睡眠呼吸暂停低通气综合征与子痫前期的相关性及其可能的发病机制

发布时间：2018-05-26 17:43

本文选题：睡眠呼吸暂停低通气综合征 + 子痫前期　；参考：《南方医科大学》2010年硕士论文

【摘要】：背景随着睡眠研究的深入,人们不仅了解到睡眠对人类的重要性,而且逐步了解到不正常的睡眠对人类所产生的重大的影响。人的一生有1／3是在睡眠中度过的,在这1／3的夜色中,发生于睡眠中的众多现象如做梦、梦游、失眠等睡眠障碍性疾患虽早就引起医务人员的注意,但人们未给予重视,至于睡眠对其他疾病的影响人们更是知之甚少。生活中常常有这些情况发生：一个素来健康的朋友在睡眠中莫名其妙的突然去世；一些不明原因的原发性高血压患者,一辈子痛苦的过着药罐子的生活；殊不知这些意外的死亡或不明原因的常见疾病很可能与睡眠中司空见惯的一种现象——打鼾及呼吸暂停有关。随着人们对睡眠的进一步认识及传感记录技术的发展,从20世纪70年代在世界范围内将睡眠呼吸紊乱作为一种疾病予以关注并认真研究的。睡眠呼吸紊乱(Sleep Disorder Breathion,SDB)包括单纯性鼾症、肥胖低通气综合征、睡眠呼吸暂停低通气综合征、上气道阻力综合征,其中睡眠呼吸暂停低通气综合征(Sleep Apnea Hypopnea Syndrom,SAHS)分为阻塞性睡眠呼吸暂停低通气综合征(Obstructive Sleep Apnea Hypopnea Syndrom,OSAHS)、中枢性睡眠呼吸暂停低通气综合征(Central Sleep Apnea Hypopnea Syndrom,CSAHS)、混合性睡眠呼吸暂停低通气综合征(Mixed Sleep Apnea Hypopnea Syndrom,MSAHS)。我国SAHS的研究从无到有,从局部地区发展到全国,走过了近20年的历史,最初阶段是一些开拓与探索性工作,真正的发展是近几年的事情,随着睡眠试验室数量的增加,被诊治的患者数量有了相应的增加,诊治技术不断地提高,开展了与SAHS相关学科领域的科研工作,包括基础与临床研究,流行病学调查等,目前已研究证实SAHS是导致高血压的独立危险因素。睡眠呼吸暂停低通气综合征主要表现为睡眠时打鼾并伴有呼吸暂停和呼吸表浅,夜间反复发生低氧血症、高碳酸血症和睡眠结构紊乱,导致白天嗜睡,工作效率降低等,且常并发心脑血管疾病,严重影响患者的生活质量和寿命。学者研究发现SAHS患者夜间反复缺氧及再灌注导致血清中炎症因子(IL-6、TNF-a等)明显增高并进一步导致高血压等疾病的发生。妊娠高血压疾病是妊娠期特有以高血压为主要临床表现的疾病,其发病率达10.5%,而子痫前期是妊娠期高血压疾病中一经诊断均需住院治疗的更为严重的一个发展阶段,是孕产妇和围生儿发病率及死亡率的主要原因,如何及早发现、积极预防和干预是产科医务工作者一直在探索的问题,至今子痫前期病因及发病机制尚未完全阐明,虽然建立了胎盘缺血学说,血管内皮损伤学说,免疫学说和遗传学说等。但还只是停留在学说上,多数学者研究发现子痫前期患者血清中炎症因子(IL-6、TNF-a)明显高于正常妊娠者,且与子痫前期疾病病情的严重程度呈明显相关性；Williams等研究发现子痫前期患者在临床症状出现之前就已有外周血及羊水中TNF-a及其受体含量的显著升高。但炎症因子增多的原因尚不清楚。 IL-6与TNF-a都是近10余年来发现的细胞因子,它们均具有广泛的生物学活性。在正常妊娠时均维持在较低水平,调节胎盘组织的正常生长和功能发挥,参与正常妊娠的维持,促进滋养层细胞的增殖和侵袭性,增加子宫胎盘血供,促进胎儿生长发育及调节母胎之间的免疫调节。TNF-a和IL-6持续增高可导致人体病理损害的发生,如促进内皮细胞黏附白细胞,刺激内皮细胞分泌炎性介质,激活凝血系统、抑制纤溶,增加炎性渗出和氧自由基的产生,促进细胞黏附分子的表达等等,进一步导致血管收缩痉挛,血压增高,影响肾脏血管,导致蛋白尿的出现。近几年国外多数学者研究发现SAHS与子痫前期、宫内胎儿生长受限、早产等有明显相关性,且对存在SAHS的孕妇给予nCPAP治疗后可明显降低子痫前期患者的血压并生产出正常体重胎儿。