STRENGTHS AND LIMITATIONS OF THIS STUDY

This study is the first double-blind, randomised controlled trial to assess and compare the effects of cifropol and propofol on haemodynamic changes in patients undergoing bronchoscopy under general anaesthesia.

Data on haemodynamic effects (blood pressure and heart rate variability) and the incidence of injection pain and cough will be obtained.

The COVID-19 pandemic affected patient inclusion and increased the number of participating clinicians.

In view of limited resources, the follow-up period will be the interval from awakening from anaesthesia to 24 hours after bronchoscopy.

Introduction

Flexible bronchoscopy is a valuable tool for diagnosing and treating bronchial, lung and pleural diseases.1 Bronchoscopic examinations are performed while the patient is awake, potentially causing violent coughing and near-death attacks.2 Owing to the strong discomfort associated with endoscopic treatment and the proposal to provide comfortable treatments, the demand for painless bronchoscopy has been growing annually.

Bronchoscopic examination under general anaesthesia has improved over the years, enabling patients to complete the examination without discomfort.3 However, because of the short operation time, severe cough reflex and functional decline associated with older age, anaesthesiologists often need to deepen anaesthesia rapidly during bronchoscopy to minimise violent coughing. Nonetheless, patients may present high blood pressure fluctuations, which increase the risk of cardiovascular and cerebrovascular events and pose substantial challenges for anaesthesia application and management.

Propofol was approved for clinical use in 19864 and is widely used in outpatient and inpatient settings, including painless abortion,5 painless gastroscopy6 7 and painless bronchoscopy.8 However, the incidence of injection pain with propofol is 28%–90% in adults.9–11 Moreover, this intravenous anaesthetic is linked to cardiorespiratory depression, including hypotension, especially during bronchoscopy in elderly patients.12

The anaesthetics used during bronchoscopy should achieve rapid and deep anaesthetic induction, rapid awakening from anaesthesia, prevent drug accumulation and maintain haemodynamic stability. Consequently, there is an urgent need for anaesthetics and sedatives with high efficacy and few adverse effects.

Ciprofol (HSK3486), a novel 2,6-disubstituted phenol derivative, is a short-acting γ-aminobutyric acid (GABA) receptor agonist that is more potent than propofol. The mechanism of action of Ciprofol involves enhancing GABA-mediated chloride influx, leading to sedation or anaesthesia. Ciprofol has several advantages including (1) rapid onset of action, time of induction similar to that of propofol (1.09 vs 1.13 min) and an awakening time of 3 min; (2) an anaesthetic/sedative effect that is 4–5 times higher than that of propofol, reducing the need for anaesthetic drugs; (3) fewer respiratory adverse events (AEs) than propofol (p=0.0172); and (4) a lower rate of injection pain than propofol (4.9% vs 52.4%).13 Furthermore, ciprofol has good anaesthetic characteristics, high efficacy and safety and can achieve rapid induction and awakening from anaesthesia.14–16 However, these findings are limited to healthy individuals, patients undergoing elective surgery and those patients undergoing colonoscopy or gastroscopy.17 In only two studies, a brief mention was made that patients in the ciprofol group exhibited more stable haemodynamics compared with the propofol group.18 19 The effects of ciprofol and propofol on blood pressure and heart rate variability in patients undergoing bronchoscopy under general anaesthesia have not been assessed.

This study is designed to assess and compare the effects of ciprofol and propofol on haemodynamic changes in patients undergoing bronchoscopy under general anaesthesia. The primary outcomes are changes in heart rate and blood pressure in the two groups before and after induction, laryngeal mask airway (LMA) placement and endotracheal tube placement. Based on previous research, we postulate that the influence of an equivalent dosage of ciprofol on haemodynamic changes might be more advantageous compared with that of propofol in patients undergoing bronchoscopy under general anaesthesia.

Methods and analysisTrial design

This is a prospective, double-blind, randomised, positive-controlled clinical trial. It will commence in August 2022 and is planned to be completed within 2 years.

The cohort will be randomised into two groups (propofol and ciprofol) in a 1:1 ratio. This study comprises four periods: screening (days 1 and 2 before anaesthesia), preparation (day 1 before anaesthesia), induction of anaesthesia (day 0) and follow-up (interval from awakening from anaesthesia to 24 hours after bronchoscopy). Table 1 shows the time points in detail.

Table 1

Timetable of the study period

Study setting

This study will be conducted at the Department of Anaesthesia and Perioperative Medicine, Shanghai Fourth People’s Hospital, which has extensive experience in anaesthesia management, total intravenous anaesthesia and LMA management.

