Strengths and limitations of this study

This is the first non-inferiority trial to investigate haemodynamic fluctuations during anaesthesia induction in patients undergoing cardiac surgery using remimazolam tosylate or etomidate.

The participants will be specifically patients undergoing off-pump coronary artery bypass grafting where maintaining haemodynamic stability is critical and challenging.

General anaesthesia will be maintained with either remimazolam tosylate or propofol and the postoperative cognitive function of the patients will be evaluated.

A potential limitation is that the study will employ a single-blind design where the attending anaesthesiologist is not blinded to the investigational drugs for patient safety while blinding of other investigators will help reduce potential bias.

Introduction

With increasing morbidity associated with coronary artery disease (CAD), ischaemic heart disease has become the second leading cause of mortality among the general population in China.1 Despite the increasing popularity of percutaneous coronary intervention, coronary artery bypass grafting (CABG) remains the preferred treatment for complex, severe and multivessel CAD. The compromised coronary perfusion and diminished cardiac reserve function make it crucial but challenging to maintain haemodynamic stability during anaesthesia induction. Furthermore, manipulation or compression of the heart significantly disturbs the haemodynamics during off-pump CABG (OPCABG) surgery, presenting a substantial challenge for haemodynamic management.

Its minimal direct inhibitory effects on myocardial contractility make etomidate the most commonly used inducing agent for general anaesthesia (GA) in critically ill patients. However, etomidate has obvious side effects such as injection site pain and myoclonus. Specifically, its suppressive effect on adrenal cortex function severely restricts its use in anaesthesia maintenance.

Remimazolam tosylate, a novel benzodiazepine sedative, is an ultra-short-acting agonist of γ-aminobutyric acid subtype A receptor with the properties of fast onset and offset and minimal depression of cardiovascular and respiratory function.2 3 The safety and efficacy of remimazolam have been tested in sedation for bronchoscopy and anaesthesia induction in American Society of Anaesthesiologists (ASA) Class III patients and the findings indicated fewer adverse effects during induction than with propofol.4–6 Recently, several case reports and randomised controlled trials have focused on haemodynamic changes during anaesthesia induction with remimazolam tosylate for cardiopulmonary bypass surgery compared with propofol or etomidate.7 8 However, these conclusions are controversial and are insufficient to draw any non-inferior conclusions regarding haemodynamic fluctuations during anaesthesia induction. This protocol outlines the design of a single-centre, non-inferiority, randomised controlled trial aimed at assessing the efficacy and safety of remimazolam tosylate for the induction and maintenance of GA in patients undergoing OPCABG. We hypothesised that haemodynamic stability during anaesthesia induction using remimazolam tosylate is non-inferior to that of etomidate.

Methods and analysisPatient and public involvement

Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of this research.

Trial design

This is a randomised, controlled, surgeon and patient-blinded, non-inferiority trial with two parallel groups to compare the efficacy and safety of remimazolam tosylate and etomidate for the induction and maintenance of anaesthesia in patients undergoing OPCABG. Patients will be randomly assigned to either the remimazolam tosylate group (Group R) or the etomidate group (Group E) in a 1:1 ratio. The study protocol conforms to the SPIRIT 2013 (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Recruitment for the trial commenced in January 2024 and the study is scheduled to be completed by November 2024. The study design is illustrated in figure 1.

Figure 1

Flow diagram of the trial design.

Study setting

This single-centre study will be conducted in a teaching hospital at Zibo Central Hospital (Zibo, China).

Participants

Life expectancy in mainland China is expected to increase to 81.3 years by 2035.9 An increasing number of elderly people are undergoing CABG at present. Taking this into consideration, we will set the inclusion age cut-off value at 75 years old for this study. Patients scheduled to undergo elective OPCABG at Zibo Central Hospital aged 18–75 years old will be recruited for this study.

Inclusion criteria

Aged 18–75 years old.

Patients scheduled to undergo OPCABG.

ASA physical status II–III.

Body mass index 18–30 kg/m2.

Written informed consent was obtained from the patients or their legal representative.

Exclusion criteria

Severe arrhythmia including severe sinus bradycardia (heart rate, HR≤50 beats per minute), atrial fibrillation, third-degree atrioventricular block, frequent atrial premature beats and frequent ventricular premature beats.

