Abstract
Objective
To explore the effect of preoperative application of remimazolam on electroencephalogram (EEG) epileptiform discharges in children under sevoflurane anesthesia, and whether it can affect the incidence of emergence delirium (ED) by influencing epileptiform discharges.
Methods
Sixty-two children aged 1 to 6 years who were scheduled to undergo tonsillectomy or adenoidectomy under sevoflurane anesthesia were selected as the research subjects and randomly divided into the remimazolam group (Group R) and the control group (Group C), with 31 cases in each group. Group R received remimazolam (0.2 mg/kg IV bolus) 2 min before induction; Group C received equivalent normal saline. The primary outcome was the incidence of ED. The secondary outcomes were the incidence of EEG epileptiform activity during induction, the time from sevoflurane induction to the appearance of the first epileptiform discharge, the peak score of the Paediatric Anaesthesia Emergence Delirium (PAED), extubation time, changes in hemodynamic during induction, postoperative pain conditions and postoperative adverse events.
Results
There was no significant difference in the incidence of ED between the two groups (P = 0.605), and there was no significant difference in the peak PAED score (P = 0.210). The application of remimazolam reduced the incidence of EEG epileptiform discharges in group R (P = 0.041) and prolonged the time of first epileptiform activity (P < 0.001). Patients in group R demonstrated better hemodynamic stability and well postoperative pain management. There was no significant difference between the two groups in terms of extubation time and postoperative adverse events during anesthesia emergence.
Conclusion
The use of remimazolam before sevoflurane anesthesia reduced epileptiform EEG activity and improved hemodynamics during induction. However, it did not reduce the incidence of ED.
Trial registration
Chinese Clinical Trial Registry, ChiCTR2500104743(date:14/7/2025).
Keywords: Emergence delirium, Remimazolam, Epileptiform discharges, Sevoflurane
Introduction
Sevoflurane is a rapid and highly effective anesthetic agent, characterized by a low blood-gas partition coefficient, a swift onset of action, and minimal irritation. It is commonly employed for the induction and maintenance of anesthesia in pediatric patients [1]. However, children after sevoflurane induction anesthesia often experience Emergence delirium (ED), which can affect up to more than 40% of preschool-aged children [2]. ED is a cognitive dysfunction after anesthesia, characterized by confusion of consciousness, impaired cognitive ability towards people or things, and uncontrollable tension, excitement and fear [3]. This condition not only inflicts distress on children but also heightens the risk of accidents during the perioperative period [4].
Current research indicates that the frequency of epileptiform discharges observed on electroencephalogram (EEG) during the anesthesia induction period correlates positively with the incidence of ED [5]. Furthermore, studies have shown that children undergoing sevoflurane anesthesia frequently exhibit epileptiform discharges on the EEG during this induction phase [6], which may be the reason why children under sevoflurane anesthesia are prone to experience ED.
As a short-acting benzodiazepine drug, remimazolam has the characteristics of rapid onset, lack of accumulation, and potent sedative effects. It can reduce the incidence of ED in children [7], and its potential to enhance the quality of the anesthesia recovery period is garnering increasing attention. From the perspective of EEG, benzodiazepines can promptly suppress the background patterns of amplitude-integrated EEG and diminish both total and absolute band power [8]. A study on epileptic rats demonstrated that benzodiazepines effectively reduce epileptiform discharges on the EEG, thereby alleviating the severity of seizures in these animals [9]. Consequently, we hypothesize that children receiving remimazolam before sevoflurane anesthesia may have a lower incidence of ED by reducing epileptiform discharges during induction phase. This study aims to administer remimazolam to children scheduled for tonsillectomy or adenoidectomy under sevoflurane anesthesia before induction. We observed EEG epileptiform discharges during the induction period and monitored for delirium during the recovery phase to provide further insights into enhancing the quality of pediatric anesthesia recovery.
Methods and materials
Study overview
This trial was conducted in the Department of Anesthesiology of the First Affiliated Hospital of Bengbu Medical College. The study followed the principles of the Declaration of Helsinki, with all participants providing signed informed consent.
