Efficacy and Safety of Remimazolam Tosilate Combined with Propofol in Digestive Endoscopy: A Randomised Trial

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Introduction
Gastrointestinal endoscopic diagnosis and treatment technology have been widely used because of their reliable effcacy; however, they can cause signifcant discomfort. With the continuous development of medical technology, the demand for patient comfort has gradually increased. Painless gastrointestinal endoscopic diagnosis and treatment and the use of anaesthetic drugs and related technologies, to reduce or avoid possible uncomfortable symptoms in the diagnosis and treatment process, reasonably improve patients' acceptance, reduce their fear, and create a comfortable medical environment for patients and digestive endoscopists [1].
Propofol is one of the most common drugs for anaesthesia induction and maintenance. Propofol is highly lipophilic, can cross the blood-brain barrier, and is rapidly efective. Its metabolites are excreted by the kidney, are highly controllable, have a short action time, and are fast to awaken and become complete. Its extensive use also involves a high safety profle. However, in high-risk patients, signifcant cardiovascular inhibition may lead to adverse medical outcomes, and select healthy patients have experienced cardiac arrest when receiving propofol. Propofol infusion syndrome may also occur when high doses are taken. Lastly, injection pain has become a limitation to the use of propofol.
Remimazolam (CNS7056) is an ultra-short-acting phenyl ester benzodiazepine. It can be rapidly hydrolysed into its inactive carboxylic acid metabolite CNS7054 by liver esterase [2], which allows the early recovery of cognitive function compared to midazolam and provides both predictable and controllable sedative efects [3]. However, it also shows the familiar pharmacological characteristics of classical benzodiazepine drugs and the spectrum of adverse reactions [4,5].
Many factors, such as age, sex, race, ethnicity, weight, and American Society of Anesthesiologists (ASA) classifcation of physical status (ASA I: A normal healthy patient; ASA II: A patient with mild systemic disease; ASA III: A patient with severe systemic disease; ASA IV: A patient with severe systemic disease that is a constant threat to life; ASA V: A moribund patient who is not expected to survive without the operation; ASA VI: A declared brain-dead patient whose organs are being removed for donor) and obesity status have relatively small efects on remimazolam. Additionally, this compound presents no damage to hepatocytes in vitro. Compared with propofol, remimazolam causes limited cardiovascular and respiratory depression, less injection pain, and a safe and efective reversal of fumazenil that might alter routine procedural sedation. Remimazolam may also be more benefcial for high-risk patients, although its sedative depth and long-term sedation efects are lower [6][7][8][9][10][11].
To help determine a better sedation regimen, we compared the efcacy and safety of remimazolam tosilate combined with propofol, remimazolam tosilate, and propofol. Te results of exploring whether remimazolam combined with propofol is safer and more efective could provide a single dose reference for future studies. Patients were not eligible due to any of the following factors: communication disorder; extra drug use outside of the preoperative preparation regimen for a variety of reasons; women during pregnancy or lactation; history of severe motion sickness; severe vertigo and sleep apnoea syndrome; difcult airway; clear refusal to participate; history of drug abuse; alcohol abuse in the previous 2 years; and history of general anaesthesia within 1 month prior to the study or an operation within 1 month was planned. Participants were selected for an anaesthesia appointment for a painless digestive endoscopy and signed an informed consent form. Teir personal information was also collected at this time.

Randomization and Grouping.
Investigator PZ generated the random allocation sequence and randomised the patients into three groups: remimazolam combined with propofol (RMP group), remimazolam (RM group), and propofol (P group). Both the patient and endoscopic doctor were unaware of the grouping. In addition, the appearances of remimazolam and propofol were diferent. Terefore, the drug administration investigator, LC, was aware of the grouping.

Progression.
According to the gastrointestinal endoscopic diagnosis and treatment routine, patients abstained from consuming food and drink before. Open the venous access in the preparation room. In the endoscopy room, the right-hand pulse rate (PR), left upper limb blood pressure (systolic blood pressure (SBP)/diastolic blood pressure (DBP)), and right-hand oxygen saturation (SpO 2 ) were continuously monitored and recorded. Each patient underwent nasal catheter oxygen inhalation with a controlled oxygen fow of approximately 3-5 L/min [9].
All three groups received 0.1 μg/kg sufentanyl analgesia. An induction dose of 0.1 mg/kg remimazolam and 1 mg/kg propofol was administered to the RMP group, 0.3 mg/kg remimazolam to the RM group, and 2 mg/kg propofol to the P group. Patients received an additional dose of 0.05 mg/kg remimazolam in the RMP and RM groups or 0.5 mg/kg propofol in the P group per 5 min [12][13][14][15]. Te gastroscope operation began when the score for the Modifed Observer's Assessment of Alertness/Sedation (MOAA/S) scale was ≤1 (Supplementary File Table 5). Sedation administration complied with an individualised principle (if the endoscopic standard was met before the intended administered dose was reached, the actual administered dose was recorded, and the examination started; if the total amount of induction is reached but the lens access requirements cannot be met, additional doses should be administered until the depth of sedation is sufcient). If the patient still had physical movement and obvious swallowing movements, the corresponding drug was administered again until sedation was achieved, and the next administration was postponed for 5 min. If extra doses were given more than fve times within 15 min, satisfactory sedation could not be ofered, a sedation failure was recorded, and midazolam was used as a sedation remedy.

