DeliriumB-FreeNCT03928236
Benzodiazepine-free Cardiac Anesthesia for Reduction of Postoperative Delirium
A study testing Limited Intraoperative Benzodiazepine and Liberal Intraoperative Benzodiazepine in people with Delirium and Post-cardiac Surgery, run by Population Health Research Institute at 20 sites in 2 countries.
Trial summary
B-FREE is a pragmatic, multicentre, cluster crossover trial evaluating whether a policy limiting the use of intra-operative benzodiazepine reduces post-operative delirium when compared with a policy of 'ad libitum' administration. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Delirium, Post-cardiac Surgery
- What is being tested?
- Limited Intraoperative Benzodiazepine and Liberal Intraoperative Benzodiazepine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15,886 participants
- Where
- 20 sitesin 2 countries
- Study dates
- 18 Nov 2019to 30 Apr 2025
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Hospital is a major surgical center with a minimum of 250 cases of cardiac surgery per year.
- Equipoise by the hospital physicians regarding the use of benzodiazepines during surgery (≥ 95% of hospital cardiac anesthesia group agrees to manage adult patients (age >18 years) as per the benzodiazepine policy in place during a given crossover period).
- Hospital routinely assesses patients (age >18 years) for postoperative delirium at least once every 12 hours during the initial 72 hours after cardiac surgery as a part of routine clinical care using either the Confusion Assessment Method-ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC).
Who cannot join
- Hospital does not meet inclusion criteria
Trial locations and contacts
20 sites in 2 countries.
20 sites in 2 countries
Canada18 sites
Mazankowski Alberta Heart Institute
Edmonton, Alberta, T6G 2B7
Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia, B3H 3A7
Hamilton Health Sciences, Hamilton General Hospital
Hamilton, Ontario, L8L 2X2
Kingston General Hospital
Kingston, Ontario, K7L 2V7
London Health Sciences Centre
London, Ontario, N6A 5W9
Montreal Heart Institute
Montreal, Quebec, H1T 1C8
Jewish General Hospital
Montreal, Quebec, H3T 1E2
Royal Columbian Hospital
New Westminster, British Columbia, V3L 3W7
Hôpital Laval
Québec, Quebec, G1V 4G5
Regina General Hospital
Regina, Saskatchewan, S4P 0W5
Royal University Hospital
Saskatoon, Saskatchewan, S7N OW8
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, J1H 4C6
Sunnybrook Health Sciences Centre
Toronto, Ontario, M4N 3M5
St. Michael's Hospital
Toronto, Ontario, M5B 1W8
Toronto General Hospital
Toronto, Ontario, M5G 2C4
Vancouver General Hospital
Vancouver, British Columbia, V5Z 1M9
St. Paul's Hospital
Vancouver, British Columbia, V6Z 1Y6
St. Boniface General Hospital
Winnipeg, Manitoba, R2H 2A6
United States2 sites
Weill Cornell Medicine
New York, New York, 10065
Washington University School of Medicine
St Louis, Missouri, 63110-1010
About this study
B-FREE is a pragmatic, multicentre, cluster crossover trial evaluating whether a policy limiting the use of intra-operative benzodiazepine reduces post-operative delirium when compared with a policy of 'ad libitum' administration. The knowledge generated by this study will provide the basis for cardiac anesthesia practice guidelines.
Read the detailed description
Delirium, an acute state of confusion, occurs in approximately 1 in 5 adults after open heart surgery. Even though it is a temporary state, patients who experience delirium are at increased risk of serious problems that last after the delirium has resolved. These problems include decreases in thinking, mobility, self-care, and the ability to live independently in a community setting. Patients who experience delirium have longer stays in hospital, are more likely to be discharged to a nursing home, and are more likely to die. Benzodiazepines are a sedative and amnestic medication that may be associated with delirium. As such, benzodiazepines are rarely used for sedation in the intensive care unit after cardiac surgery. However, benzodiazepines continue to be used frequently in the operating room by anesthesiologists during open heart surgery because of their amnestic effects and limited impact on blood pressure. Nevertheless, practice is divided among cardiac anesthesiologists, with some never using benzodiazepines and others using them for nearly all patients.