Study population and eligibility requirements
This study included patients aged 1 to 6 years between July 2025 and October 2025. Inclusion criteria comprised patients falling within American Society of Anesthesiologists (ASA) class I- II, aged 1–6 years, undergoing tonsillectomy or adenoidectomy under general anesthesia, with a Body Mass Index (BMI-for-age) between the 25th and 85th percentiles, informed consent was obtained from family members for participation in this study. Exclusion criteria encompassed patients with developmental delays or neuropsychiatric disorders (e.g., autism), had experienced acute respiratory tract infections within the past two weeks, systemic diseases (e.g., cardiac, hepatic, renal diseases), allergy to the study medication’s active ingredients, severe congenital conditions (e.g., high fever, convulsions, or a history of gastroesophageal reflux), other factors deemed unsuitable for participation by the researcher (e.g., receiving special care, residing in a social welfare institution), or any other circumstances that may impact involvement in this study. Patients would be withdrawn from the study if they met any of the following criteria: transfer to the ICU post-surgery, experience of a serious intraoperative adverse reaction (e.g., hemorrhage), loss to follow-up, or unanalyzable EEG data.
Randomization and blinding
In this randomized controlled trial, preoperative visits were conducted by an anesthesiologist who was not involved in the execution of the study, and patients were subsequently included in the cases. Patient numbering was conducted using SPSS 27.0 software, generating and ranking random numbers. The ranks were then sorted in ascending order, with odd ranks assigned to the first group and even ranks to the second. Random grouping and drug preparation for the trial were carried out by independent third-party personnel, utilizing the envelope method for both grouping and concealment. Prior to the operation, an anesthesiologist not involved in the surgery opened the envelope to determine group assignments and prepare the drugs. All drugs were diluted with normal saline and stored in identical syringes to maintain blinding. The patients, operating anesthesiologists, and other study team members were blinded to the group assignments and intervention procedures. The anesthesiologists performing the induction were unaware of the patient groups and the drugs, they carried out standardized anesthesia induction procedures.
Anesthesia and monitoring
Patients were assigned to two groups using a random number method: the remimazolam group (Group R) and the control group (Group C). Prior to the procedure, all patients were instructed to fast for 8 h and refrain from water intake for 4 h. Upon hospital admission, intravenous access was established for both groups, and electrocardiogram and electroencephalogram monitors were connected to track various vital signs, including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and EEG activity. All procedures were conducted under anesthesia by the same experienced anesthesiologist, ensuring that patients remained still throughout the operations. After the EEG was stable, the test drug was intravenously injected: In group R, remimazolam (Jiangsu Hengrui Pharmaceutical Co., Ltd., Lianyungang City, Jiangsu Province, China) was intravenously injected at a dose of 0.2 mg/kg; while group C received an equivalent volume of normal saline. After 2 min, sevoflurane inhalation induction was performed using the tidal volume method: The respiratory circuit was pre-filled with 8% sevoflurane for 5 min, after which 8% sevoflurane was delivered via a mask at an oxygen flow rate of 6 L/min. Once the patient’s eyelash reflex had ceased, the concentration of sevoflurane was decreased to 4%. Enable the child to breathe independently or with manual assisted control of breathing (the end-tidal CO2 was maintained between 35 and 45 mmHg), intravenously use sufentanil at 0.3 µg/kg and cisatracurium at 0.2 mg/kg. After reaching the sedation depth, proceed with tracheal intubation and connect the anesthesia machine for mechanical ventilation. Set the following parameters: tidal volume (VT) at 8–10 ml/kg, fraction of inspired oxygen (FiO2) at 50%, inspiratory to expiratory ratio (I: E) at 1:2, respiratory rate (RR) at 14–20 breaths per minute. Both groups maintained a sevoflurane concentration of 2%. Maintain PetCO2 at 35 to 45mmHg, SpO2 at ≥ 98%, and the fluctuation range of HR, SBP, and DBP within 20% of the baseline value. Provide symptomatic treatment as necessary to stabilize vital signs. 5 min before the end of the operation, acetaminophen (10 mg/kg) was administered. At the end of the surgery, sevoflurane was discontinued, and neuromuscular blockade will be reversed with neostigmine (0.02 mg/kg) and atropine (0.01 mg/kg).When the patient’s spontaneous tidal volume ≥ 6 ml/kg and the RR ≥ 15 times /min, the tracheal tube was removed, the patient was then transferred to the post-anesthesia care unit (PACU) for resuscitation.
