【作者】 陈懿宇；

【导师】 陈可冀； 张京春；

【作者基本信息】 北京中医药大学 ， 中西医结合临床， 2011， 博士

【摘要】 1目的1.1系统评价分析西药钙离子通道阻滞剂治疗伴睡眠呼吸暂停(obstructive sleep apnea, OSA)高血压患者的疗效,以及中药治疗OSA的疗效,为伴OSA高血压患者选择合理的药物降低血压并改善OSA提供一定的荟萃分析依据。1.2研究伴及不伴OSA高血压患者的血压变异性、内皮功能和OSA的相关性,以及中药清眩颗粒对血压变异性、内皮功能和OSA的影响,为此类患者的中西医诊治提供一定的临床研究依据。2方法2.1系统评价研究方法本研究有2个系统评价,分别是钙离子通道阻滞剂治疗伴OSA高血压患者降压疗效Meta分析,以及中药治疗OSA疗效的Meta分析。两个Meta分析方法大致相同,具体包括：检索CNKI、CBM、VIP、MEDLINE、Embase、Cochrane图书馆(C1)中Cochrane系统评价资料库(CDSR)及Cochrane对照试验注册资料库(CCTR),检索至2011年1月各资料库所有可得文献。采用Cochrane协作网提供的Revman5 (Review Manager5)软件分别分析钙离子通道阻滞剂治疗伴OSA高血压患者降压疗效以及中医药治疗OSA的疗效,根据Cochrane协作网推荐的GRADE (Grading of Recommendations Assessment, Development and Evaluation)标准用GRADEprofiler软件对RCT的质量进行评价。2.2临床试验研究方法本研究采用分层随机双盲安慰剂对照方法。2.2.1纳入阴虚阳亢型轻中度高血压患者90例,对患者行便携式睡眠仪监测、24小时动态血压(ABPM)监测,观察并分析患者血压的均值、变异性、及昼夜节律和OSA的关系；用肱动脉超声技术评价内皮依赖性血管舒张功能(flow-mediated dilation,FMD),并从内皮相关指标(NO/ET-1、hs-CRP和肾素-血管经张素-醛固酮系统)探讨其作用机理。采用多元逐步回归法分析OSA和血压及内皮功能的关系。2.2.2根据患者OSA诊断结果,分为伴OSA高血压和不伴OSA高血压两个亚组,每个亚组再随机分为试验组和对照组。在氨氯地平常规治疗的基础上,试验组加予清眩颗粒,对照组加予安慰剂,一共干预2个月。用广义线性模型协方差分析血压、内皮和OSA各相关指标治疗前后的差值,以比较清眩颗粒的疗效,并分析OSA对治疗结果的影响。3结果3.1系统评价结果3.1.1钙离子通道阻滞剂治疗伴OSA高血压患者降压疗效Meta分析钙离子通道阻滞剂在改善收缩压、舒张压方面与对照组比较有改善的趋势,但是无统计学意义(P>0.05)。在降低心率方面与对照组比较有统计学意义(P<0.05)。在改善睡眠时间、睡眠效率、深睡眠、REM期睡眠方面与对照组比较无统计学意义(P>0.05)。GRADE评分表明研究结果质量均为低或极低质量。3.1.2中医药治疗OSA的疗效Meta分析与常规西医治疗相比,加上中药汤剂可改善OSA患者总睡眠时间、低通气指数、低通气总时间、90%以下氧饱和度时间,和对照组比较,差异有统计学意义(P<0.05)。但在改善临床有效率、暂停指数AI、90%以下氧饱和度次数、平均心率方面,则中药组和对照组差异没有统计学意义(P>0.05)。GRADE评分表明研究结果质量均为低或极低质量。3.2临床试验研究结果3.2.1伴和不伴OSA的高血压患者血压比较与不伴OSA的高血压患者相比,伴OSA患者的血压变异性和非杓型血压发生率明显增高,夜间血压下降率明显降低(P<0.05)；其中夜间平均收缩压、24h收缩压SD与睡眠呼吸暂停低通气指数(apnea hypopnea index, AHI)呈正相关,夜间收缩压下降率和AHI呈负相关(P<0.05)；3.2.2伴和不伴OSA的高血压患者内皮功能比较和不伴OSA的高血压患者相比,伴OSA患者FMD%、NO、NO/ET明显降低,ET-1、PRA、AngⅡ、ALD明显增高(P<0.05)；其中PRA、AngⅡ和AHI呈正相关,NO/ET与AHI呈负相关(P<0.05)。3.2.3中药清眩颗粒干预伴和不伴OSA的高血压患者疗效分析3.2.3.1总体患者试验组和对照组疗效分析在扣除了是否伴OSA和指标基线水平差异的干扰后,发现总体患者以下指标的下降幅度试验组大于对照组(P(a)<0.05)：24h收缩压SD、日间收缩压SD、夜间收缩压SD、24h舒张压SD、24h舒张压CV、日间舒张压SD、夜间舒张压SD、心率、ET、AngⅡ;总体患者以下指标的升高幅度试验组大于对照组(P(a)<0.05):FMD、NO/ET比值。3.2.3.2 OSA对疗效影响在扣除了不同药物和指标基线水平的干扰后,发现OSA可以减少以下指标的下降幅度(P(b)<0.05)从而减弱了药物的疗效：夜间平均收缩压、24h收缩压SD、日间收缩压SD、夜间收缩压SD、24h舒张压SD、24h舒张压CV、日间舒张压SD、夜间舒张压SD、夜间舒张压CV、心率、hs-CRP、PRA、AngⅡ、ALD; OSA可以减少以下指标的升高幅度(P(b)<0.05)夜间收缩压下降率、夜间舒张压下降率、FMD、NO、NO/ET比值。3.2.3.3亚组内分析：伴OSA患者：24h收缩压SD、24h舒张压SD、日间收缩压SD、日间舒张压SD、夜间收缩压SD、夜间舒张压SD、AngⅡ下降幅度试验组大于对照组(P<0.05); NO/ET比值升高幅度试验组大于对照组(P<0.05)。不伴OSA患者：24h收缩压SD、24h舒张压CV、日间收缩压SD、日间舒张压SD、夜间舒张压SD、ET-1、hs-CRP、AngⅡ下降幅度试验组大于对照组(P<0.05); FMD、NO/ET比值升高幅度试验组大于对照组(P<0.05)。3.2.3.4清眩颗粒对OSA的影响清眩颗粒没有加重OSA患者的病情(P>0.05),还可以减少HI(P<0.05),改善OSA患者低通气情况。4结论4.1系统评价提示钙离子通道阻滞剂对血压水平及OSA的改善没有明显优势,中药可以一定程度改善OSA,但仍需大量高质量研究进一步验证。4.2伴OSA患者的血压变异性增高,昼夜节律紊乱；内皮舒缩功能、炎症反应和RAAS异常；OSA还可减弱降压药对这些指标的治疗作用。4.3清眩颗粒可以改善高血压患者的血压变异性,促进内皮功能恢复,平衡内皮舒缩因子比例,抑制AngⅡ的过度升高；同时对OSA的低通气指数还有一定的改善作用,可在临床上进一步研究加以验证。更多还原

【Abstract】 1 Objectives1.1 To evaluate the effect of calcium channel blockers on hypertensive patients with obstructive sleep apnea(OSA), and to assess the effect of Chinese medicine on OSA patients, so as to provide evidences for reasonable medicine selection to lower blood pressure and improve OSA for these patients.1.2 To analyze the correlation among blood pressure variability, endothelial function and obstructive sleep apnea in hypertensive patients with and without OSA, and to observe the effect of Qingxuan granule on these patients, so as to provide clinical basis for the diagnosis and treatment of these patients.2 Methods2.1 Methods of systemic reviewThis study includes two systemic reviews, one is to evaluate the effect of calcium