血清IL-6、NSE及颅脑超声对早产儿WMI的诊断价值以及GM-1对其的疗效

发布时间：2018-05-10 13:21

本文选题：脑白质病变 + 早产儿　；参考：《南方医科大学》2012年硕士论文

【摘要】：[背景资料] 由于产科技术和新生儿重症监护技术不断提高,小胎龄早产儿成活率明显提高,早产儿脑损伤发生率也随之提高了。新生儿脑白质损伤(white matter injury, WMI)是早产儿常见的脑损伤形式,严重者可发展为脑室周围白质软化(periventricular leucumalacia, PVL)。早产儿脑损伤的发生与胎龄密切相关。胎龄越小,体重越低,脑损伤发生率越高。由于胎龄小的婴儿脑血管发育不成熟,在胎龄26～32周时,其生发基质区(好发部位)血管密度明显高于白质区并且面积大于白质区,而生发基质区的血管常常为单层内皮,缺少平滑肌中弹力纤维的支持,故对血流冲击的抵抗力较差,易发生破裂出血。随着胎儿发育,生发基质区面积渐小,至36周时,才几乎完全消失。早产儿好发WMI与脑缺血有关,脑血管结构发育的不成熟和脑血管自动调节功能受损是形成早产儿好发脑缺血的基础。胎龄越小,特别是胎龄小于28周时,越容易导致早产儿发生新生儿脑白质损伤。由于胎龄小的婴儿脑血管发育不成熟,长穿支的侧支发育不全,短支较少,长短支较少汇合,致使脑室周围成为脑血流分布最少的部位,一旦全身血压降低,这些部位最易受缺血性损伤,从而出现新生儿脑白质损伤。大脑动脉的短穿支供血给皮层下白质,大脑动脉的长穿支供血给脑室周围深部白质。未成熟的早产儿,其脑室周围动脉长穿支稀少,同时缺少侧支循环；而皮层下的大脑动脉短穿支尚未完全成熟,因而给白质区供血少,加重缺血引起的早产儿脑室周围白质软化。大脑的静脉呈扇形分布于脑室周围白质,在脑室旁经生发基质区汇入终末静脉。在静脉压增高时,导致白质区回流受阻,易发生静脉充血、出血性梗死。特别是使用机械通气的早产儿,静脉压增高时,可出现明显的脑血流调节受损,血压降低,脑血流减少,随后出现血管的末梢及周边区域的脑白质缺血,导致早产儿脑白质损伤的发生。胎龄达32周以后,随着血管发育的日趋成熟,WMI的发生率也因而降低。因此,早产儿脑室周围白质软化的发生与脑室周围的血管发育情况有密切关系,胎龄越小,脑室周围的血管发育越不成熟,发生早产儿脑室周围白质软化的可能性也越大。在早产儿的脑白质中存在3种类型的少突胶质细胞,分别为少突胶质细胞前体、不成熟少突胶质细胞以及成熟少突胶质细胞,后者主要构成髓鞘。在早产儿,特别是32周以前,脑白质中绝大部分为分化十分活跃的少突胶质细胞前体,而少突胶质细胞前体是早产儿脑室周围白质软化病变中十分关键的靶细胞。少突胶质细胞前体易于受到缺血、缺氧、感染等因素的损伤,进而使脑组织受损。少突胶质细胞前体的损伤将使脑白质的髓鞘化受损,其后遗病理改变是缺乏髓鞘化,脑白质量的减少和脑室的增大,这是窒息早产儿好发早产儿脑室周围白质软化主要因素。研究发现围产期的缺氧缺血性脑损伤还可引起神经节苷脂水平下降,神经节苷脂下降的程度与脑损伤程度相关。 WMI常见受损部位为侧脑室前角附近、半卵圆中心区域及侧脑室后角三角区附近,这些部位的脑白质呈弥漫性损伤。国内外对于早产儿脑白质损伤还没有明确的治疗手段。患儿的预后往往与早期诊断和干预相关。但是在临床上,脑白质损伤早产儿往往缺乏明显的特异性神经系统症状和体征,根据临床表现很难早期诊断。颅脑超声检查操作简单,无需搬动患儿,并能连续监测新生儿病情变化,可成为早产儿脑损伤早期诊断、判断其严重程度及估计预后的有效手段。白介素-6(interleukin-6, IL-6)是一种炎症调节和免疫反应有关的多功能细胞因子,它主要由单核细胞、B细胞、T细胞、成纤维细胞和内皮细胞产生。在脑组织内主要由星形胶质细胞和小胶质细胞产生。神经元特异性烯醇化酶(neuron specific enolase, NSE)是脑损伤的敏感性和特异性指标,它能反映脑损伤的严重程度,并且随脑损伤程度加重而升高。本研究通过检测脑白质损伤早产儿颅脑超声变化情况以及血清IL-6、NSE的变化水平,以探讨它们对早产儿脑白质损伤早期诊断的实用意义和应用前景。目前,药物治疗脑白质损伤的效果尚处于探索阶段。而单唾液酸四己糖神经节苷脂(monosialoteterahexosyl ganglioside, GM-1)是神经节系列神经节苷脂之一,在神经发生、生长及分化中起必不可少的作用。它能增加受损脑组织血流量,促进轴突生长,提高神经细胞存活率,调节突触间的信号传导,改善神经传导速度,促进脑电活动的恢复,从而减低脑损伤后的继发性神经毒性,增强神经营养活性,加强神经重构,促进脑损伤后的恢复,从而达到治疗目的。本研究通过在常规治疗基础上对脑白质病变早产儿应用GM-1治疗,并豁测血清IL-6、NSE及用颅脑超声观察脑室周围白质,探讨GM-1疗效。 [目的] 1.了解血清白细胞介素-6(IL-6)及神经元特异性烯醇化酶(NSE)的变化对早产儿脑白质损伤早期诊断的价值； 2.探讨颅脑超声对早产儿脑白质损伤早期诊断和预后判断的价值； 3.探讨GM-1对早产儿脑白质损伤的治疗效果。 [方法] 1.分组方法： 1.1.临床资料：我院新生儿科2011年1月至2011年10月收治住院的早产儿,共109例,男57名,女52名,胎龄30～37周,体重850-2600g。4例未能完成治疗。最后完成实验共105名,男54名,女51名。 1.2.