临床麻醉与管理德赢娱乐国际

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研究文章
子痫前期是妊娠期腹内高血压综合征——假设会变成理论吗?

Marshalov DV1*舵手2.Salov IA1.彼得连科AP1.Ioscovich一3.

1.妇产科,v.i.a Razumovsky Saratov国立医科大学,Saratov,俄罗斯
2.俄罗斯莫斯科国家预算医疗机构麻醉学和危重病护理医学系
3.以色列耶路撒冷希伯来大学麻醉学系Sael-ZeDek医学中心

*通讯作者:俄罗斯萨拉托夫国立医科大学医学院妇产科Dmitry Marshallov V,电子邮件:Marshald@mail.ru


条信息

文章类型:研究文章

引文:Marshallov DV,Shifman EM,Salov IA,Petrenko AP,Ioscovich A(2017)先兆子痫是妊娠期腹内高压综合征-假设会成为理论吗?.临床杂志2(1):doihttp://dx.doi. org/10.16966/2470-9956.122

版权:©2016 Ioscovich A,等。这是一篇开放获取的文章,在知识共享署名许可协议的条款下发布,该协议允许在任何媒体上无限制地使用、发布和复制,前提是注明原作者和来源。

出版历史:

  • 收到日期:2016年4月6日

  • 接受日期:2017年1月10日

  • 出版日期:2017年1月14日

  • 摘要

    最近的研究提供了预先坦克萨西亚(PE)的开发的新假设,强调了腹内高血压(IAH)的重要性。IAH是肠道灌注改变的重要因素,从理论上可以提高孕妇的渗透性,导致细菌和内毒素易位,全身炎症,导致PE症状发展;但是,所有现有假设都基于经验数据和逻辑结论。本研究旨在证实PE发展,IAH与肠道障碍功能之间的关系。在妊娠6至40周的时间内,在343名孕妇中进行了腹内压力(IAP)动态的调查。它们分为3组:I-215组怀孕简单的患者;第三组 - 患者患有怀孕和分娩结果的并发症的患者,没有PE发展(n = 97);第三组 - PE患者(n = 31)。为了确定PE和受影响的肠道屏障功能之间的关系,随着IAP的研究,从怀孕的第二个三个月开始,并行检查肠道渗透性和细菌内毒素的水平。我们间接测量IAP通过测量膀胱内压力,并计算腹壁的顺应性。 The “lactulose/mannitol” test was used to assess the barrier function of the intestinal mucosa. Endotoxin levels were determined in serum by activated particles method (IRA - Endotox spp.).

    IAP呈线性增加,在整个妊娠期每两周增加约1mmHg。腹壁顺应性水平的动态变化与IAP呈反比线性关系。54.8%的病例中,IAP升高先于PE的发生。增加率在PE的发生中起到的作用更为显著IAP的绝对值。妊娠2周内,PE发展的阈值是IAP增加超过2-4mm Hg。2周间隔内IAP不同增加值的预后指数为0.806。该研究证实了IAH妇女的肠道通透性增加,其程度取决于年龄IAP的动态变化与发生PE的严重程度相关(r=0.77)。肠道通透性的增加与内毒素血症的发生相关(r=0.82)妊娠期IAH是增加肠道通透性和内毒素血症的因素之一。细菌和内毒素的易位引发全身炎症反应,多系统破坏。监测孕妇的IAP动态为预测PE提供了新的机会。

    关键字

    怀孕;腹腔内高血压;肠道渗透性;Preclampsia.