我们发现SAHS与子痫前期有众多重叠因素如：均有炎症因子及氧化应激产物水平的升高,上气道狭窄、腹型肥胖等使胸廓活动度减小的因素存在,内分泌的的变化等等,另外临床表现都有高血压、夜间片段睡眠、白天嗜睡等表现。鉴于以上研究的基础及国际上认可的SAHS诊断手段——多导睡眠监测,我们对入选的患者进行多导睡眠监测以评估其是否存在SAHS,并从炎症因子水平初步探讨SAHS与子痫前期之间相关性及炎症因子在其可能的发病机制中的作用,另外对于存在SAHS的患者给予国际认可的治疗SAHS的有效方法之一——持续气道正压通气治疗,并观察治疗效果以进一步证实SAHS与子痫前期之间的相关性。第一章炎症因子水平初步观察并探讨SAHS与子痫前期的相关性目的通过检测血清中的炎症因子水平初步观察并探讨SAHS与子痫前期的相关性。方法 1、病例与分组选取2008年7月～2009年6月在重症孕产妇救治医院产检并住院分娩的符合纳入标准的子痫前期孕妇及同期入院产检的年龄、孕龄无显著差异的正常孕妇,对其均进行整晚的多导睡眠监测(Polysomnogram,PSG),其中正常妊娠组25例,子痫前期无SAHS组43例,子痫前期并SAHS组27例。以上孕妇均为单胎妊娠,且既往无高血压、心脏病、肾病、糖尿病和慢性肺部疾病等可引起低氧的疾病。 2、睡眠监测对入选的孕妇均进行整晚至少7h的多导睡眠监测,监测内容包括：脑电、眼电、下颌肌电、心电、口鼻气流、鼾声、体位、胸腹运动和血氧饱和度。多导睡眠监测(PSG)监测的数据先后经电脑自动分析和人工校正,参考中华医学会制定的《阻塞性睡眠呼吸暂停低通气综合征诊治指南(草案)》成人SAHS诊断标准,其中AHI作为主要判断标准,LSaO2作为参考,做出是否存在SAHS及其严重程度的诊断。 3、血压测量于睡眠监测结束后平卧10分钟,采用立式水银柱袖带式血压计(上海医用设备厂生产)测量血压,为方便比较,取其平均动脉压(Mean Arterial Pressure,MAP), MAP=舒张压+1／3(收缩压—舒张压)。 4、24小时尿蛋白定量测定收集7Am以后至次日7Am共24小时尿液,采用考马斯亮蓝G25O4法测定24小时尿蛋白并作记录。 5、血清IL-6和TNF-a检测于第二日清晨睡眠监测完毕醒后静卧10分钟静脉采血6ml,放于4℃冰箱中待分离,3000r／min离心10min,分离血清并分装于EP管中,-80℃保存待检。血清TNF-a和IL-6水平的检测采用酶联免疫吸附试验(Enzyme-Linked Immunosorbnent Assay, ELISA),试剂盒由武汉博士德公司提供,检测方法严格按照说明书进行操作。 6、统计分析采用统计软件SPSS13.0进行统计学处理和分析。试验数据计量资料采用均数加减标准差(x±SD)表示。组间比较采用One-Way ANOVA,两组间比较采用LSD检验,相关性分析采用Pearson。所有统计数据以P0.05作为有显著性差异的界限。结果 1、一般资料组间年龄(27.5±6.0 vs 29.0±5.3 vs 29.2±5.0,P0.05)、孕龄(31.1±4.9 vs 31.0±4.0 vs 30.6±4.6,P0.05)比较无显著性差异,具有可比性。 2、组间临床及试验室指标统计学分析三组间体重量指数(BMI)、平均动脉压(MAP)、24h尿蛋白定量、睡眠呼吸暂停低通气指数(AHI)、最低血氧饱和度(LSaO2)、IL-6及TNF-a水平有显著差异(P0.01)。但子痫前期无SAHS组与子痫前期并SAHS组BMI无显著差异(P=0.083)。正常妊娠组和子痫前期无SAHS组比较AHI和LSaO2无显著差异(P=0.797,0.862)；子痫前期两个重要的临床指标血压和24h尿蛋白定量与SAHS的严重程度呈显著的相关性(P0.01)；与炎症因子指标IL-6及TNF-a相关系数更大,IL-6和TNF-a与AHI和LSaO2也有显著相关性。同时发现血压和尿蛋白与BMI有一定的相关性,但相关性较弱。结论 1、子痫前期孕妇夜间发生睡眠呼吸暂停低通气的次数较正常妊娠妇女明显增多,说明子痫前期孕妇发生SAHS的机率相对增加。 2、炎症因子(IL-6和TNF-a)可能在子痫前期合并SAHS的发病机制中起到重要的作用。 