channel blockers on hypertensive patients with obstructive sleep apnea(OSA), and the other is to assess the effect of Chinese medicine on OSA. The two systemic reviews are of the same methods:Databases of CNKI、CBM、VIP、MEDLINE、Embase、CDSR、CCTR were searched for all available data till January 2011. RevMan 5 software was used to conduct meta-analysis. GRADE profiler was used to assess the quality of the included trials.2.2 Clinical trial of Qingxuan granuleThis study is a stratified, randomized, doubled-blind, placebo-controlled clinical trial.2.2.1 90 mild and moderate hypertensive patients with Yin deficiency and Yang hyperactivity syndrome were enrolled into the study. Each one received portable sleep monitoring,24hour Ambulatory Blood Pressure monitoring(ABPM), and blood pressure mean values, blood pressure variability(BPV), blood pressure circadian rhythm and obstructive sleep apnea(OSA) were collected and their correlation was analyzed:endothelial function was evaluated by flow-mediated dilation (FMD), also nitric oxide/endothelin-1(NO/ET-1)、high-sensitivity C-reactive protein(hs-CRP)、and rein-angiotensin-aldosterone system (RAAS) were tested to explore the functional mechanism. Stepwise regression was used to analyze the correlation of OSA,blood pressure and endothelial function.2.2.2 According to the OSA diagnosis, the hypertensive patients were assigned into two subgroups, one with OSA, the other without OSA; and in each subgroup, patients were randomized into treatment group and control group. All of the patients were treated by amlodpine, in addition, Qingxuan granule was given to the treatment group, and placebo was given to the control goup, respectively. After 2months treatment, the difference (D-value) of the blood pressure, endothelial and OSA index between pretreatment and post-treatment were analyzed by covariance analysis in generalized linear model, so as to investigate the treatment effects of Qingxuan granule, and the impacts of OS A on the D-value in these patients.3 Results3.1 Results of systematic review3.1.1 The effect of calcium channel blockers on hypertensive patients with obstructive sleep apnea(OSA), a Meta-analysis.Compared with control group, though not statistically significance, calcium channel blockers shows a tendency to improve systolic pressure(SBP), diastolic pressure(DBP), (P>0.05) Heart rate was significantly lower after the treatment with calcium channel blockers than the control group; and no significant difference was found in total sleep time, sleep efficiency, deep sleep, and REM stage sleep between these two groups (P>0.05). According to GRADE, the quality of all the results was low or very low.3.1.2 The effect of Chinese medicine on OS A patients, a Meta-analysis. Compared with conventional western treatment, the addition of Chinese medicine could significantly improve the OSA patients’total sleep time, hypopnea index(HI), total hypopnea time, the time of desaturation less than 90% (P<0.05). No significant difference was found in improving clinical efficiency, apnea index(AI), the numbers of times of desaturation less than 90%,mean heart rate (P>0.05). According to GRADE, the quality of all the results was low or very low.The results of clinical trials3.2.1 Comparison of blood pressure between hypertensive patients with OSA and without OSA The blood pressure variability and the occurrence of non-dipper hypertension were significantly higher in hypertensive patients with OSA than those without OSA, while night time blood