一。此为国内外首次报道,需进一步研究证实。
[Abstract]:Research background
1, the incidence and mechanism of patent ductus arteriosus
Patent ductus arteriosus (PDA) is one of the important early complications after birth in preterm infants. The smaller the gestational age and the lower the birth weight, the more likely it will occur. Fourth days after birth, 10% arterial ducts are still open in preterm infants over 30 weeks of gestational age, while preterm infants less than 30 weeks of gestational age can reach another report. Preterm infants whose gestational age is less than 28 weeks need drugs or surgery. In the treatment of PDA, the 30% arterial ductus arteriosus continued to open in the very low birth weight (VLBW) of the 60-70%. birth weight less than 1500g, while the majority of the ultra low birth weight (ELBW) and the gestational age of less than 27 weeks of gestational age were continuously open in the whole neonatal period, and 60% of them had symptomatic PDA. A physical or surgical treatment.
Both animal experiments and clinical studies have shown that PDA can increase the mortality of premature infants and the incidence of severe complications. Therefore, for preterm infants, especially VLBW and ELBW infants, the overwhelming majority of newborns believe that PDA should be actively intervened to reduce the incidence of complications and the death and death rate of infants.
The ductus arteriosus is open and connected with the pulmonary artery and the descending aorta. The fetal ductus arteriosus is maintained open mainly by hypoxia and high prostaglandin levels. Prostaglandins mainly include prostaglandin E2 (PGE2) and prostacyclin (PGl2). The oxygen partial pressure rises obviously after birth, and the level of PGE2 and PGI2 decreases significantly, leading to the catheterization of the ductus arteriosus. Smooth muscle cells constriction and functional closure. One of the important pathways that induces the closure of the ductus arteriosus by hyperoxia is the endothelin pathway. Hyperoxia can lead to the release of endothelin 1 (ET-1), a vasoconstrictor produced by the ductus arteriosus, but the specific role of ET-1 in the closure of the ductus arteriosus is still controversial.
2, drug treatment of patent ductus arteriosus
Premature infants are not sensitive to hyperoxic ductus arteriosus pathway. Relatively speaking, preterm infants are more sensitive to PGE2, NO pathway. Therefore, some scholars have proposed the application of non selective cyclooxygenase inhibitors in 1976 to inhibit the production of prostaglandins to improve the closure rate of PDA in premature infants. The classic drug for the treatment of PDA in premature infants.
Indomethacin can significantly reduce the renal, mesenteric perfusion and cerebral blood flow in preterm infants, which can lead to renal injury and oliguria. In recent years, ibuprofen has been paid more and more attention as another non selective cyclooxygenase inhibitor. The study shows that intravenous ibuprofen is also effective in the treatment of PDA in premature infants, and no urine, renal dysfunction, and so on. Good reaction is less than indomethacin, but there is still a lot of controversy over the time of drug use. Some scholars believe that the preventive use of ELBW PDA is high and side effects have not increased significantly. In other studies, some recent studies have shown that the prophylactic use of ELBW can cause an increase in recent complications such as intestinal perforation, and increases unnecessary drug exposure. Therefore, the preventive use of ibuprofen should be further studied.
In addition, ibuprofen intravenous preparation is more expensive and there are no ibuprofen intravenous preparations at present. Therefore, oral ibuprofen has become a possible alternative. In recent years, there has been a research report on the treatment of PDA in premature infants with oral ibuprofen, but most of the studies are limited, such as small sample size, non double blind study, and not random. So far, most newborn experts still have a negative attitude to oral ibuprofen. More research is needed to confirm whether oral ibuprofen is effective and safe.
3, the monitoring of patent ductus arteriosus
Studies have shown a high spontaneous closure rate for the ductus arteriosus in premature infants. Therefore, some scholars suggest that excessive intervention may increase the exposure rate of unnecessary drugs, advocating only limiting liquid and other basic treatments without drug intervention. However, we believe that the early postnatal birth with PDA can increase the mortality rate clearly, so we think, strict It is obviously a safer way to screen cases and actively seek effective indicators to predict the occurrence and development of PDA.
