本文選題：新生兒疼痛 + 早產(chǎn)兒�。� 參考：《南京醫(yī)科大學》2014年博士論文

【摘要】：“疼痛”是指“一種不愉快的感覺和伴有實際或潛在組織損傷的情緒體驗,或是一種傷害”。由于醫(yī)學的進步和科學技術(shù)的發(fā)展,使得那些早產(chǎn)兒及重危兒在新生兒期得以存活下來。同時,對于這些未成熟兒的醫(yī)學和護理的診療措施也包涵了未予任何鎮(zhèn)痛處理的反復致痛性操作(painful procedures),使其在生命早期暴露于頻繁的疼痛刺激中。早期疼痛刺激可導致日后的疼痛敏感性改變,行為發(fā)育遲緩和情感認知紊亂,給家庭和社會帶來沉重負擔。因此,正確認識并闡明新生兒早期反復操作性疼痛對兒童健康的影響及其病理機制,提高兒科醫(yī)護人員對疼痛的認識,建立完善疼痛鎮(zhèn)痛管理規(guī)程,已成為兒科學領(lǐng)域新的挑戰(zhàn)。 兒童的神經(jīng)心理發(fā)育和行為是交織在一起的,行為發(fā)育反映了神經(jīng)系統(tǒng)尤其是腦成熟的各種特征,各種生物因素和環(huán)境亦對大腦的解剖結(jié)構(gòu)和功能產(chǎn)生影響。生命早期(生命最初1000天)是腦發(fā)育的關(guān)鍵時期,具有很大的可塑性,尤其是早產(chǎn)兒,其神經(jīng)系統(tǒng)更具有易損性。歷經(jīng)早期反復致痛性操作可導致下丘腦-垂體-腎上腺軸(hypothalamic-pituitary-adrenal axis, HPA)的調(diào)節(jié)程序化(programming)改變,使基礎(chǔ)和應激狀態(tài)下內(nèi)分泌激素如糖皮質(zhì)激素水平持續(xù)增加或抑制。而海馬中的糖皮質(zhì)激素受體(glucocorticoid receptor,GR)作為HPA軸負反饋的調(diào)節(jié)中樞,同時又是認知、學習、記憶的重要功能區(qū)。因此,HPA軸的程序化改變伴隨行為、認知、應激及內(nèi)分泌系統(tǒng)的發(fā)育異常,這在早期經(jīng)歷虐待、母子分離、不良養(yǎng)育行為和母孕期應激等不良環(huán)境刺激致成年期表型異常改變中得到證實。但是,生后早期反復操作性疼痛如何影響發(fā)育期海馬中GR的表達以及HPA軸的調(diào)控功能尚不完全清楚。 基于新生兒早期經(jīng)歷大量致痛性操作的現(xiàn)狀和腦發(fā)育的可塑性,本研究觀察了新生兒早期操作性疼痛對嬰幼兒疼痛敏感性、行為發(fā)育和外周糖皮質(zhì)激素水平的影響,并應用動物模型,觀察早期疼痛刺激后大鼠在青春前期及成年期行為表現(xiàn),及其HPA軸程序化的改變,闡明早期疼痛刺激對兒童行為發(fā)育影響及其病理生理機制,研究結(jié)果有助于提高醫(yī)務工作者對新生兒早期反復操作性疼痛對遠期健康影響的認識,并為新生兒疼痛的早期預防和干預提供科學依據(jù)。 第一部分新生兒期反復操作性疼痛對兒童行為發(fā)育和皮質(zhì)醇的影響 第一章新生兒期反復操作性疼痛對早產(chǎn)兒疼痛反應和皮質(zhì)醇的影響 目的 探討生后早期反復疼痛刺激對早產(chǎn)兒的疼痛行為和內(nèi)分泌系統(tǒng)的影響。 方法 選取在南京醫(yī)科大學附屬南京兒童醫(yī)院新生兒重癥監(jiān)護室(neonatal intensive care unit, NICU)住院的早產(chǎn)兒(男27例,女30例),視頻記錄其從入院到出院接受的所有針刺性操作,分別應用新生兒面部編碼系統(tǒng)(Neonatal Facial Coding System, NFCS)和早產(chǎn)兒疼痛量表(Premature Infant Pain Profile, PIPP)評估疼痛程度。比較早產(chǎn)兒入院時和住院兩周后血漿皮質(zhì)醇水平。 結(jié)果 1.住院期間,平均每個早產(chǎn)兒接受了104次致痛性操作。在經(jīng)歷40次以上的針刺性疼痛之后,疼痛操作階段時早產(chǎn)兒的PIPP和NFCS評分顯著高于第一次疼痛操作時(PIPP:P40=0.035; NFCS:P40=0.046),準備階段的NFCS分值亦顯著高于第一次操作的準備階段分值(P40=0.003)。 2.早產(chǎn)兒入院兩周后血漿皮質(zhì)醇(166.3nmol/L,34.6-595.3nmol/L)較入院時(306.2nmol/L,39.1-1750.0nmol/L)顯著降低(P=0.021),并與該期間經(jīng)歷的操作性疼痛的次數(shù)呈顯著負相關(guān)(r=-0.756,P0.001)。 結(jié)論 NICU的早產(chǎn)兒在經(jīng)歷反復操作性疼痛后對后續(xù)的針刺性疼痛表現(xiàn)出痛覺過敏,對于非疼痛處理表現(xiàn)出激惹現(xiàn)象。早產(chǎn)兒住院期間血漿皮質(zhì)醇水平下降,并與致痛性操作次數(shù)負相關(guān)。 