Exploration of Appropriate BIS Range and Propofol Effect-site Concentration During Total Intravenous Anesthesia With Concomitant Adjuvants.

A Prospective, Randomized Study to Determine the Appropriate Bispectral Index Range and Propofol Effect-Site Concentration During Total Intravenous Anesthesia Combined With Midazolam, Dexmedetomidine or Esketamine.

The goal of this clinical trial is to determine the appropriate Bispectral Index (BIS) range and propofol effect-site concentration required to maintain adequate anesthesia depth during total intravenous anesthesia (TIVA) combined with midazolam, dexmedetomidine, or esketamine in patients undergoing unilateral knee replacement surgery. The main questions it aims to answer are:

1. What are the appropriate BIS range and propofol effect-site concentration for maintaining adequate anesthesia depth when combined with each of the three medications (midazolam, dexmedetomidine, or esketamine) during TIVA?
2. How these combination regimens affect the quality of recovery and postoperative pain in patients？

Participants will:

1. Receive one of four anesthesia regimens during surgery: propofol alone, propofol combined with midazolam, dexmedetomidine, or esketamine.
2. Undergo a stepwise reduction of propofol effect-site concentration towards the end of surgery.
3. Have their consciousness assessed using the isolated forearm technique, while BIS, EEG signals, and vital signs are continuously monitored throughout the procedure.
4. Have their recovery quality and postoperative pain assessed after surgery.

Study Overview

• Status: Not yet recruiting
• Conditions: Knee Osteoarthritis; Replacement, Knee; Elective Surgical Patients; ASA Class I/II Patients
• Intervention / Treatment: Drug: Propofol + Remifentanil; Drug: Propofol + Remifentanil +Midazolam; Drug: Propofol + Remifentanil + Dexmedetomidine; Drug: Propofol + Remifentanil + Esketamine

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: MA; Phone Number: +86-10-84205882; Email: maye_1316@163.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18 to 65 years
• American Society of Anesthesiologists (ASA) physical status I or II
• Body Mass Index (BMI) 18 to 30 kg/m²
• Scheduled for elective unilateral total knee replacement surgery
• Willing to participate in the study and signed informed consent form, and able to comply with the intervention and assessment procedures

Exclusion Criteria:

• History of neurological disorders
• Cognitive dysfunction assessed by the Mini-Cog scale
• History of antipsychotic or sedative medication use in the past 4 weeks
• Poorly controlled or untreated hypertension
• Sinus bradycardia, cardiac conduction block, or severe heart failure
• Acute angle-closure glaucoma
• Allergic to intravenous anesthetics
• Hearing impairment, could not cooperate in intervention and evaluation
• Contraindications to tourniquet use on the upper arm