3、SAHS可能是导致子痫前期疾病发生和发展的一个危险因素。第二章AutoCPAP治疗子痫前期合并SAHS患者疗效观察目的通过对合并SAHS的子痫前期孕妇进行AutoCPAP治疗观察治疗效果及进一步证实SAHS与子痫前期间的相关性。方法 1、病例选取经多导睡眠监测证实存在SAHS的孕妇27例,再次统计其年龄、孕龄、BMI等基本资料。 2、AutoCPAP治疗对经过多导睡眠监测证实符合SAHS诊断标准的孕妇给予进一步解释AutoCPAP治疗的一些相关情况,并签知情同意书,每天给予至少4小时的治疗,向患者详细解释该呼吸机的使用方法、面罩佩戴问题及使用过程中可能出现的问题及解决方法,在患者完全明白后开始给予治疗,因多数患者在起初使用时不太适应,所以给予延迟30分钟升压并给予湿化以使患者慢慢适应至接受。呼吸机压力范围定在4～20cmH2O。 3、血压测量于睡眠监测结束后平卧10分钟,采用立式水银柱袖带式血压计(上海医用设备厂生产)测量血压,为方便比较,取其平均动脉压(Mean Arterial Pressure,MAP),MAP=舒张压+1／3(收缩压—舒张压)。 4、24小时尿蛋白定量测定收集7Am以后至次日7Am共24小时尿液,采用考马斯亮蓝G25O4法测定24小时尿蛋白并作记录。 5、血清IL-6和TNF-a检测于第七日清晨AutoCPAP治疗疗程完毕醒后静卧10分钟静脉采血6ml,放于4℃冰箱中待分离,3000r／min离心10min,分离血清并分装于EP管中,-80℃保存待检。血清TNF-a和IL-6水平的检测采用酶联免疫吸附试验,试剂盒由武汉博士德公司提供,检测方法严格按照说明书进行操作。 6、统计学分析采用统计软件SPSS13.0进行统计学处理和分析。试验数据计量资料采用均数加减标准差(x±SD)表示。治疗前后比较采用配对t检验,所有统计数据以P0.05作为差异有显著性差异的界限。结果经AutoCPAP治疗后患者自觉白天嗜睡症状减轻,夜间觉醒次数减少,情绪较前好转。患者炎症因子IL-6和TNF-a水平及子痫前期临床指标血压和尿蛋白定量较治疗前显著降低(P0.05)。结论 1、经AutoCPAP治疗1周后炎症因子及子痫前期临床指标血压和蛋白尿明显降低,进一步证实SAHS可能是导致子痫前期发生和发展的一个危险因素。 2、对于存在SAHS的子痫前期孕妇积极给予AutoCPAP治疗可通过减轻夜间呼吸暂停指数及低氧血症来降低炎症因子水平进一步减轻子痫前期的临床症状。
[Abstract]:background
With the deepening of sleep research, people not only understand the importance of sleep to human beings, but also gradually understand the significant impact of abnormal sleep on humans. 1 / 3 of human life are spent in sleep. In this 1 / 3 night, many sleep disorders such as dreaming, sleepwalking, insomnia and other sleep disorders. Although it has long been the attention of the medical staff, people have not given attention to it, and people know little about the effects of sleep on other diseases. Live the life of drug cans; it is not known that these accidental deaths or unexplained common diseases are likely to be associated with a common phenomenon in sleep, snoring and apnea.
