【作者】 张超；

【导师】 许建明；

【作者基本信息】 安徽医科大学 ， 老年医学， 2012， 博士

【摘要】 研究背景食管曲张静脉压力增高是直接导致血管破裂出血的关键因素，测量食管曲张静脉压力，对于评价出血风险及其防治效果具有重要意义。现有的食管曲张静脉气囊测压方法，是依据血管被刚刚压陷时(通过透明气囊观察)，血管腔内外压力平衡的原理。操作者按照自己的经验判断曲张静脉被压陷时刻，决定曲张血管压力。测压结果依赖观察经验，因此存在主观性，也没有得到广泛认同与应用。本学科先期设计研制的计算机视觉的食管曲张静脉气囊测压技术（CEBM）可以克服上述缺点，但需要临床验证其预测食管曲张静脉破裂出血风险的能力。肝硬化门脉高压症的食管胃底曲张静脉破裂所引起的上消化道出血是最主要的致死原因,其病死率较高．应用外科手术防治胃底食管下段静脉曲张破裂出血具有重要临床意义。目前，尚无一种防治门脉高压症上消化道出血的理想术式，国内最常用的贲门周围血管离断术有其明显优点，但也存在术后门静脉压力降低不明显、门静脉高压性胃病发生率高等不足之处。近年来随着对食管贲门周围血管的解剖学和病理生理学深入研究后，选择性贲门周围血管离断术的提出成为热点，该术式在断流的基础上保留了机体自发性的分流，起到了分流术和断流术的双重目的，是一种合理的手术方式，但与经典贲门周围血管离断术比较临床效果文献较少。另外目前对无上消化道出血史的门脉高压症患者是否行预防性手术尚有许多争论，但是一旦发生上消化道出血，病死率又极高，因此需要开展对有食管曲张静脉压力明显增高有高度出血风险的患者施行预防性门奇断流术的研究。为了有效控制门静脉高压、预防和治疗再出血，寻找和开发效果确定的降低门静脉压力的药物也有充分的临床意义。研究发现，生长抑素是近十余年推出的控制腹腔内脏血流、降低门静脉压力，防治食管胃底曲张静脉破裂出血的药物。临床推荐的生长抑素使用方法如下：先以250μg缓慢推注(称冲击治疗)，随后以250μg/h维持静脉滴注，出血停止后(约18h)再维持48-72h。然而，生长抑素的临床用药方案仅是国外的经验，而且国外不同的研究中心甚至有不同的结论。理想的控制食管静脉曲张破裂出血的药物应该是快速降低门静脉压力和门静脉血流量，应该精确到分和秒，而且生长抑素半衰期短，可许多国内外的研究检测的却是30-240分后的生长抑素降压效果，缺少1-30分钟生长抑素直接降低门静脉压力效果的临床研究，同时需要进一步探讨提高生长抑素的冲击量或维持量是否能提高其疗效等问题。目的1.前瞻性评估计算机视觉食管曲张静脉气囊测压技术对预测曲张静脉首次出血的价值，并探讨影响食管曲张静脉破裂出血的危险因素。2证实选择性贲门周围血管离断术临床治疗效果优于经典贲门周围血管离断术，探讨预防性贲门周围血管离断术的可行性。3证实生长抑素快速(1-30分钟)降低门静脉压力的效果和安全性，验证是否提高生长抑素冲击剂量和维持剂量就能增强其临床降低门静脉压力的效果。材料与方法1前瞻性评估计算机视觉食管曲张静脉气囊测压技术对预测曲张静脉首次出血的价值：纳入未发生过食管曲张静脉出血的57例肝硬化患者，CEBM测压并随访12个月，分析年龄、性别、肝硬化病因、食管曲张静脉内镜下表现（血管大小、红色征）、曲张静脉压力、肝功能严重程度Child-Pugh分级及腹水指标对食管曲张静脉破裂出血的影响，评价CEBM对预测曲张静脉首次出血的价值，并探讨影响食管曲张静脉破裂出血的危险因素。2选择性贲门血管周围离断术治疗组23例，同期选用经典贲门周围血管离断术22例作为对照，术中经胃网膜右静脉插管至门静脉分别测量切脾前后及术毕时自由门静脉压FPP。术后观察近期并发症如脾窝积液、发热等。随访3年，随访内容包括复发出血、肝性脑病、门脉高压性胃病、存活情况等。同样比较预防性手术组和治疗性手术组近远期并发症。3比较门奇断流患者不同剂量方案的生长抑素短时(1-30分钟)对门静脉压力的效果和安全性，验证是否提高生长抑素冲击剂量和维持剂量能增强其临床降低门静脉压力的效果。结果1对57例肝硬化食管曲张静脉患者首次出血风险评估发现，1年内34例患者（34/57,59.6%）发生曲张静脉破裂出血。单因素分析表明，食管曲张静脉压力(bleeder28.87±2.61mmHg; nonbleeder20.43±2.98mmHg; P <0.001)、曲张静脉直径(bleeder8.91±2.04mm; nonbleeder7.09±2.75mm; P=0.006)、内镜下红色征(bleeding rate, bleeder81%vs nonbleeder47.2%, P=0.012)预示较高的出血风险。多因素非条件Logistic回归分析发现，食管曲张静脉压力是预测首次出血的最主要危险因子(OR=2.817, P=0.003，95.0%C.I.1.437-5.521)。食管曲张静脉首次出血时间的多因素Cox比例风险模型分析，最终进入方程变量只有曲张静脉压力。预测首次出血曲张静脉压力值的ROC曲线下面积为0.98(95%C.I.:0.95-1.00)。根据ROC曲线，计算曲张静脉压力阈值为25.3mmHg，其预测出血的灵敏度与特异度均为91%。在25.3mmHg的曲张静脉压力阈值以下患者，1年出血率明显低于25.3mmHg以上的患者（P <0.001）。影响曲张静脉压力的因素主要是血管直径与红色征表现。粗大的曲张静脉压力比细小血管内压力高（Grade Ⅲ26.56±4.46mmHg vs Grade Ⅱ21.74±4.49mmHg,P=0.02）。出血组34例病人，内镜下红色征者的食管曲张静脉压力比无红色征者增高（28.40±2.41mmHg vs23.25±3.69mmHg, P <0.001）；非出血组23例病人，具有红色征者的食管曲张静脉压力同样比无红色征者升高（26.74±4.95mmHg vs19.97±2.18mmHg, P <0.001）。2选择性贲门周围血管离断术临床治疗效果优于经典贲门周围血管离断术，脾脏切除前、后两组间自由门静脉压力(FPP)无差异(P>0.05)；术毕时对照组FPP为(28.19±2.30)mmHg。观察组为(23.25±2.17)mmHg(P<0.05)。观察组脾窝积液和术后发热发生率明显低于对照组(P<0.05)。远期随访观察组的生存率、门静脉高压性胃病、肝性脑病、再发上消化道出血的发生率均优于对照组(P<0.05)。预防性手术组患者术前食管曲张静脉压力比治疗性组高(P<0.05)，而近期并发症少(P<0.05)，远期随访效果良好(P<0.05)3三组不同浓度的生长抑素（标准剂量、冲击剂量、高倍维持剂量）均导致快速、明显的门静脉压力降低，用药后1分钟门静脉压力即显著降低，5分钟时达到峰值，一直保持到30分钟仍然在低水平。500μg/h生长抑素维持组导致门静脉压力降低似乎比250μg/h生长抑素维持组更明显，但是并没有统计学差异。首剂250μg或500μg生长抑素静注均可致门静脉压力快速下降，但两者间无明显差异，而且并不降低血压，心率和中心静脉压力。生长抑素250μg/h维持或500μg/h维持也不导致血压，心率和中心静脉压力的明显变化。结论我们研制的计算机视觉食管曲张静脉气囊测压技术有较高的准确性与可行性，据此测定的食管曲张静脉压力是预测食管曲张静脉破裂出血的主要危险因素，具有进一步开发应用的潜在价值。选择性贲门周围血管离断术较之经典断流术效果更好，综合了传统断流术及分流术的优点，作为一种新术式为我们的临床治疗又提供了一个好选择。对有食管曲张静脉压力明显增高有高度出血风险的患者施行预防性断流术是安全可行的。生长抑素可快速降低门静脉压力，具有较好的时效关系，但量效关系不明显。更多还原