第二章新生兒期反復操作性疼痛對幼兒行為發(fā)育及皮質(zhì)醇的影響 目的 觀察有NICU住院經(jīng)歷的早產(chǎn)兒在幼兒期的行為發(fā)育和應對新奇事物和認知挑戰(zhàn)時皮質(zhì)醇分泌模式,以及與父母養(yǎng)育環(huán)境的關(guān)系。 方法 選取出生后在南京醫(yī)科大學附屬南京兒童醫(yī)院NICU住院的早產(chǎn)兒,設(shè)為早產(chǎn)兒組(n=25)；選取同時期出生的足月健康兒童,設(shè)為足月兒組(n=38)。2歲時通知隨訪。父母填寫自制問卷,包括一般情況,簡式育兒壓力量表和2-3歲兒童行為量表；同時對幼兒進行體格測量,機械敏感性測試,Gesell智能發(fā)育檢查和唾液皮質(zhì)醇檢測。查閱早產(chǎn)兒住院期間的病歷資料進行相關(guān)分析。 結(jié)果 1.早產(chǎn)兒組和足月兒組的幼兒在2歲時身高、體重和頭圍體格發(fā)育方面無差異(P0.05)。但早產(chǎn)兒組足底經(jīng)皮機械敏感性閾值顯著低于足月兒組(P0.05),而家長評估的幼兒疼痛敏感性則與對照組無明顯差異(p=0.136)。 2.早產(chǎn)兒組母親的育兒壓力顯著高于足月兒組,表現(xiàn)在育兒愁苦和親子互動失調(diào)兩方面(P0.05)。 3.早產(chǎn)兒組Gesell發(fā)育評估的大動作、精細動作、適應性、語言和個人社交五個能區(qū)的發(fā)言商數(shù)(development quotient, DQ)均明顯低于足月兒組(P0.05),并與NICU疼痛刺激次數(shù),母親育兒壓力呈負相關(guān),與母親受教育時間呈正相關(guān)(P0.05)。 4.早產(chǎn)兒組父母評價兒童CBCL行為量表,內(nèi)向性行為的總分及社交退縮和抑郁分項目的得分均明顯高于足月兒組(P0.05)。早產(chǎn)兒組內(nèi)向性行為改變與母親的育兒壓力呈正相關(guān)(P0.05),分項目得分改變與精細動作DQ呈負相關(guān)(P0.05)。 5.基礎(chǔ)狀態(tài)和應對新奇事物和認知挑戰(zhàn)時唾液皮質(zhì)醇變化模式存在組間差異(F=4.879,P=0.035),各時間點之間同樣也存在差異(F=9.671,P=0.001)。早產(chǎn)兒組唾液皮質(zhì)醇變化與NICU經(jīng)歷的針刺性疼痛有關(guān)(P0.05),與母親因素無關(guān)(P0.05)。 結(jié)論 與正常足月兒比較,歷經(jīng)NICU住院經(jīng)歷的早產(chǎn)兒幼兒期機械敏感性增加,認知水平降低,內(nèi)向性行為增加,應對新奇事物和認知挑戰(zhàn)時唾液皮質(zhì)醇的變化模式和認知水平的改變均與其早期經(jīng)歷的反復針刺性疼痛有關(guān)。母親受教育時間的延長可以改善早產(chǎn)兒的認知功能。 第二部分基于下丘腦-垂體-腎上腺軸途徑研究新生大鼠反復操作性疼痛致遠期行為改變的病理機制 目的 應用大鼠動物模型,探討生后早期反復操作性疼痛對大鼠行為發(fā)育的影響以及HPA軸反應的變化。 方法 選取SPF級Sprague-Dawley (SD)孕鼠,新生大鼠出生后即對雄鼠進行隨機分組,疼痛組予以28G型細針迅速針刺足背,頻率為每六小時一次,四足輪流,對照組則用棉簽觸覺刺激。造模時間從出生當天(Postnatal day1,P0)持續(xù)至出生后第7天(P7)。每周觀察大鼠的機械敏感性閾值(von Frey mechanical test)變化,應用水迷宮實驗,測試大鼠的空間記憶,開場、懸尾和蔗糖偏好實驗測試大鼠焦慮、抑郁行為,應用生物學技術(shù),檢測皮質(zhì)酮,促腎上腺皮質(zhì)激素(adrenocorticotropic hormone, ACTH)海馬GRmRNA口蛋白表達水平。 結(jié)果 1.整個實驗階段兩組大鼠體重增長無顯著差異(P0.05)。P8開始,疼痛組大鼠左、右后足的機械敏感性閾值均低于對照組,并持續(xù)至P85(P0.001)。 2.水迷宮定位航行實驗：P25-P29以及P88-P92訓練階段,疼痛組大鼠與對照組相比,到達平臺的潛伏期無差異(P0.05)；但在P88-P92訓練階段,疼痛組大鼠的游泳速度明顯快于對照組(P0.05)。在水迷宮的空間探索實驗中：P30疼痛組大鼠第一次到達平臺潛伏期時間、穿越平臺次數(shù)以及平臺搜索策略均差于對照組(P0.05),而在P93兩組大鼠無差異(P0.05)。 3.P24開場測試時,疼痛組大鼠中心以及外周區(qū)域活動路程、外周區(qū)域活動速度、進入中心區(qū)域的次數(shù)均比對照組明顯增加(P0.05)；P87開場測試時,疼痛組大鼠中心區(qū)域活動時間和路程、進入中心以及外周區(qū)域次數(shù)和速度均比對照組顯著增加(P0.05)。P24和P87時疼痛組大鼠懸尾實驗不動時間比對照組明顯延長(P0.05),但蔗糖偏好實驗兩組無差異(P0.05)。 4.在P24及P59時,應激30分鐘后對照組大鼠血清皮質(zhì)酮比其他日齡水平明顯增加(P0.05)；而疼痛組該趨勢消失,并顯著低于對照組水平(P0.05),伴有P24血清促腎上腺皮質(zhì)激素(adrenocorticotropic hormone, ACTH)顯著低于對照組(P0.05)；在P87時,疼痛組大鼠應激后血清皮質(zhì)酮又顯著高于對照組(P0.05)。 