Assessment of retinal and sublingual microcirculation as surrogate biomarkers for cerebral microcirculatory dynamics

摘要/项目摘要 微循环血流障碍已被认为是急性脑血管疾病的关键病理生理事件。 危重病人。由于大脑对血流灌注不足、认知障碍、 尤其是老年人，会延长恢复期，并明显影响独立生活能力。 危重病患者的复苏或灌流管理主要由大循环指导 评估(即动脉血压)，很少考虑微循环，如 微循环参数在技术上很难评估。这种做法是在以下假设下运作的 旨在纠正宏观血流动力学变量的复苏在纠正微循环方面也是有效的 脑组织的灌流和氧气输送，这种关系被称为血流动力学一致性。然而， 最近对病理生理状态(如脓毒症、休克)的研究强烈表明，微血管灌流 尽管优化了大循环参数，但仍未恢复。因此，迫切需要学习。 是什么控制了大脑微循环的流动，剖析了影响血流动力学一致性和 确定有效的微循环复苏目标。此外，虽然有研究工具，但没有通用的 可以通过完整的头骨测量微循环的公认技术。因此，至关重要的是， 确定更易接近的微循环床(例如，舌下、视网膜)，可作为 脑微循环血流。将替代微循环表征为流动生物标志物是关键的一步 微循环复苏靶点的临床应用。我们的长期目标是 制定有效的策略以加强微循环灌流和向大脑的有效氧气输送 在危急的临床情况下需要复苏。这项提案的主要目标是：a)调查 微循环在脑血流动力学一致性中的作用 表征可作为非侵入性替代物开发的有效脑微循环替代物 床边临床管理的生物标志物。我们将操作心血管生理学，反映出共同的 术中情景(即出血性低血压)，并假设目前的复苏策略， 尤其是使用高浓度的血管增压剂，不但不能恢复微血管功能，反而会导致长时间的高血压。 脑微血管持续收缩，导致脑损伤。在目标1中，我们将评估大脑 失血性低血压诱导复苏中的血流动力学一致性和氧输送 多模式微血管成像技术。在目标2中，我们将确定)亚语言之间的关系 和b)视网膜和大脑微循环动力学，并研究其作为替代生物标志物的潜力 床边脑微循环灌流管理。该项目的成功完成将勾勒出 维持微循环灌流和表征替代微循环的复苏策略 可以非侵入性地监测，从而帮助将脑损伤降至最低。

Abstract/Project Summary Impairment of microcirculatory blood flow has been implicated as a pivotal pathophysiologic event in acutely critically ill patients. As the brain is particularly sensitive to insufficient perfusion, cognitive impairment, particularly in the elderly, can prolong the recovery period and significantly impact the ability to live independently. Resuscitation or perfusion management in critically ill patients is primarily guided by macrocirculatory assessment (i.e., arterial blood pressure (ABP)) with little consideration of the microcirculation, as microcirculatory parameters are technically difficult to assess. Such practice operates under the assumption that resuscitation aimed at correcting macro-hemodynamic variables is also effective in correcting microcirculatory perfusion and oxygen delivery to the brain tissue, a relationship termed hemodynamic coherence. However, recent studies in pathophysiologic states (e.g., sepsis, shock) strongly suggest that microvascular perfusion is not restored despite the optimization of macrocirculatory parameters. Thus, there is an urgent need to learn what governs cerebral microcirculatory flow, dissect conditions that compromise hemodynamic coherence and define effective microcirculation resuscitation targets. Further, while research tools exist, there is no commonly accepted technique which can measure microcirculation through the intact skull. Therefore, it is essential to identify more accessible microcirculatory beds (e.g., sublingual, retinal) which may serve as surrogates for cerebral microcirculatory flow. Characterizing surrogate microcirculations as flow-biomarkers is a critical step towards practical clinical implementation of microcirculatory targets for resuscitation. Our long-term goal is to develop effective strategies to enhance microcirculatory perfusion and effective oxygen delivery to the brain under critical clinical conditions that require resuscitation. The primary goals of this proposal are to a) investigate the role of the microcirculation in cerebral hemodynamic coherence in the gyrencephalic brain and b) characterize effective cerebral microcirculation proxies that can be developed as non-invasive surrogate biomarkers for bedside clinical management. We will manipulate cardiovascular physiology reflecting common intraoperative scenarios (i.e., hemorrhagic hypotension) and hypothesize that current resuscitation strategies, in particular the use of high concentrations of vasopressors, do not restore microvascular function but lead to long- lasting cerebral microvascular constriction and result in brain injury. In Aim 1 we will assess cerebral hemodynamic coherence and oxygen delivery during induced hemorrhagic hypotension and resuscitation using multimodal microvascular imaging techniques. In Aim 2 we will determine the relationship between a) sublingual and b) retinal and cerebral microcirculatory dynamics and investigate their potential as surrogate biomarkers for bedside cerebral microcirculation perfusion management. Successful completion of this project will delineate resuscitation strategies that maintain microcirculatory perfusion and characterize surrogate microcirculations that can be monitored non-invasively and thereby help minimize brain injury.