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Multicenter Study
. 2025 Mar 1;160(3):286-294.
doi: 10.1001/jamasurg.2024.6602.

Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium: A Cluster Randomized Crossover Trial

Jessica Spence  1   2   3   4 , P J Devereaux  1   3   4   5 , Shun-Fu Lee  1   3 , Frédérick D'Aragon  6 , Michael S Avidan  7 , Richard P Whitlock  1   3   4   8 , C David Mazer  9   10 , Nicolas Rousseau-Saine  11 , Raja Ramaswamy Rajamohan  12 , Kane O Pryor  13 , Rael Klein  14 , Edmund Tan  15 , Matthew J Cameron  16 , Emily Di Sante  1 , Erin DeBorba  1 , Mary E Mustard  17 , Etienne J Couture  18 , Raffael Pereira Cezar Zamper  19 , Michael W Y Law  20 , George Djaiani  21 , Tarit Saha  22 , Stephen Choi  23   21 , Peter Hedlin  24 , D Ryan Pikaluk  24 , Wing Lam  25 , Alain Deschamps  11 , Chinthanie F Ramasundarahettige  1 , Jessica Vincent  1 , William F McIntyre  1   4   5 , Simon J W Oczkowski  3   26 , Braden J Dulong  15 , Christopher Beaver  1 , Shelley A Kloppenburg  1 , Andre Lamy  1   4   5   27 , Eric Jacobsohn  28 , Emilie P Belley-Côté  1   3   4   27 ; B-Free Investigators and the Canadian Perioperative Anesthesia Clinical Trials Group
Collaborators, Affiliations
Multicenter Study

Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium: A Cluster Randomized Crossover Trial

Jessica Spence et al. JAMA Surg. .

Erratum in

Abstract

Importance: Delirium is common after cardiac surgery and associated with adverse outcomes. Intraoperative benzodiazepines may increase postoperative delirium but restricting intraoperative benzodiazepines has not yet been evaluated in a randomized trial.

Objective: To determine whether an institutional policy of restricted intraoperative benzodiazepine administration reduced the incidence of postoperative delirium.

Design, setting, and participants: This pragmatic, multiperiod, patient- and assessor-blinded, cluster randomized crossover trial took place at 20 North American cardiac surgical centers. All adults undergoing open cardiac surgery at participating centers during the trial period were included through a waiver of individual patient consent between November 2019 and December 2022.

Intervention: Institutional policies of restrictive vs liberal intraoperative benzodiazepine administration were compared. Hospitals (clusters) were randomized to cross between the restricted and liberal benzodiazepine policies 12 to 18 times over 4-week periods.

Main outcomes and measures: The primary outcome was the incidence of delirium within 72 hours of surgery as detected in routine clinical care, using either the Confusion Assessment Method-Intensive Care Unit or the Intensive Care Delirium Screening Checklist. Intraoperative awareness by patient report was assessed as an adverse event.

Results: During the trial, 19 768 patients (mean [SD] age, 65 [12] years; 14 528 [73.5%] male) underwent cardiac surgery, 9827 during restricted benzodiazepine periods and 9941 during liberal benzodiazepine periods. During restricted periods, clinicians adhered to assigned policy in 8928 patients (90.9%), compared to 9268 patients (93.2%) during liberal periods. Delirium occurred in 1373 patients (14.0%) during restricted periods and 1485 (14.9%) during liberal periods (adjusted odds ratio [aOR], 0.92; 95% CI, 0.84-1.01; P = .07). No patient spontaneously reported intraoperative awareness.

Conclusions and relevance: In intention-to-treat analyses, restricting benzodiazepines during cardiac surgery did not reduce delirium incidence but was also not associated with an increase in the incidence of patient-reported intraoperative awareness. Given that smaller effect sizes cannot be ruled out, restriction of benzodiazepines during cardiac surgery may be considered. Research is required to determine whether restricting intraoperative benzodiazepines at the patient level can reduce the incidence of postoperative delirium.

Trial registration: ClinicalTrials.gov Identifier: NCT03928236.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Spence reported personal fees from VarmX (consulting) and Trimedic (advisory board participation) and financial support paid to institution from AOP Pharmaceuticals outside the submitted work. Dr Devereaux reported grants from Abbott Diagnostics, AOP Pharma, Roche Diagnostics, and Siemens; medical device provision from CloudDX; consulting for Abbott Diagnostics, AstraZeneca, Renibus, Roche Canada, and Trimedic outside the submitted work. Dr Whitlock reported grants from AtriCure, Cytosorbents, Abbott, and Boston Scientific and data safety monitoring board fees from Phasebio and Artivian outside the submitted work. Dr Pryor reported grants from Patient-Centered Outcomes Research Institute outside the submitted work. Dr Couture reported personal fees from Edwards Lifesciences outside the submitted work. Dr Pikaluk reported compensation from the University of Saskatchewan for time spent on research activities. Dr McIntyre reported grants from Trimedics and personal fees from Trimedics, Atricure, and iRhythm outside the submitted work. Dr Belley-Côté reported grants from Abbott, Roche Diagnostics, Bayer, and Bristol-Myers Squibb–Pfizer and personal fees from Trimedic Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Recruitment, Policy Allocation, and Patient Flow in the B-Free Trial
Figure 2.
Figure 2.. A Priori–Specified Subgroup Analyses for Delirium up to 72 Hours
Adjusted odds ratios (aORs) were adjusted for age, sex, urgency of surgery, history of heavy alcohol consumption, and history of home benzodiazepine use. CAM-ICU indicates Confusion Assessment Method–Intensive Care Unit; ICDSC, Intensive Care Delirium Screening Checklist.
See this image and copyright information in PMC

Comment on

References

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