With the further awareness of sleep and the development of sensing recording technology, sleep breathing disorders (Sleep Disorder Breathion, SDB) including simple snoring, obesity hypopnea syndrome, and sleep apnea hypopnea have been paid attention to and studied in the world as a disease in 1970s. Syndrome, upper airway resistance syndrome, and sleep apnea hypopnea syndrome (Sleep Apnea Hypopnea Syndrom, SAHS) are divided into obstructive sleep apnea hypopnea syndrome (Obstructive Sleep Apnea Hypopnea Syndrom, OSAHS), and central sleep apnea hypopnea syndrome. S), mixed sleep apnea hypopnea syndrome (Mixed Sleep Apnea Hypopnea Syndrom, MSAHS). The research of SAHS in China is from nowhere, from local areas to the whole country. It has gone through the history of nearly 20 years. The initial stage is some pioneering and exploratory work. The real development is a matter of recent years, with the increase of the number of sleep test rooms. In addition, the number of patients diagnosed and treated has increased correspondingly, the diagnosis and treatment technology has been continuously improved, and the research work in the field of SAHS related disciplines has been carried out, including basic and clinical research, epidemiological investigation and so on. At present, SAHS is an independent risk factor for hypertension. Sleep apnea hypopnea syndrome is mainly manifested as sleep. Snoring, accompanied by apnea and superficial breathing, recurring hypoxemia, hypercapnia and disorder of sleep structure at night, resulting in daytime sleepiness and reduced work efficiency, often accompanied by cardiovascular and cerebrovascular diseases, which seriously affect the quality of life and life of the patients. The study found that repeated anoxia and reperfusion at night in SAHS patients lead to blood. Inflammatory factors (IL-6, TNF-a, etc.) in Qing Dynasty increased significantly, and further caused hypertension and other diseases.
Pregnancy induced hypertension is a disease characterized by hypertension as the main clinical manifestation. The incidence of pregnancy is 10.5%. Preeclampsia is a more serious stage for the diagnosis of hypertensive disorders in pregnancy. It is the main cause of the incidence and mortality of pregnant and parturients and perinatal infants. Extreme prevention and intervention are the problems that the medical workers have been exploring. The etiology and pathogenesis of preeclampsia have not been fully elucidated. Although the theory of placental ischemia, the theory of vascular endothelial injury, the theory of immunity, and the theory of heredity are established, the majority of scholars have found that the serum of preeclampsia patients has been found. Inflammatory factors (IL-6, TNF-a) were significantly higher than those of normal pregnancy and were significantly correlated with the severity of preeclampsia. Williams and other studies found that the levels of TNF-a and its receptors in the peripheral blood and amniotic fluid were significantly increased before the onset of clinical symptoms, but the reasons for the increase of inflammatory factors were not yet clear.
Both IL-6 and TNF-a are the cytokines that have been found in more than 10 years. They all have extensive biological activity. They are maintained at a low level in normal pregnancy, regulate the normal growth and function of placenta tissue, participate in the maintenance of normal pregnancy, promote the proliferation and invasiveness of trophoblast cells, increase the blood supply of the uterus and promote the birth of the fetus. The growth and regulation of the immune regulation of.TNF-a and IL-6 between the mother fetus can lead to the occurrence of pathological damage in human body, such as promoting endothelial cells adhering to leukocytes, stimulating endothelial cells to secrete inflammatory mediators, activating the coagulation system, inhibiting fibrinolysis, increasing inflammatory exudation and producing oxygen free radicals, promoting the expression of cell adhesion molecules, and so on. One step leads to vasospasm and increased blood pressure, which affects the blood vessels of the kidneys and leads to proteinuria.