Because the best approach (routine benzodiazepines or restricted benzodiazepines) remains uncertain, we will compare the effect of a hospital policy of intraoperative medication use that includes benzodiazepines to a policy that uses alternative medications and no benzodiazepines on the incidence of delirium after open heart surgery. The findings of the study have the potential to improve the outcomes of tens of thousands of patients around the world and will provide the basis for cardiac anesthesiology practice guidelines.
- Conditions
- Delirium, Post-cardiac Surgery
- Being tested
- Limited Intraoperative Benzodiazepine, Liberal Intraoperative Benzodiazepine
- Medical subject headings
- Delirium
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Limited Intraoperative BenzodiazepineOther
policy for limited use of intraoperative benzodiazepine
Liberal Intraoperative BenzodiazepineOther
policy for liberal use of intraoperative benzodiazepine
| Study group | Role | What they receive |
|---|---|---|
| Limited Benzodiazepine Policy | Experimental | Policy of no routine use of any intraoperative benzodiazepines. Receives: Other: Limited Intraoperative Benzodiazepine |
| Liberal Benzodiazepine Policy | Active comparator | Policy for the administration of benzodiazepine as per clinical guidelines but no lower than 0.03 mg/kg (ideal body weight midazolam equivalent) to all patients undergoing cardiac surgery. Any benzodiazepine may be used. Receives: Other: Liberal Intraoperative Benzodiazepine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of Delirium
Delirium assessed up to 72 hours after surgery using standardized and validated delirium scales
Measured: up to 72 hours post cardiac surgery
Secondary outcomes (3)
Number of Days in ICU after Cardiac Surgery
Length of Stay (LOS) in Intensive Care Unit after Cardiac Surgery
Measured: through study completion, approximately 37 months
Number of Days in Hospital after Cardiac Surgery
Length of Stay (LOS) in Hospital after Cardiac Surgery
Measured: through study completion, approximately 37 months
Incidence of In-hospital Mortality
Death from any cause after index cardiac surgery and during the index hospitalization
Measured: through study completion, approximately 37 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Apr 2019
- Study start18 Nov 2019
- Primary completion11 Dec 2022
- Study completion30 Apr 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for DeliriumStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Multicenter, cluster-randomized, crossover trial
- Masking
- None (open label)
- Enrolment
- 15,886 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Population Health Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jessica Spence, MD FRCPC, Principal investigator, Population Health Research InstituteEric Jacobsohn, MBChB MPHE, Principal investigator, University of ManitobaStuart Connolly, MD FRCPC, Study chair, Population Health Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03928236
- Sponsor's protocol ID
- B-Free.2019
- Acronym
- B-Free
- Status last verified
- Feb 2025
- First submitted
- 18 Apr 2019
- Last updated
- 4 Mar 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Spence J, Devereaux PJ, Lee SF, D'Aragon F, Avidan MS, Whitlock RP, Mazer CD, Rousseau-Saine N, Rajamohan RR, Pryor KO, Klein R, Tan E, Cameron MJ, Di Sante E, DeBorba E, Mustard ME, Couture EJ, Zamper RPC, Law MWY, Djaiani G, Saha T, Choi S, Hedlin P, Pikaluk DR, Lam W, Deschamps A, Ramasundarahettige CF, Vincent J, McIntyre WF, Oczkowski SJW, Dulong BJ, Beaver C, Kloppenburg SA, Lamy A, Jacobsohn E, Belley-Cote EP; B-Free Investigators and the Canadian Perioperative Anesthesia Clinical Trials Group. Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium: A Cluster Randomized Crossover Trial. JAMA Surg. 2025 Mar 1;160(3):286-294. doi: 10.1001/jamasurg.2024.6602.
