Traditionally, general anesthesia is maintained with inhalational anesthesia (GAS), but there is a gap in knowledge regarding whether intravenous anesthesia (IV) can prevent deleterious postoperative outcomes in the geriatric surgical population. The goal of this clinical trial is to determine whether intravenous anesthesia (IV) leads to a decreased incidence of postoperative delirium (POD), postoperative cognitive dysfunction (POCD), and functional decline, and improved patient-reported outcomes (PROs) in older adults undergoing non-cardiac surgery when compared to the standard inhalational anesthesia (GAS). This single-center, 1:1 randomized, double-blind (patient & outcome assessor) clinical trial will compare inhalational vs. intravenous anesthesia on POD, POCD, functional status, patient-reported outcomes (PROs), and blood-based biomarkers in older patients undergoing elective, inpatient, non-cardiac surgery. Upon enrollment, 260 women and men ≥ 70 years undergoing elective noncardiac surgery under general anesthesia will be randomized to 2 groups: TIVA or GAS.

Aim 1: Determine the effects of intravenous vs. inhalational anesthesia on incidence of postoperative delirium and postoperative cognitive dysfunction in older adults undergoing non-cardiac surgery.

Hypothesis: Intravenous anesthesia is associated with a lower incidence of POD and POCD compared to inhalational anesthesia.

Primary outcomes: Incidence of postoperative delirium and postoperative cognitive dysfunction Secondary outcomes: delirium severity, delirium duration Aim 2: Determine the effects of intravenous vs. inhalational anesthesia on incidence of postoperative functional decline and patient-reported outcomes in older adults undergoing non-cardiac surgery.

Hypothesis: Intravenous anesthesia is associated with a lower incidence of postoperative functional decline and improved patient-reported outcomes (PROs) compared to inhalational anesthesia.

Primary outcomes: Incidence of postoperative functional decline; patient-reported outcome scores Aim 3: Determine the effects of intravenous vs. inhalational anesthesia on blood phosphorylated tau 181 (p-tau181) and other blood biomarkers in older adults undergoing non-cardiac surgery.

Hypothesis 1: Elevated preop blood p-tau181 is associated with increased POD and POCD; Hypothesis 2: Postoperative increase in blood p-tau181 is greater with GAS relative to IV; Hypothesis 3: Postop increases in blood biomarkers of neuroinflammation and AD pathology are greater with GAS relative to IV.

Primary outcomes: preoperative levels of blood p-tau181 and change in levels from preoperative baseline to postoperative.

Secondary outcomes: Other candidate biomarkers include those previously implicated in POD or POCD: p-tau217, Aβ,54 NF-L,55 High mobility group box protein 1 (HMGB1),60 S100β,76 interleukin (IL)-6,58 IL-1β,22 IL-10,46 tumor necrosis factor (TNF)-α,22 CCL2,62 and glial fibrillary acidic protein (GFAP).77

Inclusion criteria:

• Men and women ≥ 70 years
• Sufficient vision and hearing to complete all tests
• Proficient in spoken and written English
• Scheduled for elective, inpatient, noncardiac surgery, expected to last at least 120 minutes requiring general anesthesia

Exclusion criteria:

• Urgent or emergent surgery
• Diagnosed dementia (or MoCA<19)
• History of Parkinson's disease, major psychiatric disease (Schizophrenia), or severe traumatic brain injury
• Ongoing alcohol or substance abuse (per DSM V criteria)
• Allergy to propofol or sevoflurane
• Personal or family history of malignant hyperthermia
• Planned postoperative intubation
• Brain surgery
• Surgery requiring TIVA or GAS (i.e. cases involving neuromonitoring)
• Surgical procedure requiring general anesthetic occurring within 3 months (before or after) surgical date
• Any patient or perioperative factor considered a contraindication to randomization to either experimental group by the surgeon or anesthesiologist.

In order to promote advancement of this field of study, we will make data generated from this project available. Participants will sign a data repository consent form so de-identified data is able to be maintained indefinitely on secure servers at Oregon Health & Science University. This will enable us to combine these data with other datasets for future analyses, and to share with collaborators and other interested scientists. Other researchers would sign a data use agreement and then receive the de-identified data requested.