Observation Indicators.
Te primary observational indicator was the success rate of the three induction schemes. Secondary observation indicators included PR, SBP/DBP, and SpO 2 ; adverse events such as low PR, hypotension, and low SpO 2 occurring during the process; the dose of atropine and ephedrine used during the study; bucking and body movement scores during examination; onset time; ofset time; time to discharge; incidence of injection pain; dizziness severity scores; headache; vomiting; fatigue; abdominal pain; ventosity; active bowel voice; and increased exhaust; and times of advanced doses and time of frst defaecation.
2.6. Scoring Criteria. During anaesthesia (from induction until postanaesthesia care unit (PACU) departure), 0.3 mg inatropine was administered when the PR was lower than 55 times/min, signalling low PR. When the mean arterial pressure (MAP) decreased by more than 20% of the baseline value, indicating hypotension, 6 mg ephedrine was administered. If SpO 2 ranged from 95-100%, zero points were recorded. When SpO 2 fell to 90-95%, 1 point was recorded, and 2 points were given for a drop to 80-90%. In these cases, the patient's mandibular angle was raised and oxygen fow treatment inhalation was increased or positive pressure was masked to provide oxygen. For an SpO 2 below 80%, equating to 3 points, the endoscopic operation was stopped and rescue of respiratory suppression was prepared for. Body movement/bucking Grade: 0, no; 1, slightly movement/mild cough, without afecting the examination, without additional dose; 2, obvious movement/bucking, afecting the examination and required additional doses; 3, failed to cooperate/SpO 2 was decreased, suspend examination until enough anesthesia.
Time metrics included onset time (from sedative drug injection to MOAA/S ≤ 1), examination time, ofset time (from the last dose to patient awakening), and time to discharge (from the last dose to the patient's Aldrete score of 8 using the Modifed Rete Scoring System). Te visual analogue scale (VAS) was used to assess patient pain and satisfaction; the WHO Evaluation Criteria for patient nausea and vomiting; Modifed European Vertigo Rating Form for dizziness; and the Christensen Postoperative Fatigue Rating Scale for fatigue (Supplementary File). Gastrointestinal discomfort symptoms, such as active bowel sounds and increased exhaustion, were recorded according to Gastrointestinal Symptoms Rating Scales (GSRS). Te GSRS contains many symptoms and its corresponding scoring criteria (1 point for normal/no discomfort; 2 points for slightly elevated discomfort that did not afect normal work and life without interventional treatment; 3 points for obvious discomfort, interfering with normal work and life; and 4 points for serious adverse reactions seriously interfering with normal work and life).

Statistical Analysis.
Te sample size of this study was calculated based on the incidence of hypotension under propofol anaesthesia [14] using an Online Sample Size Calculator (https://powerandsamplesize.com/Calculators/). Te estimated sample size of 35 patients in each group provided a null hypothesis of 90% confdence, with an equal proportion of rejection. Given the 20% shedding rate, a fnal sample size of at least 133 patients was required; 139 patients were recruited for this study.
Te type of analysis used for this study is per-protocol analysis. Because some participants failed to complete the study, the absence of data could interfere with analyses. Statistical analyses were performed on the software SPSS, version 25.0 (SPSS Inc., Chicago, IL, USA). Shapiro-Wilk and Levene tests were used to assess the data distribution and homogeneity of variance, respectively. Quantitative data are presented as mean ± standard deviation (SD) and were compared using one-way analysis of variance.
Comparisons of qualitative variables in the three groups were analysed using χ 2 or Fisher's exact tests, and continuous variable data were analysed using the Kruskal-Wallis H test; the criterion for rejecting the null hypothesis was P < 0.05.