PubMed 39878960Spence J, Belley-Cote E, Jacobsohn E, Lee SF, D'Aragon F, Avidan M, Mazer CD, Rousseau-Saine N, Rajamohan R, Pryor K, Klein R, Tan EC, Cameron M, Di Sante E, DeBorba E, Mustard M, Couture E, Zamper R, Law M, Djaiani G, Saha T, Choi S, Hedlin P, Pikaluk R, Lam WY, Deschamps A, Whitlock R, Dulong B, Devereaux PJ, Beaver C, Kloppenburg S, Oczkowski S, McIntyre WF, McFarling M, Lamy A, Vincent J, Connolly S; B-Free Investigators. Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial. CJC Open. 2023 Jun 8;5(9):691-699. doi: 10.1016/j.cjco.2023.06.001. eCollection 2023 Sep.
PubMed 37744662Wang ML, Min J, Sands LP, Leung JM; the Perioperative Medicine Research Group. Midazolam Premedication Immediately Before Surgery Is Not Associated With Early Postoperative Delirium. Anesth Analg. 2021 Sep 1;133(3):765-771. doi: 10.1213/ANE.0000000000005482.
PubMed 33721875
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Benzodiazepine-free Cardiac Anesthesia for Reduction of Postoperative Delirium
- ClinicalTrials.gov ID
- NCT03928236
- Acronym / sponsor ID
- B-Free / B-Free.2019
- Conditions
- Delirium, Post-cardiac Surgery
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 15,886 participants (estimated)
- Lead sponsor
- Population Health Research InstituteUniversity, hospital or other
- Study start
- 18 Nov 2019 (actual)
- Primary completion
- 11 Dec 2022 (actual)
- Study completion
- 30 Apr 2025 (estimated)
- First posted
- 26 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
B-FREE is a pragmatic, multicentre, cluster crossover trial evaluating whether a policy limiting the use of intra-operative benzodiazepine reduces post-operative delirium when compared with a policy of 'ad libitum' administration. The knowledge generated by this study will provide the basis for cardiac anesthesia practice guidelines.
Detailed description
Delirium, an acute state of confusion, occurs in approximately 1 in 5 adults after open heart surgery. Even though it is a temporary state, patients who experience delirium are at increased risk of serious problems that last after the delirium has resolved. These problems include decreases in thinking, mobility, self-care, and the ability to live independently in a community setting. Patients who experience delirium have longer stays in hospital, are more likely to be discharged to a nursing home, and are more likely to die. Benzodiazepines are a sedative and amnestic medication that may be associated with delirium. As such, benzodiazepines are rarely used for sedation in the intensive care unit after cardiac surgery. However, benzodiazepines continue to be used frequently in the operating room by anesthesiologists during open heart surgery because of their amnestic effects and limited impact on blood pressure. Nevertheless, practice is divided among cardiac anesthesiologists, with some never using benzodiazepines and others using them for nearly all patients.
Because the best approach (routine benzodiazepines or restricted benzodiazepines) remains uncertain, we will compare the effect of a hospital policy of intraoperative medication use that includes benzodiazepines to a policy that uses alternative medications and no benzodiazepines on the incidence of delirium after open heart surgery. The findings of the study have the potential to improve the outcomes of tens of thousands of patients around the world and will provide the basis for cardiac anesthesiology practice guidelines.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Multicenter, cluster-randomized, crossover trial
| Arm | Type | Receives |
|---|---|---|
| Limited Benzodiazepine Policy | Experimental | Other: Limited Intraoperative BenzodiazepinePolicy of no routine use of any intraoperative benzodiazepines. |
| Liberal Benzodiazepine Policy | Active comparator | Other: Liberal Intraoperative BenzodiazepinePolicy for the administration of benzodiazepine as per clinical guidelines but no lower than 0.03 mg/kg (ideal body weight midazolam equivalent) to all patients undergoing cardiac surgery. Any benzodiazepine may be used. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Hospital is a major surgical center with a minimum of 250 cases of cardiac surgery per year.
