Clinical trial NCT06268080: Depth of Anesthesia on Postoperative Delirium and Cognitive After Surgery
Official title: Preserving Brain Health After Surgery: Does Light General Anesthesia Reduce Postoperative Delirium and Cognitive Decline Compared with Deep General Anesthesia in Older Adults?
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Delirium, Postoperative
Anesthesia
Surgery-Complications
Cognition Disorder
Delirium
Cognitive Decline
Keywords: randomized controlled trial
multicentre
clinical trial
depth of anaesthesia
postoperative delirium
Lead sponsor: Auckland City Hospital
Sponsor class: OTHER_GOV
First posted: 2024-02-20
Enrollment: 2766
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre, prospective, randomized, active control, parallel group, intention to treat, safety and efficacy study.
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of postoperative delirium (POD)
timeFrame: Administered twice a daily for up to 3 postoperative days or until discharge if discharge occurs before day 3, including weekends. Further once daily testing from days 4 to 7 if screens positive.
Secondary outcomes:
measure: Incidence of severe delirium
timeFrame: 7 days after surgery
measure: Incidence of new mild and major postoperative neurocognitive disorders
timeFrame: Assessed at 90 days and 1 year after surgery
measure: Postoperative cognitive decline
timeFrame: Assessed at 90 days and 1 year after surgery
measure: Functional decline
timeFrame: Assessed at 90 days and 1 year after surgery
measure: All-cause mortality
timeFrame: Assessed at 1 year after surgery
measure: Duration of delirium
timeFrame: 7 days after surgery
Other outcomes:
measure: Incidence of awareness
timeFrame: Assessed once, between postoperative days 1 to 3
measure: Adverse and serious adverse events
timeFrame: Up to 1 year
Locations:
city: Grafton
country: New Zealand
facility: Auckland City Hospital, Health New Zealand
state: Auckland
Study officials:
affiliation: Auckland City Hospital, Health New Zealand
name: Carolyn Deng
role: PRINCIPAL_INVESTIGATOR
References:
citation: Evered LA, Chan MTV, Han R, Chu MHM, Cheng BP, Scott DA, Pryor KO, Sessler DI, Veselis R, Frampton C, Sumner M, Ayeni A, Myles PS, Campbell D, Leslie K, Short TG. Anaesthetic depth and delirium after major surgery: a randomised clinical trial. Br J Anaesth. 2021 Nov;127(5):704-712. doi: 10.1016/j.bja.2021.07.021. Epub 2021 Aug 28.
citation: Sumner M, Deng C, Evered L, Frampton C, Leslie K, Short T, Campbell D. Processed electroencephalography-guided general anaesthesia to reduce postoperative delirium: a systematic review and meta-analysis. Br J Anaesth. 2023 Feb;130(2):e243-e253. doi: 10.1016/j.bja.2022.01.006. Epub 2022 Feb 17.
citation: Deng C, Sidebotham D. Using the Delphi process to determine the minimum clinically important effect size for the Balanced-2 randomised controlled trial. Clin Trials. 2023 Oct;20(5):473-478. doi: 10.1177/17407745231173058. Epub 2023 May 5.
citation: Evered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, Oh ES, Crosby G, Berger M, Eckenhoff RG; Nomenclature Consensus Working Group. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. Br J Anaesth. 2018 Nov;121(5):1005-1012. doi: 10.1016/j.bja.2017.11.087. Epub 2018 Jun 15.