【作者】 杨林；

【导师】 朱长连； 徐发林；

【作者基本信息】 郑州大学 ， 儿科学（专业学位）， 2018， 硕士

【摘要】 随着产科及新生儿科救治技术的不断提高,早产儿存活率也有了较大的提升,而伴随的一系列并发症,如支气管肺发育不良(BPD)、早产儿视网膜病变(ROP)、坏死性小肠结肠炎(NEC)、神经系统损伤等仍困扰着我们。尤其是早产儿脑损伤,发病率高,起病隐匿,原因复杂,无特异性临床症状,给其诊断和治疗带来了巨大的障碍,同时其高致死率、致残率也给家庭和社会带来了沉重的经济及精神负担。因此,探索新的、有效的早期诊断及干预方法一直是新生儿研究人员工作的重点。咖啡因为新生儿重症监护室(NICU)最常应用的药物之一,临床应用咖啡因来防治早产儿呼吸暂停(AOP)已有超过40年的历史,其凭借较好的安全性和有效性已经得到了广泛的认可。在不断应用的过程中,研究者发现咖啡因不仅能够治疗呼吸暂停,也对早产儿的近期和远期预后有着影响。尤其在防治早产儿脑损伤方面也有一定的贡献,它能降低早产儿脑瘫发生率,改善运动和认知功能,从而改善早产儿的神经发育结局。弥散张量成像(DTI)是一种磁共振成像技术,它通过定量分析水分子在磁共振图像中各单位体积内扩散的程度及方向,并结合弥散纤维束成像(DTT)来呈现脑白质纤维束的走形、方向、排列密度等。其参数各项异性分数(FA)随着脑白质髓鞘化程度增高而增大,因此可以用来定量评估脑发育情况。DTI技术是目前评估脑白质发育最好的影像学手段,但目前国内应用此技术来评价早产儿脑发育刚刚处于起步阶段,研究较少。本研究旨在利用DTI技术评价早期预防性应用枸橼酸咖啡因对早产儿脑发育及预后的影响,并探讨其安全性。目的探讨早期预防性应用枸橼酸咖啡因对早产儿脑发育及其预后的影响,评估早期应用枸橼酸咖啡因对早产儿的安全性。方法研究对象为2016年8月-2017年2月郑州大学第三附属医院新生儿重症监护病房(NICU)收治的胎龄≤32周的早产儿100例。生后24小时内入住NICU,排除先天颅脑畸形、围生期有重度窒息史、染色体病、先天遗传代谢性疾病、严重颅内出血(分组前)、复杂型先天性心脏病、分组前生命体征不稳定(多脏器功能衰竭)后纳入本研究。纳入研究者随机分为咖啡因组(n=50)与安慰剂组(n=50)。咖啡因组于生后72小时内静脉应用枸橼酸咖啡因,应用至纠正胎龄34周。安慰剂组应用等剂量的灭菌注射用水,如有呼吸暂停时给予氨茶碱。主要观察指标:出院前(平均35.80±0.65周)行头颅常规核磁共振MRI及DTI评估,比较两组10个感兴趣区(ROI)的FA值,以及白质纤维束形态、数量、走形。纠正胎龄8-9个月时行CDCC婴幼儿智力发育量表评分,比较两组智力发育指数(MDI)和运动发育指数(PDI)。次要观察指标:比较两组呼吸暂停(AOP)、BPD、NEC、ROP、喂养不耐受、颅内出血、败血症的发生率以及使用辅助通气时长、住院时长等。结果1.两组常规MRI序列观察到的早产儿脑损伤差异无统计学意义(P>0.05)。2.咖啡因组DTI 10个感兴趣区中额叶白质、顶叶白质、枕叶白质、胼胝体压部、内囊后肢、小脑、大脑脚区FA值较对照组增高,差异有统计学意义(P<0.05)。纤维示踪成像(DTI)显示共16例出现纤维束排列稀疏,咖啡因组4例(8%),对照组12例(24%),咖啡因组少于对照组,差异有统计学意义(P<0.05)。3.随访至纠正胎龄8-9个月时,咖啡因组智力发育障碍(MDI<80分)、运动发育障碍(PDI<80分)发生率低于对照组,差异有统计学意义(P<0.05)。4.咖啡因组呼吸暂停发生率、辅助通气时长较对照组低,差异有统计学意义(P<0.05);两组喂养不耐受、颅内出血、恢复出生体重时长、BPD、NEC、ROP发生率差异均无统计学意义(P>0.05)。结论早期预防性应用咖啡因可促进早产儿脑白质髓鞘化发育、白质纤维形成,减少纠正胎龄8-9个月时智力发育障碍、运动发育障碍的发生率,且无明显不良反应。更多还原