分组： 1.2.1分组方法：将胎龄小于37周的早产儿进行颅脑MRI检查,未发现脑白质损伤的早产儿独自纳入对照组；发现脑白质损伤的早产儿采用随机化方法(随机数字表)随机分为了观察组和干预组。 1.2.2对照组35例,胎龄小于37周,颅脑MRI未发现脑白质损伤的患儿排除感染性疾病及神经系统发育异常者。 1.2.3观察组35例,胎龄小于37周,颅脑MRI发现脑白质损伤的患儿(颅脑超声灰度值增高)。排除感染性疾病及神经系统发育异常者。 1.2.4干预组35例,胎龄小于37周,颅脑MRI发现脑白质损伤的患儿(颅脑超声灰度值增高)。排除感染性疾病及神经系统发育异常者。三组早产儿在样本量、日龄、胎龄、分娩方式、出生体重和性别组成上均无统计学差异(P0.01)。 2.治疗方法 2.1基础治疗： 2.1.1精心护理： ①合理给氧；②保暖；③科学喂养；④严密监测病情。 2.1.2三支持疗法： ①维持良好的通气、换气功能,使血气和PH值保持在正常范围；②维持外周和各脏器足够的血液灌流,使心率和血压保持在正常范围；③维持血糖在正常高值(5.0mmol/L),以保证神经细胞代谢所需。 2.1.3三对症处理： ①控制惊厥；②降低颅内压；③消除脑干症状。 2.2干预方式对照组不给予相关治疗观察组给予基础治疗干预组(GM-1治疗组)：在基础治疗基础上,第一天起静脉给予GM-1(施捷因,阿根廷TRB药厂生产,规格20mg/2m1)20mg加入50g/L葡萄糖溶液20mL静脉滴注,1次/d,14天为1个疗程。 3.观察方法 3.1标本采集：将三组早产儿分别于生后第1、7、14天早晨,由专人分别取股静脉血2ml,室温下放置1h,常温2000r/min离心10min后分离血清,-80℃冷冻保存待测。 3.2标本检测：IL-6和NSE的试剂盒由美国ADL公司生产。用多功能免疫荧光分析系统分析；均采用双抗体夹心ELISA法测定,操作严格按说明书进行。 3.3颅脑超声：应用GE VOLUSON730EXPERT超声检测仪。采用颅脑超声参数条件相同(扇形小突阵扫描探头频率为5-9mHz),两组患儿在生后1天、7天、14天进行检查,取矢状面扫描的侧脑室中央部-后角层面图像,白质回声异常者视为异常。 4.统计学方法采用SPSS19.0统计软件包建立数据库。三组比较采用单向方差分析,方差不齐时,采用Welch法；两两比较采用LSD法,方差不齐时采用Dunnett T3法。以α=0.01作为检验水准,P0.01差异有统计学意义。 4例患儿因放弃治疗失访,未能完成试验,直接剔除。 [结果] 1.基线资料：纳入的早产儿在日龄、胎龄、分娩方式、体重和性别组成上差异均无统计学意义(P0.01)。 2.观察组及干预组生后第1天、7天及14天血清IL-6和NSE水平显著高于对照组,颅脑超声灰度显著高于对照组。差异均有统计学意义；(P0.01) 3.经治疗,干预组生后第7天、第14天,血清NSE、IL-6水平均显著低于观察组,颅脑超声灰度显著低于观察组。差异均有统计学意义。(P0.01)。 [结论] 1.脑白质损伤早产儿血清IL-6和NSE的浓度明显高于对照组。监测早产儿血清中IL-6和NSE的水平,对脑白质损伤的诊断和治疗效果的评价具有一定的临床价值。 2.颅脑超声可作为早产儿脑白质损伤早期诊断和预后评估有力的依据。 3.GM-1治疗早产儿脑白质病变有脑神经保护作用。
[Abstract]:[background information]
Due to the continuous improvement of obstetric techniques and neonatal intensive care technology, the survival rate of premature infants in small fetal age is obviously improved, and the incidence of brain injury in premature infants is also increased. White matter injury (WMI) is a common form of brain injury in premature infants, and the serious persons can develop into periventricular softening (periventricular Leu). Cumalacia, PVL).
The occurrence of brain injury in premature infants is closely related to the gestational age. The smaller the gestational age, the lower the body weight, the higher the incidence of brain damage. The vascular density in the germinal matrix area is obviously higher than the white matter area and the area is larger than the white matter area at the age of 26~32 gestational age. For the monolayer endothelium, the support of the elastic fibers in the smooth muscle is lacking, so the resistance to the impact of blood flow is poor, and it is prone to rupture and bleeding. With the development of the fetus, the area of the germinal matrix area is gradually smaller and almost completely disappeared at 36 weeks.