Uncontrolled or poorly controlled hypertension (systolic blood pressure, SBP≥180 mm Hg and/or diastolic blood pressure, DBP≥110 mm Hg).

Abnormal liver or kidney dysfunction (Child-Pugh class B or C, blood urea nitrogen exceed 1.5 times the upper limit of the medical reference value and/or creatinine exceeds the upper limit of the medical reference value.

Adrenal cortical dysfunction (serum cortisol<3 µg/dL).

Allergy to the investigational drugs such as remimazolam tosylate, etomidate, rocuronium.

Taking sedatives, hypnotics, antidepressants.

History of drug abuse, alcoholism.

Myasthenia gravis.

Patients with schizophrenia, severe depression, cognitive impairment and inability to communicate.

Other patients were deemed unsuitable for inclusion by the investigators.

Patients with acute myocardial infarction, a severe decrease in ejection fraction (EF, <30%), or severe valvular disease are not eligible to participate in the trial because their ASA physical status is classified as grade IV.

Interventions

All patients will be required to fast for at least 8 hours before surgery and will receive premedication with intramuscular morphine 50–100 mg. On arrival in the operating room, 100% oxygen will be administered through a face mask and monitored for non-invasive blood pressure, 5-lead ECG, pulse oxygen saturation (SpO2) and bispectral index (BIS). A 20-gauge intravenous catheter will be placed in the forearm for fluid administration at 6–8 mL/kg/hour and a 22-gauge arterial puncture needle will be inserted into the right radial artery under local infiltration anaesthesia using lidocaine for continuous invasive blood pressure monitoring.

Group R will receive 0.2 mg/kg remimazolam tosylate intravenously for anaesthesia induction whereas Group E will receive 0.3 mg/kg of etomidate. Intravenous remimazolam tosylate or etomidate should be administered slowly for approximately 1 min. Subsequently, all patients in both groups will receive a slow intravenous injection of 1.0 mcg/kg sufentanil. Once the BIS value reaches≤70, 0.6–1.0 mg/kg of rocuronium will be administered. 5 min after the induction begins, when the BIS value is≤60 and the muscle relaxation criteria are met, endotracheal intubation will be performed. If the BIS value is still>60, patients in Group R will receive an additional dose of 0.05 mg/kg of remimazolam tosylate while Group E will receive an additional dose of 0.05 mg/kg of etomidate. The BIS value will be reassessed 2 min later and further injections of the same hypnotic agent may be performed if deemed necessary. In the case of a significant decrease tendency in SBP or SBP decreases>20% baseline during induction, a bolus injection of 40–100 mcg phenylephrine will be administered intravenously to maintain SBP within±30% of the baseline and≥90 mm Hg. After completion of the induction process, a central venous catheter will be inserted into the right internal jugular vein to measure the central venous pressure and administer vasoactive drugs.

Anaesthesia will be maintained using total intravenous anaesthesia. Group R will receive a remimazolam tosylate infusion of 0.2–2.0 mg/kg/hour while Group E will receive a propofol infusion of 4–10 mg/kg/hour. The infusion rates of remimazolam tosylate or propofol will be adjusted based on BIS monitoring to maintain BIS values between 40 and 60. The maximum infusion rate for remimazolam tosylate should not exceed 2 mg/kg/hour. Otherwise, sevoflurane inhalation or propofol infusion will be administered as an alternative which is deemed a failure of anaesthesia induction. Both groups will receive continuous infusion of sufentanil at 0.6 mcg/kg/hour and rocuronium at 0.5 mg/kg/hour.

Anaesthesia maintenance will be supervised by the attending anaesthesiologist, ensuring that the HR and SBP remain within±30% of the baseline values. Before the start of surgery, all patients have transoesophageal ultrasound probes inserted to continuously assess ventricular function and cardiac filling. To maintain haemodynamic stability, fluid infusion, blood transfusion and vasoactive agents will be used as necessary according to the patient’s circulatory status as guided by intraoperative transoesophageal echocardiography.

