Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial

Jessica Spence¹, Emilie Belley-Côté², Eric Jacobsohn³, Shun Fu Lee⁴, Frederick D'Aragon⁵, Michael Avidan⁶, C David Mazer⁷, Nicolas Rousseau-Saine⁸, Raja Rajamohan⁹, Kane Pryor¹⁰, Rael Klein⁹, Edmund Chong-How Tan¹¹, Matthew Cameron¹², Emily Di Sante¹³, Erin DeBorba¹³, Mary Mustard¹⁴, Etienne Couture¹⁵, Raffael Zamper¹⁶, Michael Law⁹, George Djaiani¹⁷, Tarit Saha¹⁸, Stephen Choi¹⁷, Peter Hedlin¹⁹, Ryan Pikaluk¹⁹, Wing Ying Lam²⁰, Alain Deschamps⁸, Richard Whitlock²¹, Braden Dulong¹¹, P J Devereaux², Chris Beaver²², Shelley Kloppenburg²³, Simon Oczkowski²⁴, William Finlay McIntyre²⁵, Matthew McFarling²⁶, Andre Lamy²⁷, Jessica Vincent¹³, Stuart Connolly²⁸; B-Free Investigators

Affiliations

¹ Departments of Anesthesia and Critical Care and Health Research Methods, Evaluation, and Impact, McMaster University; and Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
² Departments of Medicine (Cardiology and Critical Care), and Health Research Methods, Evaluation, and Impact, McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
³ Departments of Anesthesia and Perioperative Medicine and Medicine (Critical Care), University of Manitoba, Winnipeg, Manitoba, Canada.
⁴ Department of Health Research Methods, Evaluation, and Impact, McMaster University, and Population Health Research Institute, Hamilton, Ontario, Canada.
⁵ Département d'anesthésiologie, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
⁶ Department of Anesthesia, Washington University at St. Louis, St. Louis, Missouri, USA.
⁷ Department of Anesthesia and Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.
⁸ Département d'anesthésiologie, Université de Montréal, Montréal, Quebec, Canada.
⁹ Department of Anesthesia, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁰ Department of Anesthesiology, Weill Cornell Medical College, New York, New York, USA.
¹¹ Department of Anesthesia, Dalhousie University, Halifax, Nova Scotia, Canada.
¹² Department of Anesthesia, McGill University, Montreal, Quebec, Canada.
¹³ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
¹⁴ St. Michael's Hospital, Toronto, Ontario, Canada.
¹⁵ Département d'anesthésiologie, Université Laval, Quebec City, Quebec, Canada.
¹⁶ Department of Anesthesia, University of Western Ontario, London, Ontario, Canada.
¹⁷ Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department of Anesthesia, Queen's University, Kingston, Ontario, Canada.
¹⁹ Department of Anesthesia, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
²⁰ Department of Anesthesia, University of Alberta, Edmonton, Alberta, Canada.
²¹ Departments of Surgery (Cardiac Surgery) and Health Research Methods, Evaluation, and Impact, McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
²² Sheridan College, Brampton, Ontario, Canada.
²³ Population Health Research Institute, Hamilton, Ontario, Canada.
²⁴ Department of Medicine (Critical Care), McMaster University, Hamilton, Ontario, Canada.
²⁵ Department of Medicine (Cardiology), McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
²⁶ Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada.
²⁷ Departments of Surgery (Cardiac Surgery) and Health Research Methods, Evaluation, and Impact, McMaster University, Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
²⁸ Department of Medicine (Cardiology), McMaster University, and Population Health Research Institute, Hamilton, Ontario, Canada.

PMID: 37744662
PMCID: PMC10516716
DOI: 10.1016/j.cjco.2023.06.001

Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial

Jessica Spence et al. CJC Open. 2023.

. 2023 Jun 8;5(9):691-699.

doi: 10.1016/j.cjco.2023.06.001. eCollection 2023 Sep.