5.與對照組比較,P59疼痛組大鼠雙側(cè)腎上腺比重顯著降低(P0.05)；但在P87時,雙側(cè)腎上腺比重又顯著增高(P0.01)。 6.與對照組比較,P24和P45疼痛組大鼠海馬GRmRNA和蛋白表達水平以及CA1區(qū)GR的平均光密度明顯增高(P0.05),而在P59和P87時又顯著降低(P0.05)。 結(jié)論 生后早期反復致痛性操作可以引起大鼠對機械刺激的敏感性持續(xù)性增高,青春前期空間記憶的保留功能受損,并使焦慮性、抑郁樣行為從青春前期持續(xù)到成年期；應激后HPA軸程序化改變和異常調(diào)控。 綜上,我們圍繞新生兒疼痛對機體近期和遠期影響這一科學問題,以新生兒期和兒童期為重點,以行為學和HPA軸為研究主線,動態(tài)觀察出生后NICU內(nèi)的反復操作性疼痛對早產(chǎn)兒行為和內(nèi)分泌系統(tǒng)的影響,證明生后早期反復操作性疼痛可以增強NICU住院期間早產(chǎn)兒的疼痛反應,造成住院期間及幼兒期皮質(zhì)醇的重塑(reset),2歲時機械敏感性增加,認知水平降低,內(nèi)向性行為的增加,母親育兒壓力增加進一步加重不良影響。進一步,應用動物模型,證明生后早期反復操作性疼痛引起機械敏感性持續(xù)性增高,從青春前期持續(xù)至成年期的行為改變；同時,機體應激反應系統(tǒng)重塑,HPA軸的反應呈現(xiàn)年齡特征改變：青春前期應激刺激后HPA軸低反應性和成年后HPA軸的過度反應。提示大腦發(fā)育關(guān)鍵期,反復致痛性操作導致HPA軸的程序化改變可能是日后心理行為、神經(jīng)和內(nèi)分泌系統(tǒng)發(fā)育障礙的重要病理生理機制�；谛律鷥浩跒橹袠猩窠�(jīng)系統(tǒng)程序化影響的關(guān)鍵時期,迫切需要在NICU建立新生兒疼痛管理,以避免遠期行為和認知功能的損害,提高早產(chǎn)嬰兒遠期生活質(zhì)量。
[Abstract]:"Pain" refers to "a feeling of unpleasant feeling and emotional experience with actual or potential tissue damage, or a kind of injury." due to the progress of medicine and the development of science and technology, the premature and critically ill infants survive in the newborn period. At the same time, the medical and nursing measures for these immature children are also taken. The repeated pain - induced manipulation (painful procedures), which has not been given to any analgesic treatment, has been exposed to frequent pain stimulation in the early life. Early pain stimulation can lead to changes in pain sensitivity, behavioral retardation and emotional cognitive disorders, and bring a heavy burden to family and society. The effect of early recurrent operational pain on children's health and its pathological mechanism, improving the understanding of pain by the pediatrics medical staff and establishing a management procedure for pain analgesia have become a new challenge in the field of Pediatrics.