Anesthesia recovery
In the PACU, a single trained anesthesiologist who was blinded to the group allocations, was responsible for documenting the Pediatric Anesthesia Emergence Delirium (PAED) score and Face, Legs, Activity, Cry, Consolability (FLACC) score after emergence from anesthesia. In the first 30 min, an assessment will be conducted every 10 min (the first 1, 10, 20, and 30 min). When the PAED score ≥ 10 points and the FLACC score < 4 points, it is considered that ED exists and documented. At the same time, initial comfort measures such as insulation are given [10]. If these measures proved ineffective, propofol was administered at a dose of 1 mg/kg. When the PAED score < 10 points and the FLACC score ≥ 4 points, pain is considered to exist and acetaminophen at a dose of 10 mg/kg is administered for analgesia. When the PAED score ≥ 10 points and the FLACC score ≥ 4 points, analgesic treatment is given priority. The PAED score was re-evaluated after 5 min. Regardless of the FLACC score, if the PAED score ≥ 10 points, it confirmed the existence of ED and was recorded. Additionally, if any patient behavior during the assessment interval suggested signs of ED, an assessment should be conducted and corresponding treatment should be carried out based on the results.
Outcome measures
The primary outcome measure was the incidence of ED during the recovery period in patients, defined as a PAED score of ≥ 10 points. The secondary outcome measures included the incidence of EEG epileptiform discharges during the induction period (from the beginning of sevoflurane inhalation to 2 min after tracheal intubation), the time from sevoflurane induction to the appearance of the first EEG epileptiform discharge, the peak score of the PAED scale, extubation time, changes in hemodynamic during induction (heart rate and blood pressure before induction and intubation), the postoperative pain (FLACC scale scores at each time) and postoperative adverse events (postoperative nausea or vomiting, bradycardia, hypotension, hypoxaemia and laryngospasmnausea).
The PAED scale is a screening tool for pediatric delirium that has been verified for reliability and validity, and is currently recognized as a diagnostic criterion for pediatric ED [7]. The PAED scale comprises five items: lack of eye contact, aimless movement, unconsciousness of the surrounding environment, restlessness and difficulty in comforting (the first three items assess consciousness and cognitive impairment, while the latter two evaluate psychomotor behavior and emotional changes).
The FLACC Scale is utilized to evaluate pain levels in non-verbal patients, particularly in infants, young children, elderly individuals, and those with cognitive impairments. It consists of five indicators: facial expression, leg movement, arm movement, crying and sleep. Each indicator will be scored, and higher scores reflecting greater pain severity.
Spectral processing
EEG data were acquired using the SedLine Brain Function Monitor (Masimo Corporation), equipped with four electrodes to capture EEG activity in the left (Fp1, F7 locus) and right (Fp2, F8 locus) hemispheres simultaneously. After cleaning the skin on the forehead with alcohol, an EEG patch was affixed to the patient’s forehead. The sampling rate was set at 150 Hz, with the impedance of each channel maintained below 5 kΩ. Record the EEG from the beginning of sevoflurane inhalation to 2 min after tracheal intubation. The EEG data was processed using the Eeglab toolbox of Matlab software (version R2023b) to remove bad segments and artifacts. The data were analyzed by an independent neuroelectrophysiologist, and then reanalyzed by another independent neuroelectrophysiologist. The results of the two analyses were submitted to a more experienced neuroelectrophysiologist for confirmation, and the ambiguous cases would be addressed. All of them were blinded to patient grouping and additional clinical data.
