Discharge readiness after remimazolam versus propofol for colonoscopy: A randomised, double-blind trial : European Journal of Anaesthesiology | EJA

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Discharge readiness after remimazolam versus propofol for colonoscopy

A randomised, double-blind trial

Yao, Yusheng; Guan, Jinsheng; Liu, Linwei; Fu, Bingbing; Chen, Lei; Zheng, Xiaochun

Author Information
European Journal of Anaesthesiology: December 2022 - Volume 39 - Issue 12 - p 911-917
doi: 10.1097/EJA.0000000000001715



  • Remimazolam provides a noninferior discharge time to propofol for colonoscopy.
  • Remimazolam is associated with less injection pain than propofol.
  • Remimazolam is associated with a lower risk of hypotension and bradycardia than propofol.


Colorectal cancer occurred globally in more than 1.9 million new cases and with 935 000 deaths in 2020, ranking third in incidence and second in mortality.1 Colonoscopy is recommended for earlier cancer detection and prevention, resulting in a significant risk reduction in incidence and mortality, especially in relation to colorectal polyps.2–4 Unfortunately, colonoscopy is generally accompanied by pain or discomfort, which may hamper the acceptance of colonoscopy as an outpatient-based public health screening test. Procedural sedation is widely performed to attenuate pain and anxiety in patients undergoing colonoscopy.

Considering the disadvantages of the existing anaesthetic options and the increasing demand for comfortable medical care, physicians are searching for an ideal drug with a more tolerable profile.5,6 Propofol and midazolam are both the first-choice sedation agents for colonoscopy. Propofol is preferred because of its rapid onset and offset properties, allowing for timely recovery. However, outcomes using propofol are not ideal, including injection pain, hypotension, apnea and fatigue.7,8 These drawbacks may hinder functional recovery and delay discharge. Midazolam is associated with less injection pain and stable during the procedure.9 However, midazolam may delay discharge and take recovery room resources because of its prolonged elimination half-life and active metabolite, especially in patients with renal or hepatic dysfunction.10,11

Remimazolam is a novel ultrashort-acting intravenous benzodiazepine sedative with a short half-life and rapid recovery.12 Several recent studies have indicated that remimazolam might be an attractive candidate drug for procedural sedation in many settings, such as endoscopy and bronchoscopy.13,14 Nevertheless, concerning the discharge time after colonoscopy, there is need for further evidence comparing remimazolam and propofol. Hence, we conducted this randomised study to test the hypothesis that remimazolam could provide a noninferior discharge time in comparison with propofol in patients undergoing ambulatory colonoscopy.


Study design and participants

This is a prospective, single-centre, randomised, double-blind, parallel-group, noninferiority clinical trial. The Fujian Provincial Hospital's Institutional Review Board approved the study protocol (reference number K2021-06-016, Chairperson Professor Lian Fayang, 24 June 2021). The trial was registered at the Chinese Clinical Trials Registry (http://www.chictr.org.cn, identifier: ChiCTR2100048678) on 12 July 2021. We conducted this trial in the endoscopy suite of Fujian Provincial Hospital (Fuzhou, China) between July 2021 and October 2021. The trial adheres to the Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.15,16 No changes to the methods occurred after trial commencement. Participants aged 18 to 65 years with an ASA physical status of I to II who were scheduled to undergo ambulatory colonoscopy were eligible for this study. Exclusion criteria consisted of a history of allergy to study medications, weight less than 40 kg, BMI greater than 30 kg m−2, obstructive sleep apnoea, chronic use of opioids or benzodiazepines, inability to ambulate without assistance, preexisting cognitive impairment, a suspected or diagnosed disorder of the lower gastrointestinal tract that required advanced therapeutic endoscopy, a history of drug or ethanol abuse, pregnancy or lactating female patients, and inability to communicate in Mandarin Chinese.

Randomisation and blinding

After obtaining informed written consent, 132 participants were randomly assigned in a 1 : 1 ratio to either the remimazolam or propofol group using a computer-generated random number table. The study code number and group allocation were typed by a nonparticipant in the trial on separate pages, folded and concealed in sequentially numbered opaque envelopes. On the morning of the procedure, an independent nurse not involved in the study dispensed numbered syringes previously filled with the study drugs according to the randomisation sequence. The study drugs were prepared and injected with nontransparent black syringes, infusion tubing and connectors. All participants, attending anaesthetists, operating endoscopists and investigators involved in data collection, analysis and interpretation were unaware of the group allocation.