Premature infants' good hair WMI is associated with cerebral ischemia, immature cerebral vascular structure development and impaired cerebral vascular automatic regulation are the basis for forming preterm infants with good cerebral ischemia. The smaller the gestational age, especially when the gestational age is less than 28 weeks, the more prone to premature infants' brain white matter injury. The lateral branch of the perforator is not fully developed, the short branch is less, the long short branch is less confluence, and the cerebral blood flow distribution is the least part around the ventricle. Once the whole body blood pressure is reduced, these parts are most vulnerable to ischemic injury, thus the white matter injury of the newborn brain appears.
The short perforator of the cerebral artery supplies the subcortical white matter, and the long perforator of the cerebral artery supplies the deep white matter around the ventricle. The immature premature infant is rare and lacks collateral circulation in the periventricular artery, while the short perforating branch of the subcortical cerebral artery is not fully mature, thus giving less blood to the white matter area and aggravating the ischemia. The cerebral veins are softening around the ventricles of the brain in preterm infants. The veins of the brain are fan-shaped in the white matter around the ventricle and enter the terminal vein near the ventricle. When the venous pressure increases, the white matter reflux is obstructed and the venous congestion and hemorrhagic infarction are easy to occur. The cerebral blood flow regulation was impaired, blood pressure decreased, cerebral blood flow decreased, and cerebral white matter ischemia occurred in the end of the blood vessels and the peripheral region of the brain, which resulted in the occurrence of white matter injury in premature infants. After 32 weeks of fetal age, the incidence of WMI was reduced as the development of blood vessels matured.
