PATHOPHYSIOLOGIC RESPONSE TO FETAL CARDIAC SURGERY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。这个正在进行的项目的目标是继续胎儿心脏手术的发展。某些先天性缺陷在出生后无法矫正，宫内矫正手术具有明显的优势。这种方法需要了解手术干预和体外循环对胎儿的生理影响。迄今为止，我们在这一领域的工作使我们对这些问题有了实质性但不全面的了解。三个主要的病理生理反应，限制胎儿生存后的干预和体外循环（我们确定在原来的拨款建议）包括：1。在胎儿介入手术的搭桥前阶段胎儿心血管稳态的丧失。2.在建立胎儿旁路时，胎儿血管阻力的“阶跃函数”升高与急性失代偿有关。3.在胎儿转流期间和之后，胎盘血管阻力逐渐升高，导致胎盘血流降低。本项目的具体重点是确定这三种反应的介质和详细的病理生理机制，着眼于这些信息的临床应用，以促进人类胎儿心脏手术的发展。将对这三项答复中的每一项进行系统评价。检查旁路前问题的实验将集中在胎儿应激反应的作用上。对这种反应的进一步理解目前受到我们的胎儿动物模型（绵羊）的限制。我们建议研究麻醉剂麻醉在钝化的压力反应的仪器灵长类动物模型的疗效。解决胎儿血管阻力的“阶跃函数”上升的实验将使用专门设计的旁路电路来检查这种反应的抑制。我们的方法将包括超声流量传感器，以连续测量器官流量的瞬时变化，除了我们更具体的微球技术，不具有这种能力。认识到影响胎盘血管系统的多种因素，除了类花生酸的作用外，解决旁路后胎盘阻力逐渐上升的实验将检查胎盘血管功能障碍的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this ongoing project is to continue the development of fetal cardiac surgery. Certain congenital defects are uncorrectable after birth and there is a clear advantage for intrauterine corrective surgery. This approach requires an understanding of the physiological effects of surgical intervention and extracorporeal circulation on the fetus. Our work in this area to date has allowed us to gain a substantial but incomplete understanding of these issues. The three major pathophysiological responses which limit fetal survival following intervention and extracorporeal circulation (which we identified in the original grant proposal) include: 1. The loss of fetal cardiovascular homeostasis in the pre-bypass phase of fetal intervention. 2. The "step function" rise in fetal vascular resistance at the institution of fetal bypass which is associated with acute decompensation. 3. The gradual rise in placental vascular resistance during and after fetal bypass which results in depressed placental blood flow. The specific focus of this project is to identify the mediators and detailed pathophysiologic mechanisms of these three responses with an eye towards clinical application of this information to advance the development of human fetal cardiac surgery. Each of the three responses will be systematically evaluated. Experiments examining the pre-bypass problem will focus on the role of the fetal stress response. Further understanding of this response is presently limited by our fetal animal model (sheep). We propose to study the efficacy of narcotic anesthesia in blunting the stress response in an instrumented primate model. Experiments addressing the 'step function' rise in fetal vascular resistances will examine the inhibition of this response using specifically designed bypass circuitry. Our methodology will include ultrasonic flow transducers to continuously measure instantaneous changes in organ flow in addition to our more specific microsphere techniques, which do not have this capability. In recognition of the multiple factors effecting the placental vasculature, experiments addressing the gradual rise in post bypass placental resistance will examine the role of placental vascular dysfunction in addition to the role of eicosanoids.