Study interventions

All participants underwent bowel preparation following the local standard protocol. Participants were allowed a low fibre diet on the day preceding colonoscopy. Then, a 2 l polyethylene glycol purgative formulation was prescribed and administered in split doses. Participants were required to start the last amount of this liquid bowel preparation within 5 h of colonoscopy and complete it at least 2 h before the procedure. Procedural sedation was standardised and performed by a single attending anaesthetist. All participants were systematically monitored by noninvasive arterial blood pressure measurements, continuous pulse oximetry and electrocardiographic monitoring during the procedure. Sufentanil (5 μg) was administered intravenously over 10 s before the assigned sedative drugs. Then, an initial dose of either 0.2 mg kg−1 remimazolam (2 mg ml−1, Jiangsu Hengrui Pharmaceutical Co. Ltd, China) or 1 mg kg−1 propofol (10 mg ml−1, Fresenius Kabi Deutschland, Germany) was administered over 30 s for the induction of sedation. Endoscopy was started when adequate sedation, with a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score less than or equal to three was achieved.17 All procedures were performed by a single experienced endoscopist. If the sedation was insufficient to start the procedure with the initial dose, a bolus of 3 ml study drugs (remimazolam 6 mg or propofol 30 mg) was allowed, no less than 2 min apart. Boluses of 3 ml of the study drugs were administered to maintain sedation with a MOAA/S less than four throughout the procedure at the discretion of the attending anesthesiologist. During the course, all participants breathed spontaneously and received oxygen at a rate of 3 l min−1 via a nasal catheter.

Study outcomes assessments

The primary outcome was the discharge time after colonoscopy, defined as the time interval between the end of the procedure and the Modified Postanaesthetic Discharge Scoring System scale reaching greater than or equal to nine (Supplementary Table 1, https://links.lww.com/EJA/A729).18 Secondary outcomes included induction time, emergence time, extent of recovery upon arrival in the postanaesthesia care unit (PACU), fatigue, endoscopist and patient satisfaction, and adverse events. Induction time was defined as the interval from the administration of sufentanil to patient exhibiting a MOAA/S level less than or equal to three. Emergence time was defined as the interval from the end of colonoscopy to fully alert (MOAA/S = 5). The modified Aldrete recovery scale evaluated postoperative recovery in the PACU.19 Fatigue level was graded upon emergence using an 11-point numerical rating scale (NRS), where 0 represented no fatigue and 10 represented extreme fatigue. Endoscopist satisfaction with sedation quality was assessed using an 11-point rating scale from 0 to 10, where 0 equals totally unsatisfied, 10 equals completely satisfied. Patient satisfaction with the sedation procedure was self-reported similarly on a scale of 0 to 10: 0 representing completely unsatisfied, and 10 representing totally satisfied.

All adverse events were documented during the trial, including injection pain, the occurrence of hypotension, bradycardia, hypoxemia, postoperative nausea or vomiting (PONV) and hiccup. Injection pain was self-reported using a verbal NRS score, where 0 represents no pain, 1 to 3 represents mild pain, 4 to 6 represents moderate pain and 7 to 10 represents severe pain. We explained all the above scoring criteria and confirmed that the participants understood preoperatively. In this trial, hypotension was the largest decrease in mean arterial pressure at least 20% from the baseline value. We described bradycardia as heart rates less than 50 beats min−1. Hypoxaemia was defined as oxygen saturation less than 92% during the study. All measurements were recorded by a single investigator blinded to the group allocation.

Statistical analysis

This study aimed to identify whether remimazolam is not inferior to propofol at discharge time for an ambulatory colonoscopy. Regarding the study design, there were no preexisting data to indicate a minimal clinically important difference between groups regarding discharge times. Consequently, we convened a panel of anaesthesia and endoscopy experts not involved in this study to define a suitable appropriate estimate for the noninferiority margin. The panel concluded that the minimal significant clinically relevant difference for discharge time was 5 min, and so this was set as our noninferiority margin. On the basis of our preliminary study, the SD of discharge times in participants receiving propofol for colonoscopy was approximately 5.5 min. Assuming a one-sided α = 0.025 and β = 0.2, 59 participants per group were needed. Anticipating a 10% dropout rate, we enrolled 132 participants in the study.

We used IBM SPSS statistics software for Windows (version 25; SPSS Inc, Armonk, USA) to analyse the data. The normality distribution of the continuous quantitative variables was tested using the Shapiro–Wilk test and Q-Q plots. Quantitative variables were described as the mean ± SD or median [IQR] and compared using a two-sample t test or Mann–Whitney U test. Whenever appropriate, categorical variables were summarised as numbers (percentages, %) and compared using Fisher's or χ2 test.