Therefore, the occurrence of periventricular softening in preterm infants is closely related to the development of blood vessels around the ventricle. The smaller the gestational age, the less mature the vascular development around the ventricle is, the greater the possibility of the occurrence of periventricular softening in preterm infants.
There are 3 types of oligodendrocytes in the white matter of preterm infants, which are oligodendrocyte precursors, immature oligodendrocytes and mature oligodendrocytes, and the latter mainly form myelin sheath. In preterm infants, especially before 32 weeks, most of the white matter in the brain is a very active oligodendrocyte precursor and oligodendrocyte. The precursor of the glial cell is the key target cell in the periventricular softening of preterm infants. The precursor of oligodendrocyte is vulnerable to ischemia, hypoxia, infection and so on, and then the brain tissue is damaged. The injury of the precursor of oligodendrocytes will damage the myelination of the white matter, and the pathological changes are the lack of myelination and brain. The decrease of white mass and the enlargement of the ventricle are the main factors in the periventricular softening in preterm premature infants with asphyxia. The study found that hypoxic-ischemic brain injury in perinatal period can also cause the decline of ganglioside, and the degree of ganglioside decline is related to the degree of brain damage.
WMI is commonly seen in the vicinity of the anterior horn of the lateral ventricle, near the central area of the oval circle and the trigone of the posterior horn of the lateral ventricle.
There is no clear treatment for premature brain white matter injury at home and abroad. The prognosis of children is often associated with early diagnosis and intervention. But in clinical, premature infants with brain white matter injury often lack obvious specific nervous system symptoms and signs. Early diagnosis is difficult according to clinical manifestations. Craniocerebral ultrasound examination is simple and no need. Moving children, and continuous monitoring of the changes in the condition of the newborn, can be an effective means for early diagnosis of premature brain injury, to judge the severity and to estimate the prognosis. Interleukin -6 (interleukin-6, IL-6) is a multifunctional cytokine associated with inflammatory regulation and immune response. It is mainly composed of monocytes, B cells, T cells, and fibroblasts. Cells and endothelial cells are produced. In brain tissue, it is mainly produced by astrocytes and microglia. Neuron specific enolase (NSE) is a sensitive and specific index of brain damage. It can reflect the severity of brain damage and increase with the degree of brain damage. This study was conducted by detecting brain white. The changes of craniocerebral ultrasound and the level of serum IL-6 and NSE in premature infants with qualitative injury are discussed in order to explore their practical significance and application prospects for early diagnosis of brain white matter injury in premature infants.
At present, the effect of drug treatment for brain white matter damage is still at the exploratory stage. Monalosialic acid four hexose Ganglioside (Monosialoteterahexosyl ganglioside, GM-1) is one of ganglioside gangliosides, which is essential for neurogenesis, growth and differentiation. It can increase the blood flow of damaged brain tissue and promote axonal birth. Long, improving the survival rate of nerve cells, regulating the signal conduction between synapses, improving the speed of nerve conduction, promoting the recovery of brain electrical activity, reducing secondary neurotoxicity after brain injury, enhancing neurotrophic activity, strengthening nerve remodeling and promoting recovery of brain injury, thus achieving the purpose of treatment. This study is based on the routine treatment basis. GM-1 was applied to preterm infants with white matter lesions, and serum IL-6 and NSE were measured, and periventricular white matter was observed by cranial ultrasound. The efficacy of GM-1 was evaluated.
[Objective]
1. to understand the value of serum interleukin -6 (IL-6) and neuron specific enolase (NSE) changes in early diagnosis of white matter damage in preterm infants.
2. to explore the value of cranial ultrasound in early diagnosis and prognosis of white matter damage in premature infants.
3. to explore the therapeutic effect of GM-1 on white matter damage in premature infants.
[method]
The 1. grouping method:
1.1. clinical data: a total of 109 preterm infants were admitted to the hospital from January 2011 to October 2011 in our hospital. A total of 109 cases, 57 men, 52 women, 30~37 weeks of gestational age, and a body weight 850-2600g.4 failed to complete the treatment. Finally, 105 men were completed, 54 men and 51 women.
1.2. grouping:
1.2.1 grouping method: preterm infants whose gestational age was less than 37 weeks were examined by MRI, and the premature infants who had not found white matter injury were included in the control group alone. The early infants with brain white matter injury were randomly divided into the observation group and the intervention group by randomization (random number table).