According to Vakkuri’s research [11], The EEG epileptiform discharges are classified into four types: DSP (delta with spikes: delta activity of any frequency with regular or irregular spikes), PSR (rhythmic polyspikes: waveform with more than two negative and positive deflections appearing at regular intervals, associated with slow wave or mixed frequency EEG activity between spike complexes), PED (periodic EEG epileptiform discharges: periodic complexes occurring in a bilateral and synchronized manner) and SSP (suppression with spikes: short episodes consisting mostly of a single spike appearing during complete EEG suppression) (Fig. 1).
Fig. 1.
Typical examples for the EEG patterns delta with spikes (DSP), rhythmic polyspikes (PSR), periodic epileptiform discharges (PED), and suppression with spikes (SSP)
Statistical analysis
This randomized controlled trial comprised an remimazolam group and a control group. According to the literature review results, the incidence of ED in children under sevoflurane anesthesia is 44%, while the incidence of ED after remimazolam intervention is 13% [7]. We hypothesize that the incidence of ED in the control group is 44% and in the remimazolam group is 13%. With a two-sided α = 0.05 and a test efficacy of 1-β = 80%, the sample size was calculated with PASS software (version 15.0), resulting in 30 subjects for each group. Factoring in a 10% dropout rate and referencing previous relevant clinical studies [12, 13], the final sample size for each group was determined to be 34 cases, yielding a total of 68 cases across both groups.
Data from this trial were statistically analyzed using SPSS version 27. (IBM, Armonk, NY) and GraphPad Prism version 10. (San Diego, CA). Patients were categorized into subgroups, and analyses were conducted following strict experimental procedures. The Shapiro-Wilk test assessed the normality of continuous variable distributions. Normally distributed variables were presented as mean ± standard (mean ± SD) deviation and compared using independent samples t-tests. Non-normally distributed data were expressed as median and interquartile range [M(Q)] and compared using the Mann-Whitney U test. For the secondary outcomes, ordinal and continuous data were computed using two-tailed t test or two-way ANOVA corrected with the Bonferroni test. Count data were presented descriptively and compared using the X2 test or Fisher exact test. A significance level of α = 0.05 was set, with P < 0.05 indicating statistical significance.
Results
Demographic and clinical characteristics of the patients
We invited 90 patients to participate in this trial and excluded 22 patients (5 did not meet the inclusion criteria, 9 declined to participate, 3 had recent upper respiratory tract infections, and 5 for other reasons). 68 patients were initially included in the trial, 2 patients from group R were lost to follow-up and the EEG data of 1 patient could not be analyzed. Similarly, 3 patients from group C were lost to follow-up, leading to their exclusion based on the predetermined criteria. Ultimately, 62 patients were included in the final statistical analysis (Fig. 2).
Fig. 2.
Flow chart of participating patients. A total of 90 patients were evaluated. Initially, 68 patients were enrolled, with 5 lost to follow-up and the EEG of 1 patient could not be analyzed. Ultimately, 62 patients were included in the statistical analysis. Group R, remimazolam group. Group C, control group
The two groups of patients were designated as group R and group C, with 31 cases in each group. There was no significant difference between the two groups in terms of age, height, weight, ASA grading, operation time and anesthesia time. The data were comparable. (Table 1).
Table 1.
Basic data of patients in the two groups
| Variables | Remimazolam gruop | Control group | P-value |
|---|---|---|---|
| Sample size | 31 | 31 | |
| Female, n(%) | 14(45) | 12(39) | 0.797 |
| Age(year) | 6(5,6) | 5(4,6) | 0.248 |
| Height(cm) | 118.5 ± 7.61 | 116.2 ± 9.79 | 0.288 |
| Weight(kg) | 21.74 ± 4.42 | 21.58 ± 6.31 | 0.908 |
| ASA Class, n(%) | |||
| Ⅰ | 30(97) | 29(94) | > 0.999 |
| Ⅱ | 1(3) | 2(6) | |
| Surgery time(min) | 33.61 ± 8.80 | 35.19 ± 5.08 | 0.390 |
| Anesthesia time(min) | 53.10 ± 5.02 | 55.13 ± 7.51 | 0.215 |
Data are presented as mean ± SD, [M(Q)], number (%)
Abbreviations: ASA American Society of Anesthesiologists
PAED score
There was no significant difference in the peak PAED score between the two groups (Group R: 8 [6, 11] vs. Group C: 9 [7, 12], P = 0.210) (Fig. 3A). Among the 31 patients in Group R who received remimazolam, 11 cases (35%) experienced ED, and among the 31 patients in Group C who received saline, 14 cases (45%) experienced ED (Fig. 3B). There was no statistically significant difference between the two groups (P = 0.605).
