Noninvasive Portal Pressure Measurements in Children

小儿门静脉高压症的常见并发症是胃食管静脉曲张，静脉曲张出血是 相关死亡率为1- 3%，而据报道， 肝硬化儿童目前，儿科医生通过间接手段评估门静脉高压症，因为 成人的临床标准（肝静脉压梯度- HVPG）未常规用于儿童。那里 儿童肝脏疾病的原因有很多（胆道闭锁，先天性肝纤维化，α-1-抗胰蛋白酶 缺乏症、自身免疫性肝病等），每一种都有独特的病程，这也使得成年人 很难适用于儿童。因此，发展一种准确的和非侵入性的 门静脉压力的测量技术将代表诊断的一个重大进展， 儿童门静脉高压症的治疗。我们的团队开发了SHAPE的基本概念， 产生了有史以来第一个体内形状估计（在犬中）。我们还进行了一项首次在人类身上进行的初步研究， 这项技术的能力，估计门静脉压力的45名成人患者的支持下，NIDDK挑战 Grant（RC 1 DK 087365），显示门静脉和肝脏之间的SHAPE梯度显著较高 门静脉高压症组（HVPG > 10 mmHg）与HVPG较低组相比（1.37 ± 0.59 vs. -1.68 ± 0.27，p < 0.001）。最近，我们扩展了使用SHAPE进行门静脉压力估计的概念 在一项正在进行的大型多中心临床试验中（由R 01 DK 398526支持）。120例受试者的初步结果 使用造影剂Sonazoid（GE Healthcare，奥斯陆，挪威）获得的结果非常令人鼓舞， 诊断门脉高压的准确率为94.2%，结合最近FDA批准的 用于儿科应用的超声造影剂（Lumason; Bramson，米兰，意大利）鼓励我们将 来自托马斯杰斐逊大学（TJU）和费城儿童医院的研究人员 （CHOP）与一流的超声扫描仪制造商（GE Healthcare）合作，以生产用于 无创准确评估儿童门静脉高压症。首先，SHAPE算法将 在现有技术的超声扫描仪（具有C2-9儿科探头的Logiq E9; GE Healthcare， 密尔沃基，WI）进行儿童真实的时间压力测量。以下体外研究比较了Sonazoid 直接向Lumason，我们将在CHOP进行一项初步临床试验，在患有临床疾病的儿童中进行体内SHAPE。 诊断为门静脉高压症，与患有慢性肝病但没有 门静脉高压我们还将监测儿童的疾病进展或治疗反应， 通过比较SHAPE结果与临床结局的门静脉高压。因此，本研究旨在进一步发展 一种新颖和创新的基于超声的技术（即，SHAPE）用于无创评估门静脉 并在儿童中进行初步临床试验，以确定可行性和初步准确性 儿科SHAPE用于评估门静脉高压症。

A common complication of pediatric portal hypertension is gastroesophageal varices and variceal bleeds are associated mortality rates of 1-3 %, while life-threatening complications have been reported in up to 20 % of children with cirrhosis. Currently, pediatricians evaluate portal hypertension through indirect means, since the clinical standard in adults (the hepatic venous pressure gradient – HVPG) is not used routinely in children. There are many causes of liver disease in children (biliary atresia, congenital hepatic fibrosis, alpha-1-antitrypsin deficiency, autoimmune liver disease, etc.), each with a unique disease course, which also makes adult guidelines difficult to apply to children. Consequently, the development of an accurate and noninvasive technique for measurement of portal venous pressure would represent a major advance in the diagnosis and management of portal hypertension in children. Our group developed the fundamental concept of SHAPE and produced the first ever in vivo SHAPE estimates (in canines). We also conducted a first-in-humans, pilot study of this technique's ability to estimate portal pressures in 45 adult patients supported by an NIDDK Challenge Grant (RC1 DK087365), which showed significantly higher SHAPE gradients between the portal and hepatic veins in subjects with portal hypertension (HVPG > 10 mmHg) than in those with lower HVPGs (1.37 ± 0.59 vs. -1.68 ± 0.27, p < 0.001). Recently, we have expanded the concept of using SHAPE for portal pressure estimation in an ongoing larger multi-center clinical trial (supported by R01 DK398526). Preliminary results in 120 subjects obtained with the contrast agent Sonazoid (GE Healthcare, Oslo, Norway) have been very encouraging with an accuracy for diagnosing portal hypertension of 94.2% and combined with the recent FDA approval of an ultrasound contrast agent (Lumason; Bracco, Milan, Italy) for pediatric applications have encouraged us to bring together researchers from Thomas Jefferson University (TJU) as well as the Children's Hospital of Philadelphia (CHOP) with a premier manufacturer of ultrasound scanners (GE Healthcare) in order to produce a device for noninvasive and accurate assessment of portal hypertension in children. First the SHAPE algorithm will be implemented on a state-of-the-art ultrasound scanner (Logiq E9 with a C2-9 pediatric probe; GE Healthcare, Milwaukee, WI) for real time pressure measurements in children. Following in vitro studies comparing Sonazoid directly to Lumason, we will conduct an initial clinical trial at CHOP of in vivo SHAPE in children with a clinical diagnosis of portal hypertension compared to a matched group of children with chronic liver disease but without portal hypertension. We will also monitor disease progression or treatment response in children identified with portal hypertension by comparing SHAPE results to clinical outcomes. Hence, this study aims to further develop a novel and innovative ultrasound based technology (i.e., SHAPE) for the noninvasive evaluation of portal hypertension and to conduct an initial clinical trial in children to establish the feasibility and preliminary accuracy of pediatric SHAPE for the assessment of portal hypertension.