Patient Demographics and Baseline Characteristics.
Doctor HY enrolled participants and assigned them to the interventions. A total of 139 participants were recruited, and 26 were excluded. Two patients refused to participate, and six did not meet the inclusion criteria (two had low body weight, one was overweight, one was undergoing chemotherapy, one had severe vertigo and sleep apnoea syndrome, and one had a planned gynaecological operation 2 days later). Eighteen patients were lost to follow-up, and 113 were included in the statistical analysis ( Figure 1). Tere was no signifcant diference in the general data among the three groups (Table 1).

Primary Outcome.
Te primary outcome of the study was the success rate within the three groups. Tere were no remedies in the RMP and P groups; 40 cases were included in the RM group, two of which involved the use of remedial drugs, with a success rate of 95%. Tere was no signifcant diference in three-component powers (P � 0.113).

Secondary Outcomes.
Te incidences of adverse cardiovascular events included hypotension, low PR, and low SpO 2 (SpO 2 < 95%). Te incidence of hypotension was 40.0% in the RMP group, 18.4% in the RM group, and 44.7% in the P group (P � 0.037; RM vs. P, P � 0.048). Te incidence of low PR was 5.7% in the RMP group, 2.6% in the RM group, and 5.3% in the P group (P � 0.771). Low oxygen saturation severity scores were assessed in this study, with no signifcant diference among the three groups (P � 0.148). Te incidence of injection pain was much lower in the RM group than that in the RMP and P groups (RM, 2.6%; RMP, 11.4%; P, 26.3%; P � 0.007; RM vs. P, P � 0.008) ( Table 2).

Journal of Clinical Pharmacy and Terapeutics
Te incidences of hypotension and respiratory depression in the PACU showed no clinically signifcant diferences between the groups (P > 0.05).
Tere were signifcant diferences in SBP and DBP among the groups (SBP: P � 0.002; DBP: P � 0.004). In addition, the RM group was more hemodynamically stable than the other groups ( Analysed for primary outcome (n=40) and secondary outcomes (n=38) Analysed (n=35) Analysed (n=38) Allocation Analysis Figure 1: Flow diagram of the study selection.

Journal of Clinical Pharmacy and Terapeutics
Continuously measured vital signs, MAPs, and PRs were also analysed. Tere were no statistically signifcant diferences in any of the vital signs among the three groups (P > 0.05). Furthermore, no clinically signifcant diferences were found with regard to onset time (P � 0.153) or ofset time (P � 0.296), and there were no statistically signifcant diferences among the groups in terms of time to discharge (P � 0.05). Te durations of the gastrointestinal endoscopic examinations were almost the same between all three groups (P > 0.05) ( Table 4).
Patients had almost the same sleep quality before the examination and on the frst, third, and seventh days after the examination (P > 0.05). After anaesthesia, adverse reactions, such as fatigue, dizziness, headache, nausea, and vomiting, were not signifcantly diferent among the three groups (P > 0.05). Gastroscope-related discomfort symptoms, such as abdominal pain, abdominal distension, active bowel sounds, and increased exhaust, were comparable among the groups (P > 0.05).

Journal of Clinical Pharmacy and Terapeutics
Compared to the preoperative conditions (baselines), the patients' degree of fatigue was signifcantly higher postexamination on the same day (P < 0.0001) and was slightly better on the frst day after examination (P � 0.0338); it was similar to baseline values on the third and seventh days after examination (Figure 3(a)). Te bowel voice was active, exhaustion was increased postexamination on the same day (P < 0.0001), and symptoms disappeared after the frst day (Figures 3(b) and 3(e)). One patient was signifcantly dizzier than at baseline at the end of the examination (P � 0.0017), and their return visits did not signifcantly difer on the frst, third, and seventh days (P > 0.05) (Figure 3(c)). Postoperative nausea and vomiting (PONV) increased postexamination on the same day (P � 0.0002) (Figure 3(d)). At the same time, ventosity and exhaust scores also increased postexamination on the same day, returned to baseline levels on the frst day, and symptoms disappeared on the third and seventh days after examination (Figure 3(f )).
Abdominal pain scores increased postexamination on the same day compared to preoperative baseline values. Te scores decreased on the third and seventh days after examination, compared to preoperative baseline values (baseline values: 0.53 ± 1.29 vs. postexamination on the same day: 1.07 ± 1.59, P � 0.004; vs. the frst day: 0.48 ± 1.05, P � 0.624; vs. the third day: 0.17 ± 0.66, P � 0.001; and vs. the seventh day: 0.15 ± 0.678, P � 0.001). Tere was no signifcant diference in time of frst defaecation between the three groups (P � 0.089); the mean for the RMP group is 2.55 ± 0.88 days after examination, and those for the RM and P groups are 2.16 ± 1.4 days and 2.68 ± 1.23 days, respectively ( Figure 4).