Fig. 3.
The peak PAED scores and the incidence of ED during the first 30 min in the postanesthesia care unit. A Differences in peak PAED scores between the two groups. B Differences in incidence of ED between the two groups. PAED, pediatric anesthesia emergence delirium. ED, emergence delirium
EEG epileptiform discharge
In Group R, 11 cases (35%) of epileptiform discharges were observed: 8 cases (26%) of DSP, 9 cases (29%) of PSR, and 3 cases (10%) of PED. Among them, 8 cases (26%) exhibited more than one type of epileptiform activity. In Group C, 20 cases (65%) of epileptiform discharges were observed: 17 cases (55%) of DSP, 14 cases (45%) of PSR, 6 cases (19%) of PED, and 1 cases (3%) of SSP. Among them, 14 cases (45%) exhibited more than one type of epileptiform activity. The incidence of DSP in Group R was lower than Group C (Group R:8 of 31 [26%] vs. Group C:17 of 31 [55%] P = 0.037), the overall number of patients with epileptiform discharge in Group R was lower than Group C (Group R:11 of 31 [35%] vs. Group C:20 of 31 [65%], P = 0.041) (Table 2).
Table 2.
Number and percentage of patients with epileptiform EEG activity
| EEG activity | Remimazolam gruop | Control group | P-value |
|---|---|---|---|
| DSP | 8(26) | 17(55) | 0.037 |
| PSR | 9(29) | 14(45) | 0.293 |
| PED | 3(10) | 6(19) | 0.473 |
| SSP | 0 | 1(3) | N/A |
| epileptiform discharge, n(%) | 11(35) | 20(65) | 0.041 |
Data are presented as number (%)
Abbreviations: DSP Delta with spikes, PSR Rhythmic polyspikes, PED Periodic epileptiform discharges, SSP Suppression with spikes, N/A Not applicable
Compared with Group C, the time to the appearance of first EEG epileptiform discharge in Group R was prolonged (Group R: 190.2 ± 36.29 vs. Group C: 130.1 ± 55.32, P < 0.001) (Table 3). No clinical epileptic seizures were observed in both two groups.
Table 3.
Time from the beginning of sevoflurane to first EEG epileptiform discharge
| Remimazolam gruop | Control group | P-value | |
|---|---|---|---|
| Time to first epileptiform discharge | 190.2 ± 36.29 | 130.1 ± 55.32 | < 0.001 |
Data are presented as mean ± SD
Hemodynamic
The heart rate of patients in Group R before intubation was lower than Group C (Group R: 97.10 ± 7.68 bpm vs. Group C: 103.50 ± 8.66 bpm, P = 0.003) (Fig. 4A), and there were no statistically significant differences in HR, SBP and DBP between the two groups at other times. The SBP of patients in Group R before intubation was lower than that before induction (93.35 ± 5.71 mmHg vs. 98.00 ± 9.09 mmHg, P = 0.019) (Fig. 4B). In Group C, the HR before intubation was higher than that before induction (103.50 ± 8.66 bpm vs. 98.00 ± 9.09 bpm, P = 0.017) (Fig. 4A), and the SBP and DBP before intubation were lower than those before induction in Group C(95.55 ± 4.43 mmHg vs. 100.50 ± 4.73 mmHg, P < 0.001) (51.68 ± 3.15 mmHg vs. 56.00 ± 9.09 mmHg, P = 0.015) (Fig. 4B and C). These findings indicate that the hemodynamic of patients treated with remimazolam were more stable before and after induction (Table 4).
Fig. 4.