    介绍

    最近,在科学医学文献中出现了有关PE与IAH发展的有趣出版物。这些研究综述了PE的现有理论,并提出了新的致病机制,其病因或多或不与妊娠期腹内压(IAP)升高有关[1-9]。新的假设是基于R.H. Paramore的研究结果和他在上世纪初提出的PE发展的“机械论”概念[10-13]。在2000年代,一些出版物讨论了IAH和PE之间可能的联系,但IAH的首要地位受到了质疑[14,15]。IAP和PE之间因果关系的确定受到了阻碍,因为之前的研究作者仅在研究结果存在的情况下调查IAP,而不是作为一种预测方法。2011年,三名作者几乎同时独立地对PE发展的机理概念进行了第一次更新[2-4]。概念的细节有一些不同,相互补充。这一假设源于对肾血管紧张素-醛固酮系统失衡的识别[2-4]。后来,这一IAH相关PE发展的情景得到了其他作者的支持,他们用新的信息证实了A. van Dalfsen和H.J. Sugerman的假设[7- 9]。研究表明,免疫对IAH的发展和PE的发生具有重要作用,这与肠壁的通透性增加、细菌易位和内毒素(脂多糖- LPS)的渗透有关。微生物细胞的微粒及其代谢产物进入内部环境。 The same view was followed by other scientists. Developing their hypothesis, D.J. Sawchuck et al. [6] extended the understanding of the possible causes of PE, reinforcing information about the role of external and internal environmental factors: atmospheric pressure, living conditions, ecology and intestinal microbiome. In theory, the degree of translocation of LPS in pregnancy depends on two factors: the qualitative content of the intestinal microbiome and the degree of intestinal permeability. The intestinal microbiome is altered during pregnancy featured by an increase in titer of opportunistic gram-negative bacteria [16]. It has been shown in vitro that bacterial intestinal contents selected in the third trimester had significantly greater ability to activate the synthesis of pro-inflammatory cytokines compared with the microflora allocated in the first trimester of pregnancy [16]. In case of injury of the barrier function of the intestinal wall, LPS translocation occurs in the mesenteric lymph nodes and then moves through the portal vein to the liver [17,18]. LPS initiates a cytotoxic immune response in Kupffer cells with CD14 protein. Certain pro-inflammatory cytokines are genetically linked to the DNA of LPS that mediate the action of endotoxin in the systemic circulation and leads to a systemic inflammatory response, oxidative stress, accumulation of macrophage foam cell in capillaries, formation of atherosclerotic plaques and subsequent multiorgan failure [16]. The conventional opinion about the leading role of the placenta and fetus as a major factor of the immune response in PE is in doubt in the context of the above.IAH is an important factor for intestinal perfusion disorder that theoretically can increase intestinal permeability in pregnant women, leading to bacterial and LPS translocation, systemic inflammation, and development of PE symptoms. The study of relations between PE and IAP is impossible without evaluation of IAP preceding the arising complications. It is necessary to know not only the actual level of IAP, but also have an understanding of the normal values of this indicator in different periods of gestation. Until now, reference values of IAP during pregnancy were not available. Publications that contain factual information on the IAP during pregnancy and the postpartum period are rare and represent data of small samples [19-26].

    目标

    探讨子痫前期的发生、腹内高压与肠屏障功能损害的关系。

    方法

    为了实现这一目标,前瞻性队列研究在2008年至2015年期间进行。这项研究得到了V.I. Razumovsky Saratov国立医科大学伦理委员会的批准。前提条件是接受患者的知情同意,以参与声称的研究。对343例妊娠6 ~ 40周的孕妇进行IAP动态研究。对同意参与研究的女性在门诊登记时(6-8周)和超声筛查期间(20-24周和30-34周)的IAP进行了测量。对因无症状菌尿转院检查的孕妇进行不同妊娠阶段的IAP研究,具有发生产科和围产期并发症的危险因素(年龄较大的妇女和不同程度的肥胖),以及已诊断出住院妊娠并发症(胎胎盘功能不全、胎儿生长迟缓、妊娠高血压和PE)。在38-40周的妊娠期,研究了在监护下的孕妇和无并发症妊娠、产前入院的患者的IAP。大多数孕妇重复调查:不同妊娠期两次127例,3次54例。4乘以- 22。 140 patients -once before delivery.

