Remimazolam vs Midazolam to Reduce Delirium in Adults ≥65 Undergoing CPB Valve Surgery

Effect of Remimazolam on Delirium After Cardiac Surgery: Randomized Controlled Trial With Midazolam

"Postoperative delirium is a common and serious complication following cardiac surgery, particularly among older adults who require intensive care. Its incidence is reported to range between 20% and 70% after cardiopulmonary bypass (CPB), and has been associated with prolonged hospitalization, increased medical costs, higher morbidity and mortality, and long-term cognitive decline. Benzodiazepines are frequently used during anesthetic induction in cardiac surgery due to favorable hemodynamic stability, although multiple clinical guidelines have recommended limitation of benzodiazepine exposure because of concerns for delirium. However, robust clinical evidence in cardiac surgery remains limited.

Midazolam is currently the most commonly administered benzodiazepine in this setting, though metabolism through hepatic pathways and accumulation of active metabolites may increase the risk of postoperative delirium, especially in older patients and those with organ dysfunction. Remimazolam, a recently approved benzodiazepine, undergoes rapid hydrolysis by plasma esterases and demonstrates predictable pharmacokinetic properties with a markedly shorter context-sensitive half-time compared to midazolam. These pharmacologic features suggest a potentially reduced impact on postoperative delirium risk. Despite this rationale, no randomized controlled trial has evaluated the effect of remimazolam versus midazolam on delirium after CPB-assisted valve surgery.

This randomized double-blind controlled trial aims to determine whether remimazolam reduces the incidence of postoperative delirium compared with midazolam in patients aged ≥65 years undergoing valve surgery with CPB. Eligible participants will be randomized in a 1:1 ratio to receive either remimazolam or midazolam for anesthetic induction according to a computer-generated allocation sequence. All other anesthetic management will follow standardized institutional protocols, including depth of anesthesia monitoring. Delirium assessment will be performed three times daily in the intensive care unit using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or Intensive Care Delirium Screening Checklist (ICDSC) and twice daily on the ward using 3-Minute Diagnostic Interview for CAM (3D-CAM) for four postoperative days.

The primary endpoint is the incidence of delirium within four postoperative days. Key secondary outcomes include in-hospital or 30-day mortality and a composite of major postoperative complications. A total of 300 patients (150 per group) will be enrolled to provide 90% statistical power to detect the hypothesized difference in delirium risk between groups, accounting for a 10% dropout rate. Findings from this study are expected to provide high-quality evidence regarding the comparative impact of remimazolam and midazolam on postoperative delirium and may inform anesthetic strategy selection in high-risk cardiac surgical populations."

Study Overview

• Status: Not yet recruiting
• Conditions: Delirium; Critical Illness; Cardiopulmonary Bypass; Benzodiazepines; Aged
• Intervention / Treatment: Drug: Midazolam; Drug: Remimazolam

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 4

Contacts and Locations

Study Locations

• South Korea
  • Seoul, South Korea, 120-752
    • Department of Anaesthesiology and Pain Medicine, Yonsei University College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged 65 years or older undergoing heart valve surgery involving cardiopulmonary bypass.

Exclusion Criteria:

• Emergency surgery, Surgery involving total arch replacement, History of remimazolam anaphylaxis, History of major neurocognitive disorder, Alcohol or substance dependence/abuse, Major depressive disorder, Schizophrenia, Participation in other clinical studies that may affect outcomes, Inability to provide informed consent due to illiteracy, foreign language barrier, or cognitive impairment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Midazolam group; Patients allocated to receive midazolam during anesthetic induction and rewarming period of cardiopulmonary bypass.	Drug: Midazolam; Participants receive intravenous midazolam 0.05 mg/kg for anesthetic induction and an additional dose (0.065 mg/kg) administered via the cardiopulmonary bypass circuit during rewarming, with all other anesthetic management identical to the experimental arm.; Other Names: Control group
Experimental: Remimazolam group; Patients allocated to receive remimazolam during anesthetic induction and rewarming period of cardiopulmonary bypass.	Drug: Remimazolam; Participants receive intravenous remimazolam 0.2 mg/kg for anesthetic induction and an additional dose (0.26 mg/kg) administered via the cardiopulmonary bypass circuit during rewarming, together with standard cardiac anesthesia care.; Other Names: Byfavo group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of postoperative delirium within 4 days after surgery	Occurrence of delirium assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Intensive Care Delirium Screening Checklist (ICDSC), or 3-Minute Diagnostic Interview for CAM (3D-CAM) during the first 4 postoperative days.	From the day of surgery (POD 0) to postoperative day 4

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2025
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: November 23, 2025
• First Submitted That Met QC Criteria: November 23, 2025
• First Posted (Estimated): December 4, 2025

Study Record Updates

• Last Update Posted (Estimated): December 4, 2025
• Last Update Submitted That Met QC Criteria: November 23, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Pathologic Processes; Disease Attributes; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Delirium; Critical Illness; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Epidemiologic Research Design; Epidemiologic Methods; Research Design; Methods; Benzazepines; Benzodiazepines; Midazolam; Control Groups; remimazolam
• Other Study ID Numbers: 4-2024-0976

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No