In the 1.2.2 control group, 35 cases, with a gestational age of less than 37 weeks, were excluded from the MRI.
1.2.3 observation group 35 cases, fetal age less than 37 weeks, craniocerebral MRI found brain white matter injury in children (higher craniocerebral ultrasound grayscale value). Exclude infectious diseases and nervous system dysplasia.
1.2.4 intervention group 35 cases, fetal age less than 37 weeks, brain MRI detection of brain white matter injury (craniocerebral ultrasound gray value increased). Excluding infectious diseases and nervous system dysplasia. Three groups of premature infants in the sample size, age, gestational age, delivery mode, birth weight and gender groups have no statistical difference (P0.01).
2. treatment methods
2.1 basic treatment:
2.1.1 meticulous care:
(1) reasonable oxygen supply; (2) keep warm; (3) scientific feeding; (4) closely monitor the condition.
2.1.2 three support therapy:
(1) maintain good ventilation, ventilation function, keep blood gas and pH in normal range; maintain adequate blood perfusion in peripheral and viscera, keep heart rate and blood pressure in normal range; maintain blood glucose at normal high (5.0mmol/L), in order to guarantee the metabolism of nerve cells.
2.1.3 three symptomatic treatment:
(1) controlling convulsion; (2) reducing intracranial pressure; (3) eliminating brainstem symptoms.
2.2 mode of intervention
No related treatment was given to the control group
The observation group was given basic treatment
Intervention group (GM-1 treatment group): on the basis of basic treatment, GM-1 (Shi Jie, Argentina TRB pharmacy production, specification 20mg/2m1) 20mg was added to 50g/L glucose solution 20mL intravenous drip on the first day, and the 1 /d and 14 days were 1 courses.
3. observation method
3.1 collection of specimens: the three groups of preterm infants were taken on the morning of 1,7,14 day after birth. The femoral vein blood was taken by the special people respectively, 2ml was placed at room temperature, 1H was placed at room temperature, 2000r/min centrifuged at normal temperature after 10min, and -80 C was frozen to be measured.
3.2 specimen detection: the IL-6 and NSE kits were produced by ADL company in the United States. The multi function immunofluorescence analysis system was used. Both the double antibody sandwich ELISA method was used and the operation was carried out strictly according to the instructions.
3.3 craniocerebral ultrasound: the GE VOLUSON730EXPERT ultrasonic detector was used. The parameters of the craniocerebral ultrasound were the same (the frequency of the scanners of the scalloped array of scans were 5-9mHz). The two groups were examined at 1 days, 7 days and 14 days after birth. The images of the central part of the lateral ventricle of the lateral ventricle were taken in the sagittal plane, and the abnormal white matter echoes were regarded as abnormal.
4. statistical method
SPSS19.0 statistical software package was used to set up a database. The three groups were compared with one-way ANOVA, when the variance was not homogeneous, Welch was used, and 22 was compared with LSD, and Dunnett T3 was used when the variance was not homogeneous. The difference of P0.01 was statistically significant by using alpha =0.01 as a test level.
4 children failed to complete the test because of abandoning treatment.
[results]
1. baseline information: there was no significant difference in age, gestational age, mode of delivery, body weight and sex composition between premature infants (P0.01).
2. the level of serum IL-6 and NSE in the observation group and the intervention group was significantly higher than that of the control group at the first day after birth, 7 and 14 days, and the gray level of the brain was significantly higher than that of the control group. (P0.01)
3. after treatment, the average serum NSE and IL-6 water in the intervention group were significantly lower than that in the observation group at seventh days after birth and fourteenth days. The gray level of the brain was significantly lower than that in the observation group. (P0.01).
[Conclusion]
The concentration of serum IL-6 and NSE in premature infants with 1. brain white matter injury is significantly higher than that of the control group. It is of certain clinical value to monitor the level of IL-6 and NSE in the serum of preterm infants and to evaluate the diagnosis and treatment effect of brain white matter injury.
2. craniocerebral ultrasound can be used as a powerful basis for early diagnosis and prognosis evaluation of white matter damage in preterm infants.
3.GM-1 has protective effects on cerebral white matter in preterm infants.

【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R722.6

【参考文献】