【Abstract】 Background:Variceal pressure has been identified as the key factor leading to variceal rupture.Measuring variceal pressure is important in predicting esophageal variceal bleeding andtreatment efficacy. Noninvasive balloon techniques assume that varices behave as anelastic structure because of their thin walls and lack of external tissue support; thus, thepressure needed to compress a varix (which can be sensed under direct vision usingclear balloons) equals the pressure inside the varix. Manometry uses an endoscopicballoon to measure variceal pressure. Up until now, this method relied on the visualappearance of the varices and, therefore, was subjected to observer bias. Endoscopicballoon methods of measuring variceal pressure have not gained wide popularity. Wehave recently developed a computerized endoscopic balloon manometry (CEBM), withcomputer visualization to determine the moment of variceal wall collapse duringballoon manometry instead of the visual evaluation of variceal compression used in thetraditional balloon method. In this paper, we report the preliminary results of in-vitroand in-vivo testing of CEBM. Whether CEBM can predict efficiently risk of esophagealvariceal bleeding in patients with liver cirrhosis or not haven’t reported until now.Portal hypertension can damage living severely and esophageal varices withsubsequent variceal hemorrhage leads to significant mortality in patients with livercirrhosis. Surgery used for the treatment of esophageal varices with subsequent varicealhemorrhage has important clinical significance; however, the ideal surgical modalityhas not yet been identified. The pericardial devascularization appears to be effective forthe control of variceal hemorrhage due to portal hypertension, but also lack of thereaserch of the portal vein pressure and the rate of portal hypertensive gastropathy occurred. With the in-depth study of the pathophysiology and anatomy ofperipheral vascularesophageal, selective periesophagogastric devascularizationcombines advantages of traditional devascularization and shunt, has become a hotpoint, it is a reasonable surgical approach, but lack of more clinical effectliterature. Now, there is still a lot of controversy about carrying out preventive surgeryor not for the portal hypertension patients but without gastrointestinal bleeding. Butthere were more risk of death when the upper gastrointestinal bleeding happened. So,we need take more research about preventive surgery for the patients who have highervariceal pressure and high risk of bleeding.To search and explore drugs which can decrease portal hypertension and preventvariceal hemorrhage effectively is very important. Somatostatin (SST) is used for thetreatment of acute variceal bleeding based on its ability to decrease portal pressure andcollateral blood flow in past two decades. The usual schedule for SST administration isan initial bolus of250g, followed by an infusion of250g/h which is maintained untila48to72-hour bleed-free period is achieved. However, the dose of SST infusedclinically (250g/h) is largely empirical. Hemodynamic studies have shown that toeffectively decrease portal pressure and azygos blood flow, a larger dose may berequired (500g/h). A higher infusion dose of SST (500g/h) resulted in morepronounced effects on the hepatic venous pressure gradient than the classic dose of250g/h. Moreover, bolus administration of SST can cause transient, but dramaticdecreases in portal pressure, porto-collateral blood flow and variceal pressure, however,the effects of SST have not been adequately evaluated.To produce effective tamponadeof actively bleeding varices, the