【Abstract】 With the continuous improvement of Obstetric and Neonatal care,the survival rate of premature infants has also been greatly improved.But the complications of premature infants,such as bronchopulmonary dysplasia(BPD),retinopathy of prematurity,necrotizing enterocolitis,nervous system damage still haunt us.Especially for the brain injury of preterm infants,the incidence is high,the onset is insidious,the etiology is complex,and no specific clinical symptoms are present,which brings huge obstacles to diagnosis and treatment.The high mortality and disability rate also bring heavy economic and mental burden to families and society.Therefore,exploring new methods of diagnosis and treatment has always been the focus of the work of newborns.Coffeine is presently one of the most frequently prescribed medications in neonatal intensive care.It has been used for more than 40 years to prevent premature infants from apnea.It has been widely recognized for its safety and effectiveness.In the process of application,researchers found that caffeine can not only cure the apnea,also had an influence on the short-term and long-term outcomes of premature infants.in the protection of brain injury in preterm infants also have certain contribution,it can reduce the incidence of cerebral palsy,improve motor and cognitive function,so as to improve the premature infant neurodevelopmental outcomes.Diffusion tensor imaging(DTI)is a magnetic resonance imaging technology,it quantitatively analyzes the degree and direction of water diffusion within individual units of volume within the magnetic resonance image and combines the diffusion tractography(DTT)to show cerebral white matter fiber shape,orientation,packing density etc.The fractional anisotropy(FA)increases with the increase of myelination of white matter,which can be used to assess brain development of prematures quantitatively.Up to date,DTI is the best imaging method to evaluate the development of white matter.However,this technology used to evaluate premature brain development in our country is just at the initial stage.The objective of this study is to evaluate the effect of early preventive caffeine citrate on brain development and prognosis in premature infants by using DTI technology,and to explore its safety.ObjectiveThe objective is to determine the effects and adverse reactions of early administration caffeine on the brain development and outcome of premature infants.Methods100 preterm infants <1500 g birth weight who were hospitalized in the Neonatal Intensive Care Unit of The Third Affiliated Hospital of ZhengZhou University from August 2016 to February 2017 were recruited.The subjects were randomly allocated to either caffeine group(n=50)or placebo group(n=50).The infants of the caffeine group within the first 3 days were allocated to caffeine citrate which was used to the corrected gestational age of 34 weeks.The control group were administrated with an equal dose of Sterile Water for Injection,and aminophylline was given if there was an apnea.The primary outcome of this study was the comparison of Head MRI and DTI which were performed before discharged(at average corrected gestational age of 35.80 weeks±0.65 weeks).Fractional anisotropy(FA)was measured for the same regions of interest(ROI)in the two groups.At the corrected gestational age 8-9 months,the mental development index(MDI)and psychomotor development index(PDI)were assessed by the Chinese children’s Development Center(CDCC)’s developmental scale.Secondary outcomes were the comparison of the incidence of apnea of preterm(AOP),bronchopulmonary dysplasia(BPD),necrotizing enterocolitis(NEC),retinopathy of prematurity(ROP),feeding intolerance,intracranial hemorrhage(ICH),spesis,duration of assisted ventilation and length of hospitalization between the two groups.ResultsThere were no significant differences between the two groups in the extent of MR-defined cerebral injury or macrostructural cerebral development(P>0.05).In contrast,caffeine exposure was associated with increase in the fractional anisotropy of 10 ROI in the white matter of frontal lobe and parietal white matter,occipital lobe,corpus callosum,posterior limb of internal capsule,cerebellum,cerebral pedunclein the superior brain regions(P<0.05).Fiber tracts of 16 cases were sparsity showed by fiber tractography,4 caffeine groups,and 12 controls(8%vs24%,P<0.05).The incidence of mental retardation(MDI<80 score)and dysplasia(PDI<80 score)in caffeine group was lower than that of the control group at 8-9 months of gestational age correction(P<0.05).The incidence of AOP and the duration of ventilation in the caffeine group were lower than those in the control group(P<0.05).There was no significant difference in the incidence of feeding intolerance,intracranial hemorrhage,NEC,BPD,and ROP between the two groups(P>0.05).ConclusionEarly administration of caffeine can promote myelin development,fiber tracts formation,reduce the incidence of mental retardation and dysplasia at 8-9 months of gestational age,and have no obvious adverse reactions in premature infants.更多还原