Development of a Multi-scale closed loop model for hemorrhagic shock: a platform to assess REBOA performance

项目摘要 出血性休克是创伤性损伤后可预防死亡的主要原因， 军事和35%的平民在创伤后死亡。不可压缩腔内区域的损伤，例如 躯干和腹部，由于缺乏适当的干预措施，是一个主要的临床挑战，并代表30- 40%的早期死亡。为了解决这个问题，血管内出血控制（EHC）装置和最低限度 诸如主动脉的复苏性血管内球囊闭塞（REBOA）的侵入性技术已经 越来越多地采用。REBOA涉及主动脉中球囊导管的完全膨胀，这限制了血流 从而使出血最小化。虽然REBOA在恢复近端 在缺血再灌注中，血流量的减少可导致缺血再灌注损伤，这增加了缺血再灌注的风险。 随后发生肾衰竭。因此，迫切需要确定最佳闭塞尺寸、时机和持续时间 REBOA部署。到目前为止，这些重要的知识差距受到昂贵和耗时的阻碍， 大型动物模型减缓了创新的步伐。为了解决这一重大差距，我们建议制定和 验证一种新的多尺度计算模型，使我们能够模拟体内生理反应 失血性休克使用心血管系统的3D-0D闭环方法，我们将能够 模拟关键反馈回路和生物反应功能，以呈现生理相关模型。 这些方法以前曾被用于指导心血管支架和下腔静脉的设计 过滤器，但据我们所知，没有一个被用于REBOA或任何其他EHC设备的评估。 我们的中心假设是，主动脉和全身血管内血流的计算建模 网络将生成准确和强大的压力，流量和剪切速率的值，误差在0.5%以内， 模仿体内行为。我们的目标是使用这个计算框架：1）量化的本地和 全身血液动力学（即，压力、流速、剪应力、氧气输送等）在活动阶段， 出血、REBOA主动脉闭塞和复苏，2）识别易受 由于血流动力学改变导致的缺血性损伤，3）预测与以下相关的关键生理反应： 出血和主动脉闭塞期间的血管顺应性、氧输送和肾自动调节，以及4） 确定最佳主动脉闭塞尺寸和部分与完全闭塞策略的持续时间，以防止缺血- 再灌注损伤和肾衰竭。这种计算机模型的成功开发和验证将大大 有助于EHC器械的临床前测试和优化，最大限度地减少对大型动物研究的需求 并且还为研究心血管系统内的其它瞬时血液动力学状况打开了大门。

Project Summary Hemorrhagic shock is the leading cause of preventable death after a traumatic injury, and accounts for 91% of military and 35% of civilian fatalities after trauma. Injuries to non-compressible intracavity regions, such as the torso and abdomen, are a major clinical challenge due to a lack of appropriate interventions, and represent 30- 40% of early fatalities. To address this problem, endovascular hemorrhage control (EHC) devices and minimally invasive techniques such as Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) have been increasingly adopted. REBOA involves full inflation of a balloon catheter in the aorta, which restricts blood flow distal to the occlusion and consequently minimizes bleeding. While REBOA is effective at restoring proximal perfusion, the reductions in blood flow can result in ischemia-reperfusion injuries that increase the risk of subsequent renal failure. As such, there is a pressing need to identify optimal occlusion size, timing, and duration of REBOA deployment. To date, these important knowledge gaps are hindered by expensive and time intensive large animal models that slow the pace of innovation. To address this major gap, we propose to develop and validate a novel multi-scale computational model that will allow us to simulate the in vivo physiologic response to hemorrhagic shock. Using a 3D-0D closed loop approach of the cardiovascular system, we will be able to simulate the critical feedback loops and biologic response functions to render a physiologically relevant model. These methods have been previously used to inform the design of cardiovascular stents and inferior vena cava filters, but none to our knowledge have been exploited for the evaluation of REBOA or any other EHC device. Our central hypothesis is that computational modeling of blood flow within the aorta and systemic vascular network will generate accurate and robust values for pressure, flow and shear rates within  5% error, closely mimicking in vivo behavior. The objective is to use this computational framework to: 1) quantify the local and systemic hemodynamics (i.e., pressure, flow rate, shear stress, oxygen transport, etc.) during phases of active hemorrhage, aortic occlusion with REBOA, and resuscitation, 2) identify vascular regions that are vulnerable to ischemic damage as a result of the altered hemodynamics, 3) predict key physiologic responses related to vascular compliance, oxygen delivery and renal autoregulation during hemorrhage and aortic occlusion, and 4) determine optimal aortic occlusion size and duration of partial vs. full occlusion strategies to prevent ischemia- reperfusion injuries and renal failure. Successful development and validation of this in silico model will greatly contribute to the preclinical testing and optimization of EHC devices, minimizing the need for large animal studies and also open doors for the study of other transient hemodynamic conditions within the cardiovascular system.