Safety and efficacy of remimazolam tosilate combined with low-dose fentanyl for procedural sedation in obese patients undergoing gastroscopy: study protocol for a single-centre, double-blind, randomised controlled trial

Introduction

Respiratory depression, airway obstruction and subsequent hypoxaemia commonly occur during painless gastrointestinal endoscopy in obese patients1–3 due to altered airway anatomy and respiratory insufficiency.1 4 5 Hypoxaemia is usually defined as peripheral pulse oxygen saturation (SpO2) less than 90%.5 The reported incidence of hypoxaemia ranges from 30.8% to 38.5%.1 6 Hypoxaemia is associated with several adverse events related to the heart and brain.7 Increased body mass index (BMI), greater than 30 kg×m–2, is frequently linked to obstructive or restrictive lung diseases, which can result in cardiopulmonary adverse events during procedural sedation.8–10 Sedatives can increase the probability of respiratory depression and further exacerbate hypoxaemia during procedural sedation due to airway obstruction, particularly in obese patients. Therefore, it is essential to optimise the sedation strategy when selecting a sedative agent for obese patients undergoing painless gastroscopy.

In China, propofol combined with low-dose opioids is commonly used as a sedation strategy for painless gastrointestinal endoscopy.7 11 12 Fentanyl is often used in combination with propofol to reduce the required dosage of each drug, reduce stress reactions and enhance pain management.13–15 Clinical practice guidelines recommend delaying propofol administration until after the anticipated peak effect of the administered opioid, allowing for the benefit of opioid analgesia while minimising the risk of respiratory depression and apnoea.15 Propofol is the first-line anaesthetic agent for procedural sedation but is prone to respiratory depression and haemodynamic instability depending on the injection rate and dose.16 17 However, it is worth noting that obese patients have a higher proportion of fat than muscle. Propofol is a lipophilic agent with a higher distribution volume in adipose tissue-rich individuals, resulting in greater potential for drug accumulation in the body and more frequent occurrence of propofol-related adverse events.18–20 Therefore, extra airway protection and adequate preoxygenation must be ensured when administering it to obese patients.21–23

Remimazolam, a novel ultra-short-acting benzodiazepine with rapid onset of action, rapid elimination and minimal haemodynamic effects,24 can present satisfactory sedative efficacy with a better safety profile than propofol.25 26 It has advantages in its application in vulnerable patients such as the elderly.27–29 Unlike other benzodiazepines, remimazolam is classified as a water-soluble ‘soft drug’30 with favourable liver and kidney safety profiles.31–35 It is rapidly hydrolysed into inactive metabolites by non-specific tissue esterase,30 35 resulting in minimal accumulative effects even during long-term or high-dose infusions. This contributes to accurate transitions between awake and sedated states rather than deep or prolonged sedation.36 37 In addition, it has an important protective effect on respiratory centre sensitivity,7 and its potential benefits have been demonstrated in patients with obstructive sleep apnoea-hypopnoea syndrome undergoing drug-induced sleep endoscopy.38 When combined with esketamine, it can prevent severe hypoxaemia in 10% of patients with obese patients undergoing painless gastrointestinal endoscopy.7 Thus, remimazolam appears to be an optimal and alternative sedative for obese patients.

Since morbidly obese patients are relatively contraindicated for moderate-deep sedation, this study will concentrate on subjects with mild-to-moderate obesity who are suitable candidates for the study design.39 Our pilot study has demonstrated that a sedation strategy combining remimazolam tosilate with low-dose fentanyl is viable for obese individuals undergoing painless gastroscopy. In this study, sedation depth will be guided during the procedure by using the Modified Observer’s Assessment of Alertness and Sedation (MOAA/S)40 scale and individualised reference Bispectral Index (BIS)-guided titration of sedatives (remimazolam and propofol).

Methods and analysis

Trial objective

This study aims to determine whether the usage of remimazolam tosilate instead of propofol, in combination with low-dose fentanyl, can be effective in reducing the incidence of hypoxaemia during painless gastroscopy in patients with mild-to-moderate obesity. Additionally, we anticipate that this optimal sedation strategy could reduce sedation-related adverse events and shorten the turnover time of procedural sedation, providing significant benefits to high-volume, fast-paced ambulatory endoscopy centres.