Discussion
Previous studies have shown that the sedation success rates of 0.10, 0.15, and 0.20 mg/kg induction doses of remimazolam were 32%, 56%, and 64%, respectively, and increased with the opioid analgesic fentanyl (92% in the remimazolam group and 75% in the midazolam group) [16]. Remimazolam had synergistic efects with opioid analgesics [17], along with the same result as the current study in that the RM group's sedation success rate was 95%. We found that during the combined induction of anaesthesia, an additional intraoperative dose of remimazolam, similar to that in the RM group, could achieve sufcient sedation. Although the induction dose of remimazolam in the RMP group was lower than that in the RM group, remimazolam can provide basic sedation whether used respectively or in combination with propofol.
Te adverse reaction profle of remimazolam was largely consistent with the other classic benzodiazepines, including common changes in blood pressure and heart rate, decreased respiratory rate, and vomiting, the incidence of which was comparable to that of midazolam [18,19]. Tis study found that the inhibitory efect of remimazolam on the cardiovascular system was lower than that of propofol, but this advantage was obviously weakened when combined with propofol, which may be due to an inappropriate drug-dosage ratio. More studies are needed to explore rational drugdosage ratios and achieve better dosing regimens. It has been reported that the safety profle of remimazolam in high-risk patients (ASA III, IV) is similar to that in low-risk patients; thus, selecting remimazolam rather than propofol for induction is preferred [9,11].
When gastroenteroscopy was induced by remimazolam anaesthesia, the incidence of bucking was higher than that in the other two groups (RM, 31.6% > P, 7.9% > RMP, 5.7%), and additional medication was needed. Low SpO 2 adverse events in the RM group were mostly associated with patient bucking, which was diferent from the respiratory depression associated with propofol. Tis may be because the remimazolam induction dose of 0.3 mg/kg was improper for all patients or because the sedation with remimazolam was not as deep as that with propofol. Drug administration researchers have found that some elderly patients were able to undergo sufcient sedation with a remimazolam dose of 0.2 mg/kg, while younger patients (especially women) experienced obvious agitation and coughing when gastroscopy was introduced at a remimazolam dose of 0.3 mg/kg. Even when additional doses were added, a few patients (two young women) could not complete the diagnosis and treatment operation and received remedial midazolam. However, none of the patients were recalled after surgery at the 7-day visit. Previous studies have shown that the sensitivity of elderly patients to sedation with benzodiazepines has increased [20]. Young women require higher doses of medication, possibly due to oestrogen afecting the GABA receptor in the . Each point represents one patient receiving the corresponding score or advance times. Points with diferent shapes represent diferent groupings. Body movement/bucking grade: 0, no; 1, slightly movement/mild cough, without afecting the examination, without additional dose; 2, obvious movement/bucking, afecting the examination and required additional doses; 3, failed to cooperate/ SpO 2 was decreased, suspend examination until enough anesthesia. * P < 0.05; * * P < 0.01; * * * P < 0.001; * * * * P < 0.0001. hippocampus and in other regions of the limbic system [21]. For midazolam, the plasma clearance is 11% higher in women than in men [17].
Onset times of the three groups were similar, indicating a remimazolam efect as rapid as propofol's in clinical anaesthesia. Te node of the investigator's recording time was a patient score of MOAA/S ≤ 1, and even if patients in the RM group reached the sedation standard, some patients still coughed during engagement with the microscope, and additional doses were needed to meet the operational requirements. Furthermore, this study revealed that there was no signifcant diference in the ofset time of anaesthesia between the three groups. Te time to discharge is ordered as follows: RM > RMP > P, and the diference among the groups was not signifcant (P � 0.05). Tus, expanding the experimental sample size may yield positive results. Tese fndings may also stem from painless endoscopy being a shorter procedure, which might not be enough to produce signifcant diferential results; if remimazolam was applied to the induction and maintenance of general anaesthesia, it might lead to delayed awakening compared to propofol [22,23]. Most previous studies have included gastroscopy or colonoscopy alone, while the participants included in the current study underwent both gastroscopy and colonoscopy at the same time, and the operation and turnover times were longer. Based on the results of this study, we concluded that the application of remimazolam in shorter surgeries does not afect the awakening and recovery of patients and has no adverse efect on PACU turnover.