    215名孕妇的数据从总组中选择了标准以确定IAP的参考值。纳入分析的标准如下:首先,单例简单怀孕。包括排除标准:IAH的危险因素(肥胖,肠功能障碍,前腹壁术后疤痕,腹部,腹部,多络合物,胎儿麦克风的粘连过程)。我们履行了我们研究中包含的所有妇女的怀孕结果,以解决IAP和PE之间的致病关系和原始问题。PE是根据妊娠(ISSHP)的高血压研究会(ISSHP)[27]作为妊娠高血压(收缩压> 140mm Hg或舒张压> 90mm Hg后的妊娠期或多个控制测量妊娠20周的妊娠)用蛋白尿(> 300mg)。重新审查患者的结果被纳入妊娠结算对IAP的依赖性研究,因为有必要分析I(6-8周)和II的数据(20-24周)TrimeSters.due到与IAP相关的多个因素,有必要研究IAP的水平,达到IAP临界值的时期,以及这些测量持续存在的持续时间。因此,我们研究了PE不仅取决于IAP的特定妊娠术语的绝对值,而且在某些时间间隔内的IAP的生长速率上,定义为ΔIAP。为了确定体育和受伤的肠道障函数之间的关系,以及IAP的研究,我们同时研究了妊娠第二三个月的细菌内毒素血症水平。我们使用M.L的间接方法检查IAP。 Cheatham et al.[28] with a closed system measuring an intravesical pressure Unometr商标AbdoPressure商标(联合医疗)由一个尿计和一个步长为1毫米汞柱的刻度管组成的测量部分组成。在仰卧位时,通过连接unmeter连接器的Foley尿管进行膀胱导尿商标Abdo-Pressure商标,然后20ml温、无菌等渗氯化钠溶液通过无针孔孔孔注入膀胱商标.一旦系统中填充的溶液中,该仪器的测量部分在垂直位置通过。我们设定的零级规模的联合和测量IAP.Latex双向8通道/ FR Apexmed导管使用导管插入过程中,尽量减少不适。无菌尿道内凝胶Cathejell利多卡因(Pharmazeutische Fabrik的Montavit G.m.b.H.,Salzbergstrasse 96 6060阿布萨姆/蒂罗尔奥地利)施加到尿道和在导管引入抗微生物和局部麻醉作用之前。该程序的药物的治疗效果发病后开始5分钟。在IAP检查我们根据下式评估腹壁通过计算顺应性:腹壁= 100 /ΔIAP,其中ΔIAP是的100ml溶液给药后IAP之间的差进入膀胱和的柔初始IAP [29]。所有门诊检查的孕妇通过电话检查排尿后2周时接受采访的困难和痛苦的存在。测试«乳果糖/甘露醇»测试用于评估肠黏膜的屏障功能。根据该方法在过夜禁食和完整膀胱排空之后进行该测试,证明对于怀孕的患者,患者喝450毫升含40克蔗糖,7.5克2克乳果糖和甘露糖醇的溶液中的一小时期间 8 a.m. to 9 a.m.. Sucrose provides pregnant with energy during fasting. Then the urine was collected in a sterile plastic container containing 10 ml of 10% thymol in isopropyl alcohol to prevent bacterial growth for 5 hours after administration of the prepared solution. Urine volume was measured and the samples were frozen at a temperature below 20°C until analysis. The analysis was performed using amperometric pulse detector by the method of ion chromatography. Results were expressed as the percentage of sugar in the urine samples. The ratio of lactulose/mannitol excretion was calculated by excretion percent [30]. The level of endotoxin was measured in the serum by the activated particles (IRA-Endotox spp), developed in Bakoulev Center for Cardiovascular Surgery (the committee’s decision on new medical technologies Health Ministry from 24.03.2004 g.) using standard kits. The sensitivity of the method was up to 7.5 pg / ml of lipopolysaccharide (LPS) of E. coli or Sal. typhi. The specificity of the method was 98.7-99.2%. STATISTICA software package was used for statistical processing (StatSoft Inc., USA, version 10.0). The results describing quantitative traits which empirical distribution did not show a statistically significant difference from the normal distribution, were presented in the form of (M ± σ), where M – the average value of sample, σ – standard deviation of the sample; if the difference between the normal law and empirical distribution was statistically significant, the results were presented as a median and an interquartile interval (Me [Q1; Q3]), where Me - median; Q1-1 (25%) quartile; Q3-3 (75%) quartile).