For the primary outcome, time-to-event (discharge time) was evaluated using a log-rank test and summarised using Kaplan–Meier survival analysis during the 40 min PACU stay. Moreover, we calculated the hazard ratio of discharge time using an unadjusted Cox model with a corresponding two-sided 95% CI. Additionally, a two-sided 95% CI of intergroup discharge time difference was calculated to clarify the hypothesis using the Hodges–Lehmann estimate. When the upper bound of the 95% CI did not exceed the noninferiority range, the noninferiority of remimazolam was confirmed. All analyses were prespecified in the statistical analysis plan. A two-sided P value less than 0.05 was defined as the threshold for statistical significance.


This study flow diagram is presented in Fig. 1. From July 2021 to October 2021, 132 participants scheduled for colonoscopy completed the trial according to the study protocol. No participant was lost to follow-up. We provide an overview of the baseline characteristics of the enrolled participants in Table 1. Overall, the patient and clinical data were well balanced between the two groups.

Fig. 1:
Flow diagram of the eligibility, randomisation, and follow-up of participants.
Table 1 - Patient demographic and clinical parameters
Group remimazolam (n = 66) Group propofol (n = 66) P
Age (years) 49 [41 to 56] 48 [39 to 56] 0.776
Female sex 37 (56) 32 (49) 0.384
BMI (kg m−2) 22.4 [19.8 to 24.6] 22.0 [20.1 to 25.3] 0.562
ASA physical status 0.486
 I 36 (55) 32 (49)
 II 30 (45) 34 (51)
Mean blood pressure (mmHg) 82 ± 13 85 ± 12 0.174
Oxygen saturation (%) 99 [98 to 100] 100 [98 to 100] 0.318
Heart rate (beats min−1) 75 ± 11 73 ± 14 0.578
Duration of colonoscopy (min) 12 [10 to 14] 12 [9 to 14] 0.494
Preexisting conditions
 Hypertension 9 (14) 11 (17) 0.627
 Diabetes 4 (6) 6 (9) 0.511
 Cardiovascular disorder 4 (6) 1 (2) 0.365
Data are presented as mean ± SD, median [IQR], or n (%).

The median discharge time based on the Kaplan–Meier survival curve was 24 [21 to 26] min in the remimazolam group and 21 [20 to 24] min in the propofol group (unadjusted hazard ratio 1.49, 95% CI, 1.05 to 2.11; log-rank test, P = 0.018; Fig. 2). In addition, the per-protocol statistics for the discharge time are shown in Fig. 3. The estimated median difference was 2 min (95% CI, 0 to 4 min, P = 0.038). Noninferiority of remimazolam could be confirmed, as the upper bound of the CI did not exceed the predetermined noninferiority criterion of 5 min.

Fig. 2:
Kaplan–Meier curves and hazard ratios for discharge time after a colonoscopy.
Fig. 3:
Noninferiority plot of discharge time after the colonoscopy procedure.

As detailed in Table 2, there were no significant differences between the two groups concerning emergence time, modified Aldrete score, fatigue or endoscopist satisfaction. Of note, patient satisfaction with sedation was higher in the remimazolam group than in the propofol group (P < 0.001), with a median difference of 1 point (95% CI, 1 to 2).

Table 2 - Secondary outcomes during the study period
Group remimazolam (n = 66) Group propofol (n = 66) P
Induction time (seconds) 90 [74 to 106] 78 [70 to 92] 0.003
Emergence time (seconds) 134 [102 to 222] 138 [91 to 252] 0.864
Endoscopist satisfaction, NRS 9 [7 to10] 9 [8 to 10] 0.322
Patient satisfaction, NRS 9 [8 to10] 8 [7 to 9] 0.001
Modified Aldrete score 5.5 [5.0 to 9.0] 6.5 [5.0 to 8.3] 0.993
Fatigue 5 [2 to 6] 3 [0 to 6] 0.476
Adverse events
 Injection pain 11 (17) 32 (49) 0.001
  Mild (NRS 1 to 3) 8 (12) 19 (29)
  Moderate (NRS 4 to 6) 3 (5) 9 (14)
  Severe (NRS 7 to 10) 0 4 (6)
Hypotension 13 (20) 31 (47) 0.001
Bradycardia 4 (6) 13 (20) 0.019
Hypoxaemia 8 (12) 11 (17) 0.457
PONV 0 2 (3) 0.496
Hiccup 2 (3) 0 0.496
Data are presented as median [IQR] or n (%). NRS, numerical rating scale (range 0 to 10); PONV, postoperative nausea and vomiting.

