Anaesthesia 2025, 80, 259–268 doi:10.1111/anae.

16475

Original Article

Safety and efficacy of remimazolam tosilate for general

anaesthesia in paediatric patients undergoing elective
surgery: a multicentre, randomised, single-blind,
controlled trial
Yu-Bo Fang,1,2 John Wei Zhong,3,4 Peter Szmuk,3,4 Yun-Long Lyu,1,2 Ying Xu,5,6
Shuangquan Qu,7 Zhen Du,7 Wangning Shangguan1,2 and Hua-Cheng Liu1,2

1 Department of Anaesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s
Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
2 Key Laboratory of Paediatric Anaesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou,
Zhejiang, China
3 Department of Anaesthesiology and Pain Management, University of Texas Southwestern Medical Centre, Dallas,
TX, USA
4 Outcome Research Consortium, Cleveland, OH, USA
5 Department of Anaesthesiology, Children’s Hospital of Chongqing Medical University, Chongqing, China
6 National Clinical Research Centre for Child Health and Disorders, Ministry of Education Key Laboratory of Child
Development and Disorders, Chongqing, China
7 Department of Anaesthesiology, Hunan Children’s Hospital, Changsha, Hunan, China

Summary
Introduction Remimazolam is an ultra-short-acting benzodiazepine sedative drug. This study aimed to
compare the efficacy and safety of remimazolam with propofol for induction and maintenance of general
anaesthesia in children undergoing elective surgery.
Methods Children (aged 3–6 y, ASA physical status 1 or 2, BMI 14–25 kg.m-2) undergoing elective surgery
under general anaesthesia with tracheal intubation were eligible for inclusion. Children were allocated
randomly using a web-based system to receive either remimazolam or propofol in a 3:1 ratio. After receiving
fentanyl 3 lg.kg-1, children received their allocated drug for both induction and maintenance of general
anaesthesia. Induction doses were remimazolam 0.3 mg.kg-1 or propofol 2.5 mg.kg-1, with a second dose
given should they not achieve loss of consciousness. After neuromuscular blockade and tracheal intubation,
maintenance anaesthesia was achieved with an infusion either remimazolam 1–3 mg.kg-1.h-1 or propofol
4–12 mg.kg-1.h-1, alongside a remifentanil infusion (0.1–0.5 lg.kg-1.min-1) titrated to surgical stimulus and
haemodynamic parameters. Primary outcomes were the incidence of successful induction and maintenance
of anaesthesia. Secondary outcomes included: time to loss of consciousness, awakening and tracheal
extubation; incidence of emergence delirium and moderate or severe pain in post-anaesthesia care unit;
incidence of negative behaviour change after surgery at postoperative day 3; and incidence of adverse
events.
Results A total of 187 children were analysed (140 allocated to remimazolam and 47 to propofol). All children
achieved successful induction of anaesthesia. Successful maintenance of anaesthesia was achieved in 139
(99%) children who received remimazolam compared with 46 (98%) who received propofol (rate difference
1.4%, 95%CI -2.9–5.8%, p = 0.441). Adverse events occurred in 27 (19%) children who received remimazolam
and 23 (49%) who received propofol.

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Anaesthesia 2025, 80, 259–268 Fang et al. | Paediatric anaesthesia with remimazolam

Discussion Remimazolam was well tolerated for the induction and maintenance of general anaesthesia in pre-
school-age children and was non-inferior to propofol.

.................................................................................................................................................................
Correspondence to: Hua-Cheng Liu
Email: [email protected]
Accepted: 5 October 2024
Keywords: efficacy; general anaesthesia; paediatric patients; propofol; remimazolam
This article is accompanied by an editorial by Anderson et al., Anaesthesia 2025; 80: 243–247.
Twitter/X: @JohnZho93109426