    为评估两组定量指标均值差异的统计学意义,对方差相等和不等的选项采用Student检验。两组间统计学差异方差的假设检验采用Fisher’s检验。定性特征以百分比(%)和绝对值(n)描述。由于比较频率较低,采用χ2检验和Yates校正,通过定性属性确定组间差异。采用Spearman秩相关系数(r)评估定量指标之间的关系。采用相关操作特征曲线分析(ROC-analysis)评估总体预后潜力,确定研究参数不同值的预后指标,并以最佳的灵敏度和特异性确定其阈值。为了确定PE发育对一定时间间隔内压增长率的依赖性,我们使用Kaplan和Meier的方法计算了妊娠期间内压增长率不同的患者发生无并发症妊娠的累积概率。我们的计算是基于对每个登记的复杂结局的非复杂妊娠条件概率的定义。为了直观评估体育发展的时间,我们绘制了良好结果在时间上的函数图(Kaplan-Meier曲线)。为了检测组间的统计学显著差异,使用学生t检验。如果p<0.05,则认为差异显著。

    结果

    3组患者在研究过程中被分开。将无并发症单胎妊娠患者分为i组,如前所述,将这些患者的结果作为计算不同妊娠阶段IAP参考值的材料。有妊娠并发症和分娩结局危险因素但未发育PE的孕妇被分配到第二组。妊娠合并PE的患者分为III组。表1数据显示,II组和III组患者的流行病学特征无明显差异。PE患者的胎盘功能不全和胎儿生长迟缓率仅根据PE症状发生前登记的病例确定。研究表明,无并发症单胎妊娠患者妊娠6 ~ 8周平均IAP为1.40±0.96 mmhg;II期(妊娠20 - 24周)为-11.54±3.40 mmhg, III期(妊娠27 - 41周)为-18.56±1.35 mmhg。腹壁顺应性动力学与IAP呈反向线性依赖关系。妊娠期腹壁顺应性平均值为(43.20±8.77)ml/mm Hg,妊娠期为(20.65±5.10)ml/mm Hg。III期腹壁顺应性均值继续下降至13.03±1.30 ml/ mmhg。表2为不同妊娠阶段IAP均值。 increases of IAP for a two-week interval in normal pregnancy did not exceed 1 mm Hg. The survey of patients in 2 weeks after ambulatory IAP measurement did not reveal any cases of catheterization related patient morbidity. The results of investigation of relationship between IAP and PE showed that the baseline (trimester I) values of IAP in the group with uncomplicated pregnancy were not significantly lower and not statistically significant compared with the group with PE. There were significant differences between groups in the second trimester. Meanwhile, the research of the strength of the relation between the level of IAP at the 20-24 weeks of pregnancy and the development of PE showed very weak correlation –r=0.023. p=0.752. The quality of analyzing the operating characteristics curves (ROC curves) for assessing the overall prognostic potential, determining prognostic indices of different values IAP and determining their threshold values was unsatisfactory –AUC=0.518. In the analysis of the results, it was noted that the reason for the lack of predictive value of the indicator “level of IAP” was significant difference between “normal” values of IAP in patients with different body mass index: patients with normal weight and uncomplicated gestation had average IAP of 10.83 ± 3.71 mm Hg; pregnant women with obesity I degree – 13.78 ± 1.68 mm Hg, with obesity II degree – 14.60 ± 1.52 mm Hg; with obesity III degree – 16.15 ± 1.14 mm Hg. The patients with PE complicated pregnancy had the following values of IAP at 20-24 weeks: patients with initially normal weight had IAB of 13.36 ± 3.93 mm Hg; with obesity I degree – 16.71 ± 0.76 mm Hg; with obesity II degree – 17.86 ± 1.96 mm Hg; with obesity III degree – 19.60 ± 2.06 mm Hg. IAP level preceding PE was significantly higher in pregnant women with obesity than in patients with normal weight (by 18- 32%, p<0.001). The reference values of IAP at 20-24 weeks of pregnancy in patients with obesity were: 13-15 mm Hg (obesity I degree), 14-15 mm Hg (obesity II degree), and 15-17 mm Hg (obesity III degree).

