Remimazolam vs. Propofol: Impact on Postoperative Delirium in Neurosurgical Patients

Effect of Remimazolam Versus Propofol Anesthesia on Postoperative Delirium in Neurosurgical Patients: A Randomised, Controlled, Noninferiority Trial

The investigator aimed to evaluate the incidence of postoperative delirium after remimazolam-based total intravenous anestheisa (TIVA) compared to the propofol-based TIVA in patients undergoing neurosurgery.

Study Overview

• Status: Recruiting
• Conditions: Postoperative Delirium
• Intervention / Treatment: Drug: Remimazolam; Drug: Propofol

Detailed Description

Remimazolam, a short-acting benzodiazepine, has recently gained approval for use in the induction and maintanance of general anesthesia. In American Society of Anesthesiologists (ASA) physical status class I and II patients undergoing general anesthesia, the remimazolam-based TIVA has shown comparable efficacy to propofol-based TIVA while demonstrating a superior safety profile. Remimazolam has exhibited a lower incidence of hypotension, reduced vasopressor requirements, and fewer instances of bradycardia compared to the propofol-based TIVA.

The use of benzodiazepine has been associated with an increased risk of postoperative delirium, but there is currently no randomized controlled trial investigating the relationship between remimazolam, a new short-acting benzodiazepine, and postoperative delirium. Therefore, the investigators designed this prospective, randomized, double-blinded, active comparator-controlled, non-inferiority trial to investigate the incidence of postoperative delirium after remimazolam-based TIVA compared with propofol-based TIVA in neurosurgery patients.

• Study Type: Interventional
• Enrollment (Estimated): 696
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: jeayoun kim; Phone Number: +821039268786; Email: kimjy0705@naver.com

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center
    • Contact: jeayoun kim, MD; Phone Number: +821039268786; Email: kimjy0705@naver.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• American society of anesthesia (ASA) class I - III

Exclusion Criteria:

