【作者】 李训军；

【导师】 蒋晓江；

【作者基本信息】 第三军医大学 ， 神经病学， 2009， 硕士

【摘要】 背景:流行病学的证据表明,大约有10~13%的成年人忍受着慢性失眠带来的痛苦,还有25~35%成年人曾经有过短暂或偶尔的失眠。慢性失眠患者常常处于睡眠剥夺状态,引起烦躁、注意力不集中、疲乏等不适,以及应激、呼吸、免疫和内分泌功能不全,严重影响患者的工作、学习和生活。目前临床上对慢性失眠症患者的治疗多采用镇静催眠药物治疗,辅以中药及理疗等方法,认知行为疗法在我国现有的国情下还少有开展。由于对镇静催眠药物剂量依赖性的恐惧,加上患者甚至有些医务人员对药物的不正确认识,使得大多数患者的服药依从性降低。近年来的研究表明,异丙酚全身麻醉与自然睡眠在行为学上的相似性和发生机制上的相互作用说明全麻镇静可能通过激活大脑内调节睡眠的神经网络,恢复大脑兴奋性神经递质与抑制性神经递质系统的平衡,从而逆转失眠患者的睡眠债务。异丙酚麻醉具有半衰期短、作用时间快、浓度易控制、患者苏醒快、不良反应少等优点,但应用异丙酚麻醉治疗慢性失眠症目前国内文献尚未见有关报道。有研究表明,慢性失眠症患者大脑内兴奋性神经递质与抑制性神经递质平衡被破坏。在动物试验中观察到,大鼠在REM睡眠剥夺后,应用异丙酚麻醉诱导睡眠的试验表明,额叶皮质内兴奋性神经递质如去甲肾上腺素、多巴胺等显著降低,而抑制性神经递质如γ-氨基丁酸等则显著增加,促进了脑内神经递质的平衡。根据这一理论,在征得医院伦理委员会同意及患者的书面知情同意后,我们与麻醉科联合开展了异丙酚麻醉诱导睡眠平衡术治疗慢性失眠症的新技术,有效率达97%,为慢性失眠症患者的治疗提供了一种可靠的临床治疗方法。目的:1.本研究通过改良多平台法建立大鼠REM睡眠剥夺的动物模型,应用Morris水迷宫测试系统观察REM睡眠剥夺对学习记忆能力的影响,应用高效液相色谱-电化学方法检测额叶皮质5-HT的含量,探讨REM睡眠剥夺对学习记忆能力影响的可能作用机制,并进一步观察异丙酚麻醉诱导睡眠对睡眠剥夺带来的睡眠债务的恢复情况,以及异丙酚麻醉诱导睡眠对睡眠剥夺恢复后大鼠学习记忆的改善情况;2.在临床中遴选慢性失眠症患者,在征得患者本人书面同意及医院伦理委员会同意后,通过异丙酚麻醉诱导睡眠对慢性失眠症患者进行治疗,观察异丙酚麻醉诱导睡眠对慢性失眠症患者的近期与中远期临床疗效。材料与方法:1.试验动物与分组选用健康成年雄性Sprague-Dawley大鼠(S-D大鼠)随机分为空白对照组(CC组n=10),大平台对照组(TC组n=40),REM睡眠剥夺组(RSD组n=40),异丙酚麻醉诱导睡眠组(异丙酚组n=40),脂肪乳对照组(脂肪乳组n=40),各组大鼠分为24h、48h、72h、96h四个时相点;2.动物模型制备采用改良多平台法制备S-D大鼠REM睡眠剥夺模型;3.学习记忆测量运用Morris水迷宫的定位航行及空间搜索实验来观察睡眠剥夺对大鼠空间学习记忆的影响;4.额叶皮质5-HT含量的检测应用高效液相色谱-电化学法检测大鼠额叶皮质5-HT浓度的变化情况;5.慢性失眠症患者的遴选选取我科住院治疗的慢性失眠症患者共25例(其中1例因患者个人原因退出治疗),排除合并有其他疾病者;6.异丙酚麻醉诱导睡眠患者入院后经常规检查排除各系统严重疾病,治疗前禁食水8小时,开放外周液体,监测心电、呼吸、血氧饱和度、血压等,采用具有靶浓度控制输注技术(TCI)功能的微量注射泵泵注异丙酚,Marsh模式下预设效应浓度为3.0ug/L,治疗从晚间10点开始,静脉注射2mg咪唑安定后开始麻醉诱导,血压维持在术前值的±20%,异丙酚共输注2小时,停药后等待患者苏醒,然后撤去生命体征监测,患者进食;7.临床疗效的判定分别在治疗前与治疗后采用脑电超慢涨落技术(ET)检测患者脑内神经递质活动的变化情况;采用多导睡眠检测系统(PSG)分别在治疗前与治疗后对患者的睡眠结构进行检测;采用里兹睡眠评估问卷(LSEQ)和匹兹堡睡眠质量指数(PSQI)对慢性失眠症患者治疗后近期及中远期睡眠状况进行评估。结果:一、Morris水迷宫的实验结果显示,对照组和睡眠剥夺组大鼠在实验中搜索平台潜伏期、游泳路程变化的总趋势相同,越来越趋向于在平台的位置搜索,但睡眠剥夺组较对照组潜伏期1(L1)所用时间增长,有显著性差异,潜伏期2(L2)之间比较没有显著性差异;二、随着REM睡眠剥夺的时间延长,大鼠额叶皮质内5-HT的含量逐渐升高,在3d、4d时与大平台组及空白对照组相比具有显著统计学差异;三、睡眠剥夺后,异丙酚麻醉诱导睡眠组较脂肪乳对照组搜索平台潜伏期所用时间减少,二者有统计学差异。异丙酚组较脂肪乳组额叶皮质内5-HT的含量下降,具有统计学意义;四、脑电超慢涨落(ET)中枢神经递质活动分析:与期望值相比较,治疗前兴奋性神经递质活动明显增强(P <0.01),而抑制神经递质活动明显减弱(P <0.01),治疗后兴奋性神经递质活动较治疗前明显减弱(P <0.05),治疗后兴奋与抑制平衡得到明显恢复;五、多导睡眠图结果表明:异丙酚麻醉诱导睡眠后患者总睡眠时间有所延长(P <0.05),而觉醒次数明显减少(P <0.01),相应的觉醒时间也明显缩短(P <0.01),但睡眠潜伏期无明显变化;睡眠结构中的S1期睡眠较治疗前明显减少(P <0.01),S3期、S4期及REM期睡眠则明显增加(P <0.05),而S2期睡眠却未见明显变化;六、以慢性失眠患者LSEQ因子评分及总分评价疗效,在治疗前、后的测量中,麻醉睡眠诱导后患者在入睡情况、睡眠质量、警觉行为和总分等方面有明显改善(P <0.05),而在宿醉症状改善不明显。治疗后近愈5例(增分>300分,占21%),显效10例(增分>200分占42%),有效7例(增分>100分占29%),无效2例(增分<100分占8%);总有效率92%(22例);七、患者经异丙酚麻醉诱导睡眠治疗后匹兹堡睡眠质量指数提示:在睡眠质量、入睡时间、睡眠效率及日间功能等睡眠指标上较治疗前有明显改善(p<0.05)。结论:一、REM睡眠剥夺导致大鼠学习记忆能力下降可能与额叶皮质内5-TH含量增加有关;异丙酚麻醉诱导睡眠可有效降低REM睡眠剥夺后大鼠额叶皮质内5-HT的含量,提高大鼠的学习记忆能力;二、异丙酚麻醉诱导睡眠是短期内纠正慢性失眠患者睡眠债务行之有效的方法,为药物依赖性慢性失眠患者的临床治疗提供了新的治疗方法。更多还原

