Background The Balanced trial was designed to answer the question of whether anaesthetic depth affects postoperative mortality when a vulnerable patient undergoes major surgery. Patients were recruited between 2012 and 2017 at 73 centres in seven countries. In the intention-to-treat analysis (n=6644), there was no significant difference in one year mortality between patients randomised to surgery under deep (target BIS 35) or light anaesthesia (target BIS 50). However the separation between randomised groups was only 8.4 BIS units and the trial was criticised for being underpowered. Methods In a secondary analysis of this trial's data, we made alternative per-protocol estimates designed to improve the power of the trial. We added an additional covariate - each patient's deviation from target BIS - to the original analysis, statistically recreating the desired separation of 15 BIS units between randomised groups. We used multiple imputation to recover missing BIS values. We also assessed whether a proportional hazards Cox model was appropriate for the analysis of one year mortality. Results Our alternative per-protocol estimates did not differ materially from the original per-protocol estimate. The gain in precision through using all intent-to-treat patients for our per-protocol estimates was offset by the additional variance introduced when modelling missing BIS values. When modelling missing BIS, we found regional differences: in China, the separation between randomised groups was far higher (13.6 BIS units) than in any other region. Estimates and plots assessing proportional hazards suggested increasing late mortality under deep anaesthesia, most notably in China. Conclusion Our hypothesis is that deep anaesthesia in the Balance trial led to higher postoperative delirium, which in turn led to an increase in late mortality. In future trials, patients should be followed for more than a year and cause of death recorded.

TS is a consultant to Becton Dickinson (Melbourne, Victoria, Australia) and has received research funding from Boehringer Ingelheim. LAS has received speaker honoraria and research support from Medtronic. JY and SDK declare no competing interests.

ACTRN12612000632897

This study did not receive any funding. The Balanced trial was supported by grants from the Health Research Council of New Zealand (12-308-Short), the Australian National Health and Medical Research Council (APP1042727), the Research Grants Council of Hong Kong (number 61513), the National Institute for Health and Research in the UK (portfolio status), and the National Institutes of Health in the USA (P30 CA 008748).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

A protocol for this study and a statistical analysis plan (Appendix A) were approved by the New Zealand Health and Disability Ethics Committees (EXP13559; H Walker, Chair; 15 November 2022) and by the Research Review Committee Te Toka Tumai Auckland (A+9688; M-A Woodnorth, Manager, Research Office; 16 December 2022). Data sharing was subject to a data management plan and a formal signed agreement (12 May 2023).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Individual, de-identified participant data used in these analyses will be shared 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.