Changes in hemodynamic parameters between the two groups. A Differences in HR between the two groups. B Differences in SBP scores between the two groups. C Differences in DBP between the two groups. HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure. #P < 0.05: statistically significant difference compared to time before induction.*P < 0.05: statistically significant difference compared with group C
Table 4.
Hemodynamic parameters
| Index | Remimazolam gruop | Control group | P-value |
|---|---|---|---|
| HR(bpm) | |||
| Before induction | 95.58 ± 5.34 | 98.00 ± 9.09 | 0.206 |
| Before intubation | 97.10 ± 7.68 | 103.50 ± 8.66# | 0.003 |
| SBP(mmHg) | |||
| Before induction | 98.00 ± 9.09 | 100.50 ± 4.73 | 0.188 |
| Before intubation | 93.35 ± 5.71# | 95.55 ± 4.43# | 0.096 |
| DBP(mmHg) | |||
| Before induction | 54.32 ± 5.48 | 56.00 ± 9.09 | 0.382 |
| Before intubation | 52.61 ± 7.13 | 51.68 ± 3.15# | 0.507 |
Data are presented as mean ± SD
Abbreviations: HR Heart rate, bpm beat per minute, SBP Systolic blood pressure, DBP Diastolic blood pressure
#P < 0.05: statistically significant difference compared to time before induction
Postoperative situation
The FLACC scale score for patients in Group R, measured 20 min postoperatively, was lower than Group C (Group R: 1[0,2] vs. Group C: 0[0,1], P < 0.001). There were no significant differences in the FLACC scores between the two groups at other times. No child received an additional dose of cisatracurium during the surgery. There were no statistically significant differences in extubation time, cases of rescue analgesia and cases of rescue sedation between the two groups. In Group R, 2(6%) cases experienced PONV, 1(3%) cases had hypoxemia, and 1(3%) case had laryngospasm. In group C, 3(10%) cases experienced PONV, 2(6%) cases had hypoxemia, and 1(3%) cases had laryngospasm. No instances of bradycardia or hypotension were found during the study period (Table 5).
Table 5.
Postoperative outcomes among different groups
| Variables | Remimazolam gruop | Control group | P-value |
|---|---|---|---|
| Extubation time(min) | 16.90 ± 6.78 | 18.00 ± 9.09 | 0.592 |
| Rescue analgesia, n(%) | 4(13) | 6(19) | 0.732 |
| Rescue sedation, n(%) | 3(10) | 5(16) | 0.707 |
| FLACC score | |||
| 1 min | 2(1,2) | 1(1,2) | 0.752 |
| 10 min | 2(1,2) | 2(1,2) | 0.426 |
| 20 min | 1(0,2) | 0(0,1) | < 0.001 |
| 30 min | 1(0,2) | 1(0,1) | 0.297 |
| Adverse events, n(%) | |||
| PONV | 2(6) | 3(10) | > 0.999 |
| Bradycardia | 0 | 0 | N/A |
| Hypotension | 0 | 0 | N/A |
| Hypoxaemia | 1(3) | 2(6) | > 0.999 |
| Laryngospasm | 1(3) | 1(3) | > 0.999 |
Data are presented as Data are presented as mean ± SD, [M(Q)], number (%)
Abbreviations: FLACC Face Legs Activity Cry Consolability, N/A Not applicable, PONV Postoperative nausea or vomiting
Discussion
In this study, we found that intravenous administration of remimazolam at a dose of 0.2 mg/kg, administered 2 min prior to anesthesia induction for tonsillar or adenoid surgery, can lower the incidence of EEG epileptiform discharge and delay the occurrence time. Furthermore, intravenous remimazolam contributes to greater stability in hemodynamic both before and after induction, and will not increase the occurrence of postoperative adverse events. However, it does not reduce the incidence of ED under sevoflurane anesthesia.
