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

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Postoperative Delirium

Intervention / Treatment
-----------------
* Drug: Remimazolam
* Drug: Propofol


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remimazolam<br>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<br>* General anesthesia will be induced and maintained using continuous infusion of intravenous remimazolam.<br>* Other names: byfavo inj;|
| Active Comparator: Propofol<br>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<br>* General anesthesia will be induced and maintained using target-controlled infusion of intravenous propofol.<br>* 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 7 or patient discharge, whichever came first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 7 | 
| Delirium subtypes | Hypoactive/hyperactive/mixed | assessed twice a day up to postoperative day 7 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 7 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 7 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 7 or patient discharge, whichever came first | 
| Delirium symptoms | Subsyndromal delirium plus syndromal delirium | assessed twice a day up to postoperative day 7 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 7 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 7 or patient discharge, whichever came first | 
| Emergence agitation | defined as Richmond Agitation-Sedation Scale ≥+1 | within 30 min after extubation | 
| Postoperative pain score | Pain level will be assessed using numeric rating score (NRS) | assessed once a day up to postoperative day 7 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 7 or patient discharge, whichever came first | 
| 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 | 
| Fall | postoperative fall-down and associated injury | 3-month 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 | 
| Death | All-cause mortality | In hospital, 3, 6, and 12-month after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Postoperative delirium, Remimazolam, Total intravenous anesthesia, Neurosurgery