Study design

This study is an open-label, single-centre, randomised controlled trial (RCT) conducted at the Endoscopy Centre of the First Affiliated Hospital of Xiamen University. The study includes consenting participants who meet the predefined inclusion criteria, and they will be randomly assigned to either the intervention or control group in a 1:1 ratio. The study begins by administering a low-dose fentanyl intravenous injection to all patients. Remimazolam tosilate or propofol will be administered separately to the intervention and control groups until the MOAA/S scale (table 1) reaches 1. Thereafter, the procedure will be conducted with a stable sedation depth based on individualised reference BIS-guided titration of remimazolam and propofol. Following the examination, all patients will be transferred to the post-anaesthesia care unit (PACU) for resuscitation and will be allowed to discharge only when they have stable vital signs without any complications. The use of a combination of remimazolam tosilate and low-dose fentanyl is anticipated to effectively reduce the incidence of hypoxaemia. Figure 1 outlines the flow chart that will be followed during the study.

Figure 1
Figure 1

Flow chart of study process.

Table 1

Modified Observer’s Assessment of Alertness and Sedation

Participants

From November 2023 to June 2025, patients with mild-to-moderate obesity scheduled for painless gastroscopy will be recruited. The clinic handles a monthly volume of over 2000 patients undergoing painless gastroscopy, with the proportion of obese patients in this population exceeding 1%. Prior to the examination, all patients will undergo an evaluation, and receive education on the study objectives, procedures, potential risks and precautions at the anaesthesiology clinic. All participants will only be granted following written informed consent. Participants will retain the right to withdraw from the study at any time.

All obese patients who have scheduled a painless gastroscopy are eligible to be study candidates. They will be screened according to the detailed inclusion and exclusion criteria explained later in this document. Patients who satisfy the shedding criteria will be eliminated from participation in the study.

Inclusion criteria

Exclusion criteria

  • Patients with known contraindications to any of the drugs in this study.

  • Patients requiring gastroscopic treatment.

  • Patients with a full stomach.

  • Pregnant women.

  • Patients classified as ASA Class III or higher.

  • Patients with a history of sedative or opioid use in the past 6 months.

  • Patients with mental disorders.

  • Patients with anaemia (haemoglobin ≤90 g/L).

  • Patients with preoperative AIS scores higher than 6.

Shedding criteria

  • Patients who have serious complications such as bleeding during the examination and require emergency resuscitation or surgery.

  • Patients or their clients request to withdraw from this study.

Randomisation

All participants will be randomly assigned to either an intervention or control group by using computer-generated random numbers and opaque envelopes. Before the study’s commencement, the anaesthesia provider will unseal the allocated envelopes and administer the medication accordingly.

Blinding

This is a double-blind trial. Due to the different appearance of remimazolam tosilate and propofol, syringes and drug infusion tubes will be covered with opaque materials. This will blind the endoscopist, data collectors and patients will be blinded. We will bring in a third anaesthesia staff who will be blinded to the subsequent assessments. A research assistant who is responsible for reminding patients to complete the AIS scoresheets will be blinded. All statistical analysis will be conducted by a designated biostatistician who will be blinded to the randomised allocation of subjects.

In addition, the anaesthesiologist responsible for procedural sedation cannot be blinded and will be instructed not to disclose information about group allocation to any study personnel.

Study interventions

This study aims to compare the safety and efficacy of the two sedation strategies. Patients will receive either remimazolam tosilate or propofol in combination with low-dose fentanyl according to the results of randomisation. The infusion rate and dosage of sedatives and fentanyl are determined by existing evidence and clinical practice guidelines.15 41 The doses of all drugs will be administrated according to the adjusted body weight (ideal body weight + 0.4 × (total body weight − ideal body weight)).7 The BIS value when the MOAA/S score reaches 1 will be defined as the reference BIS, which will be used to monitor the sedation depth of the examination. In addition, each subject will refer to their individualised reference BIS in subsequent sedation maintenance due to the variability of individual patient responses. The schedule of enrolment, interventions and assessments is displayed in table 2.

