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

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.