Eligibility criteria

Participants undergoing bronchoscopy with an LMA under general anaesthesia

Age of 18–80 years.

ASA (American Society of Anaesthesiologists) grade I–III.

Body mass index of 18–30 kg/m2.

Respiratory frequency of 10–24 breaths per minute during screening and preparation, SpO2 ≥93%, systolic blood pressure ≥90 mm Hg, diastolic blood pressure ≥55 mm Hg and heart rate of 50–100 beats per minute.

Ability to understand the study procedures and methods, provide written informed consent and comply with the clinical research protocol.

Sample size calculation

The incidence of hypotension using propofol for general anaesthesia and sedation is 36% to 43.3% (average 39.65%).20 21 Assuming an α-value of 0.05 with a statistical power of 90% and a relative risk of 0.5 or lower for decreasing in the incidence of hypotension in ciprofol group versus propofol group. Considering a potential dropout rate due to possible AEs and serious adverse events (SAEs) at around 10%, we estimated that each group should have a sample size close to 121 participants. To obtain more accurate experimental results, an integer value of 125 was chosen for each group simultaneously. Thus, a total of 250 patients will be enrolled in this study.

Randomisation and blinding

Participants will be assigned to one of the two groups (propofol and ciprofol, 1:1 ratio) using a computer-generated random number table by the allocation manager, who will store the randomisation table. Patients will be informed preoperatively that they will be randomly assigned to either group. The randomisation numbers will only be provided to a specific nurse who will prepare the study medicine in a closed room until the end of the trial and will not be involved in data analysis. Patients, anaesthesiologists, surgeons, data collectors, independent statisticians and evaluators were independent of patient allocation. The grouping information was known only by the allocation manager and the specific nurse. Independent statisticians will solely focus on medicine efficacy without knowing any allocation information. The evaluators would not have access to unblock the blinding.

Data management and monitoring

All information generated during the study will be anonymised. The principal investigator will take responsibility for data management as well as checking data accuracy. The research would also be managed and monitored by a specific steering committee at the Department of Anaesthesia and Perioperative Medicine.

Study intervention

Patients in the propofol group will receive 200 mg/20 mL of propofol (2 mg/kg) by intravenous injection within 30 s. Patients in the ciprofol group will receive 40 mg/20 mL of ciprofol (0.4 mg/kg) by intravenous injection within 30 s.

None of the patients will be medicated before bronchoscopy, and the peripheral vein will be routinely cannulated before anaesthesia induction. Non-invasive blood pressure, electrocardiographic parameters, respiratory rate, heart rate and pulse will be measured at 1 min intervals.

At the beginning of general anaesthesia induction, intravenous cisatracurium (0.05 mg/kg), sufentanil (0.2 µg/kg) and an anaesthetic (propofol (2 mg/kg) or ciprofol (0.4 mg/kg)) will be injected while the patients receive 100% oxygen through a mask at a rate of 2 L/min, with a respiratory rate of 12 breaths per minute and tidal volume of 6 mL/kg. The LMA will be inserted 3 min later. An additional anaesthetic (0.1 mL/kg) may be administered 1 min before the bronchoscope enters the glottis through the LMA. Propofol (4–12 mg/kg/hour) and remifentanil (0.05–2 µg/kg/min) will be administered for anaesthesia maintenance.

Ephedrine (6–12 mg) or phenylephrine (20–100 µg) may be administered intravenously if the blood pressure drops lower than 20% of the baseline value during induction and maintenance. Additional test drugs (ciprofol or propofol) (2–4 mL/time) may be administered if the heart rate or blood pressure increases by 20% of the baseline. Propofol (1 mg/kg) may be administered if the repeated use of anaesthetics (≥3 times) does not achieve adequate sedation. Atropine (0.3–0.5 mg) may be administered intravenously if the heart rate is lower than 50 beats per minute. The flow chart of this trial is represented in figure 1.

Figure 1

The flow chart of this trial.

Primary and secondary outcomesPrimary outcomes

The primary outcomes are changes in heart rate and blood pressure in the two groups before and after induction, LMA placement and endotracheal tube placement.

Secondary outcomes

The secondary outcomes are as follows:

Incidence of coughing and injection pain (the assessment of injection pain includes the observation of vocal responses, facial expressions indicative of discomfort, withdrawal of the arm, presence of tears and instances where the patient sought clarification or expressed discomfort verbally）.

Type and dosage of intraoperative vasoactive drugs.

The postoperative degree of satisfaction of surgeons, anaesthesiologists and patients.

