Efficacy and safety of remimazolam besylate in patients with obesity undergoing painless colonoscopy: a prospective, double-blind, randomized controlled trial

2.1 Inclusion and exclusion criteria

A prospective, double-blind, randomized controlled trial was performed in the Deyang People’s Hospital between 07 February 2021, and 30 November 2023. Patients admitted for selective painless colonoscopy were eligible for participation in this study if they: (I) had an American Society of Anesthesiologists (ASA) physical status II–III; (II) were 18–65 years old; (III) had a body mass index (BMI) ≥28 kg/m²; (IV) volunteered to sign the informed consent form; and (V) did not experience painless colonoscopy within the past 3 months.

The exclusion criteria was consistent with one of the following: (I) refusal to participate in this study; (II) resistance to opioid drugs; (III) sleep disorders and mental illnesses; (IV) exposure to similar anesthetic drugs within 3 months; (V) severe cardiovascular or cerebrovascular diseases or severe renal insufficiency; (VI) contraindications to use of propofol, sufentanil or benzodiazepines; (VII) history of head, chest, and intracranial surgery, or stroke within 4 weeks before operation; (VIII) history of hypertension, hypotension; (IX) pregnant or lactating women; (X) respiratory infection; and (XI) other situations that were not suitable for entering the experiment.

2.2 Randomization and blinding

All eligible subjects were screened by a preoperative evaluation at the anesthesia clinic in the Deyang People’s Hospital. Participates signed an informed consent form and were subsequently divided into two groups using a computer-generated randomized number table. The subject list was maintained by a nurse anesthetist who did not participate in the consequent procedures of this study. According to the grouping results, the participants were grouped to remimazolam besylate or propofol groups namely group RB and group P respectively. Group RB patients were intravenously injected with remimazolam besylate (0.15 mg/kg) plus sufentanil (0.1 μg/kg) for anesthesia induction while in group P received intravenous infusion of propofol (2 mg/kg) plus the same dose of sufentanil which group RB patients received. To sustain blinding to the investigation, the nurse anesthetist who kept the subject list helped preparing and distributing the medicines in identically opaque syringes marked with research numbers merely. Specifically, it meant that each anesthetic drug was divided into induction and addition purpose using an independent syringe. The dose of the required drug in the syringe during induction was marked as inducer 1, inducer 2. Drugs for once additional dosage were also prepared in advance, and labeled as additional drugs 1, 2, 3, 4, 5, etc. When additional sedative was required, it was taken according to the marked number. The anesthetic drugs were injected by the frontline anesthesiologist who performed the anesthesia work on the day (this anesthesiologist did not involve in this study), and data collection and evaluation were carried out by the research team. Blindness could only be uncovered when severe security incidents occurred.

2.3 Interventions and assessments

All participants fasted before the examination, and none of medication was used preoperatively except the necessary reagent for intestinal preparation. Intestinal preparation was performed using polyethylene glycol electrolyte powder (I) with drinking water (2000 mL). After the patient entered the anesthesia preparation room, the baseline vital signs were collected in the left lying position, including noninvasive blood pressure (NIBP), electrocardiogram (ECG), heart rate (HR), and peripheral oxygen saturation (SPO₂), respiratory rate (RR) and reliable peripheral venous access was opened immediately before painless colonoscopy slowly infusing with 500 mL physiological saline solution. After entering the endoscopy room, patients were routinely monitored for basic vital signs. Oxygen was inhaled at a rate of 4 L/min through a breathing mask. Anesthesia machines, emergency tracheal intubation tools and laryngeal masks were in standby mode.

