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

评估视网膜和舌下微循环作为脑微循环动力学替代生物标志物

• 批准号: 10790198
• 负责人: Ulrike Hoffmann
• 金额: $ 24.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10790198
• 关键词: Acute; Biological Markers; Blood Pressure; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Injuries; Cardiovascular Physiology; Cerebrum; Clinical; Clinical Management; Complex; Critical Illness; Data; Development; Disease Outcome; Elderly; Event; Failure; Family suidae; Goals; Hematocrit procedure; Hemorrhage; Heterogeneity; Homeostasis; Human; Hypotension; Iatrogenesis; Imaging Techniques; Impaired cognition; Impairment; Lead; Learning; Measures; Microcirculation; Microcirculatory Bed; Modeling; Mus; Outcomes Research; Oxygen; Pathologic; Patients; Perfusion; Proxy; Quality of life; Recovery; Regulation; Research; Resuscitation; Retina; Role; Sepsis; Shock; Surrogate Markers; Techniques; Time; Tissues; Vasoconstrictor Agents; Work; aged; brain tissue; cerebral hemodynamics; clinical implementation; clinically relevant; cranium; density; genetic manipulation; hemodynamics; improved; indexing; insight; mouse model; multimodality; non-invasive monitor; novel therapeutic intervention; older patient; restoration; tool; vasoconstriction

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.

摘要/项目摘要 微循环血流受损被认为是急性发作的关键病理生理事件 危重病人。由于大脑对灌注不足、认知障碍特别敏感， 特别是对于老年人来说，可能会延长恢复期并显着影响独立生活的能力。 危重患者的复苏或灌注管理主要由大循环指导 评估（即动脉血压（ABP））很少考虑微循环，因为 微循环参数在技术上很难评估。这种做法的运作假设是： 旨在纠正宏观血流动力学变量的复苏对于纠正微循环也有效 脑组织的灌注和氧气输送，这种关系称为血流动力学一致性。然而， 最近对病理生理状态（例如脓毒症、休克）的研究强烈表明，微血管灌注是 尽管优化了大循环参数，但仍未恢复。因此，迫切需要学习 是什么控制着大脑微循环流动，剖析损害血流动力学一致性的条件，以及 确定有效的微循环复苏目标。此外，虽然存在研究工具，但没有通用的 可以通过完整头骨测量微循环的公认技术。因此，有必要 确定更容易接近的微循环床（例如舌下、视网膜），可以作为替代 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 走向复苏微循环目标的实际临床实施。我们的长期目标是 制定有效的策略来增强微循环灌注和有效地将氧气输送到大脑 在需要复苏的危急临床情况下。该提案的主要目标是 a) 调查 微循环在环脑脑血流动力学一致性中的作用和 b) 表征有效的脑微循环指标，可开发为非侵入性替代指标 用于床边临床管理的生物标志物。我们将操纵反映常见的心血管生理学 术中情况（即失血性低血压）并假设当前的复苏策略 特别是使用高浓度的血管升压药，不仅不能恢复微血管功能，反而会导致长期 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 诱导失血性低血压和复苏期间的血流动力学一致性和氧输送 多模态微血管成像技术。在目标 2 中，我们将确定 a) 舌下含服之间的关系 b) 视网膜和大脑微循环动力学，并研究它们作为替代生物标志物的潜力 床边脑微循环灌注管理。该项目的顺利完成将划定 维持微循环灌注并表征替代微循环的复苏策略 可以进行非侵入性监测，从而有助于最大限度地减少脑损伤。