The duration from the end of the procedure to extubation and the total procedure duration.

Statistical analysis

Statistical analysis will be performed using SPSS V.27.0 (IBM Corporation, Armonk, NY, USA). Baseline data are defined as clinical data collected before the first intervention. Normally distributed continuous variables will be analysed using a t-test and expressed as mean and SD, median, minimum and maximum. Non-normally distributed continuous variables will be analysed using the Mann-Whitney U test. Categorical variables will be expressed as frequency and percentage. A p value of <0.05 will be considered statistically significant. For missing data, we have no imputation plans.

Adverse events and serious adverse events

AEs are any unpredictable or unfavourable clinical outcomes resulting from medical interventions during the study period. The principal investigator will enter data on the occurrence time, severity, duration and management of these events into the AEs record form. The AEs are classified into five categories according to the Common Terminology Criteria for AEs V.5.0 (CTCAE vs 5.0). Anaphylaxis is a potential AE in this study that will be systematically collected. All AEs should be followed up until they are properly resolved or the clinical condition is stable. A SAE is defined as an event resulting in death, prolonged hospital stays, disability, lethal reaction or teratogenicity. The principal investigator will report all harms to the hospital anaesthesia department and clinical research ethics committee within 24 hours after the occurrence.

Plans for communicating important protocol amendments to relevant parties

This protocol was approved by the Medical Ethics Committee of Shanghai Fourth People’s Hospital and registered in the Chinese Clinical Trials Registry (ChiCTR2200063048). All revisions and adjustments were submitted to the ethics committee before the approval of the study.

Patient and public involvement

Discussion

Owing to the severe cough reflex caused by traditional bronchoscopy, painless bronchoscopy is becoming increasingly popular. Anaesthesiologists are required to deepen anaesthesia quickly. However, propofol is associated with high blood pressure variability, cardiorespiratory depression and injection pain, increasing surgical risk, especially among older patients with systemic diseases.

Ciprofol, a novel 2,6-disubstituted phenol derivative used clinically for the induction and maintenance of general anaesthesia, was first marketed in December 2020. The advantages of this anaesthetic over propofol are a faster onset of action, higher potency, reduced central cardiorespiratory depression and reduced injection pain. Ciprofol completed phase 1a and 1b clinical trials in Australia22 and has entered a phase 3 trial in China.23 However, the haemodynamic effects and pain associated with the injection of ciprofol during bronchoscopy have not been assessed.

To address the aforementioned drawbacks, combination drug applications have emerged. For instance, using ketamine and propofol together during flexible bronchoscopy under local anaesthesia has been shown to enhance comfort and efficacy, reduce complications and improve patient tolerance.24 Additionally, recent studies have indicated that during flexible bronchoscopy, the combined use of esketamine and propofol, compared with remifentanil, can reduce the required dosage of propofol. This combination results in more stable intraoperative haemodynamics, a lower incidence of AEs and higher satisfaction among the performing physicians.25 However, the disadvantages of combination drug therapy include the potential for increased complexity in dosing and monitoring, the risk of drug interactions and the possibility of compounded side effects. Therefore, ciprofol has emerged as a solution. This study exhibits certain limitations. First, it was conducted at a single medical centre, thereby presenting constraints on sample representation. This may potentially lead to an oversight of population heterogeneity, limiting the broader applicability of the results to a specific medical environment. To enhance the study’s robustness, future research endeavours should consider multi-centre collaborations. This approach would not only address the current limitations related to sample representation but also facilitate a more diverse participant pool, improving the generalisability of outcomes. Second, gender differences and their potential impact on experimental outcomes were not discussed separately in this study, representing another limitation. Finally, considering the ageing population in our country, the inclusion age range was set from 18 to 80 years. However, this may introduce a potential bias toward the elderly population. Therefore, in subsequent data analyses, we plan to conduct age-based subgroup analyses (18–65 years and 65–80 years) for a more rigorous examination of the experimental results.

This study is the first prospective, double-blind, randomised controlled trial to assess and compare the effects of ciprofol and propofol on haemodynamic changes in patients undergoing bronchoscopy under general anaesthesia. We hope that it will provide evidence for the safe use of ciprofol during bronchoscopy.

Ethics and dissemination

This trial was approved by the Medical Ethics Committee of Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, and registered at the Chinese Clinical Trials Registry (Identifier: ChiCTR2200063048) on 29 August 2022. The findings of this study will be disseminated through multiple channels. Academic dissemination will include publication in peer-reviewed journals and presentations at national and international conferences

Ethics statementsPatient consent for publication

Consent obtained directly from patient(s).