For anesthesia induction, a bolus intravenous injection of sufentanil (0.1 μg/kg) was administered, followed by remimazolam besylate (0.15 mg/kg) in group RB or propofol (2 mg/kg) in group P. When the eyelash reflex disappeared, there was no obvious body movement, and the modified observer’s assessment of alertness/sedation scale (MOAA/S) (Table 1) reached smaller than 3 points, the endoscopist began the colonoscopy. Fluctuations of blood pressure and heart rate were evaluated at various time intervals during the operation process to maintain the MOAA/S score less than or equal to 3 points. If the MOAA/S score was greater than 3 points, an additional dose of remimazolam besylate (2.5 mg) was administered in group RB, while propofol (0.5 mg/kg) was administered in group P. Once the NIBP decreased (exceeding 30% of the baseline value), metaraminol 0.4 mg was intravenously injected. When there was an increase in blood pressure (exceeding 30% of the baseline value), the score of MOAA/S was evaluated again. If the score of MOAA/S was greater more than 3 points, sedative drugs were added. If it was less than or equal to 3 points, nicardipine (0.4 mg) was intravenously injected. Atropine (0.5 mg) was administered when HR was below 45/min, which was repeated if needed, with a maximum dose of 2 mg. When there was an increase in heart rate (exceeding 20% of the baseline value), if the MOAA/S score was greater than 3 points, an additional dose of sedative drug was administered, and if that was less than or equal to 3 points, esmolol was administered. The treatments for opening the airway, such as head-tilt, chin lift, and jaw-thrust, were performed by the anesthesiologist when the SpO₂ was below 95%. If the SpO₂ decreased below 90% and hypoxemia wasn’t alleviated by the previously mentioned treatments, the operation was stopped immediately. Positive pressure ventilation by anesthesia machine was consequently applied and emergency tracheal intubation or laryngeal mask insertion was performed if necessary. Other perioperative security incidents were also noted and treated in accordance with the clinical operation standards of Deyang People’s Hospital.

After completion of the colonoscopy, patients were transferred into the post anesthesia recovery room with continuous monitoring. Symptoms of nausea and vomiting, dizziness and headache, drowsiness and fatigue, abdominal pain and bloating were noted. The patients with a Steward score ≥4 and stable vital signs were allowed to leave the anesthesia recovery room accompanied by their family members. Satisfaction scores of patients, endoscopists and anesthesiologists were evaluated in the both groups by a 10-point Likert scale (1 = highly unacceptable, 10 = outstanding) (Table 2) [21, 22, 23].

The induction time was the seconds from the beginning of sufentanil medication to the status that MOAA/S score reached ≤3 points and eyelash reflex disappeared. The examination time was the time from the entry to exit of the colonoscope. The orientation recovery time was the time from exit of the colonoscope to the patient’s eyes opening and being consciousness. The post anesthesia recovery room stay time was defined as the time from exit of the colonoscopy to patients leaving the recovery room. The patients could leave the anesthesia recovery room accompanied by their family members when they reached a Steward score ≥4 and had stable vital signs. Apnea was defined as the cessation of respiratory activity of the chest and abdomen for more than 20 seconds with stopwatch timing observed by the researcher, and hypoxemia was SpO₂ less than or equal to 90%.

The basic characteristics of the patients were collected. During the procedure, the addition of remimazolam besylate or propofol was considered as repeated medication, and the rate of repeated medication was the percentage of all additional patients in this group. Pain at the injection site during the induction period was recorded. Simultaneously, changes in basic vital signs including apnea, hypoxemia, hypotension, hypertension, heart rate slowing, heart rate increasing, body movement reaction, anaphylaxis, manual airway opening assisted breathing and mask positive pressure ventilation during the procedure were also noted.

The primary outcome was defined as the incidence of hypoxemia and sample size was calculated based on incidence of hypoxemia. Hypoxemia was the most concerning and desirable indicator for optimization in the present study. Secondary outcomes included the duration of induction, procedure, orientation recovery time, PACU stay time, sufentanil consumption, repetitive medication ratio, incidence of injection pain, incidence of security events and adverse reactions of various systems, and the satisfactions of patients, endoscopists and anesthesiologists.

2.4 Statistical analysis

According to preliminary experimental of ten cases per group (Supplementary Table 1), 50% of obese patients who underwent colonoscopy experienced hypoxemia. To detect a 30% difference in hypoxemia rate between both groups with a 90% power and a type I error rate of 0.05, 48 cases were needed in each group. Considering the 10% dropout, 108 patients were enrolled.