Introduction trials in paediatric populations are lacking. The primary aim

Volatile anaesthetic drugs are recognised as contributing to of this study was to compare the efficacy and safety of
altered postoperative behaviour including emergence remimazolam with propofol when used for induction and
delirium and emergence agitation in children [1]. Propofol maintenance of general anaesthesia in pre-school-age
is the most popular intravenous drug used for general children undergoing elective surgery. We hypothesised that
anaesthesia in children due to its rapid onset, impressive remimazolam would have fewer adverse effects and be
speed and quality of recovery, minimisation of emergence non-inferior to propofol.
delirium and reduced incidence of laryngospasm and
bronchospasm [2, 3]. However, shortcomings such as Methods
injection site pain, anaphylaxis, contraindication in some This multicentre, single-blind, non-inferior randomised trial
mitochondrial diseases and propofol-related infusion was conducted at three Chinese medical centres following
syndrome all impact on its use in children [2]. ethical approval. Written informed consent was obtained
Remimazolam, a novel ultra-short-acting benzodiazepine, from each child’s parents or legally authorised
is currently approved in multiple countries for use in adults for representative. Children aged 3–6 y, ASA physical status 1
general anaesthesia, procedural sedation and ICU sedation or 2 and BMI of 14–25 kg.m-2 scheduled for elective surgery
[4]. It has high specificity and affinity for the brain under general anaesthesia with tracheal intubation
benzodiazepine site on the gamma-aminobutyric acid type A were eligible for inclusion. Children were not recruited if
(GABAA) receptor to potentiate the action of the inhibitory they met any of the following criteria: cardiothoracic,
neurotransmitter GABA [4, 5] and its sedative effect is neurosurgical or hepatic surgery; recent general
completely antagonised by flumazenil [6]. anaesthesia; participation in other clinical trials; serious
In studies in adults, the maximum observed diseases of other systems; respiratory management
concentration after a single intravenous bolus of difficulties; or allergies/contraindications for the study
remimazolam was not affected by hepatic or renal drugs. Further information on eligibility is available in online
impairment [7]. Phase 1 studies showed a higher clearance Supporting Information Table S1.
compared with midazolam, with faster onset and offset, and Children were allocated randomly using an interactive
a predictable sedation effect over a wide dose range, web response system at a 3:1 ratio, receiving either
without significant cardiorespiratory depression [8, 9]. A remimazolam or propofol, respectively. All study drugs
phase 2b/3 trial in adults showed the non-inferior efficacy of were prepared by a designated researcher as propofol
remimazolam compared with propofol for general 10 mg.ml-1 and remimazolam tosilate 1 mg.ml-1 (Jiangsu
anaesthesia, with better respiratory management and Hengrui Pharma Corporation, Lianyungang, China). Patients
haemodynamic stability, and a lower incidence of injection and trained outcome evaluators were blinded to group
site pain [10]. allocation, but the anaesthetists were not due to the
A recent pharmacokinetic study of a remimazolam differences in drug colour and dose selection. To reduce
intravenous infusion in children who were anaesthetised the risk of bias for outcome evaluation during induction of
showed a high clearance, small volume of distribution and anaesthesia, a nurse with no prior exposure to anaesthetic
short half-life [11]. These suggest the suitability of pharmacology assessed loss of consciousness and injection
remimazolam for use in children but randomised clinical site pain.

