Aim of the study
This study mainly aims to investigate whether obstructive jaundice affects the pharmacodynamics of remimazolam, and the sensitivity of remimazolam increases among icteric patients.
The study is designed as a prospective, controlled, multicenter trial. It is reported following the SPIRIT reporting guidelines . The sponsor of this trial is the Department of Anesthesiology, Shidong Hospital of Shanghai, University of Shanghai for Science and Technology. The sponsor is responsible for the design, collection, management, analysis, interpretation of data, writing, and the decision to submit the report for publication. The study is supported by the Yangpu District Good-Doctor Program funding. Figure 1 shows the SPIRIT checklist that we follow in this report.
Number of patients needed
We plan to divide the patients into obstructive jaundice group (total bilirubin (TBL) value > 17.1 μmol/L) and control group (TBL < 17.1 μmol/L) based on their diagnosis and TBL value. The primary endpoint is the difference in the requirement of remimazolam.
Group sample size was calculated based on differences in remimazolam requirement to reach BIS 50 in our previous study, in which the mean remimazolam requirement was 0.13±0.04 mg/kg (n = 6) in the obstructive jaundice group and 0.16±0.04 mg/kg (n = 6) in the non-obstructive jaundice group, The following formula: n = 15.7/ES2 + 1, where ES = effect size = (difference between groups)/(mean of the SD between groups), with α = 0.05 and power = 0.8 was used to determine that the study would be adequately powered with n = 29 per group. Considering a dropout rate of 10%, the estimated sample size will be at least 32 patients per group, thus a total of 64 patients will be needed.
The study takes place at three centers: the Department of Anesthesiology, Shidong Hospital of Shanghai, University of Shanghai for Science and Technology; Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University and the Department of Anesthesiology, Changzhen Hospital, Second Military Medical University beginning March 2021 to March 2022. Eligible patients for participation in this clinical trial are 32 patients with obstructive jaundice (serum TBL > 17.1 μmol/L) secondary to neoplasm of the bile duct or the head of the pancreas and 32 non-jaundiced patient controls with chronic cholecystitisor intrahepatic bile duct stones. All patients enrolled in this clinical trial are aging 40 to 75 years, American Society of Anesthesiologists (ASA) grade I to III, and given written informed consent, who are scheduled to undergo surgery under sedation with remimazolam.
Patients are excluded whose medical history appear the following criteria:
- Age range < 40 years or > 75 years
- ASA physical status IV or V
- weight beyond ± 20% of ideal
- Allergic reaction to planned medication
- History of psychological problems or psychiatric disease
- Using any form of analgesic or neuromodulating medications
- known or suspected cardiac, pulmonary, renal, or metabolic disease
The schedule of enrollment, intervention, and assessment is reported according to the SPIRIT statement (Fig 1).
The number of excluded patients and the reasons for their exclusion will be reported according to the SPIRIT statement.
Written consent was obtained from all patients. The patient's history and current health status are screened during the standard anesthesia evaluation before the surgery. The investigators use anaesthesia pre-assessment sheets to screen patients for inclusion and exclusion criteria. Inclusion will not be finalized until the patient signs the informed consent on the day of surgery.
If patients refuse to participate in the study, they will be sedated with propofol according to anesthetic standards. The investigator or physician who examines the subject may decide to remove the subject from the study if the subject has an emergency medical problem (allergic reaction or acute health problem).
Patients are assigned to the obstructive jaundice group or the control group based on TBL values after they sign the informed consent form. Patient data are collected on case report forms (CRFs) in each center. Because obstructive jaundice is easy to distinguish from the appearance of skin color, it is difficult to be double-blind. However, the anesthesiologist assistant is blind to the grouping or induction method, but only records the data through a local area network (LAN) in the next room.
After 8 hours of fasting, the patients without premedication will be brought into a quiet operating room where a cannula was inserted into right internal jugular vein under local anesthesia for infusion of remimazolam and liquid. Radial artery catheterization was placed to measure invasive arterial blood pressure. Heart rate (HR), invasive blood pressure (IBP), electrocardiogram (ECG), and end-tidal carbon dioxide (ETCO2) and oxyhemoglobin saturation (SpO2) are routinely monitored during the whole process of research (Philips HP Viridia24/26 M1205A). Apply the BIS sensor (BIS™XP sensor) as recommended by the manufacturer. The patients are asked to keep their eyes closed and covered with gauze to avoid any interference with sound and light stimulation. The temperature of the room is controlled at 23℃.
The study is designed to record remimazolam requirement with BIS of 50 as the end point. The patients will be treated with remimazolam at a rate of 0.03 mg/kg/min by a Graseby 3500 syringe pump (SIMS Graseby Ltd., Herts, UK) till the BIS is ≤50 longer than 5 seconds. The assistant anesthesiologist, who is not aware of the study group, observes vital signs and BIS values in the next room via the LAN, determines the end point of titration, and records the dosage of remimazolam used and the time interval between the start and end of the infusion. Then the patients will be given 0.4-0.6 μg/kg sufentanil and 0.2mg/kg cisatracurium, and endotracheal intubation will be performed 3 minutes later for anesthesia induction. Anesthesia is maintained with sevoflurane (1.5%–2.5%) at an appropriate standard for surgical procedure. Hemodynamic data are collected and recorded at relevant points during the perintubation period.
Make sure that emergency equipment is working throughout the process. If spontaneous ventilation is insufficient (SpO2 < 92%), auxiliary mask ventilation is given to patients when necessary to maintain ETCO2 between 34-45mmHg. Cardiovascular events should be handled promptly, with 5-15mg ephedrine given if the patient's blood pressure is below 60mmHg and 5mg atropine given if the patient's heart rate is below 50 bpm.
Definition of primary endpoint
The primary endpoint of the study - reflecting the change of sensitivity of remimazolam in patients with obstructive jaundice - is remimazolam requirement with BIS of 50 as the end point.
Assessment of primary endpoint
We will record the requirement of remimazolam and the time interval between the start and end of the infusion.
Definition of secondary endpoints
Secondary endpoints focus on hemodynamic stability and safety, which is reflected in the number of cardiovascular events and the average percent change to baseline in mean arterial pressure and heart rate.
Assessment of secondary endpoint
Hemodynamic data at the designated time points will be recorded during the perintubation period.
Before surgery, general information and the surgical methods of the patients are investigated, indexes such as TBL, bile acid, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and so on are recorded. The requirement of remimazolam till the patient's BIS value reaches 50 and the time interval from the start to the end of infusion are recorded. Pulmonary and cardiovascular vital signs are recorded electronically throughout the procedure, including SpO2 measured by a pulse oximeter, HR, IBP , RR and ETCO2.
Statistical analyses will be performed by an independent statistician using SPSS 19.0 statistical software. The measurement data of normal distribution will be presented as mean ± standard deviation. Independent sample T test or rank sum test will be used for comparison between groups. And multiple linear regression analysis will be used to test the relationship between the dosage of remimazolam and TBL, TBA, ALB, AST and ALT.
The trail is approved by the Committee on Ethics of Biomedicine Research, Shidong Hospital Affiliated to University of Shanghai for Science and Technology (YPSDKY2020-004-010). It is registered in the Chinese Clinical Trial Registry (ChiCTR2100043585. Date of registration: February 23, 2021. )