Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium
Authors: Spence Jessica , Devereaux P. J. , Lee Shun-Fu , D’Aragon Frédérick , Avidan Michael S. , Whitlock Richard P. , Mazer C. David , Rousseau-Saine Nicolas , Rajamohan Raja Ramaswamy , Pryor Kane O. , Klein Rael , Tan Edmund , Cameron Matthew J. , Di Sante Emily , DeBorba Erin , Mustard Mary E. , Couture Etienne J. , Zamper Raffael Pereira Cezar , Law Michael W. Y. , Djaiani George , Saha Tarit , Choi Stephen , Hedlin Peter , Pikaluk D. Ryan , Lam Wing , Deschamps Alain , Ramasundarahettige Chinthanie F. , Vincent Jessica , McIntyre William F. , Oczkowski Simon J. W. , Dulong Braden J. , Beaver Christopher , Kloppenburg Shelley A. , Lamy Andre , Jacobsohn Eric , Belley-Côté Emilie P. ,   B-Free Investigators and the Canadian Perioperative Anesthesia Clinical Trials Group, Wyse George , Eikelboom John , Robinson Tara , Marfo Gladys , Balasubramanian Kumar , Koh Peter , Mullen Courtney , Hayward Leah , McFarling Matthew Ryan , Botsford Kim , Syed Summer , Shen Maia , Fournier Renée , Kavosh Morvarid , MacKenzie Kate , Monterola Marita , Girling Linda , St-Pierre Mathilde , Perreault Michel-Antoine , de Medicis Étienne , Gaulin Jonathan , Edward Nicola , Ree Ron , Yao Iris , Chui Clement , Biferie Michelle , Game Connie , Atherstone Juliet Ann , Mullane Darren , Atherstone Juliet , Mozel Michelle , Barton Mikaela , Hughes Ashlee , Hasnat Aiman , Arellano Ramiro , Tanzola Robert , DuMerton Debbie , Cummings Michael , Alli Ahmad , Moses Samson , Siadati-Fini Niloufar , Chin Kyle , Hare Greg , Muneer Maliha , Panek Izabela M , Fraser Kaela H , Bonazza Flynn A , Amey Sharon E , Roulston Shelley , Robichaud Sophie , Julien Marco , Rochon Antoine , Chamberland Marie-Eve , Raymond Meggie , Cogan Jennifer , Desjardins Georges , Lebon Jean-Sébastien , Ayoub Christian , Couture Pierre , Courbe Athanase , Martins Maria Rosal , Denault André Y , Wu An Ni , Beggs Kristofer , Jarry Stéphanie , Bendaoud Sarah , Cisneros-Aguilera Ester , Agoian Lana , Laurendeau Melissa , Duval Elaine , Chabane Anya , Lacroix Martine , Kennedy Liam J , Mayer Robert Christopher , Clunie Michelle , Akinlade Azeez , Tremblay Hugo , Gagné Nathalie , Bergeron Annie , Laforge François , Grenier Audrey , Morin Valérie , Bellavance Sandrine , Lafrenière-Bessi Valérie , Martin Béatrice , Lachance Joanie , Audet Olivier , Vachon-Zicat Léa , Babaki Yasmine , St-Onge Élizabeth , Lavoie Nelson , Bisson Mathilde , Charest Marie-Ève , Jerath Angela , Kaustov Lilia , Fleet Andrew , Wong Sophia , Lappin Elizabeth , Shaheen Saba , Helwani Mohammad , Budelier Thaddeus , Montes de Oca Arianna , Kronzer Alex , Fitzgerald Meghann M , Girardi Natalia I , Girardi Leonard N , Steinkamp Michele L , Evered Lisbeth A , Leibowitz Hannah R , Bitensky Dylan R , Evered Lisbeth , Turgeon Alexis , Denault André , McIssac Daniel , Sparrow Kathryn , Lalu Manoj , McCluskey Stuart , Hall Richard , Beattie William Scott 
Published: January 2025

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