ideal drug therapy should quickly reduce portal venousflow (PVF) and pressure, preferably within seconds to minutes. In view of this, it issomewhat surprising that virtually all previous hemodynamic studies have examineddrug effects at30–240min after the start of bolus administration. To date, there are nostudies which have focused on the immediate-early effects (between1–30min) of SST. ObjectiveThe aims of the present study were:1To evaluate the value of computerized endoscopic balloon manometry (CEBM)on prediction of endoscopic variceal bleeding firstly,and to explore the riskfactors of endoscopic variceal bleeding;2To understand effectiveness for the control of variceal hemorrhage due toportal hypertension of selective pericardial devascularization by comparedwith classical pericardial devascularization, and to explore the clinicalfeasibility of preventive pericardial devascularization;3To validate the clinical effectiveness and reliability of Somatostatin ondecreasing portal hypertension, to validate the clinical effectiveness ofSomatostatin on decreasing portal hypertension by increasing impact dosesand maintenance doses of Somatostatin.Materials and Methods1To assess the applicability of computerized endoscopic balloon manometry(CEBM) for predict a first variceal hemorrhage in cirrhotic patients during theprospective study, and to detect clinical factors in the evaluation of the risk ofbleeding. Fifty-seven patients with liver cirrhosis and esophageal varices whohad never experienced variceal bleeding were followed for12months. Thepatients underwent variceal pressure measurement by CEBM technique. Theendpoint of the study was the presence or absence of a variceal hemorrhage.The relation between variceal hemorrhage with age, sex, etiology of cirrhosis,endoscopic findings of varices (size of varices, red color signs), varicealpressure, Child-Pugh’s class, and ascites were studied.2Fourty-five patients with liver cirrhosis and esophageal varices were followed for3years. Twenty-three of that underwent selective pericardialdevascularization, as for treatment group, and twenty-two of that underwentclassical pericardial devascularization, as for control group. FPP was measuredrespectively with venous cannula before and after cutting spleen and the end ofoperation. Splenic fossa effusion and fever were observed after operation. Therelationship between operation with re-hemorrhage, hepatic encephalopathy,portal hypertensive gastropathy and survival were studied.3The aim of this study was to compare the efficacy of different schedules ofSST therapy with placebo on portal pressure in patients with portalhypertension treated with portal-azygous disconnection, and to test whether anincrease in bolus or infusion dose can improve the clinical efficacy of SSTtherapy through double-blind clinical trial.Results1In all57cirrhotic patients, thirty-four patients (34/57,59.6%) developed avariceal hemorrhage. In univariate analysis, the level of variceal pressure(bleeder28.87±2.61mmHg; nonbleeder20.43±2.98mmHg; P <0.001), thediameter of varices (bleeder8.91±2.04mm; nonbleeder7.09±2.75mm; P=0.006), and the endoscopic red color sign on the variceal wall (bleeding rate,bleeder81%vs nonbleeder47.2%, P=0.012) predicted a higher risk ofvariceal hemorrhage. With the results obtained from univariate analysis, amultiple logistic regression model was created which revealed that varicealpressure was major predictor