The goal of this clinical trial (Balanced-2 study) is to compare light to deep general anesthesia using widely available brain monitors, to see if 'light' anesthesia could reduce rates of delirium, cognitive decline, and disability in older adults undergoing major surgery.

Delirium is the most common serious surgical complication, occurring in an estimated one in four older adults undergoing major surgery. Delirium causes significant distress to patients and family, and is associated with prolonged hospital stay, physical disability, progression to dementia-like illnesses, and discharge to long-term care. Between 10 - 30% of adults aged 70 years and above have surgery every year, and preserving brain health and wellbeing is an important priority during this time.

Older adults (aged ≥65 years, or Indigenous, Pacific patients aged ≥55 years) undergoing major surgery with general anesthesia (excluding heart and brain surgery) and able to provide consent will be able to participate. Participants will be randomized to two groups - a lighter general anesthesia group and a deeper general anesthesia group using processed electroencephalography (a brain monitor that provides information on depth of anesthesia using brain waves). The anesthesiologist will titrate anesthetic drugs according to the brain monitor. Participants will be followed up to determine if they experience delirium after surgery, and longer term impact of delirium such as cognitive and physical decline will also be measured.

If found to be effect, this simple, cheap, and widely available treatment could reduce disability, preserve brain health and wellbeing of many older adults undergoing surgery worldwide, and save millions in healthcare dollars.

The Balanced-2 study is a randomized clinical trial studying the effects of depth of anesthesia on the incidence of postoperative delirium, and its associated longer-term impact including cognitive, physical decline and mortality. The study follows accumulating evidence that titrating general anesthesia (GA) using processed electroencephalography (pEEG) can reduce the incidence of postoperative delirium, and has the most immediate promise as a preventative strategy.

The evidence to date is limited by 1) significant statistical heterogeneity between studies, 2) poor adherence to the intervention, resulting in poor or no separation between the intervention and standard care groups in some studies, 3) exclusion of high risk patients such as those with cognitive impairment, 4) evidence limited to inhalation anesthetic agents only.

The Balanced-2 study will recruit participants who are at higher risk of postoperative delirium (based on eligibility criteria), undergoing major surgery with total intravenous anesthesia (TIVA), with robust processes to ensure adherence and group separation. Participants will be randomized in a 1:1 ratio using a web-based service in permuted blocks of 8 patients according to region and stratified by surgical urgency and pre-existing neurocognitive disorders, to either light GA or deep GA from 10 mins after induction of anesthesia to emergence. Depth of anesthesia will be titrated using pEEG monitors such as the commonly used Bispectral index (BIS) and Patient State Index (PSI). The procedural anesthesiologist will pre-specify an individual mean arterial pressure (MAP) target before randomisation to avoid confounding. There will be limitations on the use of ketamine, nitrous oxide, clonidine and dexmedetomidine due to interference with pEEG, but all other aspects of care are determined by the procedural anesthesiologist or according to standard institutional protocol.

The sample size was based on calculations using the minimum clinically important effect size, as determined by a Delphi process with 2 stakeholder groups. A statistical analysis plan will be published prior to trial commencement.

Inclusion Criteria:

• Patients aged ≥ 65 years, and Māori, Pacific or Indigenous participants aged ≥ 55 years who are undergoing major elective or non-elective surgery with expected surgical duration ≥ 2 hours and postoperative hospital stay ≥ 2 nights.
• Having general anesthesia using total intravenous anesthesia (TIVA) with pEEG monitoring
• Able to provide informed consent (including patients with mild preoperative neurocognitive disorders)

Exclusion Criteria:

• Intracranial or cardiac surgery
• Undergoing surgery with 'wake up' test
• Previous enrollment in Balanced-2 study
• Terminal illness with expected survival <3 months
• Emergency surgery within 6 hours of presentation to hospital
• Cognitive impairment with no capacity to consent or activated enduring power of attorney
• Clinically impaired and unable to consent due to acute pathology or preoperative delirium

Blinding of procedural anesthesiologist is not possible. Patients, surgeons, and all outcome assessors will be blinded. One unblinded research coordinator at each site will collect pEEG related data points. Other research coordinators will be blinded as to treatment allocation and will collect data relating to primary and secondary outcomes. Clinicians carrying out participant usual care will be able to unblind study allocation if necessary by viewing the patients anesthesia record via password protected, accessing clinician identity logged, Electronic Health Record (EHR). This record will be unavailable for access by other means.