In recent years, many foreign mathematicians have found that SAHS has a significant correlation with preeclampsia, intrauterine fetal growth restriction, preterm birth and so on, and the blood pressure of preeclampsia patients can be significantly reduced and the normal weight fetus is produced by nCPAP treatment for pregnant women with SAHS.
We found that there are many overlapping factors in SAHS and preeclampsia, such as elevated levels of inflammatory factors and oxidative stress products, upper airway stenosis, abdominal obesity and other factors that reduce thoracic activity, endocrine changes and so on. In addition, clinical manifestations include hypertension, nocturnal segment sleep, daytime sleepiness and so on. On the basis of the study and the internationally recognized SAHS diagnostic means, polysomnography, we conducted polysomnography to assess the presence of SAHS in selected patients, and a preliminary study of the correlation between SAHS and preeclampsia and the role of inflammatory factors in the possible pathogenesis of the preeclampsia from the level of inflammatory factors and the presence of SA. One of the most effective methods for the treatment of SAHS in HS is sustained airway positive airway pressure (PVV), and the therapeutic effect is observed to further confirm the correlation between SAHS and preeclampsia.
The first chapter is a preliminary observation of the level of inflammatory factors and the correlation between SAHS and preeclampsia.
objective
The correlation between SAHS and preeclampsia was preliminarily observed and detected by detecting the levels of inflammatory factors in serum.
Method
1, cases and groups selected from July 2008 to June 2009 in the severe pregnant and lying in the hospital for the treatment of hospital delivery and hospitalized childbirth in accordance with the standards of pre eclampsia pregnant women and the same period of age, no significant difference in pregnancy age, the whole night of Polysomnogram, PSG, including 25 cases in the normal pregnancy group, In preeclampsia, there were no SAHS groups in 43 cases, preeclampsia and 27 cases in group SAHS. All of the above pregnant women were single pregnancy and had no previous hypertension, heart disease, kidney disease, diabetes and chronic lung disease, which could cause hypoxia.
2, sleep monitoring performed at least 7h polysomnography for all pregnant women. The monitoring contents included EEG, eye electricity, mandibular electromyography, electrocardiogram, mouth and nose airflow, snoring, body position, thoracic and abdominal movement and blood oxygen saturation. The data of polysomnography monitoring (PSG) were analyzed by computer automatic analysis and manual correction, reference to the Chinese Medical Association. The guidelines for the diagnosis and treatment of obstructive sleep apnea hypopnea syndrome (Draft) > adult SAHS diagnostic criteria, in which AHI is the main criterion and LSaO2 is used as a reference to make a diagnosis of the existence of SAHS and its severity.
3, the blood pressure was measured at the end of 10 minutes after the end of the sleep monitoring. The vertical mercury sphygmomanometer (Shanghai medical equipment factory) was used to measure blood pressure. The mean arterial pressure (Mean Arterial Pressure, MAP), MAP= diastolic pressure +1 / 3 (systolic pressure diastolic pressure) were taken for convenient comparison.
4,24 hours urine protein quantitation was collected from 7Am to 7Am 24 hours after the next day, and 24 hours urine protein was measured by Coomassie brilliant blue G25O4 method.
5, serum IL-6 and TNF-a were tested for 10 minutes in the morning after the second day of sleep monitoring and 10 minutes of venous blood collection, placed in the refrigerator at 4 centigrade to be separated, 3000r / min centrifuged 10min, separated from the EP tube and stored in the EP tube. The serum TNF-a and IL-6 levels were detected by enzyme linked immunosorbent assay (Enzyme-Linked Immunosorbnent) Y (ELISA), the kit is provided by Wuhan doctorate company, and the testing method is strictly operated according to the instructions.