of the risk for a first variceal bleeding (OR=2.817, P=0.003,95.0%C.I. were1.437to5.521). The area under the receiveroperating characteristic (ROC) of variceal pressure for predicting varicealbleeding was0.98and at variceal pressure cutoff value of25.3mmHg,specificity and sensitivity were91%. Higher variceal pressures have been documented in patients with large varices (grade Ⅲ26.56±4.46mmHg vsgrade Ⅱ21.74±4.49mmHg, P=0.02), and in those with red color signs(bleeder,28.40±2.41mmHg vs23.25±3.69mmHg, P <0.001; nonbleeder,26.74±4.95mmHg vs19.97±2.18mmHg, P <0.001), which are those moreprone to bleed.2There was no difference in FFP before and after cutting spleen between twogroups. FFP in different group was (28.19±2.3) mmHg (in control group)andwas (23.25±2.17) mmHg (in treatment group) respectively the end ofoperation. The incidence of spleen nest effusion and postoperative fever inobservation group was significantly lower than control group (P <0.05). For along-term following-up in observation group, the results of survival rate, portalhypertensive gastropathy, hepatic encephalopathy was more good than controlgroup (P <0.05). The esophageal varicose vein pressure inpreventivesurgery patients with preoperative were higher than the treatmentgroup (P <0.05), the treatment group have an advantage than that of controlgroup with3years after surgery (P <0.05).3Patients in the three SST treatment groups demonstrated marked, rapid andhighly significant decreases in portal pressure. The decline in portal pressurewas moderate at1min, achieved a peak effect at5min and remaineddecreased at30min. Infusion of SST at a constant rate of250g/h resulted ina moderate, but significant reduction in portal pressure. The500g/h dosecaused a more pronounced decrease in portal pressure than the250g/h dose;however, there was no statistically significant difference between these2groups. A double bolus injection of SST rapidly induced a more pronounceddecrease in portal pressure than a single bolus injection at1min. However,there was no statistically significant difference between these2groups. Asingle bolus or double bolus injection of SST did not decrease HR, systemic blood pressure or CVP. A continuous infusion of either250g/h or500g/hof SST given after a single bolus injection did not induce significant changesin HR, systemic blood pressure or CVP.ConclusionOur preliminary results indicate that CEBM of esophageal varices is feasible andaccurate. This technique may become a more reliable method for noninvasivemeasurement of variceal pressure and warrants further investigation. The level ofvariceal pressure is a major predictor for variceal bleeding in cirrhotic patients.Selectiveperiesophagogastric devascularization have more advantages, such as simple operationmethods, reliable, practical, and also have a wide range of indications.The postoperative effects are better than the classic devascularization. It combines theadvantages of traditional devascularization and shunt, becomes a new techniquefor our clinical treatment. We found that carrying out preventive devascularization for apatient who had a high degree of risk of bleeding and esophageal varicose vein pressureincreased significantly is safe and feasible. This study shows that SST is effective indecreasing portal pressure within30minutes of administration in patients with livercirrhosis. The clinical schedule used in this study was reasonable and safe.更多还原