Authors

Affiliations

¹ Departments of Anesthesia and Critical Care and Health Research Methods, Evaluation, and Impact, McMaster University; and Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
² Departments of Medicine (Cardiology and Critical Care), and Health Research Methods, Evaluation, and Impact, McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
³ Departments of Anesthesia and Perioperative Medicine and Medicine (Critical Care), University of Manitoba, Winnipeg, Manitoba, Canada.
⁴ Department of Health Research Methods, Evaluation, and Impact, McMaster University, and Population Health Research Institute, Hamilton, Ontario, Canada.
⁵ Département d'anesthésiologie, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
⁶ Department of Anesthesia, Washington University at St. Louis, St. Louis, Missouri, USA.
⁷ Department of Anesthesia and Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.
⁸ Département d'anesthésiologie, Université de Montréal, Montréal, Quebec, Canada.
⁹ Department of Anesthesia, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁰ Department of Anesthesiology, Weill Cornell Medical College, New York, New York, USA.
¹¹ Department of Anesthesia, Dalhousie University, Halifax, Nova Scotia, Canada.
¹² Department of Anesthesia, McGill University, Montreal, Quebec, Canada.
¹³ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
¹⁴ St. Michael's Hospital, Toronto, Ontario, Canada.
¹⁵ Département d'anesthésiologie, Université Laval, Quebec City, Quebec, Canada.
¹⁶ Department of Anesthesia, University of Western Ontario, London, Ontario, Canada.
¹⁷ Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Department of Anesthesia, Queen's University, Kingston, Ontario, Canada.
¹⁹ Department of Anesthesia, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
²⁰ Department of Anesthesia, University of Alberta, Edmonton, Alberta, Canada.
²¹ Departments of Surgery (Cardiac Surgery) and Health Research Methods, Evaluation, and Impact, McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
²² Sheridan College, Brampton, Ontario, Canada.
²³ Population Health Research Institute, Hamilton, Ontario, Canada.
²⁴ Department of Medicine (Critical Care), McMaster University, Hamilton, Ontario, Canada.
²⁵ Department of Medicine (Cardiology), McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
²⁶ Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada.
²⁷ Departments of Surgery (Cardiac Surgery) and Health Research Methods, Evaluation, and Impact, McMaster University, Perioperative Research Division, Population Health Research Institute, Hamilton, Ontario, Canada.
²⁸ Department of Medicine (Cardiology), McMaster University, and Population Health Research Institute, Hamilton, Ontario, Canada.

PMID: 37744662
PMCID: PMC10516716
DOI: 10.1016/j.cjco.2023.06.001

Abstract
in English, French

Delirium is common after cardiac surgery and is associated with adverse outcomes. Administration of benzodiazepines before and after cardiac surgery is associated with delirium; guidelines recommend minimizing their use. Benzodiazepine administration during cardiac surgery remains common because of its recognized benefits. The Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free) trial is a randomized cluster crossover trial evaluating whether an institutional policy of restricting intraoperative benzodiazepine administration (ie, ≥ 90% of patients do not receive benzodiazepines during cardiac surgery), as compared with a policy of liberal intraoperative benzodiazepine administration (ie, ≥ 90% of patients receive ≥ 0.03 mg/kg midazolam equivalent), reduces delirium. Hospitals performing ≥ 250 cardiac surgeries a year are included if their cardiac anesthesia group agrees to apply both benzodiazepine policies per their randomization, and patients are assessed for postoperative delirium every 12 hours in routine clinical care. Hospitals apply the restricted or liberal benzodiazepine policy during 12 to 18 crossover periods of 4 weeks each. Randomization for all periods takes place in advance of site startup; sites are notified of their allocated policy during the last week of each crossover period. Policies are applied to all patients undergoing cardiac surgery during the trial period. The primary outcome is the incidence of delirium at up to 72 hours after surgery. The B-Free trial will enroll ≥ 18,000 patients undergoing cardiac surgery at 20 hospitals across North America. Delirium is common after cardiac surgery, and benzodiazepines are associated with the occurrence of delirium. The B-Free trial will determine whether an institutional policy restricting the administration of benzodiazepines during cardiac surgery reduces the incidence of delirium after cardiac surgery. Clinicaltrials.gov registration number: NCT03928236 (First registered April 26, 2019).