The neuropsychological development and behavior of children are intertwined, and behavioral development reflects the various characteristics of the nervous system, especially the brain maturation. Various biological factors and environments also affect the anatomical structure and function of the brain. Early life (first 1000 days of life) is a critical period of brain development, with great plasticity, especially early in the early years. The nervous system is more vulnerable. After early repeated pain operation, the regulation of the hypothalamus pituitary adrenal axis (hypothalamic-pituitary-adrenal axis, HPA) regulates (programming) changes and increases or inhibits the levels of endocrine hormones such as glucocorticoids in the base and stress state. Glucocorticoid receptor (GR) is the regulatory center of negative feedback of HPA axis, and is also an important functional area of cognition, learning and memory. Therefore, the programmed changes of the HPA axis are associated with behavioral, cognitive, stressful, and endocrine dysplasia, which are in the early stage of abuse, mother and child separation, bad parenting behavior and maternal stress. However, the effect of early recurrent pain on the expression of GR in the hippocampus and the regulatory function of the HPA axis in the hippocampus of the developmental stage is not completely clear.
Based on the current situation of painful operation in early newborn and the plasticity of brain development, this study observed the effects of early operative pain on pain sensitivity, behavior development and peripheral glucocorticoid levels in infants, and used animal models to observe the behavior of early and adult rats in the early stage of pain and pain. The expression, and the changes of the programmed HPA axis, clarify the effect of early pain stimulation on children's behavioral development and its pathophysiological mechanism. The results are helpful to improve the understanding of the long-term health effects of recurrent pain in the early neonates, and provide a scientific basis for the early prevention and intervention of neonatal pain.
Part one the effect of neonatal recurrent pain on behavior development and cortisol in children
Chapter 1 the effect of neonatal recurrent pain on the pain response and cortisol in premature infants
objective
Objective to investigate the effects of early postnatal recurrent pain stimulation on pain behavior and endocrine system in preterm infants.