6, statistical analysis was carried out with statistical software SPSS13.0 for statistical processing and analysis. The test data used the mean number addition and subtraction standard deviation (x + SD). The group was compared with One-Way ANOVA, the two groups were compared with LSD test, and the correlation analysis adopted all the statistical data of Pearson. as a significant difference between P0.05.
Result
1, the age between the general data groups (27.5 + 6 vs 29 + 5.3 vs 29.2 + 5, P0.05), the gestational age (31.1 + 4.9 vs 31 + 4 vs 30.6 + 4.6, P0.05) had no significant difference, and was comparable.
2, statistical analysis of clinical and laboratory indexes between groups
Three groups of body weight index (BMI), mean arterial pressure (MAP), 24h urine protein quantitative, sleep apnea hypopnea index (AHI), minimum oxygen saturation (LSaO2), IL-6 and TNF-a levels were significantly different (P0.01). However, there was no significant difference between the non SAHS group and the preeclampsia and SAHS BMI (P=0.083) in preeclampsia. There was no group in normal pregnancy and preeclampsia. There was no significant difference between AHI and LSaO2 (P=0.797,0.862).
The two important clinical indicators of preeclampsia, blood pressure and 24h urine protein quantitation were significantly correlated with the severity of SAHS (P0.01); the correlation coefficient of IL-6 and TNF-a was greater, IL-6 and TNF-a were also associated with AHI and LSaO2. Meanwhile, blood pressure and urinary protein were found to be associated with BMI, but the correlation was weak.
conclusion
1, the number of nocturnal sleep apnea hypopnea in preeclampsia pregnant women is significantly higher than that of normal pregnant women, indicating a relative increase in the incidence of SAHS in preeclampsia pregnant women.
2, inflammatory factors (IL-6 and TNF-a) may play an important role in the pathogenesis of preeclampsia complicated with SAHS.
3, SAHS may be a risk factor for the occurrence and development of preeclampsia.
The second chapter: AutoCPAP in the treatment of preeclampsia with SAHS.
objective
The effect of AutoCPAP treatment on preeclampsia pregnant women with SAHS was observed, and the correlation between SAHS and pre eclampsia was further confirmed.
Method
1, 27 cases of pregnant women with SAHS confirmed by polysomnography were selected, and their age, gestational age and BMI were re counted.
2, AutoCPAP treatment was given to pregnant women who were confirmed by polysomnography to meet the SAHS diagnostic criteria for further explanation of the AutoCPAP treatment, and signed the informed consent to give at least 4 hours of treatment a day to explain the use of the ventilator in detail to the patient, the problem of wearing the mask and the possible questions in the process of use. The problem and solution were given after the patient was fully understood. Because most patients were not very adaptable to the initial use, they were given a delay of 30 minutes and given a humidification to adapt the patient to acceptance. The pressure range of the ventilator was fixed at 4 to 20cmH2O..
3, the blood pressure was measured at the end of 10 minutes after the end of the sleep monitoring. The vertical mercury sphygmomanometer (Shanghai medical equipment factory) was used to measure blood pressure. The mean arterial pressure (Mean Arterial Pressure, MAP), MAP= diastolic pressure +1 / 3 (systolic pressure diastolic pressure) were taken for convenient comparison.
4,24 hours urine protein quantitation was collected from 7Am to 7Am 24 hours after the next day, and 24 hours urine protein was measured by Coomassie brilliant blue G25O4 method.
5, serum IL-6 and TNF-a were detected by AutoCPAP in the early morning of seventh. After 10 minutes of waking up in the venous blood collection 6ml, the serum was separated in the refrigerator at 4 centigrade, 3000r / min was centrifuged 10min, separated in the EP tube and stored at -80. The serum TNF-a and IL-6 levels were detected by enzyme linked immunosorbent assay, the kit was from Wuhan doctor The German company provides the testing methods strictly according to the instructions.
6, statistical analysis was carried out by statistical software SPSS13.0 for statistical processing and analysis. The data of experimental data were expressed by mean plus minus standard deviation (x + SD).
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2010
【分类号】：R766

【参考文献】