Inhalational Anesthesia vs. Intravenous Anesthesia

Study Overview
=================
Brief Summary
-----------------
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 ≥ 75 years undergoing elective noncardiac surgery under general anesthesia will be randomized to 2 groups: IV or GAS.

Detailed Description
-----------------
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

Official Title
-----------------
Optimizing Anesthesia to Prevent Postoperative Cognitive and Functional Decline in Older Adults: A Randomized Controlled Trial

Conditions
-----------------
Neurocognitive Disorders, Anesthesia, Post-operative Delirium, Post-operative Cognitive Dysfunction

Intervention / Treatment
-----------------
* Drug: Sevoflurane
* Drug: Propofol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Men and women ≥ 75 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 Informant available with frequent (at least 1 hour/day or 1 day/week) contact with the subject to verify CDR rating. Exclusion criteria: Urgent or emergent surgery Diagnosed dementia (or MoCA<19) History of stroke, 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, regional, or neuraxial 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.

Ages Eligible for Study
-----------------
Minimum Age: 75 Years
Maximum Age: 105 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This single-center, 1:1 randomized, double-blind (patient & outcome assessor) clinical trial will compare inhalational (sevoflurane) vs. intravenous (propofol) anesthesia on POD, POCD, functional status, PROs, and biomarkers in patients ≥ 75 years undergoing elective, inpatient, non-cardiac surgery at Oregon Health & Science University.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Inhalational Anesthesia<br>Inhalational maintenance of anesthesia group using sevoflurane | Drug: Sevoflurane<br>* Inhalational maintenance of anesthesia group using sevoflurane<br>* Other names: Inhalational Anesthesia;|
| Active Comparator: Intravenous Anesthesia<br>Intravenous maintenance of anesthesia group using propofol | Drug: Propofol<br>* Intravenous maintenance of anesthesia group using propofol<br>* Other names: Intravenous Anesthesia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of intravenous vs. inhalational anesthesia on incidence of postoperative delirium in older surgical patients with the 3D-Confusion Assessment Method (3D-CAM-S) and the CAM-ICU-7. | Incidence of postoperative delirium with the 3D-Confusion Assessment Method (3D-CAM) in non-intubated patients and the CAM-ICU-7 in intubated patients. Delirium will be assessed postoperative in PACU and twice daily on postoperative days 1-3 while the patient is in the hospital. | through postoperative day 3 | 
| Determine the effects of intravenous vs. inhalational anesthesia on the incidence of postoperative neurocognitive disorder in older adults undergoing non-cardiac surgery using neuropsychiatric composite score. | Postoperative neurocognitive disorder. Change from preoperative baseline cognitive dysfunction using neuropsychiatric composite score. Battery of neuropsychological tests: Animal Verbal Fluency Test, Trail Making Test A & B, Digit Symbol Test, Logical Memory Immediate & Delayed Recall, and CERAD Word List Immediate and Delayed recall. MASQ will be used for subjective cognitive decline. Functional status will be measured by FAQ. | Change from preoperative baseline to one year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the effects of intravenous vs. inhalational anesthesia on incidence of delirium duration (days) and severity, measured by 3D-CAM-S, and CAM-ICU-7 in older adults undergoing non-cardiac surgery. | delirium severity and duration. Delirium will be assessed postoperative in PACU and twice daily on postoperative days 1-3. | through postoperative day 3 | 
| Effects of intravenous vs. inhalational anesthesia on levels of blood phosphorylated tau 181 (p-tau181) in older surgical patients.. Change from preoperative baseline blood p-tau181 to postoperative day 1, 3 months and 12 months. | change in levels of preoperative levels of blood p-tau181 from preoperative baseline to 12 months postoperative | Change from baseline through one year. | 
| Determine the effects of intravenous vs. inhalational anesthesia on incidence of postoperative functional decline using ADL, FAQ, and FRAIL in older adults undergoing non-cardiac surgery. | Incidence of postoperative functional decline. Change from preoperative baseline postoperative functional decline to postoperative 12 months. | Change from baseline through one year | 
| Determine the effects of intravenous vs. inhalational anesthesia on patient-reported outcomes (PROMIS-29+2 Profile v2.1) in older adults undergoing non-cardiac surgery. | patient-reported outcome scores, PROMIS-29+2 Profile v2.1 (PROPr) assesses patient-reported measures of anxiety, depression, fatigue, pain interference, physical function, sleep disturbance, participation in social activities, pain, and cognition. Measured at preoperative baseline, 3 months postoperatively, and 12 months postoperatively | Change from baseline through one year |