Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies

Eugene Wang; Emilie P Belley-Côté; Jack Young; Henry He; Haris Saud; Frederick D'Aragon; Kevin Um; Waleed Alhazzani; Joshua Piticaru; Matthew Hedden; Richard Whitlock; C David Mazer; Hessam H Kashani; Sarah Yang Zhang; Amanda Lucas; Nicholas Timmerman; Cameron Nishi; Davinder Jain; Aaron Kugler; Chris Beaver; Shelley Kloppenburg; Sam Schulman; Flavia K Borges; Morvarid Kavosh; Chihiro Wada; Sabrina Lin; Serena Sibilio; Mandy Lauw; Alexander Benz; Wojciech Szczeklik; Arastoo Mokhtari; Eric Jacobsohn; Jessica Spence

doi:10.1016/j.bja.2022.12.001

Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies

Br J Anaesth. 2023 Aug;131(2):302-313. doi: 10.1016/j.bja.2022.12.001. Epub 2023 Jan 6.

Authors

Eugene Wang¹, Emilie P Belley-Côté², Jack Young³, Henry He¹, Haris Saud¹, Frederick D'Aragon⁴, Kevin Um⁵, Waleed Alhazzani⁶, Joshua Piticaru⁵, Matthew Hedden⁷, Richard Whitlock⁸, C David Mazer⁹, Hessam H Kashani¹⁰, Sarah Yang Zhang¹¹, Amanda Lucas¹², Nicholas Timmerman¹³, Cameron Nishi¹³, Davinder Jain¹⁴, Aaron Kugler¹³, Chris Beaver¹⁵, Shelley Kloppenburg¹⁶, Sam Schulman¹⁷, Flavia K Borges¹⁸, Morvarid Kavosh¹⁹, Chihiro Wada²⁰, Sabrina Lin¹, Serena Sibilio²¹, Mandy Lauw²², Alexander Benz²², Wojciech Szczeklik²³, Arastoo Mokhtari²⁴, Eric Jacobsohn²⁵, Jessica Spence²⁶

Affiliations

¹ Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.
² Departments of Medicine (Cardiology and Critical Care), McMaster University, Hamilton, ON, Canada; Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada.
³ Health Sciences Library, McMaster University, Hamilton, ON, Canada.
⁴ Départment d'anesthésiologie, Université de Sherbrooke, Quebec, QU, Canada.
⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁶ Departments of Critical Care, Medicine (Gastroenterology), and Health Research Methods, Evaluation, and Impact, McMaster University, Hamilton, ON, Canada.
⁷ Faculty of Arts and Science, Queen's University, Kingston, ON, Canada.
⁸ Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada; Departments of Surgery (Cardiac Surgery) and Health Research Methods, Evaluation, and Impact, McMaster University, Hamilton, ON, Canada.
⁹ Department of Anesthesia and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada; Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Anesthesia and Perioperative Medicine, University of Manitoba, Winnipeg, MB, Canada.
¹¹ Faculty of Medicine, McGill University, Montreal, QU, Canada.
¹² Department of Health Research Methods, Evaluation, and Impact; McMaster University, Hamilton, ON, Canada.
¹³ Department of Anesthesia, McMaster University, Hamilton, ON, Canada.
¹⁴ Department of Anesthesiology, Trillium Health Partners, Toronto, ON, Canada.
¹⁵ Sheridan College, Oakville, ON, Canada.
¹⁶ Organon, Montreal, QU, Canada.
¹⁷ Department of Medicine (Hematology), McMaster University, Hamilton, ON, Canada; Thrombosis and Atherosclerosis Research Institute, Population Health Research Institute, Hamilton, ON, Canada; Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
¹⁸ Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada; Departments of Medicine and Health Research Methods, Evaluation, and Impact, McMaster University, Hamilton, ON, Canada.
¹⁹ Department of Medicine, Coney Island Hospital, Brooklyn, NY, USA.
²⁰ Faculty of Arts, Waseda University, Tokyo, Japan.
²¹ Division of Cardiac Surgery, Instituto Clinico Sant'Ambrogio, Milan, Italy; Division of Cardiac Surgery, Centre Hospitalière Universitaire de Lille, Lille, France.
²² Population Health Research Institute, Hamilton, ON, Canada.
²³ Center for Intensive Care and Perioperative Medicine, Jagiellonian University Medical College, Kraków, Poland.
²⁴ Department of Medicine (Cardiology), McMaster University, Hamilton, ON, Canada.
²⁵ Departments of Anesthesia and Perioperative Medicine and Medicine (Critical Care), University of Manitoba, Winnipeg, MB, Canada.
²⁶ Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada; Departments of Anesthesia and Critical Care and Health Research Methods, Evaluation, and Impact, McMaster University, Hamilton, ON, Canada. Electronic address: spencej@phri.ca.

PMID: 36621439
DOI: 10.1016/j.bja.2022.12.001

Abstract

Background: Benzodiazepine use is associated with delirium, and guidelines recommend avoiding them in older and critically ill patients. Their perioperative use remains common because of perceived benefits.

Methods: We searched CENTRAL, MEDLINE, CINAHL, PsycInfo, and Web of Science from inception to June 2021. Pairs of reviewers identified randomised controlled trials and prospective observational studies comparing perioperative use of benzodiazepines with other agents or placebo in patients undergoing surgery. Two reviewers independently abstracted data, which we combined using a random-effects model. Our primary outcomes were delirium, intraoperative awareness, and mortality.

Results: We included 34 randomised controlled trials (n=4354) and nine observational studies (n=3309). Observational studies were considered separately. Perioperative benzodiazepines did not increase the risk of delirium (n=1352; risk ratio [RR] 1.43; 95% confidence interval [CI]: 0.9-2.27; I²=72%; P=0.13; very low-quality evidence). Use of benzodiazepines instead of dexmedetomidine did, however, increase the risk of delirium (five studies; n=429; RR 1.83; 95% CI: 1.24-2.72; I²=13%; P=0.002). Perioperative benzodiazepine use decreased the risk of intraoperative awareness (n=2245; RR 0.26; 95% CI: 0.12-0.58; I²=35%; P=0.001; very low-quality evidence). When considering non-events, perioperative benzodiazepine use increased the probability of not having intraoperative awareness (RR 1.07; 95% CI: 1.01-1.13; I²=98%; P=0.03; very low-quality evidence). Mortality was reported by one randomised controlled trial (n=800; RR 0.90; 95% CI: 0.20-3.1; P=0.80; very low quality).

Conclusions: In this systematic review and meta-analysis, perioperative benzodiazepine use did not increase postoperative delirium and decreased intraoperative awareness. Previously observed relationships of benzodiazepine use with delirium could be explained by comparisons with dexmedetomidine.

Systematic review protocol: PROSPERO CRD42019128144.

Keywords: benzodiazepines; intraoperative awareness; meta-analysis; perioperative medicine; postoperative delirium; systematic review.

Publication types

Meta-Analysis
Systematic Review
Review

MeSH terms

Aged
Benzodiazepines / adverse effects
Delirium* / chemically induced
Delirium* / prevention & control
Dexmedetomidine* / therapeutic use
Emergence Delirium* / epidemiology
Emergence Delirium* / prevention & control
Humans
Intraoperative Awareness*
Observational Studies as Topic
Randomized Controlled Trials as Topic

Substances

Benzodiazepines
Dexmedetomidine