PROJECT SUMMARY/ABSTRACT Background: Surgery for hip fracture can be devastating for older adults, with complications including delirium, increased risk of dementia, and inability to walk. As an anesthesiologist and clinician-scientist, I have focused on reducing delirium after surgery. In this proposal, I will build the foundation for a research career focused on the broader goals of reducing neurocognitive and functional decline after surgery in older adults. I will specifically focus on the role of optimizing intraoperative cerebral perfusion, because of pilot data suggesting that reduced cerebral perfusion during surgery is a modifiable risk factor for delirium. Career Development Plan: I am proposing specific educational goals that address gaps in my current knowledge. First, I will develop expertise in cerebrovascular physiology and monitoring under the mentorship of Dr. Koehler, an expert in cerebral blood flow regulation. Second, I will develop expertise in neurocognitive testing and dementia assessment under the mentorship of Dr. Kamath, a neuropsychologist, and Dr. Gottesman, an expert in dementia adjudication in the research setting. Third, I will gain expertise in clinical trials and measuring functional status through the mentorship of Drs. Sieber and Neuman (experts in perioperative clinical trials in older adults), and Dr. Walston (a geriatrician with expertise in functional status). Finally, I will develop as a leader through interactions with my mentors, courses, and leadership opportunities. Research Proposal: During hip fracture surgery, extreme variations in blood pressure are common in older adults, who are susceptible to cerebral ischemia and vulnerable to consequences of hypotension. However, there is no standard of care as to what constitutes adequate blood pressure during surgery. Our group has championed methodology to define optimal blood pressure in individual patients by real-time monitoring of cerebral autoregulation. Using these methods in cardiac surgery, we have shown that mean arterial pressure (MAP) below the limits of cerebral autoregulation is associated with postoperative morbidity, and that an intervention to target intraoperative MAP based on this monitoring may reduce delirium. Although promising, these results in cardiac surgery may not apply in hip fracture surgery. To address this gap in knowledge, I will extend these methods to hip fracture surgery patients. I will characterize (a) the extent of, and (b) risk factors for intraoperative MAP variation above and below the limits of cerebral autoregulation during hip fracture surgery (Aim 1). I will also examine associations of MAP variation with neurocognitive and functional outcomes (Aim 2). Based on these results, I will design a pilot feasibility/safety trial to determine whether targeting MAP within the limits of autoregulation could improve neurocognitive/functional outcomes (Aim 3). Summary: Promising results from this proposal would support a definitive trial, which would have the potential to fundamentally alter anesthetic strategies across a wide range of surgical populations. The educational plan in this proposal will support my career goal of improving outcomes for older adults after surgery.

PROJECT NARRATIVE This proposal will characterize the extent of, and risk factors for blood pressure variation outside the limits of cerebral autoregulation in older adults undergoing hip fracture surgery, and how this blood pressure variability relates to delirium, cognitive change, and functional outcomes. Based on these results, a pilot safety and feasibility trial will be designed and implemented to target optimal blood pressure during surgery based on cerebral autoregulation monitoring. The results of this trial will provide important information on a novel strategy to prevent delirium after hip fracture surgery.