Cardiac ultrasound has an irreplaceable advantage as the gold standard for PDA diagnosis. Most studies suggest that the diameter of the left ventricle (LV), the diameter ratio of the left atrial aorta (LA/AO) and the diameter of the patent ductus arteriosus (DA) can be used as an indicator of whether the PDA should be intervened. However, the ultrasonic diagnosis itself is very limited. It is difficult to perform the bedside ultrasound tracking screening for preterm PDA in the domestic primary hospitals. Therefore, it is difficult to use the heart ultrasound as the only indicator to predict and monitor the response of the treatment. It is urgent to find some relatively simple and economic safety indicators as a substitute.
In recent years, some scholars have been devoted to the study of biological indicators that can predict the occurrence and prognosis of ductus arteriosus, including B type natriuretic peptide (BNP), amino terminal B natriuretic peptide (NT-proBNP), and atrial natriuretic peptide (ANP), but there is not much research and no clear conclusion.
research objective
1, to investigate the efficacy of prophylactic oral ibuprofen in the treatment of PDA in preterm infants and whether the efficacy is better than that of conventional oral therapy.
2, monitor the changes of NT-proBNP and ET-1. PGE2 in peripheral blood of preterm infants after oral ibuprofen, and find out biological indicators that can be used to predict PDA occurrence and monitor therapeutic response.
research method
We designed a prospective double blind randomized controlled trial from July to December.2011 to December. A total of 103 children were admitted to the Department of Pediatrics of Shangdong Province-owned Hospital for a total of less than 36 weeks. They were randomly divided into three groups. The preventive treatment group took the first dose of Bloven (10mg/kg) within 24 hours after birth, and second, third doses of oral administration 24 hours after each interval. The group was examined by ultrasound at third days after birth. The same dose of ibuprofen was given to the children with the same dose of PDA. The placebo group was given an equal amount of 5% glucose at 24 hours after birth. The interval was the same as that of the preventive treatment group. The cardiac ultrasound examination was performed within 24 hours, third days, seventh days after birth, and the peripheral blood was examined for NT-proBNP, ET-1, and PGE. 2 level and renal function, blood routine, C reactive protein, and monitor whether there was any adverse reaction.
Result
1, there was no significant difference in the basic data between the three groups (P0.05), and there was no significant difference in ultrasonic examination within 24 hours after birth (P0.05).
2, there was a significant increase in the closure rate of the arterial ductus arteriosus in the prophylactic group seventh days after the birth of the placebo group (97.14% to 78.38%, P0.05). However, the difference was not significant (97.14% and 87.10%, P0.05) compared with the conventional treatment group, but the rate of closure was also significantly higher in the routine treatment group than in the placebo group, but there was no significant difference in Statistics (87.10%) For 78.38%, P0.05).
3, there was no statistically significant difference in adverse reactions between the three groups (P0.05).
4, the diameter of the catheter within 24 hours after the spontaneous closure of the patent ductus arteriosus was significantly smaller than that of the non spontaneous closure (0.11 + 0.06 to 0.19 + 0.06, P0.05).
5, the level of NT-proBNP in the peripheral blood of preterm infants decreased with the increase of age. The third day after birth and the seventh day prophylactic treatment group were significantly lower than those in the placebo group (13.27 + 8.29 pairs of 19.41 + 10.69,9.98 + 4.14 pairs 13.85 + 7.19, all P0.05).
6, there was no significant change in the level of ET-1 in the three groups of premature infants within 7 days after birth, and there was no difference between the three groups.
7, the level of ET-1 in the spontaneous closure of the patent ductus arteriosus was lower within 24 hours after the birth of the patent ductus arteriosus than those in the non spontaneous closure (16.74 + 6.50 to 20.65 + 4.61, P0.05).
8, the level of PGE2 in the peripheral blood of preterm infants decreased with the increase of age, but there was no difference between the three groups (P0.05).
conclusion
1, prophylactic oral ibuprofen can improve the closure rate of PDA in premature infants, and the side effects are not increased.
2, prophylactic oral ibuprofen has no obvious advantage compared with conventional oral ibuprofen.
3, ductus arteriosus diameter within 24 hours after birth can be used as a predictor of PDA in preterm infants.
4, the level of NT-proBNP in the prophylactic oral ibuprofen treatment was significantly decreased, suggesting that it could be used as a biological index to observe the response of preterm infants after PDA treatment. This is the first report at home and abroad.
5, the level of plasma ET-1 within 24 hours after birth is one of the promising biological indicators for predicting the occurrence of PDA. This is the first report at home and abroad and needs further research.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R722.6