Table 2

Schedule of enrolment, interventions and assessments

In the intervention group, 0.1% remimazolam tosilate (freeze-dried powder 36 mg diluted by 36 mL of 0.9% normal saline) will be administered intravenously throughout the procedure. The anaesthesiologist will initially infuse fentanyl 50 µg intravenously. 3 min later, an initial dose of 0.15 mg×kg−1 of remimazolam tosilate will take 2 min, followed by a rate of 2 mg×kg−1×hour−1 until the MOAA/S scale reaches 1. The BIS value at this point will become the reference BIS for the current patient and the gastroscopy can commence. Subsequently, the maintenance infusions will be titrated between 1 and 2 mg×kg−1×hour−1 to maintain the reference BIS while preserving spontaneous ventilation. During the examination, remimazolam tosilate 0.05 mg×kg−1 will be administered immediately as rescue sedation if sedation is inadequate.

In the control group, 1% propofol will be administered intravenously throughout the procedure. The anaesthesiologist will initially infuse fentanyl 50 µg intravenously. 3 min later, an initial dose of 0.75 mg×kg−1 of propofol will take 2 min, followed by a rate of 10 mg×kg−1×hour−1 until the MOAA/S scale reaches 1. The BIS value at this point will become the reference BIS for the current patient and the gastroscopy can commence. Maintenance infusions should then be titrated between 5 and 10 mg×kg−1×hour−1 to maintain the reference BIS while preserving spontaneous ventilation. During the examination, propofol 0.5 mg×kg−1 will be administered immediately as rescue sedation if sedation is inadequate.

All subjects will be instructed to undergo an 8-hour fasting period and a 4-hour prohibition on drinking preoperatively. On arrival at the endoscopy centre, peripheral venous access will be established using a 22 G venous catheter. The Athens Insomnia Scale (AIS)42 (online supplemental material) will be completed, followed by the administration of 500 mL of lactated Ringer’s solution. Subsequently, they will assume the left decubitus position with an elevated head and will receive continuous monitoring via electrocardiography, heart rate (HR), SpO2, non-invasive mean arterial blood pressure (MAP), nasal capnography and BIS.

Supplemental material

Patients will receive oxygen through a nasal cannula at a rate of 3 L×min−1. All patients will perform 10 deep breaths before sedation. The section above provides comprehensive details on differentiated sedation strategies. Once the MOAA/S score reaches 1, an appropriate nasopharyngeal airway will be inserted into the patient’s nasal cavity to prevent obstruction of the airway by the tongue. Moreover, this nasopharyngeal airway will also monitor end-tidal carbon dioxide levels in real-time. Gastroscopy will be performed by the same endoscopist who has more than 10 years of experience.

Rescue sedation will be administered promptly during the examination if the patient exhibits any body movements that are deemed inadequate sedation, such as raising their head, choking cough or limb movement. If body movement is detected again within a minute, rescue sedation will be administered. However, the sedation will be deemed a failure if rescue sedation is required more than three times within 5 min. At this point, 0.5 mg×kg−1 of propofol will be administered once or multiple times.

If SpO2 <90% occurs, the anaesthesiologist must determine whether the situation is due to airway obstruction or respiratory depression.5 This can be achieved by assessing respiratory airflow, end-tidal carbon dioxide, chest expansion and abdominal fluctuation. A chin lift or jaw thrust must be performed immediately in the situation of respiratory obstruction. Nevertheless, noxious stimuli or positive-pressure ventilation with bag-mask will be applied to individuals with apnoeic obese patients. If the above airway manoeuvres mentioned are invalid, mechanical ventilation will be performed urgently with endotracheal intubation.

If HR is less than 45 beats per min, atropine 0.5 mg will be injected intravenously. If MAP is less than 20% of the basal value, phenylephrine 40 µg will be administered.