Following endotracheal intubation, mechanical ventilation will be initiated to maintain the end-tidal carbon dioxide level between 35 and 45 mm Hg. Heated transfusion and warming blankets will be used to maintain the nasopharyngeal temperature within 36.0–37.5°C.

All patients will be transferred to the intensive care unit (ICU) with a tracheal cannula.

Outcomes and measurementsPrimary outcome

The primary outcome will be the haemodynamic changes during the anaesthesia induction period (from the initiation of GA induction to 5 min after tracheal intubation), represented by ΔMAP (the difference between the maximum and minimum mean artery pressure (MAP) observed during anaesthesia induction).

Secondary outcomes

Adverse events (AEs) and adverse drug reactions (ADRs). AEs include hypotension, hypertension, bradycardia, tachycardia, awareness or recall during surgery and postoperative delirium (POD) within 7 days after surgery while ADRs include injection site pain and myoclonus.

Total dosage of vasoactive drugs administered during anaesthesia induction and maintenance.

Vital signs and BIS values at different time points.

Lengths of postoperative mechanical ventilation and tracheal intubation, lengths of ICU stay and hospital stay.

Hospital mortality.

Definition and management of AEs and ADRs

Hypotension, defined as SBP<90 mm Hg or SBP decrease>30% from baseline for at least 2 min, should be managed as follows by the judgement of the attending anaesthetist: Increasing the fluid infusion rate of fluids; infusion of norepinephrine (0.02–0.1 mcg/kg/min) and/or dopamine (3–6 mcg/kg/min); intravenous injection of epinephrine 40–100 mcg as needed.

Hypertension, defined as SBP>160 mm Hg or SBP increase>30% from baseline for more than 5 min, should be conducted as follows: Adjusting the infusion rate of nitroglycerin (0.1–5.0 mcg/kg/min), intravenous injection of diltiazem 2–5 mg if necessary.

Severe bradycardia, defined as HR<45 bpm for at least 30 s, should be treated with an intravenous injection of 0.3 mg atropine.

Tachycardia, defined as HR>100 bpm, should be managed with an intravenous injection of 20–30 mg esmolol.

Injection site pain will be classified as follows: 0 points, no pain, no pain reported on enquiry; 1 point, mild pain, pain reported only on enquiry without injection-related facial expression or body movement; 2 points, moderate pain, pain reported with injection-related facial expression or body movement on enquiry or spontaneously reported pain during injection; and 3 points, severe pain, loud vocalised pain or severe facial expression, upper limb withdrawal response or tearing during injection.10

Myoclonus refers to sudden, brief and involuntary muscle jerks that can occur irregularly or rhythmically.

Intraoperative awareness and recall will be assessed using the Brice Questionnaire after discharge from ICU.11

POD will be assessed using 3D-CAM within 7 days after surgery.12

Participant timeline

The timeline of enrolment, allocation, intervention, assessment and visits for the participants is shown in figure 2.

Figure 2

Schedule of enrolment, interventions and assessments. ADRs, adverse drug reactions; AEs, adverse events; BIS, bispectral; MAP, mean artery pressure; POD, postoperative delirium.

Sample size

The size of the sample was calculated based on the primary outcome which is the ΔMAP during the induction of anaesthesia. A pilot trial involving 20 patients was conducted which showed that the ΔMAP in Group E and Group R was 25.70±8.30 mm Hg and 26.40±7.63 mm Hg, respectively. Assuming that a ΔMAP value 1/5 higher than the mean of Group E would not have clinical significance during anaesthesia induction, we selected 5.1 as the non-inferiority margin (δ). To attain a statistical power of 0.80 and with a one-sided type I error rate of 0.025, taking into account a 10% dropout rate, 88 patients should be recruited.

Randomisation and blinding

After signing written informed consent forms (online supplemental file 1), patients will be randomly assigned to either Group R or Group E in a 1:1 ratio according to a computer-generated randomisation schedule. Randomisation will be performed by a special researcher using SPSS software. Allocation information will be concealed in sequentially numbered opaque envelopes and a nurse will open the envelope and prepare the investigational drugs after the patient arrives at the operating room.