Method
The preterm infants (27 males and 30 females) were selected in the neonatal intensive care unit (NICU) of the Nanjing Children's Hospital of Nanjing Medical University, and all the needling operations were recorded from admission to discharge from hospital to hospital. The neonatal facial coding system (Neonatal Facial Coding System, NFCS) and preterm birth were applied respectively. Premature Infant Pain Profile (PIPP) was used to assess the pain level. Plasma cortisol levels were compared between the preterm infants and the two weeks after admission.
Result
During 1. hospitalization, the average preterm infants received 104 painful operations. After more than 40 needling pain, the PIPP and NFCS scores in premature infants were significantly higher than those of the first pain operation (PIPP:P40=0.035; NFCS:P40=0.046), and the NFCS score at the preparatory stage was significantly higher than that of the first operation. Segment value (P40=0.003).
2. the plasma cortisol (166.3nmol/L, 34.6-595.3nmol/L) was significantly lower than that of admission (306.2nmol/L, 39.1-1750.0nmol/L) after two weeks of admission to hospital (P=0.021), and was negatively correlated with the frequency of operational pain (r=-0.756, P0.001).
conclusion
The preterm infants of NICU showed hyperalgesia for subsequent acupuncture pain after repeated operation pain, and showed irritability for non pain treatment. The plasma cortisol level in premature infants declined during hospitalization and was negatively related to the number of painful operations.
The second chapter is about the effect of neonatal recurrent pain on behavior development and cortisol in young children.
objective
The relationship between the behavior development of preterm infants with NICU hospitalization and cortisol secretion patterns in response to novelty and cognitive challenges as well as the parental rearing environment were observed.
Method
The preterm infants who were hospitalized at NICU, Nanjing Children's Hospital, Nanjing Medical University, were selected as preterm infants (n=25), and a full term full term child was selected at the same time as the foot Moon Group (n=38) at the age of.2. The parents filled out the self-made questionnaire including the general situation, the simplified parenting pressure scale and the 2-3 year old child behavior scale; Physical measurement, mechanical sensitivity test, Gesell intelligence development examination and saliva cortisol test were carried out for young children. Related analysis was made on the medical records of preterm infants during hospitalization.
Result
There was no difference in height, body weight and physical development of head circumference (P0.05) at the age of 2, but the threshold of the plantar mechanical sensitivity of the preterm infants was significantly lower than that in the foot group (P0.05), but the sensitivity of the child's pain was not significantly different from that of the control group (p=0.136).
2. the pressure of parenting in the premature group was significantly higher than that in the full-term group, which was manifested in two aspects of childcare anxiety and parent-child interaction disorder (P0.05).
3. the Gesell development assessment of the preterm infant group was significantly lower than that of the full term group (development quotient, DQ), which was significantly lower than that of the full-term group (P0.05), and was negatively related to the number of NICU pain stimuli, and the mother's childbearing pressure was negatively correlated with the mother's education time (P0.05).
4. the parents of 4. preterm infants evaluated the children's behavior scale, the total score of introverted sexual behavior and the score of social withdrawal and depression were significantly higher than that of the full term infants (P0.05). The change of introversion in preterm infants was positively correlated with the parental pressure of parenting (P0.05), and the score change of the sub project was negatively correlated with the fine movement DQ (P0.05).
5. the difference in the pattern of saliva cortisol changes (F=4.879, P=0.035) was also different between the different time points (F=9.671, P=0.001). The change of saliva cortisol in the preterm group was related to the needling pain experienced by NICU (P0.05), and was not related to the mother's factor (P0.05).
conclusion
Compared with normal foot months, the mechanical sensitivity of premature infants who experienced NICU hospitalization increased, cognitive level decreased, and inward behavior increased. Changes in the patterns and cognitive levels of saliva cortisol change in response to new things and cognitive challenges were related to repeated needling pain in the early experience. Prolongation can improve the cognitive function of preterm infants.
The second part is based on the hypothalamic pituitary adrenal axis pathway to study the pathological mechanism of long-term behavioral changes in neonatal rats with repeated operative pain.
objective
Animal models were used to investigate the effects of early postoperative pain on behavior development and HPA axis response in rats.
