Benzodiazepine-free Anesthetic for Reduction of Delirium (B-Free): A Two-centre Pilot Study to Determine the Feasibility of a Multi-centre, Randomized, Cluster Crossover Trial

ICU data suggests that benzodiazepines are linked to delirium, and minimizing their use has been incorporated into ICU practice guidelines. Cardiac surgery patients are at elevated risk of delirium. However, benzodiazepine administration still constitutes a common part of cardiac anesthesia practice, related to the previous absence of alternate medications and techniques to ensure hemodynamic stability and prevent intraoperative awareness. However, with the advent of new medications and processed EEG monitoring, benzodiazepine use is no longer ubiquitous, with both utilization and dose varying among practitioners. These multiple approaches to cardiac anesthesia care are haphazard, which speaks to the clinical equipoise between them. As such, the investigators have decided to standardize our approach to cardiac anesthesia care, and to evaluate the impact of changes in approach on postoperative delirium, a serious problem for both individual patients and health care systems.

Studying strategies of care and their impact on delirium: There is a great need to understand if a strategy of limitation of intraoperative benzodiazepine use during cardiac surgery can reduce postoperative delirium. Cardiac surgery is done in specialized institutions performing high volumes of surgery in order to reduce complications, increase efficiency, and obtain superior outcomes. The surgical care of patients in these high volume cardiac surgery centres is undertaken using standardized procedures that optimize outcomes. The investigators would like to determine if a policy limiting the use of intra-operative benzodiazepine will reduce postoperative delirium, a question which is asked from the perspective of clinical effectiveness. The only way to answer this question is to randomize between two institutional approaches to benzodiazepine use: a policy of standard use in all patients compared to a policy of limited benzodiazepine use in select patients only. The cluster randomized trial is a methodologic approach designed to test different institutional policies. In the cluster crossover trial, each institution is randomized to use one policy or the other and then, after a treatment and suitable wash-out period, the institution crosses over to the other policy. This approach is methodologically rigorous and tests the effects of the change in practice as it would actually be used in the clinical setting. Therefore, the optimal approach to answer the question of intraoperative benzodiazepine strategy is a cluster crossover trial, which randomizes cardiac surgery centres to each of two standard approaches to intraoperative benzodiazepine use, with crossover within each site.

An institutional policy of limiting intraoperative benzodiazepine use during adult cardiac surgery, compared to a policy of 'ad libitum' intraoperative benzodiazepine use, will reduce the rate of post-operative delirium.

Our goal is to undertake a randomized cluster crossover trial, with randomization at the level of the hospital. Before such a trial can be conducted, we need to establish feasibility. We therefore propose to undertake a pilot study at two hospitals, to establish the feasibility of the trial protocol. This pilot trial will be conducted over approximately 6 months, in 4 study periods. Because of variation in the number of procedures performed within a given month, the duration of each period will be determined by the amount of time required to manage 120 patients according to the selected policy. There will be a 1-week washout period between each study period to enable staff transitions between institutional policies of cardiac anesthesia care. At the outset of the study, we will randomize the pilot site to any of 2 possible alternating sequences of benzodiazepine-minimized (A) or routine benzodiazepine administration (B) (i.e. ABAB or BABA). We call this study the B-free Pilot Trial. We will use data from this pilot in the larger study unless substantial protocol modifications are needed.

Rationale: At least 1 CAM assessment will be required to assess the primary outcome of the large trial, with one CAM per ICU ideal to assess delirium (as it has a fluctuating course).