Background: Delirium is an acute disorder of cognition and attention. It affects ~15% of patients after cardiac surgery and is associated with prolonged length of stay, cognitive and functional decline, and death.1 Receiving benzodiazepines before and after cardiac surgery is associated with postoperative delirium, such that guidelines recommend avoiding their use.2,3 Benzodiazepine use during cardiac surgery remains common because of their amnestic effects and favourable hemodynamic profile.4 Randomized evidence from the intensive care unit (ICU) suggests that a benzodiazepine-free approach after cardiac surgery may reduce delirium;2 no evidence informs intraoperative benzodiazepine use.
Objective: To evaluate whether a policy of restricted intraoperative benzodiazepine use reduces postoperative delirium when compared with a policy of liberal benzodiazepine use.
Trial design: Multicentre, randomized, cluster crossover trial.
Inclusion/exclusion criteria: All patients undergoing cardiac surgery at an enrolled site during the trial period are included in data collection through a waiver of individual patient consent; percutaneous procedures and secondary operations are excluded. Hospitals are included if: i) they perform ≥250 cardiac surgeries a year; ii) their cardiac anesthesia group agrees to manage patients as per both benzodiazepine policies as per their randomization schedule; and iii) if cardiac surgery patients are assessed for postoperative delirium using a validated scale ≥ 12 hours in routine clinical care.
Trial interventions: B-Free compares 2 hospital-based cardiac anesthesia policies, both of which fall within the standard of care. Both policies allow deviations to occur when mandated by patient condition. The study expects that only 90% of patients will be treated according to the assigned policy due to appropriate deviations as described below: The “Restricted Benzodiazepine Policy” arm consists of the following: 1. No routine use of any intraoperative benzodiazepines. 2. Accepted benzodiazepine use in the case of seizure, alcohol withdrawal, severe anxiety, history of awareness during anesthesia, or known benzodiazepine dependence. 3. Accepted benzodiazepine use in patients who are hemodynamically unstable and/or have cardiac anatomy that puts them at high risk on induction of anesthesia using other agents.
The “Liberal Benzodiazepine Policy” arm consists of the following: 1. Intraoperative administration of the equivalent of at least 0.03mg/kg midazolam equivalent. Any benzodiazepine may be used. 2. Accepted avoidance of benzodiazepine use in patients who have contraindications to the administration of these medications (e.g., documented allergy, previous adverse reaction).
Randomization: We randomize sites to one of the two policies to be used by all anesthetists. Sites cross-over to the other policy at random. An independent statistician randomizes each site to twelve to eighteen (according to local feasibility), 4-week crossover periods, such that each policy is applied an equal number of times.
Outcomes: The primary outcome is the incidence of delirium up to 72 hours after cardiac surgery. The secondary outcomes are ICU and hospital length-of-stay and in-hospital mortality.
Trial status: We completed enrollment December 11/2022 and are finalizing data collection and database cleaning. Currently, 17,452 patients have complete data in the trial database and 2,248 patients still require some data entry. We have drafted a statistical analysis plan but have not yet begun undertaking analyses.
Trial leadership: B-Free is led by a group of Canadian female early career investigators, including Principal Investigator Dr. Jessica Spence and co-Principal Investigators Drs. Emilie Belley-Côté and Shun Fu Lee, all of whom are members of the Perioperative Care Clinical Trial Network. The trial is coordinated by the Population Health Research Institute in Hamilton, Ontario, Canada. 18/20 (90%) of sites and 17489/19700 (88.8%) of patients are Canadian.