【共引文献】

中国期刊全文数据库 前10条

1 张慎荣;张园海;徐强;仇慧仙;陈其;;脑钠肽和氨基末端脑钠肽在小儿先天性心脏病心功能评估中的价值[J];中国当代儿科杂志;2009年06期

2 Maria Emília Guimar嗾es Areias;Catarina I.Pinto;Patrícia F.Vieira;Flávio Teixeira;Rosália Coelho;Isabela Freitas;Samantha Matos;Marta Castro;Sofia Sarmento;Victor Viana;Jorge Quintas;José C.Areias;;青少年和年轻成人先天性心脏病的心理社会远期转归[J];中国当代儿科杂志;2013年10期

3 徐君;林怡翔;顾若漪;王慧君;马晓静;马端;黄国英;;法洛四联症患儿组蛋白乙酰化及其酶的表达[J];中国当代儿科杂志;2013年10期

4 穆世茵;张宏艳;;胰岛因子1基因2个SNP位点与儿童先天性心脏病的相关性研究[J];中国当代儿科杂志;2013年10期

5 钱鹭葵;吕国荣;陈文龙;;实时三维时空关联成像技术对20孕周前胎儿心脏畸形的诊断价值[J];临床医学;2013年09期

6 黎新艳;田晓先;林莲恩;李雪芹;周旋;黄欢;刘萍萍;;四维时空关联成像技术在中晚孕胎儿心脏筛查中的应用[J];广西医学;2013年12期

7 朱沈华;吴柱中;庄洪涛;;海宁市0～12月活产婴儿先天性心脏病患病调查分析[J];中国儿童保健杂志;2014年02期

8 韩莉;肖宪杰;旅朝霞;郭然;;动脉导管未闭封堵术后即刻血压变化研究[J];大连医科大学学报;2014年02期

9 麦瑞芝;房晓yN;;小儿动脉导管未闭的药物治疗进展[J];发育医学电子杂志;2013年04期

10 张乐;孙美平;高卫线;洪世欣;张亚黎;;县、乡级超声医生开展胎儿期复杂先天性心脏病超声筛查的可行性研究[J];北京大学学报(医学版);2014年03期

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2 龚立;肺动脉闭锁遗传学初步研究[D];华中科技大学;2013年

3 李倩;苹果寡糖的制备、结构鉴定与抗肿瘤活性研究[D];第四军医大学;2013年

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7 骆志玲;胰岛素信号转导异常与先天性心脏病的相关性研究[D];昆明医科大学;2014年

8 周新刚;心脏缺陷少见于携带包括GATA4在内的8p23.1基因组重复的患者[D];哈尔滨医科大学;2012年

9 赵趣鸣;中国新生儿先天性心脏病筛查体系的建立与应用研究[D];复旦大学;2013年

10 陈伟呈;合并内脏异位的先心病患者术后死亡率和呼吸道并发症及其与呼吸道纤毛功能障碍关系的研究[D];复旦大学;2013年

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1 王珍珍;血清NTpro-BNP、cTNI及IMA对急性百草枯中毒心肌损伤的诊断价值及预后评估[D];郑州大学;2011年

2 惠迎春;脑钠肽及氮端脑钠肽对新生儿败血症心肌损伤的诊断价值[D];兰州大学;2009年

3 杨璐;先天性心脏病患儿围术期血浆氮末端脑钠肽前体浓度的变化及意义[D];重庆医科大学;2009年

4 张茜;N-末端脑利钠肽与内皮素在左、右心功能不全患者中水平的比较[D];中南大学;2009年

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6 李彦晓;AHA推荐的实验室指标在诊断不完全川崎病中的临床意义[D];郑州大学;2012年

7 李敏;严重脓毒症患儿各脏器功能评估及NT-Pro BNP对其早期心血管功能评估的价值[D];山东大学;2012年

8 党丹;对乙酰氨基酚与布洛芬治疗早产儿PDA的随机对照试验[D];吉林大学;2013年

9 王忠德;淄博市2000～2011年5岁以下儿童死亡状况研究[D];山东大学;2013年

10 匙莹;辛伐他汀对人牙髓细胞增殖及碱性磷酸酶活性的影响[D];河北医科大学;2013年

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