    特征 我(n = 215)
    n / %
    二世(n = 97)
    n / %
    III(n = 31)
    n / %
    p值
    平均年龄(М±σ) 23.0±3.1 28.3±5.7 28.0±3.9 0.946
    体重指数(М±σ) 27.1±2.7 35.1±4.2 32.8±5.7 0.554
    肥胖I度 - 23/23.7 9 / 29.0 0.634
    肥胖第二学位 - 16/16.5 5/16.1 1
    肥胖III学位 - 10/10.3 4/12.9 0.742
    第一次怀孕 215/100 57/58.8 22/70.9 0.660
    初生 215/100 43/44.3. 19/61.3 0.148
    动脉性高血压 - 64/65.9 20 / 64.5 0.999.
    糖尿病 - 2/2.1 1/3.2 0.568
    肾脏疾病 - 10/10.3 3/9.6 1
    胎老物质不足 - 48/49.5 20 / 64.5 0.155
    重量异常增益 - 21/21.6 6 / 19.4 1
    Multifetal - 1/1.0 2/6.4 0.145
    多络合物 - 1/1.0 2/6.4 0.145
    胎儿生长迟缓 - 10/10.3 7/22.6 0.124
    胎儿巨大胎儿 - 2/2.1 3/9.6 0.091
    早期的子痫前期 - - 9 / 29.0
    晚期子痫前期 - - 22/70.9
    温和的子痫前期 - - 25/80.6
    重度子痫前期 - - 6 / 19.4

    表格1:研究组患者的流行病学特征
    注:组与组间差异的p值显著性。

    妊娠术语 怀孕人数 IAP(毫米汞柱)
    6-8周 30 1 [0:3]
    20周 30 8 [7:10]
    24周 30 9 [8:11]
    27周 30 12 [11:13]
    32周 30 16 [3]
    33周 32 16 [16:16]
    34周 36 16 [16:17]
    35周 36 18 (17:18)
    36周 37 18 [18:19]
    37周 82 18 [18:19]
    38周 84 20 [19:20]
    39周 102. 20 [20:21]
    40周 29 20 [20:21]

    表2:不同妊娠期的腹内压平均值(Me [QL;曲)
    注:我的中值;QL-25百分位数;QU-75百分位

    IAP与PE关系的研究表明,54.8%的病例(n=17) IAP水平升高先于PE的发展。除了IAP水平,实现IAP关键值的速度也影响了复杂性。图1显示的kaplan meier曲线的三个变体IAP增加(ΔIAP < 2毫米汞柱/ 2周的妊娠,ΔIAP = 2 - 4毫米汞柱/ 2周的妊娠,ΔIAP >怀孕4 mm Hg / 2周),呈现简单的怀孕的累积概率在特定妊娠20周后。

    图1:无并发症妊娠累积概率的函数取决于妊娠2周内IAP升高的三个变量。

    后续多个两两比较的结果累积概率函数的简单的怀孕结果与PE患者显示更高ΔIAP简单的怀孕的概率有显著低于患者IAPΔ< 2毫米汞柱。体育发展时机ΔIAP > 4毫米汞柱明显这些患者出现PE临床症状的中位时间为34.0周(25% - 33.0周;75%百分位数-36.0周),Δ IAP 2-4 mm Hg -37.0周(25%百分位数-36.0;75%百分-37.0)。评估整体预后潜力,我们通过分析操作特征曲线(ROC曲线)-AUC =0.806,测定ΔIAP不同值的预后指标,并确定其阈值。ROC曲线上的点呈水平分布。妊娠2周内压增加超过2- 4mmhg为PE的阈值。研究证实了IAP与肠道通透性之间的直接关系,即由于IAP增加而导致肠道通透性增加:妊娠20-24周时,当IAP水平为25- 75%时,“乳果糖/甘露醇”比值为0.028±0.001;当IAP超过95%(大于12 mm Hg)时,“乳果糖/甘露醇”比值为0.035±0.001 (p <0.05)。IAH的增加伴随着“乳果糖/甘露醇”比值的增加:Δ IAP 2-4 mmhg / 2周对应0.052±0.003,Δ IAP>4 mmhg对应0.084±0.002。 In patients with moderate PE the ratio was 0.09 ± 0.002; in patients with severe PE the ratio was 0.158 ± 0.02 (p<0.001). The relation between “lactulose / mannitol” ratio and severity of PE was strong, correlation coefficient–0.77. The study demonstrated a relationship between the IAP and level of endotoxemia(r = 0.53, p <0.05). Women with IAP level corresponding to 25-75 percentiles showed a concentration of endotoxin of 7.2 ± 0.03 pg / ml, in pregnant women with IAP higher than the 95 percentile–9.4 ± 1 pg / ml (p <0.05). The correlation between the concentration of endotoxin in 20-24 weeks of gestation and the development of PE was below average, r=0.23, p=0.049. Endotoxin concentration was significantly increased with the progression of IAH: Δ IAP 2-4 mm Hg / 2 weeks of gestation corresponded to the concentration of 12.7 ± 2.0; Δ IAP>4 mm Hg corresponded to the concentration of 21.4 ± 3.1, and in patients the manifestation of severe PE–56.3 ± 4.2 (p<0.001). The coefficient of correlation between the ratio “lactulose / mannitol” and the endotoxemia level was 0.82.