【Abstract】 BackgroundIt is indecated by the epidemiological evidence that about 10∽13 percent adults suffered anguish with chronic insomnia, and 25∽30 percent adults had been transient or occasional hyposomnia. The chronic insomnia patients were usually in sleep deprivation, caused agitaion,warelessness,lassitude and the failure function with the stress,respiration,immunifaction and endocrine secretion, that influence the patients studying,working and living seriously. At present, the treatment on chronic insomnia was by sedative hypnotics, subsidiary traditional chinese medicine and physical treatment. The cognitive behavior therapy was developed raerely in the forthcoming condition, but the patients submiting drug compliance were cut down by the dose dependent sedative hypnotics and the patients and partial doctors uncorrected recognition. The recent study manifest that general anesthesia by propofol and natural sleep were similarity in ethology and interaction each other in generated mechanism, which indicated that general anesthesia would recover the neurotransmitters system balance by activating the entocerebrum regulating sleep neurolattice, thus reverse sleep debt. The general anesthesia by propofol are many graces, such as short demiperiod、fast effect、easy contral concentration and few adverse effect and so on. At present, it is not reported that anesthesia by propofol treat on chronic insomnia in domestic documents. The rats were anesthetized by propofol after sleep deprivation, the concentrate of exciability neurotransmitters was significantly decreased,such as NE、DA, while the rejection capability neurotransmitters was increased,such as GABA. According to this theory, we designed that propofol anesthetize sleeping balance treatment on the chronic insomnia patients, the effective power was 97%.Of course, all these measures were carried out under the agreement of hospital Ethics Committee and the patients permission in writing. Objective:1. It is established the animal model of REM sleep deprivation by modified multiple platform method in the study and investigated the effects of rapid eye movement (REM) sleep deprivation on cognitive function and the content of 5-HT in the rat frontal cortex, and approached the possible mechanism. And then, investigated the cognitive function and the level of 5-HT in frontal cortex after general anesthesia by propofol after sleep deprivation.2. The chronic insomnia patients were selected among the clinic inpatients,who would been treated by propofol anesthesia inducing sleep after the agreement of hospital Ethics Committee and the patients permission in writing, the short and long term curative effect were sdutied.Materials and Methods:1. Animals and groups: The health adult Sprague-Dawley rats were adopted and divided into groups randomly,such as blank contral group(n=10)、big platform contral group(n=40)、sleep deprivation group(n=40)、propofol anesthesia group(n=40)、fat milk contral group(n=40), each group was subdivided into 24h、48h、72h and 96h four phase point except blank contral group.2. Animal model prepare: Experimental model of sleep deprivation (SD) was established by use of modified multiple platform method.3. Learning and memory measure The variation of learning and memory was detected by Morris water maze at pre and post sleep deprivation.4. The level of 5-HT detect : High performance liquid chromatography- electrochemical detection( HPLC-ECD) techniques