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Table 1 Modified observer’s assessment of alertness/ > 5 min), followed by sevoflurane inhalation for
sedation (MOAA/S) scale. maintenance of anaesthesia. Hypotension (systolic blood
Score Responsiveness pressure < 70 mmHg + (2 9 age in y) for > 5 min) and
5 Responds readily to name spoken in normal tone bradycardia (heart rate < 70 bpm for > 5 min) were treated
4 Lethargic response to name spoken in normal tone with ephedrine/phenylephrine and atropine, respectively.
3 Responds only after name is called loudly and/or The investigator then decided whether to discontinue the
repeatedly investigational drugs. Fentanyl 1 lg.kg-1 was given for
2 Responds only after mild prodding or shaking additional analgesia (up to a total dose of 5 lg.kg-1).
1 Responds only after painful trapezius squeeze Additional boluses of cis-atracurium 0.05 mg.kg-1 were
0 Does not respond to painful trapezius squeeze given as required. Local infiltration anaesthesia, nerve block
or caudal anaesthesia occurred at the end of surgery and
Baseline observations were recorded in a quiet was determined by the local team. Neuromuscular
pre-operative waiting area with parents or legally blockade was reversed with neostigmine 0.03 mg.kg-1 and
authorised representatives present. For children unable to atropine 0.015 mg.kg-1.
co-operate with pre-operative observations, those After discontinuing all drugs, MOAA/S scale scores
recorded at the pre-anaesthesia visit were considered the were assessed every 5 min, for at least 40 min, until arousal
baseline values. The Modified Observer’s Assessment of (defined as three consecutive MOAA/S scale scores of 5)
Alertness/Sedation (MOAA/S) scale (Table 1) was used to was achieved. Children who had regular spontaneous
evaluate loss of consciousness [12, 13]. A MOAA/S scale breathing and recovery of airway reflexes underwent deep
score ≤ 1 indicated loss of consciousness and was tracheal extubation and were transferred to the
evaluated immediately after the loss of the eyelash reflex. post-anaesthesia care unit (PACU). Children who received
Anaesthetic induction included all children receiving a remimazolam received flumazenil 0.2 mg over > 60 s if they
single dose of fentanyl 3 lg.kg-1 intravenously. Around showed no arousal after 1 h. A further dose of flumazenil
3 min later, children received either an initial intravenous 0.1 mg was given if required. Emergence delirium and pain
-1 -1
dose of remimazolam 0.3 mg.kg or propofol 2.5 mg.kg in PACU were evaluated using the Paediatric Anaesthesia
over 60 s. For children who had not achieved loss of Emergence Delirium (PAED) scale and the face, legs,
consciousness within 60 s of initial induction of anaesthesia, activity, cry and consolability (FLACC) scale, respectively
a second dose of remimazolam 0.1 mg.kg-1 was given to (see online Supporting Information Tables S2 and S3) [14,
those who had already received remimazolam, or propofol 15]. Both scales were recorded every 5 min for at least
1.0 mg.kg-1 was given to those who had already received 30 min after arrival in PACU. The modified Aldrete score
propofol over 30 s. If loss of consciousness had not was recorded every 3 min after arousal, and the child was
occurred within 60 s of the second dose, propofol transferred from PACU to the ward when two consecutive
-1
1.0 mg.kg was administered as a rescue drug repeatedly modified Aldrete scores were ≥ 9. On postoperative day 3,
until the MOAA/S scale score was ≤ 1 and anaesthesia was evaluation of negative behaviour changes was performed
maintained using sevoflurane inhalation. Cis-atracurium using the Post-Hospitalisation Behaviour Questionnaire for
0.2 mg.kg-1 was then administered and the trachea was Ambulatory Surgery (PHBQ-AS) (see online Supporting
intubated 3 min later. Information Table S4) [16].
Anaesthesia was maintained with a constant infusion The primary outcome was the incidence of successful
rate of remimazolam 1–3 mg.kg-1.h-1 in children who induction and maintenance of anaesthesia. Successful
received remimazolam for induction, or propofol induction was defined as loss of consciousness being
4–12 mg.kg-1.h-1 for those who received propofol at reached without the need for rescue drugs during induction
induction. Both groups received remifentanil of anaesthesia. Successful maintenance was determined
0.1–0.5 lg.kg-1.min-1. Infusion rates were adjusted in the when there was no requirement for rescue drug
context of intensity of surgical stimuli and haemodynamic administration and the investigational drug infusion was not
parameters. Rescue drugs were given to children suffering discontinued. Secondary outcomes included: time to loss of
from light anaesthesia, defined as the appearance of at least consciousness (from the start of the investigational drug
one of the following signs: patient movement; sweating; intravenous bolus to when the first MOAA/S scale score was
tears; hypertension (increase of systolic blood pressure ≤ 1); awakening time (from the end of the investigational
> 25% of the baseline value for > 5 min) and tachycardia drug administration to when the first of three consecutive
(increase of heart rate > 25% of the baseline value for MOAA/S scale scores were 5); tracheal extubation time

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Anaesthesia 2025, 80, 259–268 Fang et al. | Paediatric anaesthesia with remimazolam