• Severe respiratory, cardiovascular, or hepatic disease (child-pugh C)
• Dependency on psychiatric drugs or alcohol
• Severe sensory impairments that impede communication
• Preoprative delirium
• Hypersensitivity, allergies, or contraindication to the study drugs.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Remimazolam; General anesthesia using continuous infusion of intravenous remimazolam and remifentanil. Remimazolam will be used for maintenance of general anesthesia and adjusted between 0.6-2mg/kg/hr until the end of surgery.	Drug: Remimazolam; General anesthesia will be induced and maintained using continuous infusion of intravenous remimazolam.; Other Names: byfavo inj
Active Comparator: Propofol; General anesthesia using target-controlled infusion of intravenous propofol and remifentanil. Propofol will be adjusted maintaining the BIS between 40-60 until the end of surgery.	Drug: Propofol; General anesthesia will be induced and maintained using target-controlled infusion of intravenous propofol.; Other Names: Fresofol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative delirium	The occurence of postoperative delirium will be assessed twice a day using confusion assessment method for the intensive care unit (CAM-ICU) and 3-minute diagnostic assessment for CAM-defined delirium (3D-CAM).	assessed up to postoperative day 5 or patient discharge, whichever came first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Emergence agitation	defined as Richmond Agitation-Sedation Scale ≥+1	within 30 min after extubation
Intraoperative awareness	Intraoperative awareness will be assess using Modified brice questionnaire.	at postoperative day 0
Undesirable patient movement	Undesirable movement of patient during surgery	Intraoperative period
Potential adverse event	hypotension, hypertension, bradycardia, tachycardia, desaturation, teeth injury, laryngeal spasm, allergic reaction, other arrhtymia, cardiac events, pruritis, nausea, vomiting etc	From the beginning of anesthesia until 24 hours after surgery
Perioperative serious adverse events	Serious adverse events are adverse events that result in hospitalization or prolong hospitalization, cause persistent or significant disability, are life-threatening, or result in death.	rom date of randomization until 24 hour after surgery
Postoperative complication	assessed by Clavien-Dindo classification Data are presented as the proportion of patients with 1 or more events (edema, vasospasm, rebleeding, seizures, and/or ischemia, etc..)	Until 30 day after surgery
Length of stay in ICU after surgery	days	from the day of surgery to the time of patient discharge from ICU, assessed up to 3 months after surgery
Length of stay in hospital after surgery	days	from the day of surgery to the time of patient discharge, assessed up to 3 months after surgery
Postoperative cognitive dysfunction	assessed by T-MOCA (Montreal Cognitive Assessment) using telephone interview	3-month after surgery
Functional status	assessed using bartel activity of daily living (ADL) index	3-month after surgery
Onset of postoperative delirium	The time of initial diagnosis of postoperative delirium	From the end of surgery until the date of first diagnosis of delirium or discharge, whichever came first, assessed up to postoperative day 5
Delirium subtypes	Hypoactive/hyperactive/mixed	assessed twice a day up to postoperative day 5 or patient discharge, whichever came first
Severity of postoperative delirium	Severity of postoperative delirium will be assessed twice a day using DRS-R-98 (delirium rating scale-revised-98)	assessed twice a day up to postoperative day 5 or patient discharge, whichever came first
Duration of postoperative delirium	Duration of postoperative delirium will be assessed twice a day	assessed twice a day up to postoperative day 5 or patient discharge, whichever came first
Subsyndromal delirium	Presence of any CAM features with absence of full syndromal delirium	assessed twice a day up to postoperative day 5 or patient discharge, whichever came first
Delirium symptoms	Subsyndromal delirium plus syndromal delirium	assessed twice a day up to postoperative day 5 or patient discharge, whichever came first
The proportion of valid delirium assessment	The percentage of valid delirium assessments (per patient) that did not involve coma or stupor out of a total of 14 delirium assessments.	assessed twice a day up to postoperative day 5 or patient discharge, whichever came first
Intensive care unit (ICU) admission with endotracheal intubation after surgery	Percentage of the patients who were not extubated in the OR and transferred to the ICU	assessed up to postoperative day 5 or patient discharge, whichever came first
Postoperative pain score	Pain level will be assessed using numeric rating score (NRS)	assessed once a day up to postoperative day 5 or patient discharge, whichever came first
Opioid consumption	The amount of opioid consumption will be coverted to parenteral morphine equivalent dose (MED).	assessed once a day up to postoperative day 5 or patient discharge, whichever came first
Acute kidney injury (AKI) after surgery	AKI assessed by KDIGO criteria	within 1 week after surgery
Myocardial injury after non-cardiac surgery (MINS)	MINS assessed by high-sensitive TnT	within 1-month after surgery
Fall	the incidence of postoperative fall-down and associated injury (presence of fracture)	3-month after surgery
Death	All-cause mortality	during hospitalization (up to day 30), within 1 year after surgery (3, 6, and 12-month after surgery)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative nausea and vomiting (PONV)	PONV substudy are pre-planned non-inferioirty substudy for this main trial. In addition to the data collected as part of the main trial, patients enrolled into the PONV substudy were assessed the frequency and severity of nausea and vomiting, and frequency of antiemetic administration using validated questinnaire.	within 3 days after surgery
Subgroup analysis of delirium incidence assessed by CAM-ICU or 3D-CAM	Subgroup analysis according to the surgery type, patients' age, and preoperative cognitive function and frailty	assessed up to postoperative day 5 or patient discharge, whichever came first
Electroencephalography (EEG)	EEG substudy are pre-planned. The association between the development of postoperative delirium, pre&postoperative cognitive function, severe postoperaitve pain and spectral power of alpha, beta, delta, and theta band. Phase-amplitude coupling of each bands	Intraoperative period

Collaborators and Investigators

• Sponsor: Samsung Medical Center
• Investigators: Principal Investigator: Jiseon Jeong, Samsung Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: October 24, 2023
• First Submitted That Met QC Criteria: October 30, 2023
• First Posted (Actual): November 2, 2023

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Neurosurgery; Postoperative delirium; Remimazolam; Total intravenous anesthesia
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Emergence Delirium; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hypnotics and Sedatives; Propofol
• Other Study ID Numbers: SMC 2023-08-135

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The dataset generated during the current study is available from the corresponding author upon reasonable request.

Drug and device information, study documents

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