ED during the recovery period is a common adverse event following general anesthesia in children. The mechanisms underlying its occurrence remain unclear and may involve multiple factors, including preoperative anxiety, postoperative pain, and rapid recovery [14]。 During an episode, children often exhibit mental symptoms, characterized by uncontrollable restlessness [4], which leads to elevated blood pressure, increased heart rate and brain hypoxia [15]. These effects can hinder postoperative recovery and may result in various complications. In this trial, approximately half of the patients who did not receive intervention experienced ED, consistent with findings from previous studies [7]. Cai et al. [16] reported that for children undergoing laparoscopic surgery, administering 0.2 mg/kg of remimazolam intravenously during skin suturing could diminish the incidence of ED during the recovery period. Similarly, Yang et al. [7] noted that administering remimazolam at a dose of 0.2 mg/kg after tonsillectomy and adenoidectomy could reduce the occurrence of ED in children following sevoflurane anesthesia. However, in this study, the current results indicate that intravenous injection of 0.2 mg/kg of remimazolam prior to the initiation of anesthesia does not decrease the incidence of ED in children under sevoflurane anesthesia. This may be attributed to the relatively short half-life of remimazolam [17]. Although the terminal half-life of remimazolam can reach 0.5 to 1 h [18], the average surgery time of this study was more than half an hour, while the anesthesia time was approximately one hour. Therefore, its effects cannot be sustained until the conclusion of surgery when administered prior to the onset of anesthesia. Consequently, the incidence of ED cannot be reduced. This suggests that although remimazolam is an effective adjuvant drug for preventing ED in children [19], the timing of administration significantly influences its efficacy. In the future, we can choose shorter surgeries to explore the possibility of remimazolam reducing the ED.
Current research suggests that epileptiform discharges in children’s EEG during the induction period are significantly associated with the incidence of ED during the awakening period [20]. A meta-analysis reveals that children’s EEG are particularly susceptible to epileptiform discharges during sevoflurane anesthesia [21]. In this trial, the incidence of epileptiform discharge during the induction period in children receiving the standard sevoflurane induction mode was 65%, consistent with findings from previous studies [22]. Vakkuri et al. [11] reported that children under sevoflurane anesthesia, whether with mechanical ventilation or spontaneous breathing ventilation, all exhibited epileptiform discharges. Stasiowski [23] noted a decrease in the incidence of epileptiform discharges as the concentration of sevoflurane gradually diminished during anesthesia. However, some studies propose that the strategy of reducing sevoflurane concentration to mitigate EEG epileptiform activity may present more advantages than disadvantages [1]. Therefore, finding an effective anesthesia strategy to mitigate epileptiform discharges in EEG during the induction period has become an urgent concern. Previous research has indicated that benzodiazepines exert their antiepileptic and anticonvulsant effects through interactions with γ-Aminobutyric acid (GABA) receptors [24]. We hypothesized that remimazolam, a benzodiazepine drug, may diminish EEG epileptiform discharges when administered during the perioperative period. This trial demonstrated that following the administration of remimazolam, the incidence of epileptiform discharges decreased compared to the control group (P = 0.041), and the time for the first observation of this EEG phenomenon was prolonged. These findings suggest that the pre-anesthetic application of remimazolam can diminish the occurrence of EEG epileptiform discharges during induction and delay their onset. Nieminen K [25] reported that when midazolam was utilized for sedation prior to anesthesia, thiopental for induction, and 2% sevoflurane for maintenance, children did not exhibit epileptiform discharges, however this outcome could not be definitively attributed to the lower concentration of sevoflurane used. This study defined the induction concentration of sevoflurane, controlled for relevant confounding factors, and confirmed that remimazolam can reduce epileptiform discharges during the induction period. We observed that patients receiving remimazolam exhibited fewer DSPS in their EEGs, with no SSPS detected. Previous studies [22] reported that when sevoflurane concentration is relatively low, DSP predominates, while PED and PSR are more prevalent at higher concentrations of sevoflurane, and SSP is associated with deep anesthesia [6]. This suggests that during the initial of anesthesia and the early decline of consciousness, epileptiform activities are predominantly DSP, while in the later stages of consciousness decline, epileptiform activities are primarily PED and PSR. In Group R, remimazolam was administered intravenously before the induction of anesthesia, consciousness had already begun to decline and progressed rapidly past the initial stage. Therefore, the use of remimazolam prior to anesthesia may reduce the incidence of DSP. Additionally, this trial used sevoflurane inhalation anesthesia. Given that remimazolam decreases the patient’s respiratory rate [26], its administration before anesthesia is likely to diminish the patient’s ventilation per minute, slow the rise in sevoflurane concentration at the end of expiration, prolong the duration required for the patient to reach the later stages of consciousness decline, and hinder the transition to a deep anesthesia state. Therefore, following the administration of remimazolam, the time for the first appearance of epileptiform activity was extended, and no SSP which is related to deep anesthesia was observed. In this study, remimazolam diminished the incidence of epileptiform discharges; however, it did not reduce the incidence of ED. This finding suggests that ED is influenced by a confluence of factors, and epileptiform discharges in EEG are not the exclusive determinants of ED occurrence. Furthermore, considering the limited electrode configuration, this might affect our confirmation of SSP.