On completing the examination, sedatives will be discontinued and patients will be expeditiously transferred to the PACU for resuscitation. In the PACU, continuous real-time monitoring of HR, MAP, SpO2 and respiratory rate will be carried out. The nasopharyngeal airway will be removed if the patient experiences intolerance. Data collectors will record the time to ambulation. All patients will be allowed to leave the PACU when the modified Aldrete score reaches 9.43 The AIS scoresheets should be completed before the examination and 1, 3 and 7 days after the examination. To avoid a loss to follow-up, patients will be contacted periodically by a research assistant blinded to the group assignment to remind them to complete the AIS scoresheets.

Outcome measurements

The primary outcome is the incidence of hypoxaemia during the procedure and in the PACU.

The secondary outcomes encompass the time to ambulation, need for airway manoeuvres and rescue sedation, sleep quality, the incidence of sedation failure, the cost of sedatives, as well as adverse events like nausea, vomiting, bradycardia and hypotension.

The period required for a patient to walk 5 m in a straight line without instability after intravenous sedation has been ceased is known as the time to ambulation.44

The incidence of airway manoeuvres such as jaw thrust, chin lift, positive-pressure ventilation with a bag-mask and the use of endotracheal intubation will be recorded by data collectors.

When a patient is in a situation of insufficient sedation or sedation failure, the accumulated dosage of remimazolam tosilate and propofol will be deemed need for rescue sedation.

Sleep quality will be assessed using the AIS scale before and at 1, 3 and 7 days after the examination. The total score of the scale ranges from 0 to 24, where 0 indicates an absence of any sleep-related problem and 24 represents the most severe degree of insomnia. A score of 6 serves as the threshold to recognise individuals with insomnia.45

The cost of sedatives shall be defined as the cost of propofol and remimazolam tosilate used, including destroyed residues.

Data collection

Data collectors will collect information as follows:

  • The primary and secondary outcomes.

  • The demographic data and pre-anaesthesia physical examination data, including age, gender, ASA classification, BMI, neck circumference, waist-hip ratio and allergy history.

  • The vital signs will be collected by the electronic medical system in real-time, including HR, MAP, SpO2 and reference BIS.

Data management and monitoring

All patient personal information and study data will be securely stored in a separate database, that is, protected by passwords and logical proofreading procedures. This database will be regularly synchronised with the backup to avoid data loss. Data entry accuracy will be monitored by an independent supervisor. Any adverse events will be appropriately handled, thoroughly recorded and regularly reviewed.

Sample size calculation

The sample size calculation is based on our preliminary study, the incidence of hypoxaemia was 0.2 in the intervention group and 0.4 in the control group. Using the sample size calculation software (http://powerandsamplesize.com/Calculators/Compare-2-Proportions/2-Sample-Equality), a sample size of 79 patients will be needed to yield 80% power with α=0.05. Taking into account a drop-out rate of 10%, we should recruit 174 obese patients and divide them equally into two groups of 87 patients each.

Statistical analysis

The Statistical Product and Service Solutions (IBM SPSS, V.20.0) statistical software will be employed to analyse all data according to the randomisation groups and the intention-to-treat principle. We will use the last observation carried forward imputation method to handle missing data. However, this study will not include interim analyses.

The continuous variables with normal distribution will be expressed as ‘mean±standard deviation’ and analysed by independent t-test. Data with skewed distribution will be tested using the Mann-Whitney U test. Count data will be expressed in numbers or percentages, and compared by the χ2 or Fisher’s exact tests. Covariance analysis and logistic regression will be implemented to reduce the impact of study factors, confounding variables and their interactions. A p value<0.05 of a two-sided test is considered statistically significant.

Patient and public involvement

None.

Ethics and dissemination

This RCT was designed following the principles of the Declaration of Helsinki. It has been reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University on 2 December 2022. The ethical amendment review has also been approved on 26 October 2023. The Ethics Committee will regularly assess the research’s scientific nature to determine whether it should continue. We expect to release the original data on the ResMan Chinese Clinical Trial Management Public Platform (http://www.medresman.org.cn) in December 2024, and the research results will be published in the form of papers in peer-reviewed journals.