(from the end of investigational drug administration to remimazolam and propofol meeting the primary outcome
removal of the tracheal tube); time to transfer out of PACU exceeded the non-inferiority margin. Missing data were
(from the end of the investigational drug administration to considered to be missing at random without data
two consecutive modified Aldrete scores of ≥ 9); need for a imputation. Available case analysis was implemented to
second dose of investigational drug during induction of handle missing data. A p value < 0.05 was considered
anaesthesia; the incidence of emergence delirium (PAED statistically significant. Data analysis was performed using
scale scores ≥ 10) and moderate or severe pain (FLACC SPSS version 26.0 for Windows (SPSS Inc., Chicago,
scores > 3) in PACU; need for additional drugs in PACU; IL, USA).
incidence of negative behaviour change (PHBQ-AS scores
> 3) at day 3 postoperatively; parental and anaesthetist Results
satisfaction divided into five grades (higher scores A total of 192 children were recruited between June 2022
indicating more dissatisfaction); and the infusion rates of the and October 2023 (Fig. 1) of which 144 were allocated to
investigational drug and remifentanil. Safety outcomes receive remimazolam and 48 to receive propofol. A total of
included: fluctuations in blood pressure or heart rate; 187 children (140 allocated to remimazolam and 47 to
injection site pain; laryngospasm; emergence delirium; propofol) were included in the final intention-to-treat
delayed awakening from anaesthesia (absence of analysis. Patient and intra-operative characteristics were
awakening 60 min after discontinuation of investigational similar between groups (Table 2).
drug); respiratory depression (respiratory rate Figure 2 shows the primary outcome non-inferiority
< 12 breaths.min-1 or SpO2 < 92% for > 10 s in 100% analyses. All patients achieved successful induction of
oxygen with a Venturi mask at a flow rate of 3 l.min-1); and anaesthesia, and 139 (99%) patients allocated to
postoperative nausea and vomiting. remimazolam achieved successful maintenance of
Sample size estimates were based on a non-inferiority anaesthesia in the remimazolam group compared with 46
design. Considering a one-sided type 1 error a = 0.025, (98%) allocated to propofol (rate difference 1.4% (95%CI -
type 2 error b = 0.10, non-inferiority margin (d) -8% and 2.9–5.8%, p = 0.441)).
98% successful induction and maintenance of anaesthesia Secondary outcomes are summarised in Table 3.
in both groups, then a sample size of 171 children was Median (IQR [range]) time to loss of consciousness during
needed (remimazolam:propofol ratio 3:1) (PASS Version induction of anaesthesia was 45 (38–51 [15–100]) s and 25
15.0 (NCSS, East Kaysville, UT, USA)). Given an expected (20–32 [10–75]) s, for children allocated to the
loss to follow-up of 10%, we aimed to recruit a total of remimazolam and propofol, respectively (p < 0.001). There
192 children (144 in the remimazolam group, 48 in were no significant differences between both groups for
the propofol group). The proportion of successful induction awakening and tracheal extubation time or time to transfer
of anaesthesia and maintenance of 98% was set from a out of PACU. Six children (4.3%) allocated to remimazolam
pre-trial study in children and previous studies in adults [10, and one (2.1%) allocated to propofol required a second
17, 18]. dose of their study drug at induction of anaesthesia
All children who received at least one treatment (p = 0.82). There were no meaningful differences in the
specified in the trial were included in the full analysis set. infusion rates of the study drugs. There were also no
Continuous variables were tested for normality using a differences between children receiving remimazolam and
Shapiro–Wilk normality test. Comparison between groups propofol in the incidence of emergence delirium; moderate
for dichotomous endpoints used the v2 test, continuity or severe pain in PACU; negative behaviour changes on day
correction v2 test or Fisher’s exact test; relative risks with 3 after surgery; need for additional drugs (opioids,
95%CI were calculated using the log-binomial model. propofol, flumazenil, ephedrine and atropine) in PACU; or
Normally distributed continuous endpoints were parental and anaesthetists’ satisfaction.
compared using independent sample t-tests with the Systolic blood pressure and heart rate were higher in
calculated difference as 95%CI between means. children allocated to remimazolam compared with propofol
Non-normally distributed continuous endpoints were throughout induction of anaesthesia (online Supporting
compared using Mann–Whitney U-test, and the difference Information Table S5). A summary of all peri-operative
with 95%CI between medians was estimated using adverse events is presented in Table 4. Adverse events
Hodges–Lehmann estimators. Non-inferiority was shown occurred in 27 (19%) children who received remimazolam
when the lower limit of a two-sided 95%CI of the and 23 (49%) who received propofol. The difference related
difference between the proportions of children receiving mostly to injection site pain (occurring in 7 (15%) patients