pressure fall rate was significantly lower in patients with OSA than those without OSA. (P<0.05). AHI had positive correlation with night time SBP and 24 hour SBP SD, and negative correlation with night time SBP fall rate (P<0.05)3.2.2 Comparison of endothelial function between hypertensive patients with OSA and those without OSAFMD%,NO,NO/ET were significantly lower in hypertensive patients with OSA than those without OSA, while ET-1、PRA、A ngⅡ、ALD were significantly higher in patients with OSA than those without OSA (P<0.05); AHI had positive correlation with PRA and AngⅡ, and negative correlation with NO/ET ratio (P<0.05)3.2.3 Analysis of Qingxuan granule’s curative effect on hypertensive patients with and without OSA3.2.3.1 Analysis of curative effect on treatment group and control group for all patients After subtracting the interference from OSA and index’baseline levels, the following indexes’ declined more in treatment group than in control group (P(a)<0.05):24hSBP SD、daytime SBP SD、night time SBP SD、24hDBP SD、24hDBP CV、daytime DBP SD、night time DBP SD、heart rate、ET、AngⅡ; and the following indexes increased more in treatment group than control group (P(a)<0.05):FMD and NO/ET ratio. 3.2.3.2 Impacts of OSA on curative effectAfter filtering out the interference from different treatments and index’baseline levels, the following indexes declined less in patients with OSA than those without OSA:night time SBP、24hSBP SD、daytimeSBP SD、night timeSBP SD、24hDBP SD、24hDBP CV、daytimeDBP SD、night time DBP SD、night time DBP CV、heart rate、hs-CRP、PRA、AngⅡ、ALD; and the following indexes increased less in patients with OSA than those without OSA:night time SBP fall rate, night time DBP fall rate, FMD,NO,NO/ET ratio.3.2.3.3 Analysis of subgroupIn hypertensive patients with OSA,the following indexes declined more in treatment group than control group:24hSBP SD、24hDBP SD、daytimeSBP SD、daytimeDBP SD、night timeSBP SD、night time DBP SD、AngⅡ(P<0.05); and the following indexes increased more in treatment group than control group:NO/ET ratio (P<0.05)In hypertensive patients without OSA, the following indexes declined more in treatment group than control group:24hSBP SD、24hDBP CV、daytimeSBP SD、daytimeDBP SD、night time DBP SD、ET-1、hs-CRP、AngⅡ; and the following indexes increased more in treatment group than control group:FMD、NO/ET ratio (P<0.05)3.2.3.4 Impact of Qingxuan granule on OSANo significant difference was found in OSA’ index after taking Qingxuan granule (P>0.05), with the exception that HI decreased and hypopnea improved (P<0.05)4 Conclusions4.1 The result of systematic review suggest that calcium channel blockers is not superior to control group in improving blood pressure level and OSA (P>0.05), while Chinese medicine could improve OSA to a certain extent (P<0.05); a large number of high quality researches are still needed to prove this result.4.2 In hypertensive patients with OSA the blood pressure variability increased, circadian rhythm was out of order; the endothelial relaxing and contracting function, inflammatory reaction, and RAAS were not normal; OSA could also weaken the curative effect of hypotensive drugs on these indexes.4.3 For hypertensive patients, Qingxuan granule could improve the blood pressure variability, promote the recovery of endothelial function, balance the endothelial relaxing and contracting ratio, control the excessive increase of AngⅡ; also Qingxuan granule could help to decrease the hypopnea index in OSA, and further study is needed to verify this result.更多还原