    讨论

    专家对PE发病机制的争议性意见和越来越多的证据表明,这种妊娠并发症的病因异质性证实PE是复合临床类别[32]。最近的研究表明,PE临床表现不同的患者在胎盘部位的临床观点、形态学和免疫组化特征、胎盘和血管损伤的生物标志物水平等方面存在差异[33-41]。我们可以假设PE的发展存在几种情况,其中之一是IAH[42]。

    该研究表明,孕妇IAP IAP以每两周间隔小于1mmHg的速度增加,妊娠期速度较少,其间隔时间小于1毫米。根据所描述的方法测量IAP没有引起任何泌尿外情并发症。结果显示在IAP和PE之间的关系中,IAP升高的水平在PE的51.6%的病例中的发展之前。IAP的升高率在体育发展中发挥着重要作用,即使在更大程度上也比IAP的绝对值在更大程度上。具有快速和大幅增加的IAP(妊娠4mm / 2周)的妊娠显着高的PE开发概率,而不是在某些时间间隔(P <0.001)的患者中的患者增加少于2 mm Hg(P <0.001),而IAP较高升高较早的并发症发生。PE的阈值是IAP高度超过2-4毫米HG / 2周的妊娠。2周间隔的IAP升高值的预测指数为0.806。结果表明,IAH在复杂妊娠结果中的原因。研究结果证实了IAP介导的IAP介导的肠道渗透性的发生,其程度取决于IAP动态的程度依赖于IAP的动态并与发达体育的严重程度相关。 Increased intestinal permeability was associated with a significant endotoxemia. The correlation between the concentration of endotoxin in 20-24 weeks of gestation and the development of PE was low –r=0.23, p=0.049. Several reasons may explain this phenomenon: one of variants involves penetration of a primarily hydrophobic form of endotoxin (without polysaccharide part) into the bloodstream and increased activity of antiendotoxin immunity that apparently occurs with a long-term and slowly progressive IAH in background in patients with obesity. The works of many researchers suggest that endotoxemia not only plays an important role in the development of PE, but the activity of antiendotoxic immunity [43-46]. Another reason for the low correlation of the initial concentration of endotoxin and PE is a rapid and significant increase of the concentration of the endotoxin with the progression of IAH, which was mainly observed in pregnant women with initially normal IAP. In its turn, this dependency can be explained by intake of hydrophilic forms of intestinal endotoxin, i.e. whole LPS molecule, with its polysaccharide part with increased intestinal permeability and rapid depletion antiendotoxic immunity on the background.

    结论

    所做的工作的Quintessence是肠道是前普尔帕西亚的门户的论点。怀孕的腹部高血压是增加导致内毒素血症的肠道渗透性的因素之一。细菌和整个LPS分子的易位触发了系统性炎症反应。监测孕妇IAP动力学提供了PE预测的新机遇。我们的研究结果呈现了Preclampsia病因的第一个多因素模型,其中触发机制是腹高血压综合征。本文提出的材料允许我们从假说转向理论。

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