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Fang et al. | Paediatric anaesthesia with remimazolam Anaesthesia 2025, 80, 259–268

Enrolment Assessed for eligibility (n=217)

Excluded (n=25)
ƒ Not meeting inclusion criteria (n=15)
ƒ Refusal (n=4)
ƒ Other (n=6)

Randomised (n=192)

Allocation
Allocated to remimazolam group (n=144) Allocated to propofol group (n=48)
ƒ Received allocated intervention (n= 140) ƒ Received allocated intervention (n=47)
ƒ Did not receive allocated intervention (n=4) ƒ Did not receive allocated intervention (n=1)
ƒ Withdrew consent (n=1) ƒ Pre-operative sedative medication (n=1)
ƒ Abnormally slow heart rate (n=1)
ƒ Pre-operative sedative medication (n=1)
ƒ Surgery cancelled (n=1)

Follow-Up
Lost to follow up (n=1) Lost to follow up (n=0)
ƒ Missing Post-Hospitalisation Behaviour
Questionnaire for Ambulatory Surgery score
(n=1)

Analysis
Analysed (n=140) Analysed (n=47)
ƒ Excluded from analysis (n=0) ƒ Excluded from analysis (n=0)

Figure 1 Study flow diagram of participants.

who received propofol and none who received exceeded the noninferiority margin, d = -8%). Secondary
remimazolam), as well as intra-operative bradycardia outcomes showed that remimazolam was associated with a
(occurring in 12 (26%) patients who received propofol and longer time to loss of consciousness during induction of
13 (9%) who received remimazolam). Three children who anaesthesia and a lower incidence of injection site pain
received remimazolam experienced delayed awakening compared with propofol.
from anaesthesia. During induction of anaesthesia, most children
achieved loss of consciousness within 60 s following
Discussion remimazolam 0.3 mg.kg-1. This contrasts with results
This multicentre, single-blind, non-inferiority randomised from a Japanese multicentre trial that reported a longer
trial has shown that remimazolam was non-inferior for both time to achieve loss of consciousness of > 80 s when a
induction and maintenance of general anaesthesia in pre- continuous intravenous infusion of remimazolam was
school-age children undergoing elective surgery compared used [10]. Our study used a single intravenous bolus of
with propofol (the lower limit of the 95%CI of the difference remimazolam (to avoid poor tolerance from pain

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Table 2 Patient and intra-operative characteristics of children receiving remimazolam or propofol for induction of anaesthesia.
Values are median (IQR [range]), number (proportion) or mean (SD).
Remimazolam Propofol
n = 140 n = 47

Age; y 4 (3–5 [3–6]) 4 (3–5 [3–6])

Sex; male 109 (78%) 40 (85%)
Ethnicity; Chinese Han 139 (99%) 46 (98%)
Weight; kg 18 (15–20 [14–18]) 18 (16–20 [14–24])
Height; cm 105 (100–112 [90–128]) 106 (100–110 [91–126])
BMI; kg.m-2 16.0 (15.0–16.9 [14.1–20.2]) 15.6 (15.1–16.6 [14.2–19.8])
ASA physical status
1 132 (94%) 45 (96%)
2 8 (6%) 2 (4%)
Site of surgery
Urogenital organs and inguinal canal 70 (50%) 22 (47%)
Limbs 23 (16%) 5 (11%)
Ear, nose and throat 18 (13%) 6 (13%)
Head and neck 13 (9%) 3 (6%)
Ophthalmic 5 (4%) 8 (17%)
Oral 3 (2%) 2 (4%)
Abdomen 5 (4%) 0
Chest wall 2 (1%) 0
Spine 1 (1%) 0
Anus 0 1 (2%)
Duration of anaesthesia; min 79 (63–98 [41–221]) 81 (66–90 [48–124])
Duration of surgery; min 46 (35–68 [15–190]) 51 (32–62 [16–96])
Systolic blood pressure at baseline; mmHg 101 (6) 101 (6)
Heart rate at baseline; bpm 99 (9) 98 (10)