SPSS 26.0 (SPSS, Inc., Armonk, NY, USA) was used for all statistical analyses. The normality of the data distribution was assessed by the Shapiro-Wilk test. Normally distributed data are summarized as mean ± standard deviation (SD), while non-normally distributed data are expressed as median (25th and 75th percentile). Categorical data are shown as frequency and percentages. Continuous data was compared by Student’s t-test or Wilcoxon-Mann-Whitney test based on viability of the normality assumption. Chi-square or Fisher’s exact test was used to compare the categorical data. Significance was set as a two-sided p value < 0.05.

3.1 Basic characteristics of the patients

The flow diagram of the study design is shown in Fig. 1. These 100 patients met the inclusion and exclusion criteria and were randomly allocated into two groups. The demographic characteristics and basic values of these patients are shown in Table 3. There were no significant differences in the demographics and basic values of patients between the two groups (p > 0.5).

3.2 The duration of induction, colonoscopy, orientation recovery time and PACU stay time

There were no statistical differences in the duration of the induction, colonoscopy, orientation recovery and PACU stay time between both two groups (p > 0.05) (Table 4).

3.3 The sufentanil intake and repetitive medication ratio

No statistically significant difference was observed regarding sufentanil consumption in both groups (p = 0.594) (Table 5). Total repetitive medication ratio was 54% and 58% in groups RB and P, respectively. The number of patients in group RB received 1 to 4 times of additional administration was 8, 10, 6 and 3, respectively. While in group P, there were 23 patients accepted once additional propofol, 6 patients accepted twice. There were statistical differences in the repetitive medication ratio between two groups (p = 0.001) (Table 5).

3.4 Cardiovascular treatment adverse events and injection pain

During induction, 8% of patients suffered from pain at the injection site in group RB, which was significantly less than 34% in group P (p = 0.003). Incidence of hypotension during induction in the two groups was statistically different (p = 0.005). There was no significant difference in the incidence of hypertension, increased heart rate, and decreased heart rate in both groups during the examination (p = 1.000) (Table 6).

3.5 Respiratory treatment adverse events

Only 26% of patients faced apnea during induction in group RB, less than the 50% in group P (p = 0.003) (Table 6). Similarly, 32% and 66% patients developed hypoxemia in group RB and P respectively, the incidence rate of group RB was significantly lower than that of group P (p = 0.001) (Table 6). Significant difference was not observed between the two groups in head-tilt/chin lift/jaw-thrust (p = 1.000) (Table 6), while no statistically significant difference between the two groups was shown in mask positive pressure ventilation (p = 0.002) (Table 6). There was no emergency tracheal intubation in both groups during the whole process of anesthesia and recovery. Finally, the cases of laryngeal mask insertion were lower in group RB than group P, but significant difference was not observed between the two groups (p = 0.487).

3.6 Others system incidence of security events and adverse reactions of various systems

There was no significant difference in the incidence of dizziness and headache between the two groups after the patient waking up, with 6 patients in group RB and 12 cases in group P (p = 0.192) (Table 6). There was no significant difference in the incidence of kinetic reaction, allergic reactions, nausea and vomiting, abdominal pain and bloating, and drowsiness and fatigue between the two groups during the examination (p > 0.05) (Table 6).

3.7 Satisfaction of patients, endoscopists and anesthesiologists

The satisfaction score of patients in group RB was higher compared to group P (8.93 ± 1.08 vs. 7.97 ± 1.31, p = 0.001), while there was no difference in satisfaction scores of endoscopists (8.94 ± 0.83 vs. 8.83 ± 1.25, p = 0.748) and anesthesiologists (8.47 ± 1.67 vs. 8.56 ± 0.83, p = 0.696), respectively (Fig. 2).

Fig. 2.The Satisfactions of Patients, Endoscopists and Anesthesiologists. The satisfaction score of patients in group RB was significantly higher compared to group P (p = 0.001, p < 0.05), while there was no significant difference in satisfaction scores of endoscopists (p = 0.748, p > 0.05) and anesthesiologists (p = 0.696, p > 0.05), respectively. *p < 0.05 compared to the group P. Group RB: group remimazolam besylate, Group P: group propofol.