The injection pain, MAP and HR changes and the lowest SpO2 during the study are presented in Fig. 4. The median injection pain score was 0.5 [0 to 3] in the remimazolam group versus 3.5 [2 to 8] in the propofol group (P < 0.001). Similarly, 11 of 66 (17%) participants receiving remimazolam versus 32 of 66 (49%) participants receiving propofol reported injection pain, relative risk (RR) of 0.34 (95% CI, 0.19 to 0.62), P < 0.001. The occurrence of hypotension was 13 of 66 (20%) participants in the remimazolam group versus 31 of 66 (47%) participants in the propofol group, with an RR of 0.36 (95% CI, 0.20 to 0.65); P < 0.001. Episodes of hypoxaemia occurred in 8 of 66 (12%) participants in the remimazolam group and 11 of 66 (17%) participants in the propofol group (P = 0.627). Among the 66 participants identified as having bradycardia, four (6%) received remimazolam, and thirteen (20%) received propofol, (P = 0.019). Of note, 2 of 66 (3%) participants complained of PONV in the propofol group, and 2 of 66 (3%) reported hiccups in the remimazolam group. Details of adverse events during the study are shown in Supplementary Figure 1, https://links.lww.com/EJA/A728.

Fig. 4:
Injection pain and changes in vital signs during the study.


Discharge time is one of the most effective indicators of patient recovery after a procedure.20 Our trial adopted the modified Aldrete scale to assess the extent of recovery from sedation and the modified postanaesthetic discharge scoring system criteria to assess the discharge readiness of patients. There was a clinically irrelevant difference between remimazolam and propofol, and the findings of our study clarified that the majority of participants had to stay in the PACU for at least 30 min until discharge. Mild gait disorders in the propofol group and dizziness in the remimazolam group may hinder rapid discharge after colonoscopy. A rapid discharge time minimises resource consumption, especially in ambulatory endoscopy centres characterised by a high turnover of patients and limited capacities of the PACU.

The experience of pain upon the injection of propofol was reported in nearly half of the participants in our study, which is slightly lower than in previous studies.21 Preinjection administration of sufentanil and the use of the medium-chain and long-chain triglycerides propofol may reduce the incidence of injection pain. One in five participants recalled the induction of anaesthesia as the most painful part of the perioperative period in this study, which is a consistent problem with propofol and a primary reason for complaints in patients. The overall incidence and intensity of injection pain in participants receiving remimazolam were significantly lower than those receiving propofol. Thus, participants receiving remimazolam reported better satisfaction in this trial.

Previous studies have demonstrated that hypotension is directly harmful, at least in high-risk patients.22 We found that nearly half of the participants developed hypotension receiving propofol, having a two-fold increased risk of cardiovascular depression compared with remimazolam, in line with corresponding previous data.23,24 Patient-related and sedation-related factors, such as dehydration after bowel preparation and the cardiovascular depression effect of propofol, may predispose participants to hypotension. Indeed, infusion of short-acting drugs could produce more stable haemodynamics than bolus administration. However, the convenience of multiple-dose bolus administration may be a determinant of its clinical acceptability. Of note, two participants receiving remimazolam experienced hiccups, which was also reported in a previous study.25 This is a self-limiting symptom but remimazolam-induced hiccups might increase the risk of reflux aspiration.

The following limitations of our study should be addressed. First, we did not assess the dose–response relationship of remimazolam in combination with sufentanil for procedural sedation in colonoscopy. The initial doses of remimazolam (0.2 mg kg−1) and propofol (1 mg kg−1) were standardised based on our pilot study and routine clinical practice, respectively. Second, this was a single-centre study conducted with a selected patient population. Thus, the findings may not be generalisable to other populations, and the external validity needs to be assessed further.


In summary, remimazolam is noninferior to propofol in terms of discharge time for ambulatory colonoscopy. Compared with propofol, remimazolam provides a similar sedative efficacy and safer profile in patients undergoing colonoscopy. These benefits indicated that remimazolam could be a potential alternative to propofol for ambulatory colonoscopy sedation.

Acknowledgements relating to this article

Assistance with the study: we gratefully acknowledge Dr Wei Liang and Dr Wanyin Deng for their support and cooperation.

Financial support and sponsorship: this study was supported by the Comfort Medical Research Project of Fujian Strait Medical and Health Exchange Association (No. 2020-HYH-03), Natural Science Foundation of Fujian Province (No. 2021J01378), National Natural Science Foundation of China (No. 821711186), and High-level Hospital Foster Grants from Fujian Provincial Hospital (No. 2020HSJJ01).

Conflicts of interest: none.

Presentation: none.


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Yusheng Yao and Jinsheng Guan contributed equally.

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