associated with a continuous propofol infusion, the children aged 2–6 y was similar to adults (41 vs. 35 l,
comparator drug) and this likely accounts for our time respectively) [11]; however, younger children have a
to loss of consciousness being much shorter than a relatively larger total body fluid volume. This may mean
continuous intravenous infusion [17, 19]. However, time the optimal bolus dose for induction of anaesthesia in
to loss of consciousness with remimazolam in our study younger children requires further investigation. During
was significantly longer than propofol (45 vs. 25 s, maintenance of anaesthesia, one child who received
respectively) replicating a previous paediatric study [20]. remimazolam and one who received propofol
A possible explanation may reflect age-related individual experienced `failure´ of the technique due to persistent
differences in drug pharmacokinetics. For remimazolam, tachycardia and hypertension during surgery,
the standardised steady-state volume of distribution for respectively. These children underwent penile surgery or

Figure 2 Rate difference (95%CI) of successful induction and maintenance of anaesthesia in children receiving either
remimazolam or propofol. Noninferiority margin set at -8%.

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Fang et al. | Paediatric anaesthesia with remimazolam Anaesthesia 2025, 80, 259–268

Table 3 Secondary outcomes of children receiving remimazolam or propofol for induction of anaesthesia. Values are median
(IQR [range]) or number (proportion).
Remimazolam Propofol Difference (95%CI)
n = 140 n = 47

Time to loss of consciousness; s 45 (38–51 [15–100]) 25 (20–32 [10–75]) 19 (16–22)

Awakening time; min 25 (20–30 [10–61]) 25 (20–30 [15–50]) 0 (-5–0)
Tracheal extubation time; min 10 (8–11 [3–20]) 10 (9–13 [4–27]) -1 (-2–0)
Time to transfer out of PACU; min 38 (33–43 [23–74]) 38 (33–43 [28–63]) 0 (-5–0)
Anaesthetist satisfaction 1 (1–2 [1–5]) 2 (1–2 [1–5]) 0
Parental satisfaction 1 (1–2 [1–4]) 1 (1–2 [1–3]) 0
Infusion rate of investigational drug; mg.kg-1.h-1 2.0 (1.8–2.2 [1.2–2.9]) 8.4 (6.9–9.6 [5.3–11.2]) -6.3 (-6.7 to -5.7)
Infusion rate of remifentanil; lg.kg-1.min-1 0.21 (0.17–0.25 [0.10–0.49]) 0.20 (0.17–0.40 [0.12–0.33]) 0.01 (-0.01–0.03)
PAED score 0 (0–4 [0–18]) 0 (0–3 [0–18]) 0
FLACC score 0 (0–1 [0–9]) 0 (0–1 [0–6]) 0
PHBQ-AS score (day 3 postoperatively) 3.00 (3.00–3.09 [2.91–3.36]) 3.00 (3.00–3.00 [2.91–3.18]) 0
Relative risk (95%CI)

Need for second dose during induction of 6 (4%) 1 (2%) 2.0 (0.2–16.3)
anaesthesia
Emergence delirium in PACU 5 (4%) 2 (4%) 0.8 (0.2–4.2)
Moderate or severe pain in PACU 10 (7%) 2 (4%) 1.7 (0.4–7.4)
Need for additional drugs in PACU 14 (10%) 4 (9%) 1.2 (0.4–3.4)
Negative behaviour changes (day 3 37 (27%) 9 (19%) 1.4 (0.7–2.7)
postoperatively)

FLACC, face, legs, activity, cry and consolability scale; PACU, post-anaesthesia care unit; PAED, paediatric anaesthesia emergence
delirium scale; PHBQ-AS, Post-Hospitalisation Behaviour Questionnaire for Ambulatory Surgery.