Discussion

The proportion of patients with overweight or obesity has already exceeded one-third worldwide.46 With the development and promotion of comfort-focused medical practices, an increasing number of individuals require safe and comfortable anaesthesia to tolerate unpleasant and painful procedures. Respiratory depression and subsequently hypoxaemia are of greatest concern in procedural sedation. However, the sedation strategies commonly used for these populations are rudimentary. Therefore, we have designed this prospective study for obese patients receiving painless gastroscopy.

Strengths of the study

First, our study represents the first instance of using an individualised reference BIS-guided titration method of sedatives, in place of conventional induction methods described in the reference, to determine sedation depth and assess the incidence of hypoxaemia during painless endoscope examinations in obese patients. This approach aims to avoid insufficient or excessive sedation.34 47 48 Furthermore, all individualised reference BIS values constitute a range that will be used to accurately guide sedation depth for obese patients receiving painless gastroscopy, simplifying procedural sedation in future clinical practice. These are the primary clinical values highlighted in our current study.

Second, during outpatient endoscopy, the incidence of severe hypoxaemia was almost six times higher in obese patients.14 Therefore, in high-volume and fast-paced ambulatory endoscopy centres, less frequency of airway manoeuvres, more desired level of sedation and faster recovery of ambulation ability are of paramount importance, which will advance comfort-focused medical practices, especially in these specific high-risk populations. To the best of our knowledge, this is the first RCT following the existing evidence and clinical practice with adequate power to assess the safety and efficacy of remimazolam tosilate combined with low-dose fentanyl in obese patients undergoing painless gastroscopy.

Third, we will also assess sleep quality in the current study. Existing evidence indicates that the combination of propofol and low-dose opioids can independently affect sleep quality during painless upper gastrointestinal endoscopy.49 Remimazolam has comparable sedative effects to propofol, as both act on gamma-aminobutyric acid receptors. So far, no studies have been conducted to determine whether remimazolam has similar effects on sleep disturbance as propofol during moderate-deep sedation. Currently, both the Pittsburgh Sleep Quality Index (PSQI) and AIS are used to assess sleep quality. It is worth mentioning that PSQI involves subjective content while the AIS is more objective,50 less complicated and user-friendly.42

Limitations

This protocol has several critical issues.

First, for medical ethics and safety, we will only select mild-to-moderate obese patients with ASA class II. If patients with BMI>40 kg×m–2 or higher ASA classification, necessary airway intervention techniques, such as a high-flow nasal cannula or endotracheal intubation, should be required to avoid hypoxaemia and ensure the safety of procedures.46 47 The updated guideline of German indicated that patients with ASA class III or higher have an increased risk of complications during sedation.51 Therefore, the future conclusion of our study should be interpreted with caution.

Second, the usage of BIS can increase the patients’ healthcare costs. Nonetheless, for this special population, better dose control and lower incidence of hypoxaemia are valuable. Compared with alternative intervention methods for improving oxygenation such as the high-flow nasal cannula46 and Wei nasal jet tube,1 the usage of BIS may facilitate the implementation of sedation strategies while being more affordable and user-friendly.

Third, the ordinary gastroscopy in this study could be completed in approximately 10 min. Our commitment remains unwavering to continuously collect data on time-consuming gastroscopies or treatment procedures such as endoscopic submucosal dissection in upcoming studies to develop a more personalised research plan for these procedures.

Fourth, due to the possibility of reduced patient compliance, this programme with a small sample size will not be followed-up in the long-term. Therefore, additional RCTs with large-scale, multicentre and extended periods of follow-up are needed to enhance the robustness and generalisability of the findings.

Trial status

This study has been reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University and registered at the China Clinical Trial Center on 26 December 2022. The preliminary experiment has been conducted in the endoscopy centre of our hospital, and the feasibility of this optimal sedation strategy has been preliminarily confirmed. We intend to recruit 174 patients screened according to inclusion and exclusion criteria from November 2023 to June 2025.

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