Vascular Determinants of Anesthesia-Induced Hypotension at the Extremes of Age

项目摘要/摘要 每年，数以亿计的患者接受全身麻醉进行手术。数以百万计 这些患者在手术中特别容易受伤，因为他们要么非常年轻(例如， 新生儿和婴儿)或以上(70岁)。麻醉师的一个关键角色是确保 血流动力学稳定和充分的器官灌流(例如，防止术中低血压)。在关心的时候 对于处于极端年龄的患者，这可能是具有挑战性的，因为高达80%的新生儿、婴儿和老年人 术中出现低血压。这是一个重大的公共卫生问题，因为在手术中 低血压已被证明在这一人群中会导致显著的发病率和死亡率，并与 每年增加数百万美元的医疗费用。尽管很明显，术中 低血压是新生儿、婴儿和老年人的一个重大问题，这是其机制的基础。 术中低血压风险增加及其后果尚不清楚。 为了解决这一问题，我们建议使用体外和体内互补的方法来提供新的见解 探讨高龄患者术中低血压升高的机制 频率这项研究计划的目标是研究血管系统的独特性质如何在 年龄的极端导致在常用的环境下发生术中低血压 全身麻醉剂。我们已发表的初步数据表明，幼年大鼠的肠系膜动脉更僵硬。 与成人相比，限制去甲肾上腺素的能力减弱。相比之下，大脑中动脉 幼年大鼠表现出僵硬程度降低和脑血流自动调节功能受损 与成年人相比。总而言之，这些数据提供了我们假设的基础 高龄患者术中低血压风险增加的潜在机制 起源于血管。 在接下来的5年里，我们建议研究极端患者的血管机制 当暴露在空气中时，大多数年龄段的人术中低血压和导致器官低灌流的风险增加 全身麻醉。通过对分离的肠系膜动脉和脑动脉的研究，我们将确定生物力学和 区分非常年轻和年长的成年人与中年成年人的细胞机制。 另外，我们将使用活体方法来确定低血压的定义，这些定义是基于 器官灌流。最后，我们将确定哪些麻醉方案最不可能产生低血压， 哪些疗法可以治疗低血压，在保持整体平衡的同时改善血压-- 身体器官灌流。这些截然不同但相辅相成的调查将是实现以下目标的重要一步 优化高龄患者的围手术期护理。

PROJECT SUMMARY/ABSTRACT Each year, hundreds of millions of patients are exposed to general anesthesia for surgery. Millions of these patients are particularly vulnerable to injury during surgery because they are either very young (e.g., neonates and infants) or older (>70 years of age). One critical role of the anesthesiologist is to ensure hemodynamic stability and adequate organ perfusion (e.g., prevent intraoperative hypotension). When caring for patients at the extremes of age, this can be challenging because up to 80% of neonates, infants, and older adults experience intraoperative hypotension. This represents a significant public health problem as intraoperative hypotension has been shown to cause significant morbidity and mortality in this population and is associated with millions of dollars in additional healthcare costs per year. Though it is clear that intraoperative hypotension is a significant problem in neonates, infants, and older adults, the mechanisms that underlie the increased risk of intraoperative hypotension and its consequences remain unclear. To address this, we propose to use complementary in vitro and in vivo approaches to provide new insights into mechanisms by which patients at extremes of age suffer intraoperative hypotension with increased frequency. The goal of this research program is to investigate how the unique properties of the vasculature at the extremes of age contribute to the development of intraoperative hypotension in the setting of commonly used general anesthetics. Our published and preliminary data show that mesenteric arteries in juvenile rats are stiffer with diminished capacity to constrict to norepinephrine compared to adults. In contrast, middle cerebral arteries from juvenile rats demonstrated reduced stiffness and impaired autoregulation of cerebral blood flow when compared to adults. Taken together, these data provide the foundation upon which we hypothesize that the underlying mechanism of increased risk of intraoperative hypotension in patients at the extremes of age is vascular in origin. Over the next 5 years, we propose to investigate vascular mechanisms by which patients at the extremes of age are at increased risk of intraoperative hypotension and resultant organ hypoperfusion when exposed to general anesthesia. By studying isolated mesenteric and cerebral arteries we will identify biomechanical and cellular mechanisms that differentiate the very young and older adults from adults of intermediate age. Separately, we will use in vivo approaches to identify definitions of hypotension that are determined based upon organ perfusion. Finally, we will determine which anesthetic regimens are least likely to produce hypotension, and which therapies used to treat hypotension best balance improving blood pressure while preserving whole- body organ perfusion. These distinct but complementary lines of inquiry will be an important step towards optimizing perioperative care for those at the extremes of age.