Patients, surgeons, care providers in the ICU and ward, outcome assessors, postoperative data collectors, data analysts and the principal investigator (PI) will be blinded to group allocation. To ensure patient safety, the attending anaesthetist and nurse will not be blinded to the assignment. The attending anaesthetist will be responsible for performing interventions and anaesthesia management while the nurse will accurately record the administration of drugs and the corresponding time points in the anaesthesia record. A researcher who is unaware of the allocation will subsequently feed the data to the case report form (CRF) from the anaesthesia record with concealed investigational drug information.

Data collection

Data collection will be divided into three periods: Preoperative, intraoperative and postoperative.

Preoperative data

Patient demographic information.

Preoperative information: Blood pressure, HR, grade of coronary artery stenosis on coronary angiography, left ventricular EF on echocardiography, ASA physical status, New York Heart Association functional classification, Mini-Mental State Examination score13 and preoperative medications.

Comorbidities: Hypertension, diabetes, respiratory diseases.

Preoperative examination results: Routine blood examinations, liver and kidney function tests, pro-B-type natriuretic peptide (BNP) and blood gas analysis.

Intraoperative data

Intraoperative vital signs: Blood pressure, HR, blood SpO2 and BIS values.

Dose of vasoactive drugs administered: Epinephrine, norepinephrine, dopamine, nitroglycerin, atropine, atenolol and urapidil.

Intraoperative AEs: Hypotension, hypertension, severe bradycardia, tachycardia.

Intraoperative ADRs: Injection pain, myoclonus.

Operative and anaesthetic duration, intraoperative blood and fluid transfusion volume, intraoperative blood loss, intraoperative urine output and number of grafts.

Postoperative data

Intraoperative awareness or recall.

POD was assessed using 3D-CAM within 7 days after surgery.

Postoperative pulmonary infection.

Length of postoperative mechanical ventilation and tracheal intubation, length of ICU stay and length of hospital stay.

Hospital mortality.

Data management

The study data obtained from electronic medical records, electronic anaesthesia records and specially designed paper CRFs will be summarised in a trial database. The participant files will be stored for a period of 3 years after trial termination. Two specialised trained nurses will record the data using a password-protected electronic data capture system with confidential participant identity information. Six months after the trial’s termination, the trial data will be uploaded to the original ResMan clinical trial data-sharing platform.

Statistical methods

Analyses will be conducted using both intention-to-treat and per-protocol approaches. The statistical software SPSS V.25.0 (IBM Corporation, Armonk, New York, USA) will be used for the analysis. Quantitative data will be presented as either mean±SD or median (25th and 75th percentile) depending on the normality or non-normality of distribution and will be tested using Student’s t-test or the Mann-Whitney U test as appropriate. Qualitative data will be compared using the Pearson χ² test or Fisher’s exact test as appropriate. The effects of treatment, time and interaction will be analysed using repeated-measures analysis of variance for vital signs and BIS values. Non-inferiority testing of the primary outcome will be conducted by comparing the 95% CI of the ΔMAP difference between groups to the non-inferiority margin of 5.1 mm Hg. A one-sided p<0.05 for the primary outcome and two-sided p<0.05 for the others will be considered statistically significant.

Data monitoring

An impartial data monitoring committee (DMC) comprising five members with no conflicts of interest has been established. The scientific research office of Zibo Central Hospital will oversee the implementation of the study. The PI, DMC and institutional scientific research office will jointly assume the responsibility for data and safety monitoring.

Ethics

The study protocol has been approved by the Medical Ethics Committee of Zibo Central Hospital (No. 202401) and registered in the Chinese Clinical Registry. Participants will be given a written study design and oral explanation and will be required to sign an informed consent form. Trial methods and results will be reported in accordance with the 2010 Consolidated Standards of Reporting Trials guidelines.14

Trial status

This protocol is version 1.1. At the time of the manuscript submission, the trial is in the participant recruitment phase.

Discussion

To the best of our knowledge, this trial will be the first non-inferiority randomised controlled trial to focus on the effects of remimazolam tosylate versus etomidate for both anaesthesia induction and maintenance in patients undergoing OPCABG. The results of this study will provide insights into whether remimazolam tosylate is non-inferior to etomidate in terms of maintaining haemodynamic stability during the induction phase and whether there are differences in postoperative cognitive function between patients undergoing remimazolam-maintained GA and those receiving propofol.