Pediatric patients are younger and their organ functions are not fully developed. Ensuring hemodynamic stability during anesthesia induction is essential for both intraoperative safety and postoperative recover [27]. Remimazolam has been shown to effectively minimize fluctuations in heart rate and blood pressure during anesthesia induction [28]. In this trial, we observed that patients who administered remimazolam prior to anesthesia induction exhibited more stable vital signs both before and after the induction process, thereby reducing the stimulation of heart rate and blood pressure fluctuations on the cardiovascular system. This finding supports the safety of using remimazolam prior to sevoflurane anesthesia.
Postoperative pain is a significant trigger for ED during the recovery period [14]. Alleviating this pain may effectively mitigate delirium during the recovery period. In our study, we utilized the FLACC scale to evaluate pain severity, implementing corresponding treatments based on the scoring outcomes. Additionally, the PAED scale and the FLACC scale were used in combination to differentiate between postoperative pain and ED, in order to controlling for any increases in PAED scale scores attributable to pain factors. We found that the pain score in Group R, measured 20 min post-extubation, was lower than that of the control group. This might because the preoperative administration of remimazolam minimized the hemodynamic fluctuations during anesthesia induction, leading to reduced blood pressure variability in patients and a decrease in inflammatory response [29]. Given that inflammation is linked to postoperative pain [30], remimazolam may alleviate postoperative pain by diminishing intraoperative inflammatory responses. The reasons why remimazolam can reduce postoperative pain still need further exploration. Furthermore, there were no significant differences in extubation time or postoperative adverse reactions between the two groups, reinforcing the notion that the preoperative use of remimazolam is both effective and safe.
This study has limitations. First, it was conducted in a single center, future multi-center studies with larger samples are needed to reduce sampling bias. The EEG equipment used in this research had a limited number of leads. In the future, multi-channel EEG equipment can be employed to enhance the comprehensiveness of data analysis. Furthermore, the absence of follow-up in this study precludes any assessment of the long-term effects of remimazolam.
Conclusion
The use of 0.2 mg/kg of remimazolam before sevoflurane anesthesia can reduce the incidence of EEG epileptiform discharges and decrease hemodynamic fluctuations during induction. However, the reduction in EEG epileptiform discharges did not correspond to a reduction in ED, ED is likely multifactorial and not solely determined by EEG activity.
Acknowledgements
The authors would like to thank all supporting staff for their assistance in this study.
Authors’ contributions
[Ruikun Zhu and Nanhai Wang]: Conceptualization; [Chongli Du]: Data curation; [Ruikun Zhu and Chenlu Wu]: Formal analysis; [Chongli Du]: Investigation; [Daqi Zhang]: Methodology; [Chongli DU]: Project administration; [Nanhai Wang]: Supervision; [Yongxing Zhang]: Validation; [Chenlu Wu and Heng Zhang]: Visualization; [Ruikun Zhu]: Writing–original draft; [Ruikun Zhu and Nanhai Wang]: Writing–review and editing. All authors have read and agreed to the published version of the manuscript.”
Funding
This research received no external funding.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of The First Affiliated Hospital of Bengbu Medical College([2025]KY051 × 01, May 29, 2025). Participants provided written informed consent prior to taking part in the study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.