Table 4 Peri-operative adverse events of children receiving orchidopexy; these are procedures characterised by an
remimazolam or propofol for induction of anaesthesia. intense and often abrupt augmentation of pain that may
Values are number (proportion). not be rapidly relieved by an increase in a remifentanil
Remimazolam Propofol infusion rate, but neither drug showed superiority in this
n = 140 n = 47
circumstance.
Adverse events 27 (19%) 23 (49%) In contrast with adult data, no significant difference was
Intra-operative shown between remimazolam or propofol for time to
Hypertension 0 1 (2%) awakening, tracheal extubation or transfer out of PACU. A
Hypotension 1 (< 1%) 1 (2%) previous study in children (age 0–17 y) showed that
Tachycardia 1 (< 1%) 0 awakening time was negatively associated with age with
Bradycardia 13 (9%) 12 (26%) propofol administration but not remimazolam [20]. This is
Injection site pain 0 7 (15%) likely explained by immature hepatic and renal functions in
Laryngospasm 1 (< 1%) 0 younger children, as propofol is mainly eliminated by
In post-anaesthesia care unit hepatic metabolism and renal excretion, whereas
Hypertension 0 0 remimazolam has the same ester linkage as remifentanil
Hypotension 0 1 (2%) leading to rapid biotransformation by tissue esterase [5, 21].
Tachycardia 0 0 This is supported by the comparable terminal half-life after
Bradycardia 1 (< 1%) 2 (4%) 1 h of continuous intravenous infusion for remimazolam
Emergence delirium 5 (4%) 2 (4%) between children and adult volunteers [11]. In this trial,
Delayed awakening 3 (2%) 0 remimazolam resulted in delayed awakening in three
from anaesthesia patients, all of whom were completely awakened within 60 s
Respiratory depression 0 0 of flumazenil 0.2 mg without any re-sedation. This suggests
Nausea 4 (3%) 5 (11%) the routine use of flumazenil may further reduce awakening
Vomiting 2 (1%) 4 (9%) time of remimazolam.

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Anaesthesia 2025, 80, 259–268 Fang et al. | Paediatric anaesthesia with remimazolam

A study in children comparing 0.9% saline with the findings suggest BIS may not be suitable to monitor the
administration of remimazolam at the end of surgery found depth of anaesthesia in children receiving
a significant reduction in the incidence of emergence remimazolam-based TIVA. Currently, there remains an
delirium (44% vs. 12%) and a lower likelihood of negative absence of a reliable depth of anaesthesia monitoring for
behaviour changes (27% vs. 36%) on postoperative day 3 remimazolam-based TIVA. While patient state index has
[22]. As expected, in our study emergence delirium shown a definite dose–response relationship under
occurred infrequently (4% of children who received remimazolam bolus injection in adults, it has not appeared
remimazolam or propofol). This is likely because to be a reliable surrogate for loss of consciousness [19]. The
emergence delirium is associated with volatile anaesthetic correlation between the Narcotrend index and MOAA/S
drugs compared with total intravenous anaesthesia (TIVA). score is relatively weak and inconsistent, but the b ratio
Interestingly, negative behaviour changes evaluated on day recorded from frontal recordings has been identified as a
3 following surgery occurred in 27% of children who suitable EEG variable for monitoring remimazolam sedation
received remimazolam compared with 19% of those [26]. The electroencephalogram features of patients who
receiving propofol. Notably, there were more children who are older and undergoing induction of anaesthesia with
experienced moderate or severe pain in PACU who remimazolam were found to be comparable to those
received remimazolam compared with those who received induced by propofol [27], and therefore, investigating
propofol (7% vs. 4%, respectively) and we hypothesise that electroencephalogram features for remimazolam in
this behaviour change may in part be explained by the children may be useful to consider the best method to
obvious pain in PACU; however, our study was not designed evaluate depth of anaesthesia with this drug.
to determine causality for secondary outcomes. Other limitations of our study include that we recruited
We found that children who received remimazolam had only pre-school-age children aged 3–6 y and the doses of
higher systolic blood pressure and heart rate than those remimazolam set in this trial may not be applicable
who received propofol during induction of anaesthesia. for children aged < 3 y. Since there are limited
Notably, intra-operative blood pressure was maintained pharmacokinetic and pharmacodynamic data available for
at a stable and acceptable level for those receiving remimazolam in paediatric populations, the doses of
remimazolam, although they did not experience a higher remimazolam used in this trial were set with reference to a
incidence of bradycardia (26% compared with 9% for pre-trial study in children and previous studies in adults [10,
those receiving propofol). This does suggest an overall 17, 18]. The children in this study were all healthy and of a
cardiovascular stability with remimazolam anaesthesia. We normal weight; therefore, it is not clear if our data can be
found a lower incidence of pain on injection for children extrapolated to more complex children or those living with
receiving propofol (15%) compared with previous studies obesity. We were also unable to blind the treating
that report an incidence up to 35% and suggest this may be anaesthetist to the drugs as they needed to adjust
accounted for by our study protocol including a single dose concentrations to maintain anaesthesia, and this could have
of fentanyl 3 lg.kg-1 during induction of anaesthesia [23]. introduced bias.
A strength of our trial was the inclusion of a wide range Given the properties of independence from liver and
of surgeries and the use of several academically validated kidney metabolism, negligible adverse effects and available
assessment tools [12–16]. However, there are several specific antagonists, it could be reasoned that remimazolam
limitations. First, we did not use a processed appears a suitable drug for use in children who are critically
electroencephalogram to evaluate depth of anaesthesia. ill. As such, future work could focus on its application in this
Other investigators have reported that some adults having setting.
intra-operative BIS values > 60 (Medtronic Inc., In conclusion, remimazolam was well tolerated for the
Minneapolis, MN, USA), intra-operative patient state index induction and maintenance of general anaesthesia in pre-
> 50 or Narcotrend index values ≥ 60 (Narcotrend Group, school-age children and was non-inferior to propofol.
Hannover, Germany) under remimazolam-remifentanil Remimazolam was also associated with haemodynamic
anaesthesia have no incidents of reported awareness [24, stability and a low incidence of adverse effects.
25]. Our pre-trial study observed that BIS values were
consistently maintained at approximately 70 in children with Acknowledgements
MOAA/S score ≤ 1, even when the infusion rate of This study was registered at the Chinese Clinical Trial
remimazolam was adjusted to the dose ceiling. These Registry (ChiCTR2100053468). The authors thank all the