- Equipoise by the hospital physicians regarding the use of benzodiazepines during surgery (≥ 95% of hospital cardiac anesthesia group agrees to manage adult patients (age >18 years) as per the benzodiazepine policy in place during a given crossover period).
- Hospital routinely assesses patients (age >18 years) for postoperative delirium at least once every 12 hours during the initial 72 hours after cardiac surgery as a part of routine clinical care using either the Confusion Assessment Method-ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC).
Key exclusion criteria (1 listed)
- Hospital does not meet inclusion criteria
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Limited Intraoperative Benzodiazepinepolicy for limited use of intraoperative benzodiazepine | Other | Limited Benzodiazepine Policy |
| Liberal Intraoperative Benzodiazepinepolicy for liberal use of intraoperative benzodiazepine | Other | Liberal Benzodiazepine Policy |
Primary outcome
Incidence of Delirium
Time frame: up to 72 hours post cardiac surgery
Delirium assessed up to 72 hours after surgery using standardized and validated delirium scales
3 secondary outcomes
Number of Days in ICU after Cardiac Surgery
Time frame: through study completion, approximately 37 months
Number of Days in Hospital after Cardiac Surgery
Time frame: through study completion, approximately 37 months
Incidence of In-hospital Mortality
Time frame: through study completion, approximately 37 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2025.
- Derived from this study: PubMed 39878960Spence J, Devereaux PJ, Lee SF, D'Aragon F, Avidan MS, Whitlock RP, Mazer CD, Rousseau-Saine N, Rajamohan RR, Pryor KO, Klein R, Tan E, Cameron MJ, Di Sante E, DeBorba E, Mustard ME, Couture EJ, Zamper RPC, Law MWY, Djaiani G, Saha T, Choi S, Hedlin P, Pikaluk DR, Lam W, Deschamps A, Ramasundarahettige CF, Vincent J, McIntyre WF, Oczkowski SJW, Dulong BJ, Beaver C, Kloppenburg SA, Lamy A, Jacobsohn E, Belley-Cote EP; B-Free Investigators and the Canadian Perioperative Anesthesia Clinical Trials Group. Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium: A Cluster Randomized Crossover Trial. JAMA Surg. 2025 Mar 1;160(3):286-294. doi: 10.1001/jamasurg.2024.6602.
- Derived from this study: PubMed 37744662Spence J, Belley-Cote E, Jacobsohn E, Lee SF, D'Aragon F, Avidan M, Mazer CD, Rousseau-Saine N, Rajamohan R, Pryor K, Klein R, Tan EC, Cameron M, Di Sante E, DeBorba E, Mustard M, Couture E, Zamper R, Law M, Djaiani G, Saha T, Choi S, Hedlin P, Pikaluk R, Lam WY, Deschamps A, Whitlock R, Dulong B, Devereaux PJ, Beaver C, Kloppenburg S, Oczkowski S, McIntyre WF, McFarling M, Lamy A, Vincent J, Connolly S; B-Free Investigators. Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial. CJC Open. 2023 Jun 8;5(9):691-699. doi: 10.1016/j.cjco.2023.06.001. eCollection 2023 Sep.
- Derived from this study: PubMed 33721875Wang ML, Min J, Sands LP, Leung JM; the Perioperative Medicine Research Group. Midazolam Premedication Immediately Before Surgery Is Not Associated With Early Postoperative Delirium. Anesth Analg. 2021 Sep 1;133(3):765-771. doi: 10.1213/ANE.0000000000005482.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jessica Spence, MD FRCPC principal investigator
Population Health Research Institute
Eric Jacobsohn, MBChB MPHE principal investigator
University of Manitoba
Stuart Connolly, MD FRCPC study chair
Population Health Research Institute
20 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Limited Intraoperative Benzodiazepine and Liberal Intraoperative Benzodiazepine in people with Delirium and Post-cardiac Surgery, run by Population Health Research Institute at 20 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 4 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 20 sites in Canada, United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Delirium (time frame: up to 72 hours post cardiac surgery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03928236, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2025.