were used to analyze the levels of 5-HT.5. Chronic insomnia patients selected: Twenty-five chronic insomnia inpatients were selected who were in hospital and had no other disease.6. Treatment method: The neurology department carried out the anesthetize duse sleeping balance treatment on chronic insomnia combining with the department of anethesiology. The insomnia inpatients were excepted serious disease by routine examination, fasting diet before treatment, the propofol was micro-injecting 2 hours with the electrocardio-monitoring, after the patient waked , withdrawed the monitoring. 7. Curative effect assessment: Compare the record of ET and score of LSEQ between before and after therapy. Polysomnography (PSG) recordings were conducted and scores of Pittsburgh sleep quality index(PSQI) were measured pre and post therapy.Results1. As compared with blank control group, the content of 5-HT in frontal cortex increasing accompanied with the REM sleep deprivation time prolonging, while the learning ability was decreasing.2. The content of 5-HT in the front cortex was increasing with the time of REM sleep deprivation prolonging, it was significant statistic difference at 72 hour and 96 hour that compared with the big platform group or the blank contral group.3. After 96 hours sleep deprivation, the latency phase time of the propofol anesthesia group rats was more decreased than the fat milk contral group rats’, while the content of 5-HT in front cortex was decreased, the difference was statistical significance.4. The activity of excitable neurotransmitters was more obviously activity and inhibitory neurotransmitters was more obviously weaken than the normal score (P<0.01). The activity of excitable neurotransmitters was more obviously decrease after therapy than before therapy (P<0.05). The patients were associated with a significantly higher response to anesthetize sleeping balance therapy in ease of getting to sleep、quality of sleep、alertness and behavioral integrity the following morning and gross score(p<0.05).;5. The score of PSQI suggested that there were 90% (27 cases)decrease more than 25%, The patients were associated with a significantly higher responses to anesthetize duse sleeping therapy in ease of getting to sleep、quality of sleep、altering and behavioral integrity the following morning and gross score. Increased total sleep duration, decreased awake frequency and decreased awake duration was found after therapy with PSG while changed sleep architecture such as decreased S1%, increased S3%, S4% and the percentage of REM time was found.Conclusion1.The dysfunction of learning ability of sleep deprivation may be associated with the content of 5-HT in the rat frontal cortex;2.The treatment of chronic insomnia by anesthetize sleeping balance was effective and safety, and was a effective method to recover sleep debt; 3.The treatment by anesthetize induce sleeping may improve the sleep architecture of partial chronic insomnia patients especially effectively recover the sleep debt of the patient with in a short duration.更多还原