L’état confusionnel est fréquent après une chirurgie cardiaque et il est associé à des complications. L’administration de benzodiazépines avant et après une chirurgie cardiaque est associée à l’état confusionnel; dans les lignes directrices, on recommande de réduire leur utilisation au minimum. L’administration de benzodiazépines pendant une chirurgie cardiaque demeure fréquente, en raison des leurs bienfaits reconnus. L’essai B-Free (Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium ou l’anesthésie sans benzodiazépine en contexte de chirurgie cardiaque pour la réduction de l’état confusionnel postopératoire) est un essai à répartition aléatoire par grappes et avec permutation, visant à évaluer si une politique institutionnelle de restriction de l’administration peropératoire de benzodiazépines (c.-à-d. que ≥ 90 % des patients ne reçoivent pas de benzodiazépines durant une chirurgie cardiaque) réduit l’état confusionnel, comparativement à une politique d’administration peropératoire libérale de benzodiazépines (c.-à-d. que ≥ 90 % des patients reçoivent ≥ 0,03 mg/kg d’équivalent du midazolam). Des hôpitaux effectuant au moins 250 chirurgies cardiaques par année sont inclus dans l’essai si leurs équipes d’anesthésie cardiaque acceptent d’appliquer les deux politiques relatives aux benzodiazépines en vertu de la répartition aléatoire et si les patients sont évalués toutes les 12 heures, en ce qui a trait à l’état confusionnel postopératoire, dans le cadre des soins cliniques habituels. Les hôpitaux mettent en œuvre la politique d’administration restreinte ou libérale de benzodiazépines durant 12 à 18 périodes de permutation de 4 semaines chacune. La répartition aléatoire de l’ensemble des périodes a lieu avant le début de l’essai à l’hôpital; les établissements sont avisés de la politique qui leur est attribuée au cours de la dernière semaine de chaque période de permutation. Les politiques sont appliquées à tous les patients qui subissent une chirurgie cardiaque durant la période de l’essai. Le critère d’évaluation principal est l’incidence de l’état confusionnel dans les 72 heures suivant l’intervention chirurgicale. L’étude B-Free inclura au moins 18 000 patients qui subiront une chirurgie cardiaque dans 20 hôpitaux en l’Amérique du Nord. L’état confusionnel est fréquent après une chirurgie cardiaque, et les benzodiazépines sont associées à la survenue de l’état confusionnel. L’essai B-Free permettra de déterminer si une politique institutionnelle de restriction de l’administration de benzodiazépines durant une chirurgie cardiaque réduit l’incidence de l’état confusionnel après une telle chirurgie.Clinicaltrials.gov registration number: NCT03928236 (First registered April 26, 2019).

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Figures

**Figure 1**
Study schematic. The top part of the diagram presents benzodiazepine administration in routine clinical practice. The bottom part of the diagram presents benzodiazepine administration as it occurs in the Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free) trial. **Blue figures** represent use of a restricted approach to intraoperative benzodiazepine administration. **Red figures** represent use of a liberal approach to intraoperative benzodiazepine administration.

**Figure 2**
Sample randomization schedule. This diagram represents a possible randomization schedule for 20 clusters completing between 12 and 18 crossover periods. **Blue squares** represent periods during which the restricted benzodiazepine policy is applied. **Orange squares** represent periods during which the liberal benzodiazepine policy is applied. **“X” squares** represent periods in which a site is not participating in the trial.

See this image and copyright information in PMC

References

1. Inouye S.K., Westendorp R.G., Saczynski J.S. Delirium in elderly people. Lancet. 2014;383:911–922. - PMC - PubMed
1. Gleason L.J., Schmitt E.M., Kosar C.M., et al. Effect of delirium and other major complications on outcomes after elective surgery in older adults. JAMA Surg. 2015;150:1134–1140. - PMC - PubMed
1. Saczynski J.S., Marcantonio E.R., Quach L., et al. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367:30–39. - PMC - PubMed
1. Berian J.R., Zhou L., Russell M.M., et al. Postoperative delirium as a target for surgical quality improvement. Ann Surg. 2018;268:93–99. - PubMed
1. Devereaux P.J., Lamy A., Chan M.T.V., et al. High-sensitivity troponin I after cardiac surgery and 30-day mortality. N Engl J Med. 2022;386:827–836. - PubMed

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Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial

Affiliations

Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial

Authors

Affiliations

Abstract
in English, French

Figures

References

Associated data

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Abstract in English, French

Figures

References

Associated data

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous

Abstract
in English, French