Method
The newborn rats were randomly divided into SPF grade Sprague-Dawley (SD) pregnant rats after birth. The pain group gave 28G fine needle to the dorsum of the foot quickly. The frequency was once every six hours, four feet were rotated, and the control group was stimulated by the cotton swab. The model time lasted from the day of birth (Postnatal day1, P0) to the seventh day after birth (P7). A weekly observation was made. The mechanical sensitivity threshold (von Frey mechanical test) of rats was changed. The water maze test was used to test the rats' spatial memory, the opening, the tail and the sucrose preference test to test the rats' anxiety, depressive behavior, the application of biological techniques, the detection of corticosterone and the hippocampal GRmRNA protein protein (adrenocorticotropic hormone, ACTH) of the adrenocorticotropin (adrenocorticotropic hormone). Expression level.
Result
1. in the whole experimental stage, there was no significant difference in weight gain between the two groups (P0.05).P8. The threshold of the mechanical sensitivity of the left and right hind feet in the pain group was lower than that of the control group, and continued to P85 (P0.001).
2. water maze navigation experiment: at P25-P29 and P88-P92 training stage, there was no difference in the incubation period between the pain group and the control group (P0.05), but in the P88-P92 training stage, the swimming speed of the rats in the pain group was faster than that of the control group (P0.05). In the space exploration experiment of the water maze, the P30 pain group first arrived. The latency of platform, the number of crossing platform and platform search strategy were equally different in the control group (P0.05), but there was no difference in P93 two groups (P0.05).
During the opening test of 3.P24, the center of the pain group and the activity of the peripheral region, the frequency of the activity in the peripheral region and the number of entering the central area were significantly increased (P0.05), while the time and distance of the center area of the pain group, the times and the speed of entering the middle and peripheral regions of the pain group were significantly higher than the control group when the P87 opened the test. At the time of adding (P0.05).P24 and P87, the immobility time of the rats in the pain group was significantly longer than that in the control group (P0.05), but there was no difference in sucrose preference test between the two groups (P0.05).
4. at P24 and P59, after 30 minutes of stress, the serum corticosterone of the control group increased significantly (P0.05), but the trend of pain group disappeared, and was significantly lower than the control group (P0.05), with P24 serum adrenocorticotropin (adrenocorticotropic hormone, ACTH) significantly lower than the control group (P0.05); in P87, pain group. Serum corticosterone in rats after stress was also significantly higher than that in control group (P0.05).
5. compared with the control group, the proportion of bilateral adrenal glands in P59 pain group decreased significantly (P0.05), but at P87, the proportion of bilateral adrenal glands increased significantly (P0.01).
6. compared with the control group, the expression level of GRmRNA and protein in hippocampus and the mean light density of GR in CA1 region were significantly higher in P24 and P45 pain groups (P0.05), but decreased significantly at P59 and P87 (P0.05).
conclusion
The early repeated pain operation after birth can cause the increasing sensitivity of the rat to mechanical stimulation, the impairment of the reservation function of the prepuberty spatial memory, and the anxiety and depressive behavior from prepuberty to adulthood, and the programmed change of the HPA axis and abnormal control after stress.
To sum up, we focus on the short-term and long-term effects of neonatal pain, focusing on neonatal period and childhood, with behavioral and HPA axis as the main line, to dynamically observe the effect of recurrent operational pain on preterm infant behavior and endocrine system in postnatal NICU, and to prove that early recurrent operational pain after birth can be proved. In order to enhance the pain response of preterm infants in NICU during hospitalization, the remodeling of cortisol during hospitalization and early childhood (reset), increased mechanical sensitivity at 2 years of age, lower cognitive level, increased inward behavior, and increased parental pressure in the mother's parenting, further aggravated the adverse effects. Further, the animal model was used to prove the early recurrent operation pain. The changes in mechanical sensitivity continue to increase from prepuberty to adulthood; meanwhile, the body stress response system reshaped, the response of the HPA axis presents a change of age characteristics: the HPA axis low responsiveness and the overreaction of the adult HPA axis after prepuberty irritation. Programmed changes to the HPA axis may be the future psychological behavior, nerves and
【學位授予單位】：南京醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R722.1

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