Anaesthetic depth and complications after major surgery: an international, randomised controlled trial - The BALANCED trial.

In this large, international, randomised controlled trial that enrolled patients aged 60 years and over with significant comorbidity and at increased risk of complications after major surgery, we found no evidence that light general anaesthesia (bispectral index 50) was superior to deep general anaesthesia (bispectral index 35) in reducing 1-year mortality. The BALANCED long term follow up study will look at whether depth of anesthesia affects long term (beyond 1 year) survival.

The primary hypothesis is that targetting BIS 50 will result in superior long term survival compared to targetting BIS 35.

The two secondary hypotheses are that BIS titration to BIS 50 will

1. reduce local cancer recurrence or metastatic spread and consequently improve long-term survival
2. reduce postoperative delirium and associated cognitive impairment and consequently improve long-term survival

Both these mechanisms would be expected to take longer to manifest as reduced survival than 1-year all-cause mortality primary outcome in the Balanced trial. Trials of cancer outcomes often use 5-year survival or similar timeframes to determine evidence of clinical benefit. A steeper cognitive trajectory due to intermediate outcomes such as delirium and cognitive impairment may take longer than 1 year to produce a clinically important difference in survival 30. The 10.6% relative risk reduction seen in the Balanced trial could translate to a statistically and clinically meaningful survival difference in this high-risk population. This population may have 5-year survival of ~80% translating to an absolute survival difference of ~2% potentially (if the ~10% RRR is maintained beyond 1 year). The alternative is that there is no long-term mortality difference which would provide continuing clinical guidance of the safety of current practice in patients who are not at high risk of delirium. This study could provide a rationale for trials in larger populations (such as the total Balanced trial population) or targeted subgroups such as cancer and delirium to provide further mechanistic insights.

Long-term survival is an important patient-centred outcome. The mechanisms described above may manifest in longer-term outcomes providing a clear rationale for the current trial.

Inclusion and exclusion criteria will be the same as the Balanced trial with participants limited to those sites described above. Survival data will be censored at date of accessing mortality database.

Inclusion

1. Age over 60 years and over
2. ASA physical status 3 or 4
3. Surgery expected to last over 2 hours
4. Hospital length of stay expected to be 2 nights or more
5. General anaesthesia with or without major regional block
6. Able to monitor BIS throughout anaesthesia

Exclusion

1. Unable to monitor BIS
2. Unable to consent
3. Surgery with 'wake up' test
4. Propofol infusion for part or all of maintenance of anaesthesia
5. Previous enrolment in Balanced study

Exclusion The intention-to-treat (ITT) population is defined as all randomised participants who met the inclusion and exclusion criteria who had surgery.

The per-protocol (PP) population is defined as all randomised participants in the study who meet all the inclusion/exclusion criteria for BALANCED with BIS group classified according to the actual median BIS value achieved irrespective of randomisation.

Participants were allocated to the BIS=50 group if the achieved median BIS is between 45 and 55 inclusive, and to the BIS=35 group if the achieved median BIS is between 30 and 40 inclusive. Participants who are not within these ranges will be excluded from these analyses.

All participants who were recruited to the BALANCED Trial and who met the inclusion and no exclusion criteria for analysis of the long term outcome.

Data sharing requests will be assessed by the Balanced Study Steering.Committee.

Individual, deidentified participant data used in these analyses will be shared 2 years after publication by request from any qualified investigator after approval of a protocol, statistical analysis plan, and receipt of a signed data access agreement via the Research Office of Auckland District Health Board, New Zealand; and after obtaining the approval of the New Zealand Health and Disability Ethics Committees for the project and data release

within 2 years

Will be available on the clintrials.govt website