CABG can be performed with or without cardiopulmonary bypass and numerous studies have shown that OPCABG is associated with a reduced risk of morbidity and mortality.15–17 By contrast, a beating heart with compromised coronary perfusion and limited cardiac function is responsible for maintaining blood pressure and systemic perfusion throughout the surgical procedure. This makes it crucial and challenging to maintain haemodynamic stability during GA induction and maintenance.

Etomidate, known for its minimal circulatory suppression, is the most commonly used induction agent for GA in critically ill patients. However, its suppressive effect on the adrenal cortex function severely limits its use in anaesthesia maintenance. Therefore, propofol has become a commonly used sedative for the maintenance of anaesthesia. Unfortunately, propofol reduces systemic vascular resistance, suppresses myocardial contractility and subsequently lowers SBP. Additionally, concerns regarding lipid accumulation and propofol infusion syndrome limit its long-term infusion applicability.18 In the 1980s, midazolam was used for anaesthesia induction in cardiac surgery and demonstrated mild cardiovascular depression.19 20 However, a critical evaluation emerged simultaneously owing to the high variability in drug responses and the slow onset and offset of midazolam.21

This novel ultra-short-acting sedative, remimazolam, offers an opportunity for benzodiazepine-based anaesthesia. Remimazolam inherits the property of mild cardiovascular depression from traditional benzodiazepine drugs and exhibits rapid onset and fast offset characteristics making it an ideal candidate for anaesthesia in patients undergoing cardiac surgery. Hu et al 8 compared remimazolam and etomidate on haemodynamics during anaesthesia induction in selective valve replacement surgery. The results demonstrated that the high-dose remimazolam group (0.3 mg/kg) presented greater haemodynamic fluctuations compared with the etomidate group (0.3 mg/kg) while the low-dose group (0.2 mg/kg) exhibited similar haemodynamic fluctuations as the etomidate group. Remimazolam was not used for anaesthesia maintenance in this trial and there is currently limited clinical research on remimazolam for anaesthesia maintenance. POD is a primary concern when using remimazolam to maintain anaesthesia. Aoki22 investigated POD in older patients undergoing cardiovascular surgery who received remimazolam in GA and reported that remimazolam was not significantly associated with POD compared with other anaesthetic agents. However, in this study, patients in the remimazolam group received remimazolam but remimazolam was not maintained. The association between remimazolam maintenance anaesthesia and POD remains unclear.

This carefully designed prospective trial will focus on two main objectives: (1) to compare the haemodynamic fluctuations produced by remimazolam tosylate and etomidate during GA induction in patients undergoing OPCABG and (2) to assess the difference in 7-day POD incidence between remimazolam maintenance GA and propofol.

There are some inevitable limitations in this study. First, it will be a single-blinded trial. This is primarily due to considerations of patient safety during the intraoperative period as the attending anaesthesiologist will not be blinded to the investigational drugs. However, the blinding of the other investigators involved in this study will help mitigate potential bias. Second, the accuracy of BIS in monitoring the depth of anaesthesia induced by benzodiazepines remains controversial. Predominant beta activation in the frontal areas produced by benzodiazepines will relatively increase BIS values.23 On the other hand, combining remimazolam with opioids may enhance BIS depression.24 Therefore, postoperative investigation of intraoperative awareness and close monitoring of vital sign changes during surgery to help assess the depth of anaesthesia is of great importance. More clinical trials are needed to determine the feasibility of using remimazolam as the main sedative in GA.

In summary, this is the first non-inferiority trial comparing the haemodynamic changes during anaesthesia induction with remimazolam tosylate and etomidate in patients undergoing OPCABG. Additionally, the study will investigate the postoperative cognitive function of patients who underwent anaesthesia maintenance with remimazolam tosylate. The trial results are expected to provide compelling evidence for the selection of new sedative drugs for OPCABG surgery.

Ethics statementsPatient consent for publication

Not applicable.

Acknowledgments

We would like to thank all the participants willing to participate in this study and Editage (www.editage.com) for English language editing.