It has been reported that propofol might be slightly better for PONV than remimazolam [6,24]. In this study, the incidence of PONV in the RM group (7.9%) was slightly higher than that in the RMP and P groups (5.9% and 2.6%, respectively). One patient who received remimazolam had severe PONV, left the PACU after half an hour, and later developed nausea and vomiting symptoms, dizziness, and headaches, accompanied by sweating. However, the patient did not return to the hospital for medical treatment. Return visits revealed that patients felt dizzy and had a headache on the frst day. Symptoms signifcantly improved on the third day, but slight discomfort was still experienced after a month. As the fnal statistics did not difer among the three groups, this might be due to the small sample size of this study. Additionally, some reports have suggested that remimazolam causes a slightly higher incidence and severity of nausea and vomiting than propofol. Further studies are needed to evaluate the incidence of PONV after remimazolam treatment [25]. One patient who received remimazolam reported increased fatigue compared to propofol for gastroenteroscopy in the last year, despite not being aware of the use of remimazolam. Recently, it was shown that remimazolam can prevent emergent delirium in children following tonsillectomy and adenoidectomy under sevofurane anaesthesia [26]. In the current study, patients still had hypotension after entering the PACU; however, there was no signifcant diference in the incidence among the three groups. Oxygen saturation was maintained at >94% under oxygen absorption. Te frst defaecation of patients in the RM group occurred slightly earlier than that in the other two groups. In this study, it was found that the times of the frst normal defaecation in the RM group (a small amount of defaecation) were not noted on the day of diagnosis and treatment. It was also slightly earlier than that in the RMP and P groups. Even if the gap was not statistically signifcant, did remimazolam promote intestinal peristalsis? Is it more suitable for general surgeries? Few relevant studies on the prevention of postoperative gastric paralysis and intestinal paralysis have been conducted to date.
Patients' uncomfortable symptoms, such as abdominal distension, increased exhaustion, and active bowel sounds, mostly disappeared on the second or third day, and the original discomforting symptoms returned to preexamination conditions on the third day. Sleep status after the examination was basically the same in all three groups. Sleep duration increased signifcantly on the day of treatment, which was consistent with patient fatigue.
Symptoms such as dizziness, headache, nausea, vomiting, and fatigue did not difer among the three groups. Gastrointestinal symptoms such as abdominal pain, abdominal distension, active bowel sounds, and increased exhaustion occurred similarly among the groups, indicating that the potential promoting efect of remimazolam on the digestive tract was mild and did not cause excessive discomfort in patients.
After their examination, patients experienced obvious abdominal pain on the same day. At the return visit by telephone on the next day, abdominal pain was signifcantly improved. On the third and seventh days, abdominal pain was improved compared to the preoperative basic condition. Te improvement might have been caused by most patients who had preoperative abdominal pain taking the relevant drugs for treatment on the third day after examination. However, it is also possible that anaesthetic drugs or gastrointestinal endoscopy can improve abdominal pain, but no relevant study has investigated long-term abdominal pain before and after gastroscopy and colonoscopy.
It is currently believed that tolerance and dependence occur with classical benzodiazepines at prolonged high doses, and none of the participants showed rapid tolerance in this study [27]. Te oral bioavailability of remimazolam is extremely low (1.1-2.2%), and it has a bitter taste. Te intranasal pathway's bioavailability of the powder preparation was increased (almost by 50%), but it can cause signifcant discomfort and pain; thus, the possibility of harm was set to be extremely low [28,29]. Additionally, none of the weekly postoperative visits indicated dependence. Flavonoids, fatty acids, and alcohol can inhibit the major metabolic enzymes of remimazolam recombining human carboxylestase1 [30], thereby increasing exposure to remimazolam [29,31]. Patients with preoperative alcohol or related drug consumption were excluded from this study. Limitations of this study included its single-centre nature, the small experimental sample size, and the lack of universality that might infuence the experiment fndings.
Tere was also only one dose ratio between remimazolam and propofol, and no further exploration. Moreover, in the combination regimen, the various adverse efects were not signifcantly diferent from those of propofol. However, this study proved that remimazolam combined with propofol is feasible for anaesthesia induction, and perhaps a more appropriate dosage ratio could be advantageous. Lastly, some of the selected patients were examined in the morning and others in the afternoon, and diferences in the durations of fasting might have afected their blood pressures.

Conclusions
Remimazolam tosilate combined with propofol can be used for gastrointestinal endoscopic diagnosis and treatment, with almost the same safety as propofol. Remimazolam tosilate contributes to a low incidence of adverse reactions and is a safe anaesthetic option for painless endoscopies.