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Fang et al. | Paediatric anaesthesia with remimazolam Anaesthesia 2025, 80, 259–268

children and staff for their support during this study. This 13. Klockars JG, Hiller A, Ranta S, Talja P, van Gils MJ, Taivainen T.
Spectral entropy as a measure of hypnosis in children.
study was supported by the Major Science and Technology
Anesthesiology 2006; 104: 708–17. https://doi.org/10.
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Science and Technology Bureau. The trial was sponsored by
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the Second Affiliated Hospital and Yuying Children’s 00000542-200405000-00015.
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psychometric properties of the FLACC scale used to assess
the ethics review boards at all participating hospitals. procedural pain. J Pain 2018; 19: 862–72. https://doi.org/10.
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available upon reasonable request by contacting the 16. Jenkins BN, Kain ZN, Kaplan SH, Stevenson RS, Mayes LC,
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corresponding author. No other external funding or postoperative recovery: development of the post
competing interests declared. hospitalization behavior questionnaire for ambulatory surgery.
Paediatr Anaesth 2015; 25: 738–45. https://doi.org/10.
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 13652044, 2025, 3, Downloaded from https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1111/anae.16475 by Xuzhou Medical College, Wiley Online Library on [08/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Anaesthesia 2025, 80, 259–268 Fang et al. | Paediatric anaesthesia with remimazolam

27. Kim H, Lee U, Sim JH, et al. Electroencephalographic features of Table S2. Paediatric Anaesthesia Emergence Delirium
elderly patients during anesthesia induction with
(PAED) scale.
remimazolam: a sub-study of a randomized controlled trial.
Anesthesiology 2024; 141: 681–92. https://doi.org/10. Table S3. Face, legs, activity, cry and consolability (FLACC)
1097/ALN.0000000000004904. scale.
Table S4. Post-Hospitalisation Behaviour Questionnaire for
Supporting Information Ambulatory Surgery (PHBQ-AS).
Additional supporting information may be found online via Table S5. Detailed haemodynamic parameters during
the journal website. induction of anaesthesia.

Table S1. Inclusion and exclusion criteria.

268 © 2024 Association of Anaesthetists.