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Propofol + Remifentanil	Drug: Propofol + Remifentanil; Participants in this arm will receive total intravenous anesthesia (TIVA) with propofol and remifentanil during the maintenance period. After placement of the knee prosthesis, the isolated forearm technique (IFT) will be initiated. Participants will wear headphones playing recorded standardized instructions. Rocuronium (0.3 mg/kg) will be administered via the non-dominant arm. The propofol plasma-site concentration will be reduced in stepwise decrements of 0.3 μg/mL, with each concentration maintained for 5 minutes, until any of the following endpoints is reached: (1) positive IFT response , (2) BIS > 60 sustained for 1 minute, (3) electroencephalogram signs of arousal, or (4) clinical judgment by the anesthesiologist that anesthesia depth is inadequate.
Experimental: Propofol + Remifentanil + Midazolam	Drug: Propofol + Remifentanil +Midazolam; Participants in this arm will receive total intravenous anesthesia (TIVA) with propofol and remifentanil during the maintenance period. After placement of the knee prosthesis, the isolated forearm technique (IFT) will be initiated. Participants will wear headphones playing recorded standardized instructions. Rocuronium (0.3 mg/kg) will be administered via the non-dominant arm. Midazolam (2 mg) will be administered intravenously.The propofol plasma-site concentration will be set to 1.8 μg/mL, then reduced in stepwise decrements of 0.3 μg/mL, with each concentration maintained for 5 minutes, until any of the following endpoints is reached: (1) positive IFT response , (2) BIS > 60 sustained for 1 minute, (3) electroencephalogram signs of arousal, or (4) clinical judgment by the anesthesiologist that anesthesia depth is inadequate.
Experimental: Propofol + Remifentanil + Dexmedetomidine	Drug: Propofol + Remifentanil + Dexmedetomidine; Participants in this arm will receive total intravenous anesthesia (TIVA) with propofol and remifentanil during the maintenance period. After placement of the knee prosthesis, the isolated forearm technique (IFT) will be initiated. Participants will wear headphones playing recorded standardized instructions. Rocuronium (0.3 mg/kg) will be administered via the non-dominant arm. Dexmedetomidine 1 μg/kg infused over 10 minutes.The propofol plasma-site concentration will be set to 1.8 μg/mL, then reduced in stepwise decrements of 0.3 μg/mL, with each concentration maintained for 5 minutes, until any of the following endpoints is reached: (1) positive IFT response , (2) BIS > 60 sustained for 1 minute, (3) electroencephalogram signs of arousal, or (4) clinical judgment by the anesthesiologist that anesthesia depth is inadequate.
Experimental: Propofol + Remifentanil + Esketamine	Drug: Propofol + Remifentanil + Esketamine; Participants in this arm will receive total intravenous anesthesia (TIVA) with propofol and remifentanil during the maintenance period. After placement of the knee prosthesis, the isolated forearm technique (IFT) will be initiated. Participants will wear headphones playing recorded standardized instructions. Rocuronium (0.3 mg/kg) will be administered via the non-dominant arm. Esketamine (0.3 mg/kg) will be administered intravenously.The propofol plasma-site concentration will be set to 1.8 μg/mL, then reduced in stepwise decrements of 0.3 μg/mL, with each concentration maintained for 5 minutes, until any of the following endpoints is reached: (1) positive IFT response , (2) BIS > 75 sustained for 1 minute, (3) electroencephalogram signs of arousal, or (4) clinical judgment by the anesthesiologist that anesthesia depth is inadequate.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BIS value	BIS value recorded at the first occurrence of IFT positivity or any predefined clinical sign of inadequate anesthesia.	From the start of the intra-operative stepwise reduction phase until the first occurrence of IFT positivity or any predefined clinical sign of inadequate anesthesia, assessed up to 30 minutes.
Propofol Effect-Site Concentration	Propofol effect-site concentration recorded at the first occurrence of IFT positivity or any predefined clinical sign of inadequate anesthesia.	From the start of the intra-operative stepwise reduction phase until the first occurrence of IFT positivity or any predefined clinical sign of inadequate anesthesia, assessed up to 30 minutes.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Brice Questionnaire	The presence of intra-operative awareness with recall is assessed using the Modified Brice Questionnaire. The questionnaire explores the patient's memory of the peri-operative period through structured questions.	From PACU admission to 48 hours postoperatively. Assessed before PACU discharge, 24 hours and 48 hours postoperatively.
Time from Discontinuation of Anesthetics to Laryngeal Mask Airway Removal	From discontinuation of anesthetics to LMA removal. Successful removal is defined as the patient being awake, able to open mouth on command, and having return of protective reflexes, without signs of respiratory distress.	From discontinuation of anesthetics to LMA removal, assessed up to 60 minutes.
Time to Modified Aldrete Score of 10 in the Post Anesthesia Care Unit	Time from post anesthesia care unit (PACU) admission until the first attainment of a Modified Aldrete Score of 10. The Modified Aldrete Score assesses five domains: consciousness, activity, respiration, blood pressure, and oxygen saturation, each scored from 0 to 2, with a maximum total score of 10. A score of 10 indicates the patient has achieved optimal recovery in all five domains.	From PACU admission to Modified Aldrete Score of 10, assessed up to 60 minutes.
Adverse Events During Emergence from Anesthesia	Adverse events during the period from anesthetic discontinuation to PACU discharge are recorded.	From discontinuation of anesthetics to PACU discharge, assessed up to 2 hours.
Postoperative Pain Intensity Measured by Numeric Rating Scale	Pain intensity is assessed using the Numeric Rating Scale, an 11-point scale from 0 to 10, where 0 represents "no pain" and 10 represents "the worst imaginable pain". Patients are asked to rate their current pain intensity at each assessment time point. The Numeric Rating Scale is a widely used and validated measure for postoperative pain assessment.	From PACU admission to 48 hours postoperatively. Assessed at PACU admission, PACU discharge, 24 hours and 48 hours postoperatively.
Analgesic Consumption	Total amount of rescue analgesic medication administered to the patient from PACU admission to 48 hours postoperatively.	From PACU admission to 48 hours postoperatively. Recorded during PACU stay, 24 hours and 48 hours postoperatively.

Collaborators and Investigators

• Sponsor: China-Japan Friendship Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: July 16, 2026
• First Submitted That Met QC Criteria: July 26, 2026
• First Posted (Actual): July 30, 2026

Study Record Updates

• Last Update Posted (Actual): July 30, 2026
• Last Update Submitted That Met QC Criteria: July 26, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Osteoarthritis; Osteoarthritis, Knee; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Acids, Acyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Imidazoles; Piperidines; Phenols; Benzene Derivatives; Propionates; Remifentanil; Esketamine; Dexmedetomidine; Propofol
• Other Study ID Numbers: 2026-HX-39

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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