PATHOPHYSIOLOGIC RESPONSE TO FETAL CARDIAC SURGERY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这个正在进行的项目的目标是继续发展胎儿心脏手术。某些先天缺陷在出生后是无法矫正的，宫内矫正手术有明显的优势。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，我们在这方面的工作使我们对这些问题有了实质性但不完整的了解。在干预和体外循环后，限制胎儿存活的三个主要病理生理反应(我们在最初的拨款提案中确定)包括：1.在胎儿干预的转流前阶段，胎儿心血管内稳态的丧失。2.胎儿转流时胎儿血管阻力“阶梯函数”升高，与急性失代偿有关。3.胎盘血管阻力在转流过程中和转流后逐渐升高，导致胎盘血流量下降。本项目的重点是确定这三种反应的介质和详细的病理生理机制，并着眼于这些信息的临床应用，以推动人类胎儿心脏手术的发展。将对三份答复中的每一份进行系统评估。研究预搭桥问题的实验将重点放在胎儿应激反应的作用上。对这一反应的进一步了解目前受到我们的胎儿动物模型(绵羊)的限制。我们建议在仪器化灵长类动物模型中研究麻醉在钝化应激反应方面的效果。关于胎儿血管阻力“阶跃函数”上升的实验将使用专门设计的旁路电路来检验对这一反应的抑制。我们的方法将包括超声波流量传感器，以连续测量器官血流的瞬时变化，以及我们更具体的微球技术，这些技术没有这一能力。在认识到影响胎盘血管系统的多种因素后，针对转流后胎盘阻力逐渐增加的实验将考察胎盘血管功能障碍的作用以及二十烷类化合物的作用。

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.